PNN July–September 2017

PNN Pharmacotherapy Line
July 5, 2017 * Vol. 24, No. 127
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 July 4 issue of JAMA (2017; 318).
Insulin Degludec v. Insulin Glargine U100: Overall risk of symptomatic hypoglycemia was reduced in patients with types 1 and 2 diabetes in the SWITCH 1 (pp. 33–44; W. Lane, mountaindiabetes@msn.com). and SWITCH 2 (pp. 45–56; C. Wysham, chwysham@comcast.net) trials. Study implications are analyzed in two related articles.
“Any basal insulin associated with a reduced rate of hypoglycemia would seem to represent an advance in therapy,” editorialists conclude after listing caveats (
pp. 31–2): “First, these insulin types were titrated using a set protocol that probably exceeds common clinical practice, so cautious clinicians may want to see the results of a more pragmatic trial. Second, the studies were funded by the manufacturer of insulin degludec; however, the study design with randomization and blinding of drug assignment to the study participants and study team helped reduce the risk of bias. Third, these results may not be generalizable to insulin glargine U300 or other alternative basal insulins. Fourth, insurance coverage and affordability are a critical component in the choice of basal insulin.” (E. R. Seaquist, seaqu001@umn.edu)
With pharmacy prices for long-acting insulin analogues such as these now exceeding $170 per vial, the costs of treating diabetes are too much for many patients with diabetes, Viewpoint authors add (
pp. 23–4). Even among patients with insurance, increased premiums and copayments are challenging, they write, adding this guidance for lower-cost human insulin: “Patients can safely switch from insulin analogues to human insulins. Total daily insulin dose can be initially reduced by 20%, because of the different profiles of action and because some patients may have been taking less analogue insulin than had been prescribed.
“For patients already treated with multiple insulin analogue injections, the number of injections and distribution of dosage can remain the same but with a 20% reduction of dosage for safety. Early contact between the physician and the patient by phone or in person is desirable to ensure that an unexpectedly large reduction of glucose has not occurred due to improved adherence.
“In summary, many patients with type 2 diabetes can be treated with human insulin. Due to high costs of analogue insulins, use of human insulin may be the only practical option for some patients, and clinicians should be familiar with its use.” (K. J. Lipska, 
kasia.lipska@yale.edu)
>>>Internal Medicine Report
Source:
 July 4 issue of the Annals of Internal Medicine (2017; 167).
Cost-effectiveness of RA Therapy: In those with active rheumatoid arthritis (RA) despite 12 weeks of methotrexate therapy, moving directly to biologic therapy without first trying triple therapy provides “minimal incremental benefit,” according to RACAT researchers (pp. 8–16). Based on 24 weeks’ or lifetime therapy and societal or Medicare perspectives, the authors found that “[incremental cost-effectiveness ratios (ICERs)] for first-line etanercept–methotrexate and triple therapy were $2.7 million per [quality-adjusted life-years (QALYs)] and $0.98 million per QALY over 24 and 48 weeks, respectively. The lifetime analysis suggested that first-line etanercept–methotrexate would result in 0.15 additional lifetime QALY, but this gain would cost an incremental $77 290, leading to an ICER of $521,520 per QALY per patient.” (N. Bansback, nick.bansback@ubc.ca)
“This [study] suggests that if biosimilars can deliver the same clinical benefits at a fraction of the cost, they may offer new opportunities to revise cost-effectiveness estimates,” editorialists write (
pp. 55–6; E. Losina, elosina@bwh.harvard.edu).
>>>PNN NewsWatch
FDA on Monday expanded approved use of the hair-preserving DigniCap Cooling System (Dignitana) to include chemotherapy for all solid tumors. The device was approved in 2015 for use during chemotherapy for breast cancer.
>>>PNN JournalWatch
* Plasma Glycated CD59, a Novel Biomarker for Detection of Pregnancy-Induced Glucose Intolerance, in Diabetes Care, 2017; 40: 981–4. (J. A. Halperin, jhalperin@bwh.harvard.edu
* Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study, in 
American Journal of Psychiatry, 2017; 174: 686–94. (A. P. Rajkumar)

PNN Pharmacotherapy Line
July 6, 2017 * Vol. 24, No. 128
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 July 6 issue of the New England Journal of Medicine (2017; 377).
Elagolix Treatment of Endometriosis-Associated Pain: An oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, elagolix improved dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain, researchers report (pp. 28–40). Both of two doses of the drug yielded positive results in phase 3 trials, as shown by these results: “A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P <0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P <0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P <0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.” (H. S. Taylor, hugh.taylor@yale.edu)
“A potential new drug for patients with this debilitating disease is welcome news,” an editorialist writes (
pp. 81–3). “Although surgical treatment of endometriosis-associated pelvic pain results in symptomatic improvement in most patients, medical treatment remains the mainstay of long-term management. However, no new class of drugs has been approved for endometriosis since the Food and Drug Administration approved the GnRH agonists, which are administered parenterally, more than 25 years ago.” (M. D. Hornstein)
Global Burden of Overweight & Obesity: The recent worldwide rapid increase in body-mass index (BMI) “highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem,” conclude Global Burden of Disease (GBD) investigators (pp. 13–27). Between 1990 and 2015, BMI trends were as follows: “In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease.” (C. J. L. Murray, cjlm@uw.edu)
Noting gaps in the GBD data set, editorialists conclude, “Better data systems would permit policymakers in the hardest hit areas of the world to respond more quickly and to shorten the long learning period that is typically required to overcome chronic diseases.” (
pp. 80–1; E. W. Gregg).
Medications & Sudden Death in Heart Failure: The “cumulative benefit of evidence-based medications” is the likely reason for substantially reduced risks of sudden death among ambulatory patients with heart failure with reduced ejection fractions in clinical trials, a study shows (pp. 41–51; J. J. V. McMurray, john.mcmurray@glasgow.ac.uk).

PNN Pharmacotherapy Line
July 7, 2017 * Vol. 24, No. 129
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Psychiatry Highlights
Source:
 July issue of the American Journal of Psychiatry (2017; 174).
Psychosis- & Antipsychotic-Related Diabetes: In a study of the Danish population, people with schizophrenia had a 3-fold greater risk of developing diabetes, and this risk was increased — but not significantly — when the condition was treated with first- or second-generation antipsychotic agents (pp. 686–94). National psychiatric and pharmacy registries yielded these estimates of endogenous and treatment-related risks for diabetes among patients with diagnoses of schizophrenia: “Of the cohort members, 14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person–years). The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71–5.41) in antipsychotic-naive schizophrenia compared with the general population. The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95–6.82) than the risk in antipsychotic-naive schizophrenia, after adjustment for family history of diabetes and other potential confounders. First-line treatment with either first-generation antipsychotics (adjusted hazard ratio, 3.06; 95% CI, 1.32–7.05) or second-generation antipsychotics (adjusted hazard ratio, 3.44; 95% CI, 1.73–6.83) increased the risk for diabetes without a statistically significant difference. Appropriate sensitivity analyses limited to type 2 diabetes corroborated these results.” (A. P. Rajkumar, anto.rajamani@kcl.ac.uk)
“Long before antipsychotic drugs became standard therapy, studies showed abnormal glucose tolerance in patients with ‘dementia praecox’ (schizophrenia),” an editorialist writes (
pp. 616–7). “Recent studies of patients in the early phase before initiating drug therapy also show impaired glucose tolerance at the group level. Together, with the data of Rajkumar et al., these findings suggest that some of the cause of diabetes in severe mental illness is linked to the disease itself.” (O. A. Andreassen, o.a.andreassen@medisin.uio.no)
>>>Circulation Report
Source:
 July 4 issue of Circulation (2017; 136).
Long-Term Metformin Outcomes in Diabetes Prevention Trial: Following 3.2 years of lifestyle and metformin interventions in patients with prediabetes, men had lower rates of coronary atherosclerosis when metformin treatment continued, researchers report (pp. 52–64). Coronary artery calcium (CAC) measurements after an average of 14 years of follow-up showed the following: “There were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity, 39.5 versus 66.9 Agatston units, P = 0.04; CAC presence, 75% versus 84%, P = 0.02), but no metformin effect was seen in women. In multivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric, or metabolic factors; by the development of diabetes mellitus; or by use/nonuse of statin therapy.” (R. B. Goldberg, dppmail@bsc.gwu.edu)
>>>PNN NewsWatch
Endo International yesterday agreed to voluntarily remove Opana ER (oxymorphone) from the market. FDA had requested the withdrawal last month, citing concerns that the product’s abuse potential created risks that exceeded benefits. Endo said that it plans to work with FDA to coordinate the orderly removal of the product “in a manner that looks to minimize treatment disruption for patients and allows patients sufficient time to seek guidance from their health care professionals.” The company also recommended that patients taking Opana ER discuss treatment options with their prescribing physician at their next visit.
* A federal judge yesterday entered a consent decree of permanent injunction yesterday between the United States and 
Medistat RX LLC of Foley, AL, the compounding company’s co-owners, and its quality manager and pharmacist-in-charge, FDA said.
* Responding to complaints, Novo Nordisk is recalling insulin cartridge holders used in a small number of 
NovoPen Echo batches because they may crack or break if exposed to certain chemicals, such as certain cleaning agents, according to an FDA news release.

PNN Pharmacotherapy Line
July 10, 2017 * Vol. 24, No. 130
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 July 8 issue of Lancet (2017; 390).
PF-00547659 in Ulcerative Colitis: In a phase 2 trial of 357 patients with moderate-to-severe ulcerative colitis, the investigational monoclonal antibody PT-00547659 was safe and well tolerated and significantly more effective than placebo for induction of remission, researchers report (pp. 135–44). The agent, which binds to human mucosal addressin cell adhesion molecule-1 to selectively reduce lymphocyte homing to the intestinal tract, was effective in some but not nearly all participants on active therapy: “Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2.7% [two of 73]): 7.5 mg (11.3% [eight of 71]), 22.5 mg (16.7% [12 of 72]), 75 mg (15.5% [11 of 71]), and 225 mg (5.7% [four of 70]).… Four of 73 (5.5%) patients had a serious adverse event in the placebo group, ten of 71 (14.1%) in the 7.5 mg group, one of 70 (1.4%) in the 22.5 mg group, three of 73 (4.1%) in the 75 mg group, and three of 70 (4.3%) in the 225 mg group. No safety signal was observed for the study drug.” (S. Vermeire, severine.vermeire@uzleuven.be)
NSAIDs in Knee and Hip Osteoarthritis: For reducing pain and maintaining function in patients with knee and hip osteoarthritis, diclofenac 150 mg/d is the most effective NSAID available, according to authors of a network meta-analysis (pp. e21–e33). Concluding acetaminophen should not be used alone in managing this condition, the authors report these results from 76 trials of 58,451 patients: “For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] −0.37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES −0.57, 95% credibility interval [CrI] −0.69 to −0.45) and etoricoxib 60 mg/day (ES −0.58, −0.74 to −0.43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for naproxen (p = 0.034).” (S. Trelle, sven.trelle@ctu.unibe.ch)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Benzodiazepines & All-Cause Mortality Risk: The risk of all-cause mortality changes little following initiation of benzodiazapine therapy in adults, according to a retrospective cohort study of a large American health care database (j2941). Among 1.2 million people in a user cohort and a nonuser control group, these trends were noted in 2004–13: “Over a six month follow-up period, 5,061 and 4,691 deaths occurred among high dimensional propensity score matched benzodiazepine initiators versus non-initiators (9.3 v 9.4 events per 1,000 person–years; hazard ratio 1.00, 95% confidence interval 0.96 to 1.04). A 4% (95% confidence interval 1% to 8%) to 9% (2% to 7%) increase in mortality risk was observed associated with the start of benzodiazepine treatment for follow-ups of 12 and 48 months and in subgroups of younger patients and patients initiating short acting agents. In secondary analyses comparing 1:1 high dimensional propensity score matched patients initiating benzodiazepines with an active comparator, ie, patients starting treatment with selective serotonin reuptake inhibitor antidepressants, benzodiazepine use was associated with a 9% (95% confidence interval 3% to 16%) increased risk.” (E. Patorno, epatorno@bwh.harvard.edu)
>>>PNN NewsWatch
FDA on Friday approved L-glutamine oral powder (Endari, Emmaus Medical) to reduce severe complications of sickle cell disease in patients age 5 years or older.
* The U. Maryland School of Pharmacy is gearing up to offer online classes to workers needing certification in the 
medical marijuana industry, the Washington Post reports.
>>>PNN JournalWatch
* Three-Part Series on Oxidative Stress & the Cardiovascular System, in Journal of the American College of Cardiology, 2017; 70: Basic BiologyHeart & VasculatureCardiovascular Risk.

PNN Pharmacotherapy Line
July 11, 2017 * Vol. 24, No. 131
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 July issue of JAMA Internal Medicine (2017; 177).
Statins in Older Adults: In a post-hoc analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT-LLT), older adults did not show benefit from pravastatin therapy for primary prevention, and those aged 75 years or older had a nonsignificant increase in all-cause mortality (pp. 955–65). Among 2,867 adults 65 years or older with moderate hyperlipidemia, pravastatin 40 mg/d or usual care (UC) produced these outcomes: “The baseline mean (SD) low-density lipoprotein cholesterol levels were 147.7 (19.8) mg/dL in the pravastatin group and 147.6 (19.4) mg/dL in the UC group; by year 6, the mean (SD) low-density lipoprotein cholesterol levels were 109.1 (35.4) mg/dL in the pravastatin group and 128.8 (27.5) mg/dL in the UC group. At year 6, of the participants assigned to pravastatin, 42 of 253 (16.6%) were not taking any statin; 71.0% in the UC group were not taking any statin. The hazard ratios for all-cause mortality in the pravastatin group vs the UC group were 1.18 (95% CI, 0.97–1.42; P = .09) for all adults 65 years and older, 1.08 (95% CI, 0.85–1.37; P = .55) for adults aged 65 to 74 years, and 1.34 (95% CI, 0.98–1.84; P = .07) for adults 75 years and older. Coronary heart disease event rates were not significantly different among the groups. In multivariable regression, the results remained nonsignificant, and there was no significant interaction between treatment group and age.” (B. H. Han, benjamin.han@nyumc.org)
“Statin therapy may be associated with a variety of musculoskeletal disorders, including myopathy, myalgias, muscle weakness, back conditions, injuries, and arthropathies,” an editorialist writes (
p. 966). “These disorders may be particularly problematic in older people and may contribute to physical deconditioning and frailty. Statins have also been associated with cognitive dysfunction, which may further contribute to reduced functional status, risk of falls, and disability. The combination of these multiple risks and the ALLHAT-LLT data showing that statin therapy in older adults may be associated with an increased mortality rate should be considered before prescribing or continuing statins for patients in this age category.” (G. Curfman, gregory_curfman@hms.harvard.edu)
Glucose Self-monitoring in Non–Insulin-Treated Type 2 Diabetes: Self-monitoring of blood glucose (SMBG) by patients with non–insulin-dependent type 2 diabetes produced no clinically or statistically significant differences at 1 year, even when enhanced with automated, tailored messaging, according to a study of glycemic control and health-related quality of life (HRQOL) (pp. 920–9). The Monitor Trial study produced the following open-label, pragmatic results at 15 North Carolina primary care practices: “A total of 450 patients were randomized and 418 (92.9%) completed the final visit. There were no significant differences in hemoglobin A1c levels across all 3 groups (P = .74; estimated adjusted mean hemoglobin A1c difference, SMBG with messaging vs no SMBG, −0.09%; 95% CI, −0.31% to 0.14%; SMBG vs no SMBG, −0.05%; 95% CI, −0.27% to 0.17%). There were also no significant differences found in HRQOL. There were no notable differences in key adverse events including hypoglycemia frequency, health care utilization, or insulin initiation.” (K. Donahue, kdonahue@med.unc.edu)
Community Health Worker Intervention in Type 2 Diabetes: Just one of three outcomes was significantly improved by a community health worker intervention in Latinos with type 2 diabetes, researchers report (pp. 948–54). Hemoglobin A1C levels dropped by 0.51% at 12 months, but LDL cholesterol levels and systolic blood pressures were unchanged. (O. Carrasquillo, oc6@med.miami.edu)
>>>PNN NewsWatch
* FDA Commissioner Scott Gottlieb yesterday called for “rigorous new safety standards for how immediate-release opioids are prescribed, in an effort to curb the nation’s opioid crisis,” the Wall Street Journal reports. “It’s time to take direct action to address the close to 200 million opioid analgesic prescriptions each year that are for the immediate-release products,” Gottlieb said. “The new training will be aimed at making sure providers who write prescriptions for the [immediate-release] opioids are doing so for properly indicated patients, and under appropriate clinical circumstances.”

PNN Pharmacotherapy Line
July 12, 2017 * Vol. 24, No. 132
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 July 11 issue of JAMA (2017; 318).
Antidepressant Switching/Augmentation in Resistant Depression: Augmentation of therapy with the second-generation antipsychotic agent aripiprazole following antidepressant failure in 1,522 VA patients with nonpsychotic major depressive disorder (MDD) yielded limited benefits but increased adverse effects, researchers report (pp. 132–45). Compared with a switch to or augmentation with bupropion, augmentation with aripiprazole produced these results during an acute treatment phase of 12 weeks in the VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study: “Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05–1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-–1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04–1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.” (S. Mohamed, somaia.mohamed@va.gov)
These findings “showed a modest yet significant advantage for the aripiprazole augmentation compared with switching to bupropion (in terms of both higher remission and response rates) and bupropion augmentation (in terms of higher response rates only) in a population of patients with MDD and inadequate response to antidepressant therapy,” writes an editorialist (
pp. 126–8). “The VAST-D study was uniquely enriched by men and by those with [posttraumatic stress disorder] comorbidity, and offers an important perspective on the role of treatment using augmentation with atypical antipsychotic agents in this population commonly seen in VA clinics.” (M. Fava, mfava@mgh.harvard.edu)
Alendronate & Hip Fracture in Older Patients Using Oral Prednisolone: An observational study of the Swedish national health database shows benefits of alendronate therapy in older patients on medium-to-high doses of prednisolone (pp. 146–55). Over a median of 1.32 years, the risk of hip fracture was as follows in patients with a mean age of 79.9 years, 70% of whom were women: “There were 27 hip fractures in the alendronate group and 73 in the no-alendronate group, corresponding to incidence rates of 9.5 (95% CI, 6.5–13.9) and 27.2 (95% CI, 21.6–34.2) fractures per 1,000 person–years, with an absolute rate difference of −17.6 (95% CI, −24.8 to −10.4). The use of alendronate was associated with a lower risk of hip fracture in a multivariable-adjusted Cox model (hazard ratio, 0.35; 95% CI, 0.22–0.54). Alendronate treatment was not associated with increased risk of mild upper gastrointestinal tract symptoms (alendronate vs no alendronate, 15.6 [95% CI, 11.6–21.0] vs 12.9 [95% CI, 9.3–18.0] per 1,000 person–years; P = .40) or peptic ulcers (10.9 [95% CI, 7.7–15.5] vs 11.4 [95% CI, 8.0–16.2] per 1,000 person–years; P = .86). There were no cases of incident drug-induced osteonecrosis and only 1 case of femoral shaft fracture in each group.” (M. Lorentzon, mattias.lorentzon@medic.gu.se)
Antipsychotics in Nursing Homes: Since the 2011 launch of the National Partnership to Improve Dementia Care in Nursing Homes, use of antipsychotic agents in U.S. nursing homes has been reduced by 33%, Viewpoint authors write (pp. 118–9). The percentage of residents on the drugs has dropped from 23.9% to 16%. (J. H. Gurwitz, jgurwitz@meyersprimary.org)
>>>PNN NewsWatch
* All lots of Andropharm’s Sten Z and M1 Alpha capsules are being recalled to the consumer level because these products contain derivatives of anabolic steroids, FDA said yesterday, rendering them unapproved drugs for which safety and efficacy have not been established and therefore subject to recall.

PNN Pharmacotherapy Line
July 13, 2017 * Vol. 24, No. 133
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 July 13 New England Journal of Medicine (2017; 377).
Clonal Hematopoiesis & Atherosclerosis: Evidence of increased risk of atherosclerotic cardiovascular disease associated with a genetic peripheral blood disorder comes from studies of mice and people (pp. 111–21). Clonal hematopoiesis of indeterminate potential (CHIP) is the presence of an expanded somatic blood-cell clone in people without other hematologic abnormalities, and it has been linked to an increased risk of hematologic cancer. Seeking to explore the relationship further, investigators conducted whole-exome sequencing of samples from four case–control studies of 8,255 participants and examined function of the Tet2 gene in atherosclerosis-prone mice. Results showed the following: “In nested case–control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case–control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.” (B. L. Ebert, bebert@partners.org)
Adjuvant Pertuzumab & Trastuzumab in Early HER2-Positive Breast Cancer: Added to trastuzumab and chemotherapy, pertuzumab significantly improved the rates of invasive-disease–free survival among patients with HER2-positive, operable breast cancer, the APHINITY study shows (pp. 122–31): “Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P = 0.045). The estimates of the 3-year rates of invasive-disease–free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease–free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease–free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P = 0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).” (G. von Minckwitz, gunter.vonminckwitz@gbg.de)
>>>PNN NewsWatch
* Based on a remission rate of 82.5% in a study of 63 patients with B-cell acute lymphoblastic leukemia, an FDA advisory panel yesterday recommended that the agency approve CTL019 (Novartis), according to articles in the Wall Street Journal and New York Times. If approved as expected, the drug would be the“first-ever treatment that genetically alters a patient’s own cells to fight cancer, transforming them into what scientists call ‘a living drug’ that powerfully bolsters the immune system to shut down the disease,” the Times reports. “To use the technique, a separate treatment must be created for each patient — their cells removed at an approved medical center, frozen, shipped to a Novartis plant for thawing and processing, frozen again and shipped back to the treatment center.”
* FDA has dropped a demand that Amicus Therapeutics conduct an additional clinical study of 
migalastat in treatment of Fabry disease, according to the Wall Street Journal. The shift in this high-profile case could be first indication of “a much more pragmatic and practical approach to drug development” at FDA with Commissioner Scott Gottlieb at the helm, an analyst says.

PNN Pharmacotherapy Line
July 14, 2017 * Vol. 24, No. 134
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Infectious Diseases Report
Source:
 July 15 issue of Clinical Infectious Diseases (2017; 65).
Pharmacist-Driven ID Care: At a single hospital, an automated, pharmacist-driven intervention improved the quality of care of patients with Staphylococcus aureus bacteremia (SAB), according to an antimicrobial stewardship program (ASP) report (pp. 194–200). A patient scoring tool integrated into the electronic health record alerted pharmacists to patients with SAB. “Pharmacists utilized the scoring tool and the institution’s evidence-based practice guideline to make standardized recommendations to promote adherence to SAB quality-of-care measures and encourage [infectious diseases (ID)] consultation,” the authors report, adding these results: “In sum, 84 patients were identified for study inclusion, 45 in the pre-intervention and 39 in the intervention group. As a whole, all 4 quality-of-care components for the management of SAB were significantly more frequently adhered to in the intervention group (68.9% vs 92.3%; P = .008). The incidence of ID consult improved significantly by almost 20% in the intervention group (75.6% vs 94.9%, P = .015). No statistically significant differences in duration of bacteremia, length-of-stay, infection-related length-of-stay, or readmission were observed between the groups. The incidence of all-cause mortality was 6-fold higher in the pre-intervention group compared to the intervention group (15.6% vs 2.6%, P = .063).” (E. Wenzler)
Subacute Sclerosing Panencephalitis After Measles: A potentially fatal complication of measles, subacute sclerosing panencephalitis (SSPE) may occur more frequently than previously thought, a study shows, especially among infants (pp. 226–32). California measles cases in 1998–2015 (n = 17) had these outcomes: “Males outnumbered females 2.4:1. Twelve (71%) cases had a history of measles-like illness; all 12 had illness prior to 15 months of age. Eight (67%) children were exposed to measles in California. SSPE was diagnosed at a median age of 12 years (3–35 years), with a latency period of 9.5 years (2.5–34 years). Among measles cases reported to [the California Department of Public Health] during 1988–1991, the incidence of SSPE was 1:1367 for children <5 years, and 1:609 for children <12 months at time of measles disease.” (K. A. Wendorf)
>>>Oncology Highlights
Source:
 July 10 issue of the Journal of Clinical Oncology (2017; 35).
ASCO Guideline on Potentially Curable Pancreatic Cancer: In an update to its guideline on management of potentially curable pancreatic cancer, the American Society of Clinical Oncology (ASCO) makes these recommendations (pp. 2324–8): “All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The doublet regimen of gemcitabine and capecitabine is preferred in the absence of concerns for toxicity or tolerance; alternatively, monotherapy with gemcitabine or fluorouracil plus folinic acid can be offered. Adjuvant treatment should be initiated within 8 weeks of surgical resection, assuming complete recovery. The remaining recommendations from the original 2016 ASCO guideline are unchanged.” (P. B. Mangu, guidelines@asco.org)
>>>PNN NewsWatch
“Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use” is the topic of a report issued yesterday by the National Academies of Sciences, Engineering, and Medicine (NASEM). “Drug overdose, driven largely by overdose related to the use of opioids, is now the leading cause of unintentional injury death in the United States,” NASEM writes. “The ongoing opioid crisis lies at the intersection of two public health challenges: reducing the burden of suffering from pain and containing the rising toll of the harms that can arise from the use of opioid medications. Chronic pain and opioid use disorder both represent complex human conditions affecting millions of Americans and causing untold disability and loss of function.” In thanking NASEM for compiling the report, FDA Commissioner Scott Gottlieb said, “We’re committed to doing our part and will continue to use our regulatory authority to reduce the scope of this immense public health crisis.”

PNN Pharmacotherapy Line
July 17, 2017 * Vol. 24, No. 135
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 July 15 issue of Lancet (2017; 390).
Intraoperative Ketamine for Delirium/Pain Prophylaxis in Older Adults: In the Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study, adults aged 60 years or older showed few postoperative benefits from a single subanesthetic dose of ketamine during surgery (pp. 267–75). The authors note that subanesthetic ketamine is “often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium.” However, among 1,360 patients undergoing major cardiac or noncardiac surgery, no decrease in delirium was noted, and the investigators conclude based on these results that the practice “might cause harm by inducing negative experiences”: “There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19.45% vs 19.82%, respectively; absolute difference 0.36%, 95% CI −6.07 to 7.38, p=0.92). There were more postoperative hallucinations (p = 0.01) and nightmares (p = 0.03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0.40) or collectively (36.9% in placebo, 39.6% in 0.5 mg/kg ketamine, and 40.8% in 1.0 mg/kg ketamine groups, p = 0.69), did not differ significantly across groups.” (M. S. Avidan, avidanm@wustl.edu)
Tildrakizumab for Chronic Plaque Psoriasis: A high-affinity, humanized, IgG1 kappa antibody that targets interleukin 23 p19 yielded positive results in patients with moderate-to-severe chronic plaque psoriasis, researchers report (pp. 276–88). Phase 3 trials, reSURFACE 1 and 2, showed that two doses were efficacious compared with placebo and had tolerable safety profiles. (K. Reich, kreich@dermatologikum.de)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Postpregnancy Hypertension Following Hypertensive Disorders During Pregnancy: Two studies examine women’s risk of hypertension after having hypertensive disorders during pregnancy.
Analysis of the Danish nationwide registry shows that hypertension during pregnancy increased women’s risk for hypertension immediately after childbirth and continuing for 20 years (
j3078). “Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy,” the investigators conclude. (H. A. Boyd, hoy@ssi.dk)
In the prospective cohort Nurses’ Health Study II conducted in 1991–2013, chronic hypertension after hypertensive disorders of pregnancy (HDP; gestational hypertension and pre-eclampsia) was reduced through lifestyle interventions (
j3024): “10% (n = 5,520) of women had a history of HDP at baseline. 13,971 cases of chronic hypertension occurred during 689,988 person years of follow-up. Being overweight or obese was the only lifestyle factor consistently associated with higher risk of chronic hypertension. Higher body mass index, in particular, also increased the risk of chronic hypertension associated with history of HDP (relative excess risk due to interaction P <0.01 for all age strata). For example, in women aged 40–49 years with previous HDP and obesity class I (body mass index 30.0–34.9), 25% (95% confidence interval 12% to 37%) of the risk of chronic hypertension was attributable to a potential effect of obesity that was specific to women with previous HDP. There was no clear evidence of effect modification by physical activity, DASH diet, or sodium/potassium intake on the association between HDP and chronic hypertension.” (S. Timpka, simon.timpka@med.lu.se)
>>>PNN JournalWatch
* From One Syndrome to Many: Incorporating Geriatric Consultation Into HIV Care, in Clinical Infectious Diseases, 2017; 65: 501–6. (H. K. Singh) 
* Traceback: A Proposed Framework to Increase Identification and Genetic Counseling of 
BRCA1 and BRCA2 Mutation Carriers Through Family-Based Outreach, in Journal of Clinical Oncology, 2017; 35: 2329–37. (G. Samimi, goli.samimi@nih.gov
* Kidney Disease and the Westernization and Industrialization of Food, in 
American Journal of Kidney Diseases, 2017; 70: 111–21. (H. Kramer, hkramer@luc.edu)

PNN Pharmacotherapy Line
July 18, 2017 * Vol. 24, No. 136
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 July 18 issue of the Annals of Internal Medicine (2017; 167).
MMR Vaccines & Pretravel Health Consultations: Providers are missing opportunities to bring travelers up-to-date on measles, mumps, rubella (MMR) vaccine, according to results of surveys completed during pretravel consultations at 24 sites associated with the CDC-funded Global TravEpiNet (GTEN) (pp. 77–84). Adults born in or after 1957 and providers who saw them in 2009–14 gave these responses on structured questionnaires: “40,810 adult travelers were included; providers considered 6,612 (16%) to be eligible for MMR vaccine at the time of pretravel consultation. Of the MMR-eligible, 3,477 (53%) were not vaccinated at the visit; of these, 1,689 (48%) were not vaccinated because of traveler refusal, 966 (28%) because of provider decision, and 822 (24%) because of health systems barriers. Most MMR-eligible travelers who were not vaccinated were evaluated in the South (2,262 travelers [65%]) or at nonacademic centers (1,777 travelers [51%]). Nonvaccination due to traveler refusal was most frequent in the South (1,432 travelers [63%]) and in nonacademic centers (1,178 travelers [66%]).” (E. P. Hyle, ehyle@mgh.harvard.edu)
“All unvaccinated travelers who are medically able to receive MMR vaccine should do so,” editorialists write (
pp. 127–8). “The risks are minimal for the individual who receives the vaccine and are greatly outweighed by the benefit to the traveler, as well as to society, on his or her return. Furthermore, travel clinics present an additional contact with the health care system, through which adults and children may receive recommendations regarding all vaccinations, not only those recommended for travel. If persons traveling abroad continue to underestimate the importance of pretravel MMR vaccination, our society is destined to be affected by imported cases of measles, leading to morbidity and mortality from this disease.” (L. K. Handy, handyl@email.chop.edu)
Race & Glucose/A1C Levels: Hemoglobin A1c (HbA1c) levels overestimate mean glucose concentrations in black patients, a study shows (pp. 95–102). “However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes,” the authors add, based on these findings in this prospective, observational study of 104 black and 104 white persons aged 8 years or older with type 1 diabetes: “The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons).” (R. L. Gal, rgal@jaeb.org)
This racial difference is not new, editorialists note (
pp. 131–2): “Data documenting this difference in the United States date back to at least the early 1980s, and much of the difference has been thought to relate to disparities in risk factors, glycemic control, access to care, and socioeconomic status.” (E. Selvin, eselvin@jhu.edu)
An Annual MIPS Fix? While the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) ended the need for the annual “doc fix” of the sustained growth rate (SGR) in Congress, a writer notes (pp. 122–4). However, problems with MACRA’s Merit-based Incentive Payment System (MIPS) may now necessitate a MIPS fix each year, the author concludes. (J. M. McWilliams, mcwilliams@hcp.med.harvard.edu)
>>>PNN NewsWatch
FDA yesterday approved the once-daily oral tyrosine kinase inhibitor neratinib (Nerlynx, Puma Biotechnology) for the extended adjuvant treatment of early-stage, HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy. The agent, the first anti-HER2 treatment approved for extended adjuvant therapy in these patients, produced a 34% reduction in risk of invasive disease recurrence or death in comparison with placebo in phase 3 trials.

PNN Pharmacotherapy Line
July 19, 2017 * Vol. 24, No. 137
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 July 18 issue of JAMA (2017; 318).
Vitamin D Doses & Wintertime Pediatric Viral Infections: In young healthy children, aggressive dosing of vitamin D supplements during winter months failed to reduce upper respiratory tract infections, researchers report (pp. 245–54). In Toronto, participants aged 1–5 years received vitamin D oral supplementation in doses of 400 IU/d or 2000 IU/d for 4 months or more between Sept. and May, with these results: “Among 703 participants who were randomized (mean age, 2.7 years, 57.7% boys), 699 (99.4%) completed the trial. The mean number of laboratory-confirmed upper respiratory tract infections per child was 1.05 (95% CI, 0.91–1.19) for the high-dose group and 1.03 (95% CI, 0.90–1.16) for the standard-dose group, for a between-group difference of 0.02 (95% CI, −0.17 to 0.21) per child. There was no statistically significant difference in number of laboratory-confirmed infections between groups (incidence rate ratio [RR], 0.97; 95% CI, 0.80–1.16). There was also no significant difference in the median time to the first laboratory-confirmed infection: 3.95 months (95% CI, 3.02–5.95 months) for the high-dose group vs 3.29 months (95% CI, 2.66–4.14 months) for the standard-dose group, or number of parent-reported upper respiratory tract illnesses between groups (625 for high-dose vs 600 for standard-dose groups, incidence RR, 1.01; 95% CI, 0.88–1.16). At study termination, serum 25-hydroxyvitamin D levels were 48.7 ng/mL (95% CI, 46.9–50.5 ng/mL) in the high-dose group and 36.8 ng/mL (95% CI, 35.4–38.2 ng/mL) in the standard-dose group.” (J. L. Maguire, jonathon.maguire@utoronto.ca)
Early-Life Weight Gain & Healthy Aging: Health professionals who gained weight between early and middle adulthood had poorer health outcomes in later life, including increased incidence of type 2 diabetes and obesity-related cancer in men and women, and cardiovascular disease and mortality in women, according to a cohort analysis of the Nurses’ Health Study and the Health Professionals Follow-Up Study (pp. 255–69). Participants were asked to recall their weights at 18 (women) or 21 (men) years of age. These relationships between weight gain at age 55 and later healthy aging outcomes were identified: “Among those who gained a moderate amount of weight [≥2.5–<10.0 kg], 3,651 women (24%) and 2,405 men (37%) achieved the composite healthy aging outcome [being free of 11 chronic diseases and major cognitive or physical impairment]. Among those who maintained a stable weight, 1,528 women (27%) and 989 men (39%) achieved the composite healthy aging outcome. The multivariable-adjusted odds ratio for the composite healthy aging outcome associated with moderate weight gain was 0.78 (95% CI, 0.72 to 0.84) in women and 0.88 (95% CI, 0.79 to 0.97) in men. Higher amounts of weight gain were associated with greater risks of major chronic diseases and lower likelihood of healthy aging.” (F. B. Hu, nhbfh@channing.harvard.edu)
“The prevalence of obesity emphasizes that it will not be possible to provide effective treatment for all of those affected,” an editorialist writes in response to these data (
pp. 241–2). “Therefore, efforts to prevent and control this widespread disease must be renewed. Reducing and preventing obesity and excessive weight gain in young adults provide a new target, and one that could offer an effective transgenerational approach for prevention.” (W. H. Dietz, dietzwcd4@gmail.com)
Engaging Parents About Vaccines: A Viewpoint author describes ways of using patient-engagement techniques to address parents’ perceptions about immunizations (pp. 237–8). Ideas include identifying common ground, coupling evidence with compelling narratives, clarifying values, and providing resources for critically evaluating news stories. (M. C. Politi, mpoliti@wustl.edu)
>>>PNN NewsWatch
FDA yesterday approved a three-drug combination product for retreatment of patients with any of the six genotypes of chronic hepatitis C virus (HCV) previously treated with an NS5A inhibitor-containing regimen, or with genotype 1a or 3 previously treated with a sofosbuvir-containing regimen without an NS5A inhibitor. Vosevi (Gilead) contains fixed doses of a new drug, voxilaprevir, with two previously marketed HCV drugs, sofosbuvir and the pangenotypic NS3/4A protease inhibitor velpatasvir.


PNN Pharmacotherapy Line
July 20, 2017 * Vol. 24, No. 138
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 July 20 issue of the New England Journal of Medicine (2017; 377).
ANGPTL3 & Cardiovascular Disease: Responding to two studies of the action of the human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with high triglyceride or LDL cholesterol levels (pp. 211–21, F. E. Dewey, frederick.dewey@regeneron.compp. 222–32, S. Tsimikas, stsimikas@ucsd.edu), editorialists write (pp. 280–3): “It is likely that lowering the levels of triglyceride-rich lipoproteins with agents that increase lipoprotein lipase activity will lead to a different spectrum of benefits and side effects than treatments that increase the activity of the LDL receptor. For example, increasing lipoprotein lipase activity might ameliorate insulin resistance and reduce the risk of diabetes. Insulin sensitization was shown in patients with ANGPTL3 mutations as well as in Angptl3-deficient mice, in which increased uptake of fatty acids into oxidative tissues such as muscle and brown adipose tissue led to decreased uptake of fatty acids and increased uptake of glucose in white adipose tissue. In humans, variants in lipoprotein lipase that increase its activity are associated with a reduced risk of coronary artery disease and a reduced risk of diabetes; the mechanisms linking lipoprotein lipase activity to decreased insulin resistance and diabetes may include storage of triglyceride in gluteofemoral rather than visceral fat. In contrast, genetic variants that compromise the function of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (the target of statins) or PCSK9 are associated with increased diabetes risk.” (A. R. Tall)
Managing Advanced HIV Infection: In an open-label study of patients in sub-Saharan Africa of patients with advanced HIV infection, enhanced antimicrobial prophylaxis plus antiretroviral therapy (ART) reduced mortality at 24 and 48 weeks without worsening viral suppression or toxic effects, researchers report (pp. 233–45). HIV-infected adults and children aged 5 years or older with advanced immunosuppression received continuous trimethoprim–sulfamethoxazole plus at least 12 weeks of isoniazid–pyridoxine, 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, or standard prophylaxis (trimethoprim–sulfamethoxazole alone), with these results: “A total of 1,805 patients (1,733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P = 0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P = 0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P = 0.02), cryptococcal infection (P = 0.01), oral or esophageal candidiasis (P = 0.02), death of unknown cause (P = 0.03), and new hospitalization (P = 0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P = 0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P = 0.08 and P = 0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.” (A. Walker, rmjlasw@ucl.ac.uk)
“With the advent of new treatment options, HIV infection has evolved from a probable death sentence to a chronic disease,” editorialists write (
pp. 283–4). “If patients start ART early, they can expect a near-normal life expectancy. Early treatment also reduces the risk of HIV transmission, and much of the focus today is on reducing the spread of new infections to achieve epidemic control. Nevertheless, the relatively consistent proportion of patients who newly present for care with a low CD4+ count, together with an additional number of seriously ill patients who return for care after a period of treatment interruption, calls for a renewed focus to respond to the needs of patients with advanced HIV infection who are at high risk for illness and death.” (N. Ford)

PNN Pharmacotherapy Line
July 21, 2017 * Vol. 24, No. 139
Providing news and information about medications and their proper use

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>>>Rheumatology Report
Source:
 July issue of Arthritis & Rheumatology (2017; 69).
Treat-to-Target Education in Rheumatoid Arthritis: Improved adherence resulted when patients with rheumatoid arthritis participated in a 9-month, group-based learning collaborative that focused on the treat-to-target (TTT) paradigm, researchers report (pp. 1374–80). At 5 U.S. sites, these results were recorded for 621 patients cluster-randomized to the intervention or a control group: “At baseline, the mean TTT implementation score was 11% in both arms; after the 9-month intervention, the mean TTT implementation score was 57% in the intervention group and 25% in the control group (change in score of 46% for intervention and 14% for control; P = 0.004). We did not observe excessive use of resources or excessive occurrence of adverse events in the intervention arm.” (D. H. Solomon, dhsolomon@partners.org)
Rituximab in Primary Sjögren’s Syndrome: The anti-B cell agent rituximab failed produce significant, cost-effective improvement in fatigue and oral dryness symptoms in patients with primary Sjögren’s syndrome (SS) (pp. 1440–50). At 25 U.K. rheumatology clinics, anti-Ro-positive patients were randomized to I.V. saline or rituximab 1,000 mg in saline in 2 courses over 26 weeks. Results showed: “All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group).” (S. J. Bowman, Simon.Bowman@uhb.nhs.uk)
“Based on [these] results of the TRACTISS trial, one might be reluctant to use rituximab to treat patients with primary SS,” editorialists write (
pp. 1346–9). “However, some studies show that rituximab has a beneficial effect in a subgroup of patients, i.e., nonresponders to rituximab treatment can be characterized, and rituximab has objective biologic effects. In other words, rituximab is not the wrong drug in primary SS, but it has to be applied in a particular subgroup of patients with the disease. The same will probably hold true for other biologic agents that are tested in primary SS. The better we can identify the specific characteristics of a patient with primary SS, the better we can prescribe a particular targeted biologic agent. Precision medicine is about to become a reality in primary SS!” (H. Bootsma, h.bootsma@umcg.nl)
>>>Allergy/Immunology Report
Source:
 July issue of the Journal of Allergy and Clinical Immunology (2017; 140).
Allergen Immunotherapy in House Dust Mite Allergy: An expert panel provides recommendations on treatment of asthma and allergic rhinitis (AR) and use of allergen immunotherapy (AIT) in patients with house dust mite (HDM) allergy (pp. 41–52): “Most guidelines and key position papers did not provide specific recommendations on treatment of allergic asthma (AA) caused by HDM allergy, although some included AIT as a treatment option for AA in general. Around half of the guidelines stated that AIT with HDM extract was an effective treatment for AR, with several indicating sublingual immunotherapy as an option. This heterogeneity is caused by quality issues affecting studies of AIT with perennial allergens in patients with AA and AR, including use of different diagnosis and severity criteria, lack of consistent scoring or grading systems for primary and safety outcomes, and lack of consensus on treatment parameters. There is a need for well-designed clinical trials to serve as a basis for guideline recommendations. Although results from recent studies strengthen the evidence base for the efficacy and safety of sublingual immunotherapy in patients with HDM-induced AA and AR, their effect on subsequent guideline updates will depend on the methodology and evidence model used by each guideline.” (P. Demoly, pascal.demoly@inserm.fr)
PNN Pharmacotherapy Line
July 24, 2017 * Vol. 24, No. 140
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Perinatal Antidepressants & Autism: Confounding may not fully explain the association between maternal use of antidepressants and development of autism, researchers report, especially in affected individuals without intellectual disabilities (j2811). In Stockholm County, Sweden, outcomes of 254,610 children born in 2001–11, including 5,378 with autism, were analyzed. Concluding that “study of the potential underlying biological mechanisms could help the understanding of modifiable mechanisms in the aetiology of autism,” the authors report these findings: “Of the 3,342 children exposed to antidepressants during pregnancy, 4.1% (n = 136) had a diagnosis of autism compared with a 2.9% prevalence (n = 353) in 12,325 children not exposed to antidepressants whose mothers had a history of a psychiatric disorder (adjusted odds ratio 1.45, 95% confidence interval 1.13 to 1.85). Propensity score analysis led to similar results. The results of a sibling control analysis were in the same direction, although with wider confidence intervals. In a negative control comparison, there was no evidence of any increased risk of autism in children whose fathers were prescribed antidepressants during the mothers’ pregnancy (1.13, 0.68 to 1.88). In all analyses, the risk increase concerned only autism without intellectual disability.” (D. Rai, Dheeraj.rai@bristol.ac.uk)
Lifestyle Interventions in Pregnancy: Using individual participant data (IPD) from studies identified through systematic review, investigators show that “diet and physical activity based interventions during pregnancy reduce gestational weight gain and lower the odds of caesarean section” (j3119): “IPD were obtained from 36 randomised trials (12,526 women). Less weight gain occurred in the intervention group than control group (mean difference −0.70 kg, 95% confidence interval −0.92 to −0.48 kg, I2 = 14.1%; 33 studies, 9,320 women). Although summary effect estimates favoured the intervention, the reductions in maternal (odds ratio 0.90, 95% confidence interval 0.79 to 1.03, I2 = 26.7%; 24 studies, 8,852 women) and offspring (0.94, 0.83 to 1.08, I2 = 0%; 18 studies, 7,981 women) composite outcomes were not statistically significant. No evidence was found of differential intervention effects across subgroups, for either gestational weight gain or composite outcomes. There was strong evidence that interventions reduced the odds of caesarean section (0.91, 0.83 to 0.99, I2 = 0%; 32 studies, 11,410 women), but not for other individual complications in IPD meta-analysis. When IPD were supplemented with study level data from studies that did not provide IPD, the overall effect was similar, with stronger evidence of benefit for gestational diabetes (0.76, 0.65 to 0.89, I2 = 36.8%; 59 studies, 16,885 women).” (K. S. Khan, k.s.khan@qmul.ac.uk)
>>>PNN NewsWatch
* Citing undeclared sildenafil and tadalafil, Ultra Shop Supplement voluntarily recalled the dietary supplement Super Panther 7K, (1 count blister card lot RO846356 and 6 count bottle lot RO246852 within expiry), distributed by SX Power Co., Brooklyn, NY, to the consumer level, FDA said on Friday.
>>>PNN JournalWatch
* Recent Literature Update on Medication Risk in Older Adults, 2015–2016, in Journal of the American Geriatrics Society, 2017; 65: 1401–5. (M. J. Koronkowski, koron@uic.edu
* Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care, in 
Journal of the American Geriatrics Society, 2017; 65: 1578–85. (S. E. Merel, smerel@uw.edu
* Treatment of Uremic Pruritus: A Systematic Review, in 
American Journal of Kidney Diseases, 2017; 10.1053/j.ajkd.2017.05.018. (C. Rigatto, crigatto@sbgh.mb.ca)
* Oncology Drug Dosing in Gilbert Syndrome Associated with 
UGT1A1: A Summary of the Literature, in Pharmacotherapy, 2017; 37: 10.1002/phar.1946. (V. Ha, Vincent.Ha@ahs.ca)
* Quantitation of Targetable Somatic Mutations Among Patients Evaluated by a Personalized Medicine Clinical Service: Considerations for Off-Label Drug Use, in 
Pharmacotherapy, 2017; 37: 10.1002/phar.1917. (J. K. Hicks, James.Hicks@Moffitt.org
* Optimizing Specialty Drug Use, in 
Pharmacotherapy, 2017; 37: 10.1002/phar.1945. (American College of Clinical Pharmacy, accp@accp.com)
* Getting It Right At The End Of Life, in 
Health Affairs, 2017; 36: 1336–9. (D. K. Moss, Dina.Moss@AHRQ.hhs.gov)


PNN Pharmacotherapy Line
July 25, 2017 * Vol. 24, No. 141
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Early-release articles from the Annals of Internal Medicine (2017; 167).
Continuing Statin Prescriptions After Adverse Reactions: Mortality and cardiovascular events occur less frequently when patients continue rather than stop statin therapy after adverse reactions, researchers report (10.7326/M16-0838). Structured electronic medical record data from primary care practices affiliated with two academic medical centers provide these estimates of risk of a primary composite outcome of time to a cardiovascular event (myocardial infarction or stroke) or death when statins were continued at any time during the 12 months after an adverse reaction: “Among 28,266 study patients, 19,989 (70.7%) continued receiving statin prescriptions after the adverse reaction. Four years after the presumed adverse event, the cumulative incidence of the composite primary outcome was 12.2% for patients with continued statin prescriptions, compared with 13.9% for those without them (difference, 1.7% [95% CI, 0.8% to 2.7%]; P < 0.001). In a secondary analysis of 7,604 patients for whom a different statin was prescribed after the adverse reaction, 2,014 (26.5%) had a documented adverse reaction to the second statin, but 1,696 (84.2%) of those patients continued receiving statin prescriptions.” (A. Turchin, aturchin@bwh.harvard.edu)
Internet propaganda promoting bizarre and unscientific criticisms of statins has given these life-saving drugs a bad reputation, according to a Commentary author (
10.7326/M17-1566): “What can thoughtful physicians do to counter these dangerous cults? We must work together to educate the public and enlist media support, and we must take the time to explain to our patients that discontinuing statin treatment may be a life-threatening mistake. Passive acceptance of harmful pseudoscience is not an option.” (S. E. Nissen, nissens@ccf.org)
>>>Chest Highlights
Source:
 July issue of Chest (2017; 152).
Anticoagulant-Related Major Bleeding: In a cohort comparison of consecutive patients older than 65 years of age at five Ontario hospitals who were taking warfarin or direct oral anticoagulants (DOACs), lower in-hospital mortality rates “support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents” (pp. 81–91): “Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19–2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49–0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61–1.03).” (A. P. Johnson, ana.johnson@queensu.ca)
IV Magnesium Sulfate for Bronchiolitis: Among 162 infants and young children with bronchiolitis, IV magnesium did not provide benefit and might have been harmful, a study shows (pp. 113–9). Outcomes following a single 100 mg/kg dose of the drug were as follows: “Geometric mean time until medical readiness for discharge was 24.1 h (95% CI, 20.0–29.1) for the 78 magnesium-treated patients and 25.3 h (95% CI, 20.3–31.5) for the 82 patients receiving placebo (ratio, 0.95 [95% CI, 0.52–1.80]; P = .91). Mean bronchiolitis severity scores over time were similar for the two groups. The frequency of clinic visits in the subsequent 2 weeks (33.8% and 27.2%, respectively) was also similar. Fifteen magnesium recipients (19.5%) vs five placebo recipients (6.2%) were readmitted to the infirmary or hospital within 2 weeks (P = .016). No acute cardiorespiratory side effects were reported.” (K. Alansari, dkmaa@hotmail.com)
>>>PNN NewsWatch
* EZ Weight Loss TX is voluntarily recalling all lots of La Bri’s Body Health Atomic and Xplode capsules to the consumer level after FDA found the products are tainted with sibutramine.



PNN Pharmacotherapy Line
July 26, 2017 * Vol. 24, No. 142
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Geriatrics Report
Source:
 July issue of the Journal of the American Geriatrics Society (2017; 65).
PPI Usage & Risk of Pneumonia in Dementia: In a retrospective cohort study based on the Taiwanese National Health Insurance Research Database, patients with dementia had an 89% increased risk of pneumonia when taking PPIs (pp. 1441–7). Pneumonia occurred with these frequencies in 786 patients on PPIs and 786 matched controls, all of whom had dementia: “Incidence of pneumonia was higher among patients with PPI usage (adjusted hazard ratio (HR) = 1.89; 95% CI = 1.51–2.37). Cox model analysis also demonstrated that age (adjusted HR = 1.05; 95% CI = 1.03–1.06), male gender (adjusted HR = 1.57; 95% CI = 1.25–1.98), underlying cerebrovascular disease (adjusted HR = 1.30; 95% CI = 1.04–1.62), chronic pulmonary disease (adjusted HR = 1.39; 95% CI = 1.09–1.76), congestive heart failure (adjusted HR = 1.54; 95% CI = 1.11–2.13), diabetes mellitus (adjusted HR = 1.54; 95% CI = 1.22–1.95), and usage of antipsychotics (adjusted HR = 1.29; 95% CI = 1.03–1.61) were independent risk factors for pneumonia. However, usage of cholinesterase inhibitors and histamine receptor-2 antagonists were shown to decrease pneumonia risk.” (C-B Yeh, sky5ff@gmail.com)
Managing Medications & Finances in Older Adults: Sizable proportions of adults aged 65 years or older need help managing medications and finances as they age, according to a prospective cohort study of 9,434 participants in the Health and Retirement Study (HRS), researchers report (pp. 1455–61): “The 10 years incidence of difficulty increased markedly with age, ranging from 10.3% (95% CI 9.3–11.6) for managing medications and 23.1% (95% CI 21.6–24.7) for managing finances in those aged 65–69, to 38.2% (95% CI 33.4–43.5) for medicines and 69% (95% CI 63.7–74.3) for finances in those over age 85. Women had a higher probability of developing difficulty managing medications and managing finances than men.” (N. Bleijenberg, n.bleijenberg@umcutrecht.nl)
>>>Health Affairs Report
Source:
 July issue of Health Affairs (2017; 36).
Reducing Antipsychotics for Dementia in Nursing Homes: Analysis of 86,163 state recertification surveys of U.S. nursing homes shows the impact of three CMS strategies initiated in 2012 and 2013 for reducing antipsychotic use for managing behavioral symptoms of dementia (pp. 1299–308): “We found that these strategies were associated with increases in citations for only one of two targeted deficiencies (unnecessary drug use) and only after the third strategy (revisions to the federal guidelines for the citations) was implemented. Each strategy was associated with a modest but significant reduction in antipsychotic prevalence in the general nursing home population. Initial reductions were greater in the ten states with the highest prevalence of antipsychotic use in nursing homes, compared to the ten states with the lowest prevalence. Use of other psychoactive medications, some of which are potential substitutes for antipsychotics, varied with each strategy and by state. Continuous monitoring and consistent enforcement are needed to ensure the continued decline in unnecessary use of antipsychotics and psychoactive medications in nursing homes.” (J. A. Lucas, Judith.Lucas@shu.edu)
>>>Medical Care Report
Source:
 Aug. issue of Medical Care (2017; 55).
Continuity of Care & Drug Interactions: Among 1 million Taiwanese beneficiaries, improved continuity of care (COC) was associated with reduced drug–drug interactions (DDIs) (pp. 744–51). In 2005 through 2013, national health insurance claims yielded these rnegative nominal regression results: “Higher COC was found to decrease the risk of DDI, and this risk reduction was even greater with physician COC and a higher Charlson comorbidity index. In the 1-year observation interval, patients exhibited a 3% reduction in DDIs for every 0.1 increment in their COC index. The ability of COC to reduce DDIs increased with the level of comorbidity. Similar results were observed when the observation interval was increased.” (J-Y Guo)
>>>PNN NewsWatch
Cantrell Drug Company has voluntarily recalled all lots of unexpired sterile drug products to the hospital and user level because of lack of sterility assurance, FDA said.

PNN Pharmacotherapy Line
July 27, 2017 * Vol. 24, No. 143
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 July 27 New England Journal of Medicine (2017; 377).
Tocilizumab in Giant-Cell Arteritis: Phase 3 results for tocilizumab, recently approved by FDA for treatment of patients with giant-cell arteritis, are presented (pp. 317–28). In the Giant-Cell Arteritis Actemra (GiACTA) trial, the agent was combined with a 26-week prednisone taper and compared with either 26- or 52-week prednisone tapering, with these results: “Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P <0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1,862 mg in each tocilizumab group, as compared with 3,296 mg in the placebo group that underwent the 26-week taper (P <0.001 for both comparisons) and 3,818 mg in the placebo group that underwent the 52-week taper (P <0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.” (J. H. Stone, jhstone@mgh.harvard.edu)
“Additional studies are needed before tocilizumab can be recommended for all patients with active giant-cell arteritis,” an editorialist writes (
pp. 385–6). “As Stone et al. emphasize, the long-term effect of tocilizumab cannot be determined in 1 year. Although tocilizumab was much more effective than prednisone alone, only approximately 50% of the patients treated with tocilizumab had prednisone-free remission. Perhaps blocking other cytokines or cells (such as T cells) or interrupting multiple pathways will be more effective. The previous report of a patient with giant-cell arteritis who appeared to have remission with tocilizumab but had a myocardial infarction and was found to have active arteritis suggests that tocilizumab may suppress manifestations of giant-cell arteritis (especially the elevated CRP level) without eliminating the arteritis.” (D. B. Hellmann)
Abiraterone for Prostate Cancer: Two clinical trials demonstrate benefits of abiraterone in men with prostate cancer sensitive to adrogen-deprivation therapy (ADT) or castration. In the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone, investigators conclude (pp. 338–51). “There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P <0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease,” the authors report. “There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P <0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease.” (N.D. James, mrcctu.stampede_publications@ucl.ac.uk)
“The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer,” according to Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators (
pp. 352–60; K. Fizazi, karim.fizazi@gustaveroussy.fr).
“The results of these two trials establish new and positive directions for oncologists who treat patients with prostate cancer and provide mechanistic challenges for investigators who study metastatic prostate cancer,” concludes an editorialist (
pp. 388–90). “A focus on metastatic, castration-sensitive prostate cancer may achieve major improvements in survival in a patient population that will tolerate multiple agents.” (C. J. Logothetis)

PNN Pharmacotherapy Line
July 28, 2017 * Vol. 24, No. 144
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Diabetes Report
Source:
 Aug. issue of Diabetes Care (2017; 40).
Metformin v. GLP-1 Receptor Agonists for First-Line Type 2 Diabetes Therapy: In a point–counterpoint exchange, authors debate the role of metformin versus liraglutide or another GLP-1 receptor agonist (GLP-1 RA) as foundational therapy in patients with type 2 diabetes (T2D). Introducing the pair of articles, the ADA Chief Scientific, Medical & Mission Officer first points to metformin’s 30-year track record of affordability and tolerability. “However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances,” W. T. Cefalu writes. “That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process.”
“The currently available clinical and scientific evidence is overwhelmingly in favor of the use of GLP-1 RAs over metformin as first-line therapy in newly diagnosed T2D patients,” proponents conclude (
pp. 1121–7). “GLP-1 RAs … (1) correct six of the eight components of the Ominous Octet, (2) prevent/reverse the progressive beta-cell failure and rise in HbA1c, and (3) lower cardiovascular risk in T2D independent of their glucose-lowering ability.” (M. Abdul-Ghani, abdulghani@uthscsa.edu)
“In order to replace metformin as the preferred initial drug in type 2 diabetes, a head-to-head trial with the proposed agent would need to be conducted, assessing the relative effects on glycemia and both macrovascular and microvascular outcomes,” the counterpoint author writes (
pp. 1128–32). He concludes, “Based on the medical community’s extensive experience and the drug’s demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the ‘foundation therapy’ for all patients with type 2 diabetes, barring contraindications. There is no convincing evidence at the present time to consider any other approach.” (S. E. Inzucchi, silvio.inzucchi@yale.edu)
A1C — The Fallacy of Average: “Estimating glycemic control from HbA1c alone is in essence applying a population average to an individual, which can be misleading,” authors write (pp. 994–9). “Thus, a patient’s [continuous glucose monitoring] profile has considerable value for optimizing his or her diabetes management. In this era of personalized, precision medicine, there are few better examples with respect to the fallacy of applying a population average to a specific patient rather than using specific information about the patient to determine the optimal approach to treatment.” (R. W. Beck, rbeck@jaeb.org)
Severe Hypoglycemia in Type 1 Diabetes: “Severe hypoglycemia persists and remains a challenge for patients with type 1 diabetes across their life span,” authors conclude based on 30 years of follow-up in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Inverventions and Complications (EDIC) cohort (pp. 1010–6): “One-half of the DCCT/EDIC cohort reported episodes of severe hypoglycemia. During EDIC, rates of severe hypoglycemia fell in the former DCCT intensive treatment group but rose in the former conventional treatment group, resulting in similar rates (36.6 vs. 40.8 episodes per 100 patient–years, respectively) with a relative risk of 1.12 (95% CI 0.91–1.37). A preceding episode of severe hypoglycemia was the most powerful predictor of subsequent episodes. Entry into the DCCT study as an adolescent was associated with an increased risk of severe hypoglycemia, whereas insulin pump use was associated with a lower risk. Severe hypoglycemia rates increased with lower HbA1c similarly among participants in both treatment groups.” (R. A. Gubitosi-Klug, rose.gubitosi-klug@case.edu)
>>>PNN NewsWatch
* Citing potential mislabeling, Apace Packaging LLC is recalling to the retail level one unit dose lot each of cyclobenzaprine HCl tablets 5 mg 50 ct, NDC 50268-190-15, lot 16710, and amantadine HCl capsules 100 mg 50 ct, NDC 50268-069-15, lot 16710.

PNN Pharmacotherapy Line
July 31, 2017 * Vol. 24, No. 145
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 July 29 issue of Lancet (2017; 390).
Gastroprotection Needed In Older Adults on Aspirin: The risk of major bleeding is excessively high in the 75-or-older age group when taking aspirin for antiplatelet therapy without PPI protection, a study shows (pp. 490–9). “Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated [number needed to treat (NNT)] for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged,” Oxford Vascular Study investigators conclude. “The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older.” (P. M. Rothwell, peter.rothwell@ndcn.ox.ac.uk)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Smoking Cessation & E-cigarette Use: As Americans have increased use of electronic cigarettes, smoking cessation rates have increased, according to data from the U.S. Current Population Survey–Tobacco Use Supplement (CPS-TUS) for time periods between 2001 and 2014 (j3262). “These findings need to be weighed carefully in regulatory policy making regarding e-cigarettes and in planning tobacco control interventions,” the authors conclude based on these findings: “Of 161,054 respondents to the 2014–15 survey, 22,548 were current smokers and 2,136 recent quitters. Among them, 38.2% of current smokers and 49.3% of recent quitters had tried e-cigarettes, and 11.5% and 19.0% used them currently (every day or some days). E-cigarette users were more likely than non-users to attempt to quit smoking, 65.1% v 40.1% (change = 25.0%, 95% confidence interval 23.2% to 26.9%), and more likely to succeed in quitting, 8.2% v 4.8% (3.5%, 2.5% to 4.5%). The overall population cessation rate for 2014–15 was significantly higher than that for 2010–11, 5.6% v 4.5% (1.1%, 0.6% to 1.5%), and higher than those for all other survey years (range 4.3–4.5%).” (S-H Zhu, szhu@ucsd.edu)
“The study findings are not entirely novel: recent research using a different methodology published in this journal from the United Kingdom drew similar conclusions,” writes an editorialist (
j3506). “Notably, both studies analysed data from populations in countries with (currently) relatively liberal regulatory approaches towards e-cigarettes. The research by Zhu and colleagues suggests that where such permissive approaches to e-cigarettes exist—ones that enable smokers to have ready access to products that deliver nicotine effectively, at a price lower than that of tobacco cigarettes—then substantial numbers of smokers will make the transition away from smoking, and a substantial population benefit can result. In light of this evidence, policy makers in countries contemplating a more restrictive approach to the regulation of e-cigarettes should pause to consider if pursuing such a course of action is the right thing to do for population health.” (C. Bullen, c.bullen@auckland.ac.nz)
>>>PNN NewsWatch
* Shifting from an any-nicotine-is-bad posture, FDA on Friday announced a multiyear effort to revamp regulations governing cigarettes and other nicotine-delivery devices in the U.S. “The goal is to ensure that the FDA has the proper scientific and regulatory foundation to efficiently and effectively implement the Family Smoking Prevention and Tobacco Control Act,” a news release said. “To make certain that the FDA is striking an appropriate balance between regulation and encouraging development of innovative tobacco products that may be less dangerous than cigarettes, the agency is also providing targeted relief on some timelines described in the May 2016 final rule that extended the FDA’s authority to additional tobacco products. The agency will also seek input on critical public health issues such as the role of flavors in tobacco products.”
>>>PNN JournalWatch
* Microbiological and Clinical Outcomes of Treating Non-Mycobacterium Avium Complex Nontuberculous Mycobacterial Pulmonary Disease: A Systematic Review and Meta-Analysis, in Chest, 2017; 152: 120–42. (R. Diel, roland.diel@epi.uni-kiel.de)
* Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review, in 
Annals of Internal Medicine, 2017; 167: 10.7326/M17-0577. (C. G. Streed Jr., cstreed@bwh.harvard.edu)

PNN Pharmacotherapy Line
Aug. 1, 2017 * Vol. 24, No. 146
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Aug. 1 issue of the Annals of Internal Medicine (2017; 167).
Outcomes in Dose Reduction or Termination of Long-Term Opioid Therapy: Options for reducing or discontinuing long-term opioid therapy (LTOT) are numerous and possibly effective, authors of a systematic review report, but interventions are supported by very low quality evidence (pp. 181–91): “Sixty-seven studies (11 randomized trials and 56 observational studies) examining 8 intervention categories, including interdisciplinary pain programs, buprenorphine-assisted dose reduction, and behavioral interventions, were found. Study quality was good for 3 studies, fair for 13 studies, and poor for 51 studies. Many studies reported dose reduction, but rates of opioid discontinuation ranged widely across interventions and the overall quality of evidence was very low. Among 40 studies examining patient outcomes after dose reduction (very low overall quality of evidence), improvement was reported in pain severity (8 of 8 fair-quality studies), function (5 of 5 fair-quality studies), and quality of life (3 of 3 fair-quality studies).” (J. W. Frank, joseph.frank@ucdenver.edu)
“Although it will be important to confirm the results with more and higher-quality studies, Frank and colleagues’ review provides evidence that patients who work with clinicians to reduce or discontinue opioid use can expect improvements in pain, function, and quality of life,” editorialists write (
pp. 208–9). “Clinicians should find comfort in being able to communicate this hope to patients. As the authors note, ‘In the realm of opioid therapy, patient safety and pain relief have often been framed as conflicting and mutually exclusive goals…[new evidence] holds the potential to fundamentally alter the conversation about opioid tapering.’ It will be heartening for many clinicians and patients to realize that indefinite continuation of opioid therapy is not always a foregone conclusion. It is possible to reduce opioid use and associated risks while reducing pain and improving function and quality of life.” (D. Dowell, ddowell@cdc.gov)
Generic Drug Prices & Market Competition: The less competition among generic drug products, the higher the prices, according to a retrospective cohort study (pp. 145–51). Over 5.5 years, 11 study periods of 6 months each provided the following insights into the Herfindahl–Hirschman Index (HHI; sum of the squares of individual manufacturers’ market shares, with higher values indicating a less competitive market): “From 1.08 billion prescription claims, a cohort of 1,120 generic drugs was identified. After adjustment, drugs with quadropoly (HHI value of 2,500, indicating relatively high levels of competition), duopoly (HHI value of 5,000), near-monopoly (HHI value of 8,000), and monopoly (HHI value of 10,000) levels of baseline competition were associated with price changes of −31.7% (95% CI, −34.4% to −28.9%), −11.8% (CI, −18.6% to −4.4%), 20.1% (CI, 5.5% to 36.6%), and 47.4% (CI, 25.4% to 73.2%), respectively, over the study period.” (C. V. Dave, chintandave19@gmail.com)
Antithrombotic Therapy in Essential Thrombocythemia: At high risk for both thrombosis and hemorrhage, patients with essential thrombocythemia (ET) are often treated with antithrombotic therapy, but evidence supporting this intervention is lacking, researchers report (pp. 170–80). No relevant randomized trials were identified in a systematic review; results of 24 observational studies showed the following: “Findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1,000 patient–years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively.” (D. M. Siegal, siegald@mcmaster.ca)
>>>PNN NewsWatch
* Adverse events involving at least 43 patients have been reported with intravitreal injections of triamcinolone and moxifloxacin compounded by Guardian Pharmacy Services in Dallas, FDA says.
* FDA announces recalls of 
Man of Steel 1 and 2 at the retail level and ICU Medical’s 0.9% Sodium Chloride Injection, USP, 1,000 mL to the hospital/user level.

PNN Pharmacotherapy Line
Aug. 2, 2017 * Vol. 24, No. 147
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Aug. 1 issue of JAMA (2017; 318).
Oral Methylprednisolone in IgA Nephropathy: In the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study, oral corticosteroid therapy increased the risk of adverse events in patients with IgA nephropathy and persistent proteinuria, researchers report (pp. 432–42). Oral methylprednisolone or placebo were administered for 2 months and tapered for 4–6 months, with these results before early study termination: “After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years’ median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%–18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%–13.9%]; P <.001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17–0.85]; risk difference, 10.0% [95% CI, 2.5%–17.9%]; P = .02).” (H. Zhang, hongzh@bjmu.edu.cn)
“Whether concomitant prescribing of prophylactic antibiotics can reduce the frequency of corticosteroid-associated infections warrants further evaluation,” editorialists write (
pp. 429–31). “The pursuit of safer and more effective alternatives to corticosteroids should also continue, despite disappointing or conflicting results from prior studies of azathioprine, mycophenolate mofetil, and rituximab. The efficacy of non–drug-based therapies, including tonsillectomy or dietary manipulation, also merit more rigorous evaluation. From a study design perspective, the TESTING trial raises some important questions regarding how best to adjudicate risks and benefits when evaluating study outcomes. Although the decision to halt TESTING prematurely due to safety concerns was reasonable, the appropriateness of the prevailing practice for [data and safety monitoring committees (DSMCs)] to examine treatment-related adverse events in isolation from likely benefits deserves further consideration. Indeed, a recent statement from the Clinical Trials Transformation Initiative outlining recommendations for DSMCs indicated that ‘attempting to assess harm alone, without the context of clinical benefit, would, in most cases, be ill advised.’ Engagement of patient advocates in study design might also be informative, because patients are best poised to weigh the relative import of beneficial and harmful effects. Patient-reported outcomes should also receive increased focus in glomerular disease clinical trials, as recently advocated.” (M. M. O’Shaughnessy, moshaugh@stanford.edu)
Fees & Finances of Medical Specialty Boards: Medical specialty boards take in substantially more money than their services cost, according to an analysis of the Internal Revenue Service returns of 24 organizations (pp. 477–9). With mean fees for initial examinations averaging nearly $2,000 and mean maintenance of certification fees of $257 per year, the specialty boards reported substantial excess revenues as well as net balances: “In FY 2013, member boards reported $263 million (95% CI, $212 million–$249 million) in revenue and $239 million (95% CI, $218 million–$258 million) in expenses; a difference of $24 million (95% CI, $22 million–$26 million) in surplus. Examination fees accounted for 87.7% (95% CI, 82.4%-93.0%) of revenue and 21.3% (95% CI, 17.0%–25.6%) of expenditures, whereas officer and employee compensation and benefits accounted for 42.2% (95% CI, 36.9%–47.5%) of expenses.
“In total, the boards reported $701 million (95% CI, $644 million–$758 million) in assets and $65.6 million (95% CI, $60 million–$71 million) in liabilities (difference, $635 million (95% CI, $584 million–$687 million).…” (B. C. Drolet, 
brian.c.drolet@gmail.com)
>>>PNN NewsWatch
FDA yesterday approved the isocitrate dehydrogenase-2 inhibitor enasidenib (Idhifa, Celgene) for treatment of adults with relapsed or refractory acute myeloid leukemia with a specific genetic mutation. It is approved for use with the RealTime IDH2 Assay (Abbott), which detects specific mutations in the IDH2 gene.


PNN Pharmacotherapy Line
Aug. 3, 2017 * Vol. 24, No. 148
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Aug. 3 issue of the New England Journal of Medicine (2017; 377).
Angiotensin II for Vasodilatory Shock: In patients with vasodilatory shock unresponsive to high-dose vasopressors, angiotensin II increased blood pressure, investigators conclude (pp. 419–30). In the placebo-controlled, phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study, 344 participants had these outcomes based on a primary end point of increased mean arterial pressure 3 hours after the start of infusion without an increase in the dose of background vasopressors: “The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P <0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (−1.75 vs. −1.28, P = 0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P = 0.12).” (R. Bellomo, rinaldo.bellomo@austin.org.au)
“The promise of a new class of vasopressor is appealing, and the results of the ATHOS-3 trial are encouraging,” editorialists conclude (
pp. 486–7). “We do, however, urge considerable thought regarding the rapidity with which this agent is advanced to the bedside and the decision as to which patients are the best candidates. There are still important questions to be answered, important subgroups to be analyzed, and important comparisons to be made.” (R. P. Dellinger)
Idarucizumab for Dabigatran Reversal: Reporting data on the full cohort of 503 participants in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) study, researchers report that “idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran” in emergency situations (pp. 431–41). Patients were categorized as requiring anticoagulant reversal for uncontrolled bleeding (group A) or an urgent procedure (group B). Results showed: “A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals.” (C. V. Pollack, Jr., charles.pollack@jefferson.edu)
IgG Endopeptidase in Transplantation: Reacting to positive results of an open-label, phase 1–2 trial of IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS) in highly sensitized patients undergoing renal transplantation (pp. 442–53; S. C. Jordan, sjordan@cshs.org), an editorialist writes, “Without doubt, future randomized, controlled trials that compare IdeS with other means of decreasing the levels of preformed antibodies and that follow the recipients long term will be important” (pp. 487–9; J. R. Ingelfinger).
>>>PNN NewsWatch
FDA yesterday expanded the approval of ibrutinib (Imbruvica, Pharmacyclics) for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more treatments. This is the first FDA-approved therapy for the treatment of cGVHD.
AMPT Life is voluntarily recalling all lots of AMPT Coffee to the consumer level because the product contains sildenafil and tadalafil as well as undeclared milk.

PNN Pharmacotherapy Line
Aug. 4, 2017 * Vol. 24, No. 149
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Psychiatry Report
Source:
 Aug. issue of the American Journal of Psychiatry (2017; 174).
Medication & CBT for Hypochondriasis: A study of 195 patients with hypochondriasis shows benefits of fluoxetine treatment but little advantage to combining the drug with cognitive–behavioral therapy (pp. 756–64). “New or more intensive approaches are needed,” the authors conclude after noting that 50% of patients had not responded to any of the study treatments at 24 weeks: “The predicted pattern of response was statistically significant, as shown by the following responder rates: joint treatment group, 47.2%; single active treatment group, 41.8%; and placebo group, 29.6%. Responder rates for each active treatment were not significantly different from the rate for placebo. Secondary analyses of the Whiteley Index as a continuous measure revealed that, compared with placebo, fluoxetine (but not CBT) was significantly more effective at week 24 in reducing hypochondriasis and had a significantly faster rate of improvement over 24 weeks. Fluoxetine also resulted in significantly less anxiety and better quality of life than placebo. Dropout rates did not differ between groups, and treatment-emergent adverse events were evenly distributed.” (B. A. Fallon)
Suicidal Behavior With Lithium & Valproate in Bipolar Disorder: Lithium should be considered for patients with bipolar disorder with possible suicidal ideation, according to data linking outcomes in multiple Swedish national registries (pp. 795–802). While noting that “risk for suicide is only one of the considerations when providing clinical care” of those with bipolar disorder, the investigators report these findings for 51,535 individuals with the condition in 2005–13: “During follow-up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78–0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89–1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4%−20%) of suicide-related events could have been avoided if patients had taken lithium during the entire follow-up.” (J. Song)
>>>Pediatrics Highlights
Source:
 Aug. issue of Pediatrics (2017; 140).
Testing in Low-Risk Penicillin Allergy Symptoms: At a pediatric emergency department, none of 100 children whose parents reported low-risk penicillin allergy symptoms had true penicillin allergy, researchers report (10.1542/peds.2017-0471). Penicillin allergy testing showed these results: “The median (interquartile range) age at testing was 9 years (5–12). The median (interquartile range) age at allergy diagnosis was 1 year (9 months–3 years). Rash (97 [97%]) and itching (63 [63%]) were the most commonly reported allergy symptoms. Overall, 100 children (100%; 95% confidence interval 96.4%–100%) were found to have negative results for penicillin allergy and had their labeled penicillin allergy removed from their medical record.” (D. Vyles)
>>>PNN NewsWatch
FDA yesterday approved a combination product, Mavyret (glecaprevir and pibrentasvir; AbbVie), to treat adults with chronic hepatitis C virus (HCV) genotypes 1–6 without cirrhosis or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. Mavyret is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both. FDA also said Mavyret is the first treatment of 8 weeks’ duration approved for all HCV genotypes 1–6 in adult patients without cirrhosis who have not been previously treated.
* Also approved yesterday by 
FDA was a fixed-dose combination of daunorubicin and cytarabine, Vyxeos (Jazz Pharmaceuticals), for the treatment of adults with two types of acute myeloid leukemia (AML): newly diagnosed therapy-related AML or AML with myelodysplasia-related changes.
* Rugby Laboratories is voluntarily recalling all lots of 
Diocto Liquid and Diocto Syrup (docusate sodium solutions) manufactured by PharmaTech because of a risk of product contamination with Burkholderia cepaciaFDA said.

PNN Pharmacotherapy Line
Aug. 7, 2017 * Vol. 24, No. 150
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Neonatal Psychotropic, Opioid Drug Withdrawal: Among 201,275 pregnant women on public insurance in the U.S., the use of psychotropic medications in addition to opioids is common, an observational study shows, leading to an increasing risk for and severity of neonatal drug withdrawal (j3326). The study included a nationwide sample of pregnancies among women exposed to opioids around the time of delivery whose records were in the Medicaid Analytic eXtract for 2000–10: “The absolute risk for neonatal drug withdrawal ranged from 1.0% in infants exposed in utero to prescription opioids alone to 11.4% for those exposed to opioids co-prescribed with gabapentin. Among neonates exposed in utero to prescription opioids, the relative risk adjusted for propensity score was 1.34 (95% confidence interval 1.22 to 1.47) with concomitant exposure to antidepressants, 1.49 (1.35 to 1.63) with benzodiazepines, 1.61 (1.26 to 2.06) with gabapentin, 1.20 (0.95 to 1.51) with antipsychotics, and 1.01 (0.88 to 1.15) with [nonbenzodiazepine hypnotics]. In utero exposure to two or more psychotropic medications along with opioids was associated with a twofold increased risk of withdrawal (2.05, 1.77 to 2.37). The severity of the withdrawal seemed increased in neonates exposed to both opioids and psychotropic medications compared with opioids alone.” (K. F. Huybrechts, khuybrechts@bwh.harvard.edu)
“These findings suggest a clear need for a comprehensive, evidence informed strategy regarding opioid use in pregnancy,” editorialists write (
j3616). “To be effective, the strategy would specify opportunities for intervention in clinical and public health settings in all time periods related to pre-pregnancy, antepartum/prenatal, peripartum/perinatal, and postpartum/infancy. There remains a paucity of clinical guidance for obstetricians and pediatricians caring for the mother–child unit; development of a strategy will help to prioritize the development of specific evidence. As the U.S. opioid epidemic accelerates in complexity, there is an urgent need to focus resources on this issue, including expansion of research funding for drug safety in pregnancy and improvement of outcomes for mothers and infants affected by opioid use disorder, more funding for the prevention of the disorder, and an expansion of treatment options for affected mothers and their infants.” (S. W. Patrick, stephen.patrick@vanderbilt.edu)
>>>PNN NewsWatch
* A federal district judge on Friday entered a consent decree of permanent injunction between the U.S. and Isomeric Pharmacy Solutions of Salt Lake City, UT, two of the company’s co-owners, and its chief operating officer, FDA said.
FDA on Friday warned parents and caregivers not to use Balguti Kesaria (or Kesaria Balguti) Ayurvedic Medicine because of the risk of lead poisoning.
* A 
curcumin emulsion product compounded by an Irvine, CA, pharmacy, ImprimisRx, has produced immediate hypersensitivity reactions in two patients, FDA said. One of the patients, a 30-year-old woman, died. Curcumin is a component of the spice turmeric, and the pharmacy compounded the product with ungraded PEG 40 castor oil.
>>>PNN JournalWatch
* Brentuximab Vedotin or Physician’s Choice in CD30-Positive Cutaneous T-Cell Lymphoma (ALCANZA): An International, Open-Label, Randomised, Phase 3, Multicentre Trial, in Lancet, 2017; 390: 555–66. (H M. Prince, Miles.Prince@petermac.org
* The Role of Behavioral Interventions in Buprenorphine Maintenance Treatment: A Review, in 
American Journal of Psychiatry, 2017; 174: 738–47. (K. M. Carroll)
* The Metabolic Syndrome in Children and Adolescents: Shifting the Focus to Cardiometabolic Risk Factor Clustering, in 
Pediatrics, 2017; 140: 10.1542/peds.2017-1603. (S. N. Magge) 
* Atrial Cardiomyopathy: A Useful Notion in Cardiac Disease Management or a Passing Fad?, in 
Journal of the American College of Cardiology, 2017; 70: 756–65. (J-B Guichard) 
* Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes, in 
Journal of the American College of Cardiology, 2017; 70: 704–12. (J. L. Januzzi Jr., jjanuzzi@partners.org)
* Stable Coronary Syndromes: The Case for Consolidating the Nomenclature of Stable Ischemic Heart Disease, in 
Circulation, 2017; 136: 437–9. (C. Berry, colin.berry@glasgow.ac.uk)
* Metabolomics as a Driver in Advancing Precision Medicine in Sepsis, in 
Pharmacotherapy, 2017; 37: 10.1002/phar.1974. (K. A. Stringer, stringek@umich.edu)

PNN Pharmacotherapy Line
Aug. 8, 2017 * Vol. 24, No. 151
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Aug. issue of JAMA Internal Medicine (2017; 177).
Electronic, Financial & Social Support After MI: In a 12-month study of patients who survived acute myocardial infarction (AMI), a “compound intervention integrating wireless pill bottles, lottery-based incentives, and social support did not significantly improve medication adherence or vascular readmission outcomes,” according to HeartStrong investigators (pp. 1093–101). Conducted in 2013–16, the study included 1,509 participants who were taking at least two of four study medications (statins, aspirin, beta-blockers, antiplatelet agents). Based on a primary outcome of time to first vascular rehospitalization or death, the medication adherence intervention produced these outcomes in comparison with usual care: “A total of 35.5% of participants were female (n = 536); mean (SD) age was 61.0 (10.3) years. There were no statistically significant differences between study arms in time to first rehospitalization for a vascular event or death (hazard ratio, 1.04; 95% CI, 0.71 to 1.52; P = .84), time to first all-cause rehospitalization (hazard ratio, 0.89; 95% CI, 0.73 to 1.09; P = .27), or total number of repeated hospitalizations (hazard ratio, 0.94; 95% CI, 0.60 to 1.48; P = .79). Mean (SD) medication adherence did not differ between control (0.42 [0.39]) and intervention (0.46 [0.39]) (difference, 0.04; 95% CI, −0.01 to 0.09; P = .10). Mean (SD) medical costs in 12 months following enrollment did not differ between control ($29,811 [$74,850]) and intervention ($24,038 [$66,915]) (difference, −$5,773; 95% CI, −$13,682 to $2,137; P = .15).” (K. G. Volpp, volpp70@wharton.upenn.edu)
Behavioral Approach to Improving Antimicrobial Prescribing: Addressing the “complex behavioral process” of changing antimicrobial prescribing can result in increased appropriateness of antimicrobial prescribing, researchers report (pp. 1130–8). In the Dutch Unique Method for Antimicrobial Stewardship (DUMAS) study, prescribers “were stimulated to choose interventions with higher potential for success based on a root cause analysis of inappropriate prescribing,” leading to these results: “A total of 1,121 patient cases with 700 antimicrobial prescriptions were assessed during the baseline period and 882 patient cases with 531 antimicrobial prescriptions during the intervention period. The mean antimicrobial appropriateness increased from 64.1% at intervention start to 77.4% at 12-month follow-up (+13.3%; relative risk, 1.17; 95% CI, 1.04-1.27), without a change in slope. No decrease in antimicrobial consumption was found.” The authors conclude, “Use of a behavioral approach preserving prescriber autonomy resulted in an increase in antimicrobial appropriateness sustained for at least 12 months. The approach is inexpensive and could be easily transferable to various health care environments.” (J. J. Sikkens, j.sikkens@vumc.nl)
Prescription Drug Price Rebates in Medicare Part D: In a special communication that details how rebates are lowering out-of-pocket costs for Part D beneficiaries but raising Medicare costs, authors propose policy alternatives that “reconfigure cost sharing to lower patient out-of-pocket costs and reduce cost shifting to Medicare” (pp. 1185–8): “The increasing cost of prescription drugs is a burden for patients and threatens the financial stability of the U.S. health care system. Rebates are a form of price concession paid by a pharmaceutical manufacturer to the health plan sponsor or the pharmacy benefit manager working on the plan’s behalf. Proponents argue that rebates result from vigorous negotiations that help lower overall drug costs. Critics argue that rebates have perversely increased the costs patients pay out of pocket, as well as the costs for Medicare as a whole. This special communication discusses how the availability of rebates for drugs covered by the Medicare Part D program may raise costs for patients and Medicare while increasing the profits of Part D plan sponsors and pharmaceutical manufacturers.” (S. B. Dusetzina, dusetzina@unc.edu)
>>>PNN NewsWatch
* Illustrating the above problems with perverse incentives involving drug product rebates, a Wall Street Journal article shows how EpiPen products have been able to maintain market share despite availability of lower-priced generic alternative through lower patient costs and higher insurer billings.

PNN Pharmacotherapy Line
Aug. 9, 2017 * Vol. 24, No. 152
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Aug. 8 issue of JAMA (2017; 318).
Levosimendan in Low Cardiac Output Syndrome: In the Levosimendan in Coronary Artery Revascularization trial, patients with low ejection fraction who were undergoing coronary artery bypass grafting with cardiopulmonary bypass did not have improved outcomes with levosimendan compared with placebo (pp. 548–56). Based on a composite end point of prolonged catecholamine infusion, use of left ventricular mechanical assist device, or renal replacement therapy, results at 13 French cardiac surgical centers showed the following: “Among 336 randomized patients (mean age, 68 years; 16% women), 333 completed the trial. The primary end point occurred in 87 patients (52%) in the levosimendan group and 101 patients (61%) in the placebo group (absolute risk difference taking into account center effect, −7% [95% CI, −17% to 3%]; P = .15). Predefined subgroup analyses found no interaction with ejection fraction less than 30%, type of surgery, and preoperative use of beta-blockers, intra-aortic balloon pump, or catecholamines. The prevalence of hypotension (57% vs 48%), atrial fibrillation (50% vs 40%), and other adverse events did not significantly differ between levosimendan and placebo.” (B. Cholley, bernard.cholley@aphp.fr)
Azithromycin & Airflow Decline–Free Survival After Allogeneic HSCT: A trial terminated early showed worse airflow decline–free survival with early administration of azithromycin in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers report (pp. 557–66). The ALLOZITHRO parallel-group trial, conducted in 19 French academic transplant centers, compared azithromycin with placebo in participants aged 16 years or older who had undergone allogeneic HSCT for hematologic malignancy. A primary efficacy end point of airflow decline–free survival at 2 years after randomization produced these findings: “Thirteen months after enrollment, the independent data and safety monitoring board detected an unanticipated imbalance across blinded groups in the number of hematological relapses, and the treatment was stopped December 26, 2016. Among 480 randomized participants, 465 (97%) were included in the modified intention-to-treat analysis (mean age, 52 [SD, 14] years; 75 women [35%]). At the time of data cutoff, 104 patients (22%; 54 azithromycin vs 50 placebo) had experienced an airflow decline; 138 patients (30%) died (78 azithromycin vs 60 placebo). Two-year airflow decline–free survival was 32.8% (95% CI, 25.9%–41.7%) with azithromycin and 41.3% (95% CI, 34.1%–50.1%) with placebo (unadjusted hazard ratio [HR], 1.3; 95% CI, 1.02–1.70; P = .03). Of the 22 patients (5%) who experienced bronchiolitis obliterans syndrome, 15 (6%) were in the azithromycin group and 7 (3%) in the placebo group (P = .08). The azithromycin group had increased mortality, with a 2-year survival of 56.6% (95% CI, 50.2%–63.7%) vs 70.1% (95% CI, 64.2%–76.5%) in the placebo group (unadjusted HR, 1.5; 95% CI, 1.1–2.0; P = .02). In a post hoc analysis, the 2-year cumulative incidence of hematological relapse was 33.5% (95% CI, 27.3%–39.7%) with azithromycin vs 22.3% (95% CI, 16.4%–28.2%) with placebo (unadjusted cause-specific HR, 1.7; 95% CI, 1.2–2.4; P = .002).” (A. Bergeron, anne.bergeron-lafaurie@aphp.fr)
Patient Recordings of Medical Encounters: Patients are covertly recording interactions with clinicians and health systems frequently, a Viewpoint article states. (pp. 513–4). Policies are needed to “facilitate the positive use of digital recordings,” the authors conclude. (G. Elwyn, glynelwyn@gmail.com)
>>>PNN NewsWatch
FDA yesterday announced plans to pursue a strategic, new public health education campaign aimed at discouraging the use of e-cigarettes and other electronic nicotine delivery systems (ENDS) by kids. The agency plans to expand its “The Real Cost” public education campaign to include messaging to teens about the dangers of using these products this fall while developing a full-scale campaign to launch in 2018. These efforts are part of the agency’s new comprehensive plan for tobacco and nicotine regulation, as well as ongoing efforts to educate youth about and protect them from the dangers associated with using all tobacco products. It is the first time FDA will be using public health education to specifically target youth use of e-cigarettes or other ENDS.

PNN Pharmacotherapy Line
Aug. 10, 2017 * Vol. 24, No. 153
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Aug. 10 issue of the New England Journal of Medicine (2017; 377).
Olaparib for Metastatic Breast Cancer With BRCA Mutation: Among 302 patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, a phase 3 trial demonstrated efficacy of the an oral poly(adenosine diphosphate–ribose) polymerase inhibitor, compared with standard therapy (pp. 523–33). Olaparib 300 mg twice daily or standard therapy with a single chemotherapy agent of the physician’s choice produced these results based on a primary end point of progression-free survival: “Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P <0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively.” (M. Robson, robsonm@mskcc.org)
Influenza Vaccine Effectiveness in 2015–16: The Influenza Vaccine Effectiveness Network reports data on the 2015–16 season in the U.S., showing overall lowering of influenza illness but ineffectiveness of the live attenuated vaccine (pp. 534–43). Results for patients aged 6 months or older who presented at ambulatory clinics in the network had these outcomes for acute respiratory illness: “Among 6,879 eligible participants, 1,309 (19%) tested positive for influenza virus, predominantly for A(H1N1)pdm09 (11%) and influenza B (7%). The effectiveness of the influenza vaccine against any influenza illness was 48% (95% confidence interval [CI], 41 to 55; P <0.001). Among children 2 to 17 years of age, the inactivated influenza vaccine was 60% effective (95% CI, 47 to 70; P <0.001), and the live attenuated vaccine was not observed to be effective (vaccine effectiveness, 5%; 95% CI, −47 to 39; P = 0.80). Vaccine effectiveness against A(H1N1)pdm09 among children was 63% (95% CI, 45 to 75; P <0.001) for the inactivated vaccine, as compared with −19% (95% CI, −113 to 33; P = 0.55) for the live attenuated vaccine.” (M. L. Jackson, jackson.ml@ghc.org)
NAD Deficiency, Congenital Malformations & Niacin Supplementation: Seeking to identify a mechanism causing common co-occurring phenotypic congenital malformations, researchers showed that disruptions in nicotinomide synthesis were linked to birth defects in people and mice and that niacin supplementation during pregnancy prevented the problems in mice progeny (pp. 544–52). Genomic sequencing in families of individuals with multiple congenital malformations, assays of in vitro enzyme activity and metabolites in plasma of patients, and engineered mouse models showed the following: “Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects.” (S. L. Dunwoodie, s.dunwoodie@victorchang.edu.au)
Acute Respiratory Distress Syndrome: Progress in defining and recognizing acute respiratory distress syndrome (ARDS) is reviewed (pp. 562–72): “We now recognize that ARDS, like asthma, is a syndrome characterized by substantial heterogeneity. A much better understanding of the biologic and genetic underpinnings of the subphenotypes of ARDS should lead the way to more targeted therapies. Until then, ICU practices that prevent ARDS, early and effective treatment of the insults leading to ARDS, and lung-protective ventilation and sensible fluid management remain the essential elements for good outcomes.” (B. T. Thompson, thompson.taylor@mgh.harvard.edu)

PNN Pharmacotherapy Line
Aug. 11, 2017 * Vol. 24, No. 154
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Infectious Diseases Report
Source:
 Aug. 15 issue of Clinical Infectious Diseases (2017; 65).
Seminal Clearance of HIV With Antiretroviral Agents: Compared with ritonavir-boosted darunavir (DRVrtv), rilpivirine (RPV) or cobicistat-boosted elvitegravir (EVGcobi) more quickly achieve undetectable HIV load in seminal plasma (SP) when administered with tenofovir-disoproxil fumarate (DF) plus emtricitabine, researchers report (pp. 551–6). A phase 2, randomized, open-label study of treatment-naive patients with HIV showed the following: “In SP, the HIV-RNA decay rate with RPV was as fast as with EVGcobi; by week 12, all participants in the RPV and the EVGcobi groups reached an undetectable viral load but only 58.3% in the DRVrtv arm (P = .003). The highest SP/BP drug concentration ratio was for EVG (0.43), followed-up by RPV (0.19), and DRV (0.10). For both EVG and RPV, the SP concentrations exceeded >2-fold the protein binding-adjusted [90% effective concentrations (EC90)] for wild-type HIV-1; for DRV, only 33.7% of the SP showed concentrations above the protein binding-adjusted EC90.” (A. Gutierrez-Valencia)
Influenza-Associated Neurological Disease in Children: Longitudinal surveillance data from Australia show that influenza-associated encephalitis/encephalopathy (IAE) is an important cause of pediatric acute neurological disease, one associated with high morbidity and mortality (pp. 653–60). In 2013 through 2015, children hospitalized with seasonal influenza often had influenza–associated neurological disease (IAND): “Over 3 influenza seasons, we identified 54 cases of IAND at 2 tertiary children’s hospitals from Australia that accounted for 7.6% of hospitalized influenza. These included 10 cases of IAE (1.4% hospitalized influenza). The mean annual incidence of IAE among Australian children (aged ≤14 years) was 2.8 per 1,000,000. The spectrum of IAND was broad and included IAE (n = 10) including distinct acute encephalopathy syndromes, simple febrile seizures (n = 14), other seizures (n = 16), acute ataxia (n = 4), and other subacute syndromes (transverse myelitis [n = 1], opsoclonus myoclonus [n = 1]). Two-thirds of children with IAND were aged ≤4 years; less than half had preexisting neurological disease or other risk factors for severe influenza. IAE caused death or neurological morbidity in half of cases.” (P. N. Britton)
>>>Oncology Highlights
Source:
 Aug. 10 issue of the Journal of Clinical Oncology (2017; 35).
Falls Among Women With Chemo-Induced Peripheral Neuropathy: Among 512 women cancer survivors, those who had chemotherapy-induced peripheral neuropathy (CIPN) frequently reported persistence of symptoms years later, a study shows, indicating a need to assess patients for the condition earlier in the clinical pathway and develop strategies to limit symptom progression and improve function (pp. 2604–12): “After an average of 6 years after treatment, 47% of women still reported symptoms of CIPN. CIPN+ had significantly worse self-report and objectively measured function than did CIPN−, with the exception of maximal leg strength and base of support during a usual walk. Gait was slower among CIPN+, with those women taking significantly more, but slower and shorter, steps than did CIPN− (all P < .05). CIPN+ reported significantly more disability and 1.8 times the risk of falls compared with CIPN− (P < .0001). Increasing symptom severity was linearly associated with worsening function, increasing disability, and higher fall risk (all P < .05).” (K. M. Winters-Stone, wintersk@ohsu.edu)
“Until [risk classification and prevention strategies are available], the current evidence suggests the need for a broader perspective and altered clinical pathways to facilitate improved CIPN symptom management that addresses balance and functional mobility deficits both during active cancer treatment and through survivorship,” writes an editorialist (
pp. 2593–4; N. L. Stout, nicole.stout@nih.gov)
>>>PNN NewsWatch
* FDA yesterday announced recalls of all Leader Brand, Major Pharmaceuticals, and Rugby Laboratories liquid products manufactured by PharmaTech and one lot of International Laboratories’ Pravastatin Sodium Tablets, USP, 40 mg. The agency also updated a Jul. 31 announcement by alerting health professionals and patients to dispose of and not use “sterile” products and from Atlantic Pharmacy and Compounding.

PNN Pharmacotherapy Line
Aug. 14, 2017 * Vol. 24, No. 155
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 Aug. 12 issue of Lancet (2017; 390).
Influenza Vaccine Delivered by Microneedle Patch: In a phase 1 trial, a dissolvable microneedle patch was used successfully for administration of the 2014–15 seasonal influenza vaccine in adults aged 18–49 years, researchers report (pp. 649–58). “Robust antibody responses” were found in the TIV-MNP 2015 study of 100 participants who were randomized to inactivated influenza vaccine delivered by a health professional using the microneedle patch or intramuscular injection, a placebo by microneedle patch administered by a health professional, or the vaccine patch administered by the participants. Results showed: “There were no treatment-related serious adverse events, no treatment-related unsolicited grade 3 or higher adverse events, and no new-onset chronic illnesses. Among vaccinated groups (vaccine via health-care worker administered microneedle patch or intramuscular injection, or self-administered microneedle patch), overall incidence of solicited adverse events (n = 89 vs n = 73 vs n = 73) and unsolicited adverse events (n = 18 vs n = 12 vs n = 14) were similar. Reactogenicity was mild, transient, and most commonly reported as tenderness (15 [60%] of 25 participants [95% CI 39–79]) and pain (11 [44%] of 25 [24–65]) after intramuscular injection; and as tenderness (33 [66%] of 50 [51–79]), erythema (20 [40%] of 50 [26–55]), and pruritus (41 [82%] of 50 [69–91]) after vaccination by microneedle patch application. The geometric mean [antibody] titres were similar at day 28 between the microneedle patch administered by a health-care worker versus the intramuscular route for the H1N1 strain (1197 [95% CI 855–1675] vs 997 [703–1415]; p = 0.5), the H3N2 strain (287 [192–430] vs 223 [160–312]; p = 0.4), and the B strain (126 [86–184] vs 94 [73–122]; p = 0.06). Similar geometric mean titres were reported in participants who self-administered the microneedle patch (all p >0.05). The seroconversion percentages were significantly higher at day 28 after microneedle patch vaccination compared with placebo (all p <0.0001) and were similar to intramuscular injection (all p >0.01).” (N. G. Rouphael, nroupha@emory.edu)
Azithromycin in Adults With Persistent Uncontrolled Asthma: In the AMAZES trial, 420 participants with persistent symptomatic asthma had “fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks,” investigators write (pp. 659–68). Those included in the trial were adults with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Treatment with azithromycin 500 mg or placebo three times per week for 48 weeks yielded these results: “Azithromycin reduced asthma exacerbations (1.07 per patient–year [95% CI 0.85–1.29]) compared with placebo (1.86 per patient–year [1.54–2.18]; incidence rate ratio [IRR] 0.59 [95% CI 0.47–0.74]; p <0.0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p <0.0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0.36 [95% CI 0.21–0.52]; p = 0.001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p = 0.001).” (P. G. Gibson, peter.gibson@hnehealth.nsw.gov.au)
>>>PNN JournalWatch
* Rewiring Microbiology and Infection (part of a supplement on “Emerging Concepts and Strategies in Clinical Microbiology and Infectious Diseases&rdquoWinking, in Clinical Infectious Diseases, 2017; 65(suppl 1): S1–S3. (D. Raoult) 
* Antibiotic Stewardship in Small Hospitals: Barriers and Potential Solutions, in 
Clinical Infectious Diseases, 2017; 65: 691–6. (E. Stenehjem) 
* Diagnosis and Management of Anaphylaxis in Precision Medicine, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 321–33. (M. Castells, mcastells@bwh.harvard.edu
* Advances in Atopic Dermatitis and Urticarial in 2016, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 369–76. (T. Honda, hontetsu@kuhp.kyoto-u.ac.jp
* Designing an Effective, Small-Scope Practice-Based Study, in 
Medical Care, 2017; 55: 765–70. (R. D. Parker)

PNN Pharmacotherapy Line
Aug. 15, 2017 * Vol. 24, No. 156
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Early-release articles from and the Aug. 15 issue of the Annals of Internal Medicine (2017; 167).
Therapeutic Effects of Plant-Based Cannabis: Two reviews and an editorial examine evidence of benefits and harms associated with use of plant-based cannabis for chronic pain and posttraumatic stress disorder (PTSD).
Neuropathic pain may be an appropriate therapeutic target for plant-based cannabis products, a systematic review shows, but data are insufficient to evaluate use in other forms of chronic pain (
10.7326/M17-0155): “From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.” (S. M. Nugent, Shannon.Nugent@va.gov)
Evidence is lacking for assessing cannabis use in patients with PTSD, researchers report, but results of ongoing studies should shed light on the issue (
10.7326/M17-0477). Available studies provide “very scant evidence with medium to high risk of bias,” the authors conclude, adding these details: “Two systematic reviews, 3 observational studies, and no randomized trials were found. The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms. The observational studies found that compared with nonuse, cannabis did not reduce PTSD symptoms. Studies had medium and high risk of bias, and overall evidence was judged insufficient. Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are ongoing and are expected to be completed within 3 years.” (M. E. O’Neil, maya.oneil@va.gov)
“The conclusions of both systematic reviews largely echo the National Academies of Sciences, Engineering, and Medicine’s recent comprehensive review on these and other health effects of cannabis, suggesting a growing consensus in the field,” an editorialist concludes (
10.7326/M17-1713). “Little high-quality evidence exists from which to draw firm conclusions about the efficacy of cannabis and cannabinoid products for treating pain and PTSD. Although several well-designed trials are under way to address this critical issue, to some degree the horse is out of the barn—and unlikely to return. Even if future studies reveal a clear lack of substantial benefit of cannabis for pain or PTSD, legislation is unlikely to remove these conditions from the lists of indications for medical cannabis. It will be up to front-line practicing physicians to learn about the harms and benefits of cannabis, educate their patients on these topics, and make evidence-based recommendations about using cannabis and related products for various health conditions. In parallel, the research community must pursue high-quality studies and disseminate the results to clinicians and the public. In this context, these reviews are must-reads for all physicians, especially those practicing in states where medical cannabis is legal.” (S. Patel, Sachin.patel@vanderbilt.edu)
Hormone Therapy in Transgender Adults: Lack of research into cardiovascular disease (CVD) among transgender adults muddles the safety of use of cross-sex hormone therapy (CSHT), according to authors of a narrative review (pp. 256–67): “For transgender adults, CSHT has been associated with the potential for worsening CVD risk factors (such as blood pressure elevation, insulin resistance, and lipid derangements), although these changes have not been associated with increases in morbidity or mortality in transgender men receiving CSHT. For transgender women, CSHT has known thromboembolic risk, and lower-dose transdermal estrogen formulations are preferred over high-dose oral formulations. In addition, many studies of transgender adults focus predominantly on younger persons, limiting the generalizability of CSHT in older transgender adults. The lack of randomized controlled trials comparing various routes and formulations of CSHT, as well as the paucity of prospective cohort studies, limits knowledge of any associations between CSHT and CVD.” (C. G. Streed Jr, cstreed@bwh.harvard.edu)

PNN Pharmacotherapy Line
Aug. 16, 2017 * Vol. 24, No. 157
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Aug. 15 issue of JAMA (2017; 318).
Evidence v. Access in FDA Decisions: Researchers and an editorialist examine quality and other characteristics of studies used to support FDA decisions regarding medical devices and medications considered on an accelerated basis.
Medications granted accelerated approval by FDA in 2009–13 often but not always had efficacy confirmed in postapproval studies, but the trials often had weaknesses such as use of surrogate outcomes that were present in preapproval research (
pp. 626–36). Using publicly available documents, investigators found the following for 22 drugs with 24 indications (19 of which were oncologic): “A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, −15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.” (H. Naci, Ph.naci@lse.ac.uk)
“Among clinical studies used to support FDA approval of high-risk medical device modifications, fewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points,” a second research team reports (
pp. 619–25). “These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved.” (R. F. Redberg, rita.redberg@ucsf.edu)
Referring to digital systems now available that link usage data with clinical end points, an editorialist concludes, “It is now time to seriously consider how to use these increasingly robust data and analytic capabilities and more efficient prospective research systems to deal with the issues raised by these articles” (
pp. 614–6). “Much of the objection to [randomized controlled trials (RCTs)] arises from the substantial cost and inflexibility of ‘traditional’ regulatory trials. But as technological improvements and nationally and globally connected networks of health systems make it feasible to conduct high-quality, low-cost RCTs and to continuously monitor product performance, the impediments to progress are mostly those built into the culture of medicine and health care.” (R. M. Califf, robert.califf@duke.edu)
Intensive Lifestyle Intervention in Type 2 Diabetes: Beneficial but not significant results followed a lifestyle intervention among 98 Danish adults whose type 2 diabetes of less than 10 years’ duration was being managed without insulin therapy, a study shows (pp. 637–46). Participants assigned to an exercise/weight loss intervention had these outcomes in comparison with those on standardized, target-driven medical therapy: “From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of −0.26% [95% CI, −0.52% to −0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose-lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group.” (M. Ried-Larsen, mathias.ried-larsen@regionh.dk)

PNN Pharmacotherapy Line
Aug. 17, 2017 * Vol. 24, No. 158
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Aug. 17 New England Journal of Medicine (2017; 377).
Low-Dose Aspirin for Preeclampsia: In 1,776 women with high-risk singleton pregnancies, treatment with low-dose aspirin lowered the incidence of preterm preeclampsia in comparison with placebo, report Collaborative Low-Dose Aspirin Study in Pregnancy (CLASP) investigators (pp. 613–22). Administered from early in pregnancy (11–14 weeks’ gestation) until the 36th week, aspirin 150 mg/d produced these outcomes on an intention-to-treat basis: “A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P = 0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.” (K. H. Nicolaides, kypros@fetalmedicine.com)
“On the basis of the 2014 systematic review, the [U.S. Preventive Services Task Force] currently recommends daily low-dose (81 mg) aspirin therapy beginning at 12 weeks of gestation in patients who are considered to be at ‘high risk for preeclampsia’ according to medical and obstetrical criteria,” editorialists write (
pp. 613–22). “The American College of Obstetricians and Gynecologists has endorsed these guidelines. Taken together with findings from other studies, [these] findings … support recommendations for the use of prophylactic low-dose aspirin in high-risk women. However, the effects of aspirin on several clinically important, preeclampsia-associated complications — in particular, perinatal mortality — remain unproved.” (M. F. Greene)
Canagliflozin & Outcomes in Type 2 Diabetes: While cardiovascular and renal outcomes were improved among patients treated with canagliflozin in two clinical trials, the risk of amputation was increased (pp. 644–57). The CANVAS program included 10,142 participants with type 2 diabetes and high cardiovascular risk. Based on a primary outcome of composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, results showed: “The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1,000 patient–years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P <0.001 for noninferiority; P = 0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1,000 patient–years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal.” (B. Neal, bneal@georgeinstitute.org.au)
Reference Pricing & Drug Selection: Use of reference pricing for medications — payment of a fixed amount based on indication — has the potential to change drug selection and spending for patients covered by employment-based insurance, an analysis shows (pp. 658–65). Over 18 months when an employee group had reference pricing, employer spending fell by $1.34 million for 1.12 million prescriptions, while patient copayments rose by $120,000. (J. C. Robinson, james.robinson@berkeley.edu)
>>>PNN NewsWatch
Amneal Pharmaceuticals is voluntarily recalling 13 lots of Lorazepam Oral Concentrate, USP 2 mg/mL, to the consumer level because of dropper marking defects.

PNN Pharmacotherapy Line
Aug. 18, 2017 * Vol. 24, No. 159
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Geriatrics Report
Source:
 Aug. issue of the Journal of the American Geriatrics Society (2017; 65).
Off-Label Antipsychotic Prescribing to Older Veterans: While prescribing of second-generation antipsychotics (SGAs) to older veterans with posttraumatic stress disorder (PTSD) has declined, “prescribing an SGA to those with dementia remained consistently higher than for those with PTSD alone and is problematic given the high prevalence of medical comorbidities in this aging population coupled with the lack of compelling evidence for effectiveness of SGAs in individuals with dementia,” investigators conclude (pp. 1789–95). National VA data for 2004–09 show these prescribing patterns : “SGA prescribing declined annually from 7.0% to 5.1% of elderly veterans with PTSD without dementia and 13.2% to 8.9% in those with dementia; findings over time consistently indicated that veterans with PTSD and dementia had at least twice the odds of being prescribed an SGA as those without PTSD (odds ratios 2.03 (95% confidence interval (CI) = 1.82–2.26) to 2.33 (95% CI = 2.10–2.58).” (T. P. Semla, todd.semla@va.gov)
Antibiotic Prescribing Pathway for Presumed UTIs in Nursing Homes: At 31 North Carolina nursing homes (NHs), 260 randomly selected cases of residents being treated for presumed urinary tract infections (UTIs) were more influenced by nonspecific signs and symptoms than urinary-tract–specific ones, researchers report (pp. 1719–25). Antibiotics were rarely stopped, with some used for “overly long periods” the authors conclude, adding these details uncovered in chart reviews: “Of 260 cases, 60% had documented signs/symptoms of the presenting illness and 15% met the Loeb criteria [for initiation of antibiotics]. Acute mental status change was the most commonly documented sign/symptom (24%). NH providers (81%) were the most common prescribers and ciprofloxacin (32%) was the most commonly prescribed antibiotic. Fourteen percent of presumed UTI cases included a white blood cell count, 71% included a urinalysis, and 72% had a urine culture. Seventy-five percent of cultures grew at least one organism with ≥100,000 colony-forming units/milliliter and 12% grew multi-drug resistant organisms; 28% of antibiotics were prescribed for more than 7 days, and 7% of cases had a subsequent death, emergency department visit, or hospitalization within 7 days.” (C. E. Kistler, christine_kistler@med.unc.edu)
Urinary Tract Dysbiosis: Rather than the “ambiguous, expansive, overused diagnosis” of urinary tract infection (UTI), the term urinary tract dysbiosis “might encourage mindful study of the relationships among host, aging, microbiome, disease, and antibiotic treatment,” a Special Article author writes (pp. 1650–5): “‘Significant bacteriuria,’ central to most definitions of ‘UTI,’ has little significance in identifying individuals who will benefit from treatment. ‘Urinary symptoms’ are similarly uninformative. Neither criterion is well defined. Bacteriuria and symptoms remit and recur spontaneously. Treatment is standard for acute uncomplicated cystitis and common for asymptomatic bacteriuria, but definite benefits are few. Treatment for ‘UTI’ in older adults with delirium and bacteriuria is widespread but no evidence supports the practice, and expert opinion opposes it.…
“Sensitive diagnostic tests now demonstrate that healthy urinary tracts host a ubiquitous, complex microbial community. Recognition of this microbiome, largely undetectable using standard agar-based cultures, offers a new perspective on ‘UTI.’ Everyone is bacteriuric.…
“Mindful decisions about antibiotic use will require a far better understanding of how pathogenicity arises within microbial communities. It is likely that public education and meaningful informed-consent discussions about antibiotic treatment of bacteriuria, emphasizing potential harms and uncertain benefits, would reduce overtreatment.” (T. E. Finucane, 
tfinucan@jhmi.edu)
>>>PNN NewsWatch
FDA yesterday approved inotuzumab ozogamicin (Besponsa, Pfizer) for treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Product labeling includes a boxed warning that hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome, occurred in some patients who took the drug; advice for stopping therapy or reducing doses is provided.

PNN Pharmacotherapy Line
Aug. 21, 2017 * Vol. 24, No. 160
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 Aug. 19 issue of Lancet (2017; 390).
Management of Non-ST-Elevation Acute Coronary Syndrome: Using a meta-analysis to identify the optimal timing of invasive management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), authors found that only high-risk patients had lower mortality with earlier interventions and even in those patients, statistics were inconclusive (pp. 737–46). The overall dataset showed no mortality difference between early and late invasive strategies, as show in these findings: “We included eight trials (n = 5,324 patients) with a median follow-up of 180 days (IQR 180–360). Overall, there was no significant mortality reduction in the early invasive group compared with the delayed invasive group HR 0.81, 95% CI 0.64–1.03; p = 0.0879). In pre-specified analyses of high-risk patients, we found lower mortality with an early invasive strategy in patients with elevated cardiac biomarkers at baseline (HR 0.761, 95% CI 0.581–0.996), diabetes (0.67, 0.45–0.99), a GRACE risk score more than 140 (0.70, 0.52–0.95), and aged 75 years older (0.65, 0.46–0.93), although tests for interaction were inconclusive.” (H. Thiele, holger.thiele@medizin.uni-leipzig.de)
Fibrinolytics in ST-Segment Elevation Myocardial Infarction: Outcomes differ among various fibrinolytic regimens available for reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI) in resource-scarce settings, researchers report (pp. 747–59). A network meta-analysis based on a systematic review of randomised controlled trials showed these outcomes based on a primary efficacy outcome of all-cause mortality within 30–35 days and a primary safety outcome of major bleeding: “A total of 40 eligible studies involving 128,071 patients treated with 12 different fibrinolytic regimens were assessed. Compared with accelerated infusion of alteplase with parenteral anticoagulants as background therapy, streptokinase and non-accelerated infusion of alteplase were significantly associated with an increased risk of all-cause mortality (risk ratio [RR] 1.14 [95% CI 1.05–1.24] for streptokinase plus parenteral anticoagulants; RR 1.26 [1.10–1.45] for non-accelerated alteplase plus parenteral anticoagulants). No significant difference in mortality risk was recorded between accelerated infusion of alteplase, tenecteplase, and reteplase with parenteral anticoagulants as background therapy. For major bleeding, a tenecteplase-based regimen tended to be associated with lower risk of bleeding compared with other regimens (RR 0.79 [95% CI 0.63–1.00]). The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy increased the risk of major bleeding by 1.27–8.82-times compared with accelerated infusion alteplase plus parenteral anticoagulants (RR 1.47 [95% CI 1.10–1.98] for tenecteplase plus parenteral anticoagulants plus glycoprotein inhibitors; RR 1.88 [1.24–2.86] for reteplase plus parenteral anticoagulants plus glycoprotein inhibitors).” (N. Chaiyakunapruk, nathorn.chaiyakunapruk@monash.edu)
>>>PNN NewsWatch
FDA said on Friday that Bella Pharmaceuticals is voluntarily recalling all lots of unexpired sterile drug products because of lack of sterility assurance. The recalled products — including compounded bevacizumab (Avastin), fluorescein sodium, and glutathione — were distributed to health care facilities nationwide.
* In an update to an earlier alert (see 
PNN, Aug. 11), Vital Rx Inc., d/b/a Atlantic Pharmacy and Compounding, has issued a recall of all lots of all compounded injectable prescription medications to the consumer level, FDA said. 
>>>PNN JournalWatch
* 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, in Arthritis & Rheumatology, 2017; 69: 1521–37. (L. Buckley, lenore.buckley@yale.edu
* 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty, in 
Arthritis & Rheumatology, 2017; 69: 1538–51. (S. M. Goodman, goodmans@hss.edu
* Urinary Incontinence, Incident Parkinsonism, and Parkinson’s Disease Pathology in Older Adults, in 
Journals of Gerontology Series A, 2017; 72: 1295–301. (N. M Buchman, noabuchman@gmail.com
* The Pharmacist and Medical Aid in Dying, in 
American Journal of Health-System Pharmacy, 2017; 74: 1253–60. (M. T. Hughes, mhughes2@jhmi.edu)

PNN Pharmacotherapy Line
Aug. 22, 2017 * Vol. 24, No. 161
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Chest Highlights
Source:
 Aug. issue of Chest (2017; 152).
Precision Medicine Needed for Inhaled Corticosteroids in COPD: A precision medicine approach should be used in management of inhaled corticosteroid (ICS) therapy in patients with chronic obstructive pulmonary disorder (COPD), according to authors of an editorial (pp. 227–31). “The excessive use of ICS in the treatment of COPD, currently estimated to be given to >70% of patients, could be reduced to target those patients who would receive greater benefit than harm,” the authors write. Based on their analysis showing that treatment of COPD with a long-acting beta-agonist (LABA) combined with an ICS instead of an LABA alone for 1 year will prevent 1 patient from having a COPD exacerbation but cause 2 patients to develop severe pneumonia, the authors conclude, “For the estimated 8 million American patients with COPD treated with ICS, … a precision medicine approach could provide a net benefit to an estimated 2 million who respond to these drugs by reducing hospitalizations by 60,000 yearly. Furthermore, it would protect the remaining 6 million from the needless harms of these drugs in the absence of any or trivial benefit, preventing an estimated 120,000 patients from being hospitalized unnecessarily for pneumonia yearly.” (S. Suissa, samy.suissa@mcgill.ca)
Clinical Characteristics of Pertussis-Associated Cough: Symptoms of pertussis differ between adults and children, according to a systematic review and meta-analysis (pp. 353–67). “In adult patients, the presence of whooping or posttussive vomiting should rule in a possible diagnosis of pertussis, whereas the lack of a paroxysmal cough or the presence of fever should rule it out,” the group concludes. “In children, posttussive vomiting is much less helpful as a clinical diagnostic test.” (A. Moore, abigail.moore@phc.ox.ac.uk)
Atorvastatin in Patients With Bronchiectasis: Reduction of systemic inflammation by atorvastatin was beneficial in patients with bronchiectasis who were infected with Pseudomonas aeruginosa, improving their quality of life, a study shows (pp. 368–78). In a double-blind crossover trial of 27 patients, atorvastatin 80 mg daily for 3 months produced these outcomes in comparison with placebo: “Atorvastatin did not significantly improve the primary end point of cough as measured by the Leicester Cough Questionnaire (mean difference, 1.92; 95% CI for difference, –0.57-4.41; P = .12). However, atorvastatin treatment resulted in an improved St. Georges Respiratory Questionnaire (–5.62 points; P = .016) and reduced serum levels of CXCL8 (P = .04), tumor necrosis factor (P = .01), and intercellular adhesion molecule 1 (P = .04). There was a trend toward improvement in serum C-reactive protein and serum neutrophil counts (P = .07 and P = .06, respectively). We demonstrated in vitro that atorvastatin 10 μM reduced formyl-methionyl-leucyl phenylalanine-induced upregulation of CD11b expression and changes in calcium flux, reflecting an ability to decrease neutrophil activation.” (P. Bedi, drpallavibedi@gmail.com)
>>>Kidney Diseases Report
Source:
 Aug. American Journal of Kidney Diseases (2017; 70).
Blood Pressure, Dialysis & Mortality: In an observational study of 17,729 U.S. veterans transitioning to maintenance dialysis therapy in 2007–11, investigators conclude that “lower predialysis [systolic blood pressure (SBP)] is associated with higher all-cause mortality in the immediate postdialysis period” (pp. 207–17). “Predialysis [diastolic blood pressure] showed no consistent association with postdialysis mortality. Further studies are needed to clarify ideal predialysis SBP levels among incident dialysis patients as a potential means to improve the excessively high early dialysis mortality.” (C. P. Kovesdy, ckovesdy@uthsc.edu)
>>>PNN NewsWatch
* The FDA’s pediatric advisory committee will focus in an upcoming meeting on use of prescription opioid products containing hydrocodone or codeine for treatment of cough in pediatric patients, including current treatment practices and benefit–risk considerations, Commissioner Scott Gottlieb said in a statement yesterday. He added, “It is vital we understand the potential complications that can occur when using opioid-containing medications in children, even according to labeled instructions.”

PNN Pharmacotherapy Line
Aug. 23, 2017 * Vol. 24, No. 162
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Aug. 22/29 issue of JAMA (2017; 318).
Natriuretic Peptide–Guided Therapy in Heart Failure With Reduced Ejection Fraction: In the Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study, high-risk patients whose drug therapy was adjusted based on natriuretic peptide levels had no better outcomes than those managed with usual care, researchers report (pp. 713–20). Study participants, all with heart failure (HF) and reduced ejection fraction (HFrEF), had these outcomes: “The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1,100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79–1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65–1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups.” (G. M. Felker, michael.felker@duke.edu)
“There is a critical need for greater focus on achieving guideline-directed target dosing of guideline-directed therapies via focused quality measures, heart failure disease management programs, and performance improvement systems,” editorialists write (
pp. 707–8). “As demonstrated in the GUIDE-IT trial published in this issue of JAMA, serial monitoring of natriuretic peptide biomarkers do not appear to add incremental value to such efforts.” (G. C. Fonarow, gfonarow@mednet.ucla.edu)
Oral Prednisolone in Nonasthmatic Lower Respiratory Tract Infection: “Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity,” conclude authors of a 401-patient study (pp. 721–30). At 54 family practices in England, adults with acute cough and 1 or more lower respiratory tract symptoms not requiring immediate antibiotic treatment and with no history of chronic pulmonary disease or use of asthma medication in the past 5 years had these outcomes when randomized to prednisolone 40 mg or placebo once daily for 5 days: “Among the 398 patients with baseline data (mean age, 47 [SD, 16.0] years; 63% women; 17% smokers; 77% phlegm; 70% shortness of breath; 47% wheezing; 46% chest pain; 42% abnormal peak flow), 334 (84%) provided cough duration and 369 (93%) symptom severity data. Median cough duration was 5 days (interquartile range [IQR], 3–8 days) in the prednisolone group and 5 days (IQR, 3–10 days) in the placebo group (adjusted hazard ratio, 1.11; 95% CI, 0.89–1.39; P = .36 at an alpha = .05). Mean symptom severity was 1.99 points in the prednisolone group and 2.16 points in the placebo group (adjusted difference, −0.20; 95% CI, −0.40 to 0.00; P = .05 at an alpha = .001). No significant treatment effects were observed for duration or severity of other acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, or nonserious adverse events. There were no serious adverse events.” (A. D. Hay, alastair.hay@bristol.ac.uk)
Cost-effectiveness Analysis of PCSK9 Inhibitors: Even considering new evidence regarding reduction of major adverse cardiovascular events (MACE) by evolocumab, PCSK9 inhibitor use in patients with atherosclerotic cardiovascular disease remains not cost-effective at 2017 prices, according to a research letter (pp. 748–50). Updating 2015 figures, investigators found these results for 8.9 million U.S. adults meeting FOURIER criteria: “Adding PCSK9 inhibitors to statins was estimated to prevent 2,893,500 more MACE compared with adding ezetimibe, at an [incremental cost-effectiveness ratio (ICER; incremental health care costs per quality-adjusted life–year [QALY] gained)] of $450,000/QALY (80% uncertainty interval, $301,000–$787,000). Reducing annual drug costs by 71% (to ≤$4,215) would be needed for PCSK9 inhibitors to be cost-effective at a threshold of $100,000/QALY. Assuming no direct effect on cardiovascular death as observed in FOURIER, the ICER increased to $1,795,000/QALY.” (K. Bibbins-Domingo, kirsten.bibbins-domingo@ucsf.edu)

PNN Pharmacotherapy Line
Aug. 24, 2017 * Vol. 24, No. 163
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Aug. 24 issue of the New England Journal of Medicine (2017; 377).
Degludec Outcomes in Type 2 Diabetes: Among 7,637 participants with type 2 diabetes in the DEVOTE study who were at high risk for cardiovascular events, insulin “degludec was noninferior to [insulin] glargine with respect to the incidence of major cardiovascular events,” investigators conclude (pp. 723–32). Insulin degludec, an ultralong-acting, once-daily basal insulin, or insulin glargine U100 was administered once daily between dinner and bedtime in this treat-to-target trial, with these results: “Of the patients who underwent randomization, 6,509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (± SD) glycated hemoglobin level was 8.4 ± 1.7%; 83.9% of the patients were receiving insulin. The primary [efficacy] outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P <0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5 ± 1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128 ± 56 vs. 136 ± 57 mg per deciliter, P <0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P <0.001 for superiority; odds ratio, 0.73; P <0.001 for superiority). Rates of adverse events did not differ between the two groups.” (S. P. Marso, smarso@gmail.com)
Intensive Blood-Pressure Treatment & Patient-Reported Outcomes: In the Systolic Blood Pressure Intervention Trial (SPRINT), patient-reported outcomes were similar when hypertension was managed using intensive- and standard-treatment approaches, researchers report, supporting use of the more effective intensive approach (pp. 733–44). A total of 9,361 participants were treated to blood-pressure targets of <120 or <140 mm Hg, with these patient-reported outcomes on the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Veterans RAND 12-Item Health Survey, the Patient Health Questionnaire 9-item depression scale (PHQ-9): “Participants who received intensive treatment received an average of one additional antihypertensive medication, and the systolic blood pressure was 14.8 mm Hg (95% confidence interval, 14.3 to 15.4) lower in the group that received intensive treatment than in the group that received standard treatment. Mean PCS, MCS, and PHQ-9 scores were relatively stable over a median of 3 years of follow-up, with no significant differences between the two treatment groups. No significant differences between the treatment groups were noted when participants were stratified according to baseline measures of physical or cognitive function. Satisfaction with blood-pressure care was high in both treatment groups, and we found no significant difference in adherence to blood-pressure medications.” (D. R. Berlowitz, dan.berlowitz@va.gov)
Cost-Effectiveness of Intensive Blood-Pressure Control: Benefits of intensive blood-pressure control as demonstrated in SPRINT were cost-effective when trial data were analyzed in a microsimulation model (pp. 745–55). Applying treatment effects and health care costs to a hypothetical cohort of adults, authors “determined that the mean number of [quality-adjusted life-years (QALYs)] would be 0.27 higher among patients who received intensive control than among those who received standard control and would cost approximately $47,000 more per QALY gained if there were a reduction in adherence and treatment effects after 5 years; the cost would be approximately $28,000 more per QALY gained if the treatment effects persisted for the remaining lifetime of the patient.” (A. P. Bress, adam.bress@hsc.utah.edu)
>>>PNN NewsWatch
* Centurion Labs is voluntarily recalling 1 lot of Ninjacof (no. 200N1601) and 1 lot of Ninjacof A (no. 201NA1601) manufactured by Vilvet and distributed by Centurion Labs to the retail level due to potential contamination with Burkholderia cepaci, FDA said yesterday.

PNN Pharmacotherapy Line
Aug. 25, 2017 * Vol. 24, No. 164
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Medical Care Highlights
Source:
 Sept. issue of Medical Care (2017; 55).
Marginal Costs of Inpatient Adverse Drug Events: The importance of accounting for confounders in analysis of anticoagulant and hypoglycemic adverse drug events (ADEs) is demonstrated in a study of the 2010 to 2013 Healthcare Cost and Utilization Project State Inpatient Databases and Medicare Patient Safety Monitoring System (pp. 856–63). Investigators estimated “the marginal cost (MC) of ADEs associated with anticoagulants and hypoglycemic agents for adults in 5 patient groups during their hospital stay and the total annual ADE costs for all patients exposed to these drugs during their stay, with these results: “Adjusted MC estimates were smaller than unadjusted measures with most groups showing estimates that were at least 50% less. Adjusted anticoagulant ADE costs added >45% and hypoglycemic ADE costs added >20% to inpatient costs. The 2013 hospital cost estimates for ADEs associated with anticoagulants and hypoglycemic agents were >$2.5 billion for each drug class.” (W. D. Spector, william.spector@ahrq.hhs.gov)
ACA Dependent Coverage Mandate & Dental Care: Extension of employee dental coverage to older dependents (up to 26 years of age) by the Affordable Care Act (ACA) had little effect on overall preventive dental service utilization, a study shows, but restorative care increased after implementation of the law, especially for women (pp. 841–7). Using difference-in-difference regression approach comparing changes in dental care utilization for 25-year olds affected by the policy to unaffected 27-year olds, the authors found these patterns: “Compared to 27-year olds, 25-year olds were 8 percentage points more likely to have private dental coverage in the 3 years following the mandate. We do not find compelling evidence that young adults increased their use of preventive dental services in response to gaining insurance. We do find a nearly 5 percentage point increase in the likelihood of dental treatments among 25-year olds following the mandate, an effect that appears concentrated among women.” (D. M. Shane, dan-shane@uiowa.edu)
>>>Health Affairs Report
Source:
 Aug. issue of Health Affairs (2017; 36).
Greater Health Gains With FDA-Expedited Drugs: Drug products expedited by FDA are resulting in greater health gains than medications approved through regular processes, according to an analysis of drugs approved in 1999–2012 through expedited (n = 26) or regular processes (n = 59) (pp. 1408–15): “We found that drugs in at least one expedited review program offered greater gains than drugs reviewed through conventional processes (0.182 versus 0.003 [quality-adjusted life–years, or QALYs]). We also found that, compared to drugs not included in the same program, greater gains were provided by drugs in the priority review (0.175 versus 0.007 QALYs), accelerated approval (0.370 versus 0.031 QALYs), and fast track (0.254 versus 0.014 QALYs) programs. Our analysis suggests that the FDA has prioritized drugs that offer the largest health gains.” (J. D. Chambers, jchambers@tuftsmedicalcenter.org)
Medicaid Hearing Aid Coverage For Older Adults: Noting that 30 million older adults in the U.S. have age-related hearing loss, authors call on “policy makers at the state and federal levels [to] consider how to make care for age-related hearing loss more accessible, affordable, and equitable nationwide” (pp. 1476–84). A total of 28 states currently offer some coverage through Medicaid; the other 22 states have no coverage. (M. L. Arnold, mlarnold@usf.edu)
>>>PNN NewsWatch
* About 60% of parents are having their older children and adolescents vaccinated against human papillomavirus (HPV), the CDC reports, but many are getting the first dose but not the second. The annual National Immunization Survey–Teen report found that 60% of teens ages 13 to 17 received one or more doses of HPV vaccine in 2016, an increase of 4 percentage points from 2015. The report also showed that HPV vaccination is becoming more common among boys. About 65% of girls received the first dose of HPV vaccine compared to 56% of boys receiving the first dose. These latest estimates represent a 6 percentage point increase from 2015 for boys and about the same for girls.

PNN Pharmacotherapy Line
Aug. 28, 2017 * Vol. 24, No. 165
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 Early-release article from and Aug. 26 issue of Lancet (2017; 390).
De-escalation of Antiplatelet Treatment in ACS/PCI: “Early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with [percutaneous coronary intervention (PCI)],” conclude investigators in the TROPICAL-ACS trial, citing noninferior results when the intervention was compared with standard prasugrel therapy at 1 year (10.1016/S0140-6736(17)32155-4). Using as a primary endpoint of net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomization, the study showed these results for a step-down prasugrel regimen of 1 week prasugrel followed by 1 week clopidogrel and platelet function testing–guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge: “Between Dec 2, 2013, and May 20, 2016, 2,610 patients were assigned to study groups; 1,304 to the guided de-escalation group and 1,306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority = 0.0004; hazard ratio [HR] 0.81 [95% CI 0.62–1.06], psuperiority = 0.12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority = 0.0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0.82 [95% CI 0.59–1.13]; p = 0.23).” (D. Sibbing, dirk.sibbing@med.uni-muenchen.de)
Procalcitonin-Guided Sepsis Treatment in Neonates: In neonates with suspected early-onset sepsis, procalcitonin-guided decisions were superior to standard care in reducing antibiotic therapy, researchers report (pp. 871–81): “Between May 21, 2009, and Feb 14, 2015, we screened 2,440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1,710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n = 866) or standard therapy (n = 844). 1,408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55.1 vs 65.0 h, p <0.0001; per protocol: 51.8 vs 64.0 h; p <0.0001). No sepsis-related deaths occurred, and 9 (<1%) of 1,710 neonates had possible re-infection. The risk difference for non-inferiority was 0.1% (95% CI −4.6 to 4.8) in the intention-to-treat analysis (5 [0.6%] of 866 neonates in the procalcitonin group vs 4 [0.5%] of 844 neonates in the standard group) and 0.1% (−5.2 to 5.3) in the per-protocol analysis (5 [0.7%] of 745 neonates in the procalcitonin group vs 4 [0.6%] of 663 neonates in the standard group).” (W. van Herk, w.vanherk@erasmusmc.nl)
>>>PNN NewsWatch
* “Ride-out teams” are maintaining patient care when feasible at Houston-area hospitals as record flooding continues as a result of the stalled Harvey tropical storm system. Ben Taub Hospital, with a key level 1 trauma center for the city, flooded and began evacuating some patients “to lower the patient census to better manage the situation for the available resources,” the hospital said on its website. Flooding was also occurring elsewhere in the Texas Medical Center area, including at MD Anderson Cancer Center, which reported on Twitter that all parking garages were inaccessible and that all surgeries and patient appointments for today have been cancelled.
>>>PNN JournalWatch
* Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease, in New England Journal of Medicine, 2017; 10.1056/NEJMoa1707914. (P. M. Ridker, pridker@partners.org)
* Insomnia and Risk of Cardiovascular Disease, in 
Chest, 2017; 152: 435–44. (S. Javaheri, sjavaheri@partners.org
* The Role of Neutrophil Elastase Inhibitors in Lung Diseases, in 
Chest, 2017; 152: 249–62. (A. Torres, atorres@clinic.ub.es)

PNN Pharmacotherapy Line
Aug. 29, 2017 * Vol. 24, No. 166
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Kidney Diseases Report
Source:
 Sept. American Journal of Kidney Diseases (2017; 70).
Community Pharmacist Training & CKD Care: In Quebec, pharmacists receiving training and patient-specific clinical summaries from hospital pharmacists provided better care to patients with chronic kidney disease (CKD), a study shows (pp. 386–96). Community pharmacies and their patients were randomized to ProFiL, a training-and-communication network program, or a control group, and performance was assessed based on a primary outcome of drug-related problems and other variables. Concluding that “providing community pharmacists with essential clinical data, appropriate training, and support from hospital pharmacists with expertise in nephrology increases pharmacists’ knowledge and reduces drug-related problems in patients with CKD who are followed up in clinics incorporating a multidisciplinary health care team,” the authors report these results: “207 community pharmacies, 494 pharmacists, and 442 patients with CKD participated. After 1 year, the mean number of drug-related problems per patient decreased from 2.16 to 1.60 and from 1.70 to 1.62 in the ProFiL and control groups, respectively. The difference in reduction of drug-related problems per patient between the ProFiL and control groups was −0.32 (95% CI, −0.63 to −0.01). Improvements in knowledge (difference, 4.5%; 95% CI, 1.6%–7.4%) and clinical competencies (difference, 7.4%; 95% CI, 3.5%–11.3%) were observed among ProFiL pharmacists. No significant differences in clinical attributes were observed across the groups.” (L. Lalonde, lyne.lalonde@umontreal.ca)
Treating to Target in Older Hypertensive Patients: In a commentary that assesses for nephrologists a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians (see PNN, Mar. 21) (ACP/AAFP), an author concludes that “future studies are needed to determine the value of more versus less intensive treatment in [older adults with hypertension] more typical of [patients] seen daily in clinical practice who commonly have multiple comorbid conditions that have excluded their participation in trials to date” (pp. 311–4). “To help nephrologists, studies are needed to determine optimal [blood pressure (BP)] thresholds and targets in patients with advanced CKD and those receiving renal replacement therapies,” the author writes, adding these details, “I find the recommendations of the current ACP/AAFP guideline to be reasonable to guide decisions on BP thresholds and targets in older hypertensive patients. A very important statement in the ACP/AAFP guideline should be kept in mind when applying any guideline recommendation to clinical practice. ‘Clinical practice guidelines are ‘guides’ only and may not apply to all patients and all clinical situations. Thus, they are not intended to override a clinician’s judgment.’ Clinicians should use all available evidence and individual patient factors to decide on best treatment thresholds and goals using the principles of shared decision making. Many patients encountered in clinical practice do not meet entry criteria for the studies used to inform guidelines.” (G. L. Schwartz, gschwartz@mayo.edu)
>>>PNN NewsWatch
* A federal medical station will be operating at the Houston convention center by tomorrow to provide care to those displaced by Hurricane Harvey, HHS said in a news release last night. The station will be staffed by members of the National Disaster Medical System and U.S. Public Health Service Commissioned Corps. HHS said it has additional federal medical stations available for patient care in Texas and has positioned two 250-bed Federal Medical Stations in Baton Rouge ready to be deployed in Louisiana should state officials determine they are needed. More than 500 HHS personnel are on the ground in the area and 1,300 more are on standby.
* FDA yesterday announced enforcement actions against 
stem-cell clinics in San Diego and Sunrise, FL. FDA said the California clinic had five vials of smallpox vaccine (Vaccinia Virus Vaccine [Live]), one of which was partially used. The Florida clinic was processing patients’ adipose tissue to isolate the stromal vascular fraction and administering these stem cells intravenously or directly into the spinal cord, FDA said. Commissioner Scott Gottlieb, MD, said the agency “will advance a comprehensive policy framework” this fall to “more clearly describe the rules of the road for this new field.”

PNN Pharmacotherapy Line
Aug. 30, 2017 * Vol. 24, No. 167
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Diabetes Report
Source:
 Sept. issue of Diabetes Care (2017; 40).
Diabetes & Hypertension: Reductions in cardiovascular events among patients with diabetes can be attributed to better control of blood pressure, the American Diabetes Association concludes in an updated position statement (pp. 1273–84). “Hypertension is a strong risk factor for atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications,” the statement notes. “ASCVD—defined as acute coronary syndrome, myocardial infarction (MI), angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin—is the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. Numerous studies have shown that antihypertensive therapy reduces ASCVD events, heart failure, and microvascular complications in people with diabetes. Large benefits are seen when multiple risk factors are addressed simultaneously. There is evidence that ASCVD morbidity and mortality have decreased for people with diabetes since 1990 likely due in large part to improvements in blood pressure control.” (G. Bakris, gbakris@medicine.bsd.uchicago.edu)
Declines in Incidence of Diabetes: “It is premature to declare victory against the epidemic of diabetes in the U.S.,” authors conclude, suggesting instead a focus on “current public health efforts, including a specific emphasis to address prediabetes” (pp. 1139–43). Based on multiple sources of data on the incidence of diabetes, these patterns are evident: “National surveillance data show a sustained decline in the incidence rate of diagnosed diabetes, which has been heralded as a success in the battle against diabetes in the U.S.… Although some of the incidence decline may represent real progress against diabetes, it is likely that there are also nonbiological factors at play, especially changes in diagnostic criteria for diabetes. We present and discuss data that suggest improved detection and changes in screening and diagnostic practices may have resulted in the depletion of the ‘susceptible population.’” (E. Selvin, eselvin@jhu.edu)
“The most important statement from [this] article is ‘the war is not yet won,’” writes an editorialist (
pp. 1152–3). “There is no inherent reason to celebrate the decline in incidence seen in adults. It is a victory of sorts, but the number of people living with diabetes is staggering and increasing. An alarmingly high and increasing proportion of our nation’s health care resources are expended in the care of diabetes and its complications and comorbidities. The burden of diabetes care not only impacts the quality of life of hundreds of millions of people globally but also stresses our health care systems and as a result our society to near the breaking point. Recent trends examining the incidence of diabetes in youth in the U.S. demonstrated significant increases, particularly in racial and ethnic groups other than non-Hispanic whites. One can only imagine the impact this will have on our health care system.” (L. A. Young, laura_young@med.unc.edu)
Glycemic Control & Hepatitis C Virus Treatment: Successful treatment of hepatitis C virus with direct-acting antiviral agents is associated with improved glycemic control in patients with type 2 diabetes, a study shows (pp. 1173–80; G. N. Ioannou, georgei@medicine.washington.edu).
>>>PNN NewsWatch
* Calls for people exposed to floodwaters in Houston to get tetanus boosters are unfounded, according to a STAT article posted yesterday. “The widespread belief may stem from the fact that being in floodwaters — which can be full of debris and too murky to see through — does increase a person’s risk of experiencing a puncture wound,” the reporter writes. “Taking part in the cleanup operations that follow these disasters also carries increased risk of puncture wounds.”
FDA yesterday approved a product that combines meropenem with vaborbactam (Vabomere, Rempex Pharmaceuticals) for use in adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by carbapenem-resistant Enterobacteriaceae.
FDA also has granted accelerated approval to benznidazole (Chemo Research, S. L.) for use in children ages 2 to 12 years old with Chagas disease, the first agent approved in the U.S. for treating this disease.

PNN Pharmacotherapy Line
Aug. 31, 2017 * Vol. 24, No. 168
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Aug. 31 issue of the New England Journal of Medicine (2017; 377).
Emicizumab Prophylaxis in Hemophilia A with Inhibitors: The recombinant, humanized, bispecific monoclonal antibody emicizumab significantly lowered the rate of bleeding events among study patients with hemophilia A with inhibitors, compared with no prophylaxis (pp. 809–18). HAVEN-1 participants were age 12 years or older and had hemophilia A with factor VIII inhibitors. Based on a primary end point of difference in bleeding rates, results showed: “The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P <0.001).” (J. Oldenburg, johannes.oldenburg@ukbonn.de)
“The results of this phase 3 trial are extremely important for the hemophilia treatment community, which has battled the hemostatic calamity of factor VIII inhibitor formation with the same bypassing therapies for the past 30 years,” writes an editorialist (
pp. 884–5). “Although the preferred treatment of the infrequent events of breakthrough bleeding during the administration of emicizumab is not clear, it is obvious that repeated high doses of activated prothrombin complex concentrate should be avoided. Similarly, how emicizumab prophylaxis will be integrated with current schedules for the induction of immune tolerance to factor VIII remains to be evaluated.” (D. Lillicrap)
Liraglutide and Renal Outcomes in Type 2 Diabetes: In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide lowered rates of development and progression of diabetic kidney disease among 9,340 participants with type 2 diabetes and high cardiovascular risk, compared with placebo, researchers report (pp. 839–48). The current article includes results of prespecified secondary renal outcomes, including a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. Investigators found these outcomes: “The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4,668 patients vs. 337 of 4,672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P = 0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P = 0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1,000 patient–years), including the rate of acute kidney injury (7.1 and 6.2 events per 1,000 patient–years, respectively).” (J. F. E. Mann, prof.j.mann@gmail.com)
>>>PNN NewsWatch
* The first gene therapy available commercially in the U.S., tisagenlecleucel (Kymriah, Novartis) was approved yesterday by FDA for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. The cell-based gene therapy carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of chimeric antigen receptor (CAR) T-cells causing high fever and flu-like symptoms, and for neurological events. Both CRS and the neurological events can be life-threatening. FDA also expanded the approval of tocilizumab (Actemra, Genentech) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older.
* FDA announced two recalls on Wednesday: 
Mid Valley Pharmaceutical is recalling one lot each of Doctor Manzanilla Cough & Cold and Doctor Manzanilla Allergy & Decongestant Relief syrup to the consumer level because of possible contamination with Burkholderia cepacia, and Lucky Mart Inc. is recalling three lots of Piyanping Anti-Itch Lotion to the consumer level because they contain unlabeled dexamethasone rather than hydrocortisone as listed in labeling.

PNN Pharmacotherapy Line
Sept. 1, 2017 * Vol. 24, No. 169
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Pediatrics Report
Source:
 Early-release articles from Pediatrics (2017; 140).
Adverse Event Recurrence Following Immunization: Reimmunization of patients who had an adverse event following immunization (AEFI) is not studied well, conclude authors of a systematic review (10.1542/peds.2016-3707). “Published studies suggest that reimmunization is usually safe,” the group concludes. “However in these studies, severe cases were often not reimmunized.” Assessment of 29 articles published in English or French produced these findings: “Among patients with a history of hypotonic hyporesponsive episode (n = 398), anaphylaxis (n = 133), or seizures (n = 60) who were reimmunized, events recurred in 0% to 0.8%. Allergic-like events recurred in 30 of 594 reimmunized patients. Fever recurred in 0% to 84% of 836 reimmunized patients, depending on the vaccine and dose number. Among children with extensive limb swelling after the fourth dose of diphtheria–tetanus–acellular pertussis vaccine, recurrence was higher when the fifth dose was given with the full-antigen formulation (78%) compared with the reduced-antigen formulation (53%, P = .02).” (G. De Serres, gaston.deserres@inspq.qc.ca)
“This article … reinforces what vaccinologists and pediatricians have known for many years: vaccines are incredibly safe,” editorialists write (
10.1542/peds.2017-1760). “Considering that the vaccines in the infant schedule are administered to millions of children each year, the list of known adverse events, even rare ones, is impressively short. Although this article does not address the recurrence risk for all known AEFIs, particularly rare ones such as immune thrombocytopenic purpura after measles-containing vaccines and intussusception after rotavirus vaccine, it is impressively comprehensive and will be a useful reference for practicing pediatricians everywhere for years to come. This article will also help to reaffirm the overwhelming value and safety of vaccines in protecting infants and children from complications and death due to infectious diseases.” (S. T. O’Leary, sean.oleary@ucdenver.edu)
>>>Psychiatry Highlights
Source:
 Early-release article from the American Journal of Psychiatry (2017; 174).
Antipsychotic Drug Trials in Acute Schizophrenia: During 60 years of placebo-controlled trials of antipsychotic agents in patients with acute schizophrenia, “approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response,” according to a systematic review, Bayesian meta-analysis, and meta-regression of efficacy predictors (10.1176/appi.ajp.2017.16121358): “The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a ‘minimal’ response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a ‘good’ response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.” (S. Leucht)
>>>PNN NewsWatch
* Based on data from two recently halted clinical trials, FDA yesterday issued a statement emphasizing the risks associated with the unapproved use of pembrolizumab (Keytruda, Merck) in combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for treatment of patients with multiple myeloma. This warning does not apply to patients taking the drug product for any of its approved indications, FDA added.
Hospira is voluntarily recalling one lot of Vancomycin Hydrochloride for Injection, USP, 750 mg/vial, lot 632153A, to the hospital/retailer level because of confirmed presence of glass particulate matter in one vial.
PNN will not be published on Mon., Sept. 4, Labor Day.

PNN Pharmacotherapy Line
Sept. 5, 2017 * Vol. 24, No. 170
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Sept. 5 issue of the Annals of Internal Medicine (2017; 167).
Prescription Opioid Use & Use Disorders: The National Survey on Drug Use and Health (NSDUH) shows that one third of Americans used opioids during 2015, suggesting “a need to improve access to evidence-based pain management and to decrease excessive prescribing that may leave unused opioids available for potential misuse” (pp. 293–301). The survey of 51,200 civilian, noninstitutionalized adults showed these patterns of prescription opioid use, misuse, and use disorders: “Weighted NSDUH estimates suggested that, in 2015, 91.8 million (37.8%) U.S. civilian, noninstitutionalized adults used prescription opioids; 11.5 million (4.7%) misused them; and 1.9 million (0.8%) had a use disorder. Among adults with prescription opioid use, 12.5% reported misuse; of these, 16.7% reported a prescription opioid use disorder. The most commonly reported motivation for misuse was to relieve physical pain (63.4%). Misuse and use disorders were most commonly reported in adults who were uninsured, were unemployed, had low income, or had behavioral health problems. Among adults with misuse, 59.9% reported using opioids without a prescription, and 40.8% obtained prescription opioids for free from friends or relatives for their most recent episode of misuse.” (W. Compton, wcompton@nida.nih.gov)
HCV Treatment by Nonspecialists: At 13 Washington, DC, federally qualified health centers (FQHCs), patients with hepatitis C virus (HCV) infection had equivalent outcomes when treatment with direct-acting agents was managed by nurse practitioners (NPs), primary care physicians (PCPs), and specialist physicians, a study shows (pp. 311–8): “516 patients achieved [sustained virologic response (SVR)], a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR.” (S. Kottilil, SKottilil@ihv.umaryland.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Nonspecific Vaccine Effects: Seeking to explain lower rates of hospitalization following measles and diphtheria, pertussis, and tetanus (DTP) vaccinations, researchers find that such nonspecific effects can occur with other vaccines and may be the result of healthy vaccinee bias (j3862). Compared with diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib)+pneumococcal vaccination (PCV) in the high-income country of the Netherlands, MMR at 2, 3, 4, and 11 months and MMR plus meningococcal C (MenC) vaccination at 14 months showed these associations with hospital admissions: “Having had MMR+MenC as the most recent vaccination was associated with a hazard ratio of 0.62 (95% confidence interval 0.57 to 0.67) for admission to hospital for infection and 0.84 (0.73 to 0.96) for injuries or poisoning, compared with the fourth DTaP-IPV-Hib+PCV as most recent vaccination. The fourth DTaP-IPV-Hib+PCV as most recent vaccination was associated with a hazard ratio of 0.69 (0.63 to 0.76) for admission to hospital for infection, compared with the third DTaP-IPV-Hib+PCV as most recent vaccination.” (M. J. Knol, mirjam.knol@rivm.nl)
>>>PNN NewsWatch
FDA on Friday approved gemtuzumab ozogamicin (Mylotarg, Pfizer) for treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML) and also for treatment of patients aged 2 years or older with relapsed or refractory CD33-positive AML.
PharMEDium is voluntarily recalling all unexpired lots of oxytocin compounded with lactated Ringers or lactated Ringers and dextrose products made between July 6 and Aug. 29 to the hospital/user level because of subpotency.
FDA cautions professionals and patients not to use alcohol pads or benzalkonium chloride antiseptic towelettes made by the Chinese company Foshan Flying Medical Products because of lack of sterility assurance and other quality issues.
>>>PNN JournalWatch
* Safety and Efficacy of Ebselen for the Prevention of Noise-Induced Hearing Loss: A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial, in Lancet, 2017; 390: 969–79. (J. Kil, jkil@soundpharma.com)

PNN Pharmacotherapy Line
Sept. 6, 2017 * Vol. 24, No. 171
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Sept. 5 issue of JAMA (2017; 318).
Immunization Exemptions in California: Medical exemptions (MEs) from compliance with California immunization requirements for schoolchildren increased in the first year under a law banning personal belief exemptions (PBEs), researchers report (pp. 863–4). “The statewide increase in the number of children with MEs in 2016 and the county-level correlation with past PBE use suggest that some vaccine-hesitant parents may have successfully located physicians willing to exercise the broader discretion provided by SB 277 for granting MEs,” the authors write. While the percentage of kindergarteners with MEs had been “largely stable” in the 20 years before passage of the law (SB 277), “the ME percentage increased from 0.17% to 0.51%. The PBE percentage decreased from 2.37% in 2015 to 0.56% in 2016, as PBEs for children who entered multiyear transitional kindergarten programs prior to 2016 remained valid. The total exemption percentage (PBEs + MEs) decreased from 2.54% in 2015 to 1.06% in 2016.” The investigators note that MEs rose in areas where PBEs had previously been high, creating a situation in which “portions of California may remain susceptible to vaccine-preventable disease outbreaks in the near future.” (P. L. Delamater, pld@email.unc.edu)
Personalized Management of Parkinson Disease: “The 2017 approach to the treatment of patients with [Parkinson disease (PD)] requires personalization of therapy and attention to the varied and changing symptoms,” conclude authors of a Viewpoint article (pp. 791–2). “Clinicians must be adept at diagnosing clusters of motor and nonmotor symptoms and mapping a comprehensive symptom-specific strategy that may necessitate involvement of a multidisciplinary team, including neurology, neuropsychology, psychiatry, neurosurgery, and rehabilitative services. Clinicians must also be aware that PD is dynamic and treatment strategies may need to shift abruptly as the disease progresses and the symptom clusters shift. The combination of medical therapy with exercise and in some cases surgical interventions can improve quality of life for most patients with PD and can transform a potentially debilitating disease into a livable condition.” (M. S. Okun, okun@neurology.ufl.edu)
Off-label Ketamine for Mood Disorders: Use of subanesthetic doses of ketamine for treating patients with mood disorders has generated enthusiasm among clinicians and patients whose depression has been refractory to standard therapies, according to a Viewpoint article (pp. 793–4). “However, considering the tremendous individual and societal burden of mood disorders, the high percentage of patients that do not achieve satisfactory responses from the currently available approved treatments, and the recent evidence of rising rates of suicide, expedited research into this potentially transformative treatment is needed,” the authors conclude. “Several ongoing studies (such as NCT01945047, NCT03113968, and NCT00088699) are attempting to address these knowledge gaps and enrollment in these trials should be encouraged when possible. In addition to the standard randomized clinical trials, the creation of a registry of patients receiving ketamine off-label as a treatment for mood disorders could serve as an efficient way to learn more about the longer-term effectiveness and safety of the treatment and could be beneficial in guiding the rational use of the treatment.” (G. Sanacora, gerard.sanacora@yale.edu)
>>>PNN NewsWatch
* CDC has awarded $28.6 million in additional funding of the Prescription Drug Overdose: Prevention for States program, the Data-Driven Prevention Initiative, and the Enhanced State Opioid Overdose Surveillance program. Funds will be used by 44 states and the District of Columbia to scale up prevention activities that include increasing the use of prescription drug monitoring programs and improving clinical feedback from these systems, expanding the reach of messages about the risks associated with opioids, and other practices such as conducting overdose fatality reviews to improve prevention efforts. 
* Hospira is voluntarily recalling one lot of 
hydromorphone HCl injection 2 mg/mL and four lots of Levophed (norepinephrine bitartrate) 4 mg/4 mL because of a potential lack of sterility assurance, FDA said.

PNN Pharmacotherapy Line
Sept. 7, 2017 * Vol. 24, No. 172
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Sept. 7 issue of the New England Journal of Medicine (2017; 377).
Third MMR Dose During Mumps Outbreaks: For managing mumps outbreaks in young adults, a third dose of measles–mumps–rubella (MMR) vaccine reverses waning immunity and improves disease control, researchers report (pp. 947–56). At the U. Iowa in 2015–16, investigators found these vaccine histories and immunity rates among 20,496 students, including 259 with mumps: “Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4,783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1,000 population, P <0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose.” (C. V. Cardemil, iyk8@cdc.gov)
Tiotropium in Early-Stage COPD: In 771 patients with mild or moderate chronic obstructive pulmonary disease (COPD), tiotropium decreased the decline in pulmonary function over a 2-year, placebo-controlled study conducted in China (pp. 923–35). Based on a primary end point of forced expiratory volume in 1 second (FEV1) before bronchodilator use, once-daily inhaled tiotropium 18 mcg produced these results: “The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial (ranges of mean differences, 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use; P <0.001 for all comparisons). There was no significant amelioration of the mean (± SE) annual decline in the FEV1 before bronchodilator use: the decline was 38 ± 6 ml per year in the tiotropium group and 53 ± 6 ml per year in the placebo group (difference, 15 ml per year; 95% confidence interval [CI], −1 to 31; P = 0.06). In contrast, the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group (29 ± 5 ml per year vs. 51 ± 6 ml per year; difference, 22 ml per year [95% CI, 6 to 37]; P = 0.006). The incidence of adverse events was generally similar in the two groups.” (P. Ran, pxran@gzhmu.edu.cn)
Editorialists speculate about the impact of more research into management of early COPD, which has historically not been treated (
pp. 988–9): “With the development of new drugs, would treatment with another drug in the class of long-acting muscarinic antagonists (LAMAs) or long-acting beta-agonists (LABAs) or a combination of LAMAs and LABAs help to improve lung function, slow the decline in lung function, improve quality of life, and decrease the incidence of exacerbations among patients with early COPD? Early intervention and treatment for patients with diabetes mellitus and hypertension certainly lead to better outcomes. Is such an early treatment strategy possible and effective for patients with mild COPD? Further studies of the newer drugs and longer-term studies are needed to improve available treatments for millions of patients with early-stage COPD worldwide. For now, the evidence supports the judicious use of treatment in patients with symptomatic early-stage COPD or in those who are recovering from an exacerbation.” (F. W. S. Ko)
Tezepelumab in Uncontrolled Asthma: In a phase 2 trial of 291 patients with asthma uncontrolled by long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, tezepelumab reduced rates of clinically significant asthma exacerbations, compared with placebo (pp. 936–46). The agent is a human monoclonal antibody specific for the epithelial-cell–derived cytokine thymic stromal lymphopoietin. (J. Corren, jcorren@ucla.edu)
>>>PNN NewsWatch
* Patients should take oral medications at least 3 hours before or 3 hours after taking sodium polystyrene sulfonateFDA advised yesterday. A study shows that the agent binds to and thereby decreases absorption of many commonly prescribed oral medicines.

PNN Pharmacotherapy Line
Sept. 8, 2017 * Vol. 24, No. 173
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Chest Highlights
Source:
 Sept. issue of Chest (2017; 152).
IVIg for Heparin-Induced Thrombocytopenia: Intravenous immunoglobulin (IVIg) treatment should be considered for patients with severe refractory heparin-induced thrombocytopenia (HIT), according to authors who described three cases and evaluated the mechanism of action in those patients and five others with severe HIT (pp. 478–85). Effects of a common polymorphism, H/R 131, in the platelet IgG receptor Fc-gamma-RIIa on IVIg-mediated inhibition of platelet activation, was also examined, with these results: “At levels attained in vivo, IVIg inhibits HIT antibody-mediated platelet activation. The constant domain of IgG (Fc) but not the antigen-binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid-phase HIT immunoassay (platelet factor 4 enzyme-linked immunoassay). The H/R131 polymorphism in Fc-gamma-RIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg-mediated inhibition of antibody-induced activation. However, at high doses of IVIg, activation of platelets of all Fc-gamma-RIIa genotypes was significantly inhibited. All three patients did well on long-term anticoagulation therapy with direct oral anticoagulants.” (A. Padmanabhan, anand.padmanabhan@bcw.edu)
“Although the concept of using IVIg for treating HIT has existed since at least 1994, it is a largely ignored treatment,” editorialists write (
pp. 453–5). “Moreover, a consensus conference guideline actually recommended against IVIg for treating HIT. However, the more recent observations describing IVIg as efficacious for HIT represent ‘rediscovery’ of an old therapy. Now, with the correlating clinical laboratory studies of Padmanabhan et al., together with the emerging concept of autoimmune HIT, it seems more likely that IVIg will become an important option for treating patients who have severe HIT.” (T. E. Warkentin, twarken@mcmaster.ca)
Statins in COPD: Administrative data from British Columbia suggest a role for statins in reducing lung-related and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD), researchers report (pp. 486–93). Statin drug exposure in the year after COPD diagnosis was associated with these primary and secondary outcomes: “There were 39,678 patients with COPD that met the study inclusion criteria. Of them, 7,775 (19.6%) had received at least one statin drug dispensed in the exposure ascertainment window. There were 1,446 all-cause deaths recorded in the cohort in the 1-year period after exposure ascertainment. In multivariate analysis, the estimated hazard ratio (HR) for statin drug exposure was 0.79 (95% CI, 0.68–0.92; P = .0016), suggesting a 21% reduction in the risk from statin drug use on all-cause mortality. For lung-related mortality, there was also a considerable reduction in the risk for all-cause mortality from statin drug use (HR, 0.55; 95% CI, 0.32–0.93; P = .0254).” (L. D. Lynd, llynd@ubc.ca)
Vitamin D in Pediatric Asthma: Short- but not long-term reductions in asthma exacerbations were associated with rapid reversal of vitamin D deficiency in pediatric patients presenting in emergency departments with moderate-to-severe asthma exacerbations and vitamin D levels of 25 ng/mL or lower (pp. 527–36): “One hundred and sixteen patients in the IM + oral cohort vs 115 in the oral-only cohort had similar mean (SD) baseline levels: 15.1 (5.4) vs 15.8 (5.2) ng/mL (range, 3–25 ng/mL). There was no difference in the primary outcome [of patient-initiated unplanned visits for asthma exacerbations] over the entire 12-month observation period. However, rapid IM + oral supplementation significantly reduced unplanned visits for asthma exacerbations for children with baseline levels of 3 to 11 ng/mL during the initial 3 months: the relative exacerbation rate for the IM + oral cohort compared with the oral-only cohort at 3 months was 0.48 (95% CI, 0.28–0.89; P = .008); average exacerbation frequency per child analysis, relative rate 0.36 (95% CI, 0.13–0.87; P = .017). Otherwise, there were no significant differences between groups.” (B. L. Davidson, brucedavidson@pobox.com)
>>>PNN NewsWatch
* Genentech is voluntarily recalling three lots of alteplase (Activase) 100 mg vials, that were copackaged with Hospira Sterile Water for Injection, to the hospital level, FDA said.

PNN Pharmacotherapy Line
Sept. 11, 2017 * Vol. 24, No. 174
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Safety Label Changes for Expedited Drugs: Medications approved by FDA under expedited pathways later need more and more serious safety labeling changes than other drugs, a study shows (j3837). Retrospective cohort analysis of public records for drugs approved in 1997–2016 showed the following: “Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1,710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.” (A. S. Kesselheim, akesselheim@bwh.harvard.edu)
Psychiatric Disorders & Antidepressant Use During Pregnancy: Exposure to antidepressants in utero is associated with increased risk of psychiatric disorders, according to data from the Danish national registry (j3668). Concluding that “focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive,” the investigators report these findings for 905,383 liveborn singletons in 1998–2012 who were followed for up to 16.5 years: “Overall, psychiatric disorders were diagnosed in 32,400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.” (X. Liu, lxq@econ.au.dk)
Dental Procedures, Antibiotic Prophylaxis & Endocarditis: In adults with prosthetic heart valves, invasive dental procedures are associated with a small proportion of cases of infective endocarditis, a study shows, but the role of antibiotic prophylaxis requires further study (j3776). A nationwide, population-based cohort and a case–crossover study from France shows these relationships among dental procedures, antibiotic prophylaxis, and endocarditis: “The cohort included 138,876 adults with prosthetic heart valves (285,034 person years); 69,303 (49.9%) underwent at least one dental procedure. Among the 396,615 dental procedures performed, 103,463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52,280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100,000 person years, 95% confidence interval 82.4 to 104.9). Compared with non-exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P = 0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P = 0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P = 0.03).” (S. Tubiana, sarah.tubiana@aphp.fr)
>>>PNN JournalWatch
* Unraveling Vascular Inflammation: From Immunology to Imaging, in Journal of the American College of Cardiology, 2017; 70: 1403–12. (H. L. Teague) 
* Efficacy and Safety of Ticagrelor Over Time in Patients With Prior MI in PEGASUS-TIMI 54, in 
Journal of the American College of Cardiology, 2017; 70: 1368–75. (M. P. Bonaca)
* The Evolution of the Use of Beta-Blockers to Treat Heart Failure: A Conversation With Finn Waagstein, MD, in 
Circulation, 2017; 136: 889–93.

PNN Pharmacotherapy Line
Sept. 12, 2017 * Vol. 24, No. 175
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 Sept. issue of JAMA Internal Medicine (2017; 177).
Antibiotic-Associated Adverse Events in Inpatients: As many as 20% of patients placed on antibiotic therapy while in the hospital have associated adverse effects, a study shows, including serious abnormalities of the gastrointestinal, renal, and hematologic systems (pp. 1308–15). Among 1,488 adults on general medicine wards at an academic medical center, these antibiotic-associated adverse drug events (ADEs) were identified within 30 days of treatment initiation: “The median age was 59 years (interquartile range, 49–69 years), and 758 (51%) participants were female. A total of 298 (20%) patients experienced at least 1 antibiotic-associated ADE. Furthermore, 56 (20%) non–clinically indicated antibiotic regimens were associated with an ADE, including 7 cases of Clostridium difficile infection. Every additional 10 days of antibiotic therapy conferred a 3% increased risk of an ADE. The most common ADEs were gastrointestinal, renal, and hematologic abnormalities, accounting for 78 (42%), 45 (24%), and 28 (15%) 30-day ADEs, respectively. Notable differences were identified between the incidence of ADEs associated with specific antibiotics.” (P. D. Tamma, ptamma1@jhmi.edu)
Long-term Opioid Therapy Guidelines in Primary Care: Use of a multicomponent intervention improved opioid treatment of patients on long-term analgesia, but the frequency of early-refill requests was unchanged, researchers report (pp. 1265–72). Cluster randomization of 53 primary care clinicians (PCCs) produced these outcomes when an intervention of nurse care management, an electronic registry, 1-on-1 academic detailing, and electronic decision tools for safe opioid prescribing was compared with a control consisting of only the decision tools: “Of the 985 participating patients, 519 were men, and 466 were women (mean [SD] patient age, 54.7 [11.5] years). Patients received a mean (SD) [morphine-equivalent daily dose (MEDD)] of 57.8 (78.5) mg. At 1 year, intervention patients were more likely than controls to receive guideline-concordant care (65.9% vs 37.8%; P <.001; adjusted odds ratio [AOR], 6.0; 95% CI, 3.6–10.2), to have a patient–PCC agreement (of the 376 without an agreement at baseline, 53.8% vs 6.0%; P <.001; AOR, 11.9; 95% CI, 4.4–32.2), and to undergo at least 1 [urine drug test] (74.6% vs 57.9%; P <.001; AOR, 3.0; 95% CI, 1.8–5.0). There was no difference in odds of early refill receipt between groups (20.7% vs 20.1%; AOR, 1.1; 95% CI, 0.7–1.8). Intervention patients were more likely than controls to have either a 10% dose reduction or opioid treatment discontinuation (AOR, 1.6; 95% CI, 1.3–2.1; P <.001). In adjusted analyses, intervention patients had a mean (SE) MEDD 6.8 (1.6) mg lower than controls (P <.001).” (J. M. Liebschutz, jane.liebschutz@bmc.org)
“Reversing the growth in opioid use for chronic pain is difficult because of the paucity of effective alternative treatments,” editorialists write (
p. 1272). “In the meantime, this study demonstrates that it is possible to increase safe prescribing habits among primary care physicians. We are encouraged by the increasing evidence of benefit of many nonnarcotic and nonpharmacologic approaches to chronic pain, such as mindfulness training or cognitive behavioral therapy, that appear as effective as opioids without the addiction and overdose risks. We hope to see more interventions focused on decreasing the use and harms of opioids among patients with chronic pain.” (S. R. Bauer, Scott.Bauer@ucsf.edu)
>>>PNN NewsWatch
* Power outages following Hurricane Irma are preventing some Florida health facilities from reopening and/or returning to normal operations, the Miami Herald reported last evening. While emergency departments are preparing “for an influx of … visits from people suffering falls, cuts and other mishaps related to the recovery,” many of the 30 hospitals, 61 nursing homes, and 280 assisted-living facilities that closed over the weekend are dealing with a lack of power and in the Keys, no water or sewer service. Moving through Georgia as a tropical storm, Irma produced flooding in Savannah, downed trees and cut off power across much of the state, and changed wind patterns at the Atlanta Airport, forcing cancellation of hundreds of flights and affecting travel plans for many of the quarter million people who go through the facility on an average day.

PNN Pharmacotherapy Line
Sept. 13, 2017 * Vol. 24, No. 176
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Sept. 12 issue of JAMA (2017; 318).
Menopausal Hormone Therapy & Mortality: During a cumulative 18-year follow-up of the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials, hormone therapy was not associated with increased risk of all-cause, cardiovascular, or cancer mortality, researchers report (pp. 927–38). Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) had these effects in comparison with placebo: “Among 27,347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7,489 deaths occurred (1,088 deaths during the intervention phase and 6,401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94–1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96–1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88–1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92–1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95–1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88–1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50–59 years) to older women (aged 70–79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43–0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76–1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
“This information will be helpful in counseling women considering whether to start hormone therapy and hopefully will alleviate concerns that many patients and physicians have about the initiation of hormone therapy,” editorialists write (
pp. 911–3). “For women with troubling vasomotor symptoms, premature menopause, or early-onset osteoporosis, hormone therapy appears to be both safe and efficacious. The data presented by Manson et al fully support the newly released 2017 hormone therapy position statement of the North American Menopause Society and are a welcome addition to current knowledge regarding hormone therapy administration.” (M. McNeil, mcneilma@upmc.edu)
Genetic Variants Related to CETP Inhibitors & Statins: Reacting to a genetic variants trial of more than 100,000 participants showing that “the clinical benefit of lowering LDL-C levels may … depend on the corresponding reduction in apoB-containing lipoprotein particles” (pp. 947–56; B. A. Ference, bference@med.wayne.edu), editorialists explain, “Trapping of an apoB particle within the arterial wall is the fundamental step that initiates the atherosclerotic process” (pp. 915–7). “The evidence summarized indicates that this process may be more closely related to the number of circulating particles as estimated by apoB levels than to the mass of cholesterol within these particles estimated by LDL-C levels. The logical next step is to reframe the lipid hypothesis as the lipoprotein particle hypothesis.” (E. D. Peterson, eric.peterson@duke.edu)
Medication Reconciliation v. Medication Review: Obtaining the medication list “should result from a thorough medication review, founded in medication reconciliation,” write authors (pp. 965–6) in response to a previous publication (pp. 2057–8; A. J. Rose, arose@rand.org). “The medication review process encompasses the 6 levels of reconciliation and adds optimizing medication impact. The medication review process must include the complementary, primary, and essential step of medication reconciliation. Medication reconciliation is a foundation from which to examine the medical appropriateness and patient-centeredness needed to create the correct medication list.” (K. M. Zimmerman, kzimmerman@vcu.edu)
>>>PNN NewsWatch
Medtronic plc has initiated a voluntary recall of specific lots of infusion sets used with all models of Medtronic insulin pumps because of a discontinued component in the infusion sets.

PNN Pharmacotherapy Line
Sept. 14, 2017 * Vol. 24, No. 177
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Sept. 14 issue of the New England Journal of Medicine (2017; 377).
Rapid Molecular Drug-Susceptibility Test for Tuberculosis: An investigational assay shows promise as a rapid point-of-care test for antibiotic susceptibility of Mycobacterium tuberculosis, researchers report (pp. 1043–54). The Xpert MTB/RIF assay and sputum culture was studied in adults in China and South Korea with symptoms of tuberculosis, with these results: “Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.” (S. E. Dorman, dorman@musc.edu)
Sibling Vaccination Rates After a Child Develops Autism: As part of a study of “high risk” younger siblings of children with autism spectrum disorder, investigators show decreased vaccination rates with measles–mumps–rubella (MMR) vaccine among these children, compared with “low risk” siblings in unaffected families (pp. 1099–101). “Families with children who had autism spectrum disorder were less likely to vaccinate subsequent children,” authors of a letter report. “Specifically, the rate of vaccination among full biologic infant siblings of children with autism spectrum disorder was 83.1%, as compared with 97.0% among low-risk infants (Pearson chi-square value with one degree of freedom, 12.62; P <0.001). These findings are consistent with reported rates of MMR vaccination among children at older ages and across broader sampling regions.” (G. Glickman, glickman@ucsd.edu)
Patent Foramen Ovale Closure or Medical Management After Stroke: “How can we now have three trials showing that [patent foramen ovale (PFO)] closure prevents recurrent stroke, given that in the past 5 years, the Journal published articles from three other trials that showed the opposite?” asks an editorialist (pp. 1093–5; A. H. Ropper) Reports in the current issue show a lower rate of stroke recurrence among those assigned to PFO closure plus antiplatelet therapy, compared with antiplatelet therapy alone (pp. 1011–21; J-L Mas, jl.mas@ch-sainte-anne.fr); find a lower rate of recurrent ischemic strokes among adults with cryptogenic ischemic strokes managed with PFO closure plus medical therapy than with medical therapy alone (pp. 1022–32; J. L. Saver, jsaver@mednet.ucla.edu); demonstrate in a multinational trial fewer strokes with PFO closure/antiplatelet therapy than antiplatelet agents alone (pp. 1033–42; S. E. Kasner, kasner@mail.med.upenn.edu). However, the third trial showed higher rates of device complications and atrial fibrillation with PFO closure plus antiplatelet therapy. Use of the Amplatzer PFO Occluder device is reviewed in an accompanying Perspective article (pp. 1006–9; A. Farb).
>>>PNN NewsWatch
* In a case–control analysis of the Vaccine Safety Datalink records from 2010–11 and 2011–12 influenza seasons, pregnant women who had received an influenza vaccination in the prior 28 days were more likely to have spontaneous abortion than controls, but the relationship was significant only for women who also had influenza vaccination in the previous season. In a study reported in Vaccine (40: 5314–22; J. G. Donahue, donahue.james@mcrf.mfldclin.edu), authors emphasize that study methodology precludes establishment of a causal relationship but add that “further research is warranted.”

PNN Pharmacotherapy Line
Sept. 15, 2017 * Vol. 24, No. 178
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
 Sept. 15 issue of Clinical Infectious Diseases (2017; 65).
Bacteriuria in VA Hospitals: The treatment of asymptomatic bacteriuria (ASB) with prolonged courses of antibiotics is quantified in a study of urinary tract infections (UTIs) among inpatients at Veterans Affairs hospitals (pp. 910–7). Manual chart review revealed these patterns of disease and treatment of inpatients with ASB or symptomatic UTIs: “Among 2,225 episodes of bacteriuria, 64% were classified as ASB. After excluding patients with non-UTI indications for antibiotics, 72% of patients with ASB received antibiotics. When evaluating only patients not meeting [Systemic Inflammatory Response Syndrome] criteria, 68% of patients with ASB received antibiotics. The mean (± SD) days of antibiotic therapy for ASB, cystitis, [catheter-associated]-UTI and pyelonephritis were 10.0 (4.5), 11.4 (4.7), 12.0 (6.1), and 13.6 (5.3), respectively. In sum, 14% of patients with ASB were treated for greater than 14 days, and fluoroquinolones were the most commonly used empiric antibiotic for ASB [245/691 (35%)]. Complications were rare but more common among patients with ASB treated with antibiotics.” (E. S. Spivak, emily.spivak@hsc.utah.edu)
Multidrug-Resistant Gonorrhea: A “cluster of genetically related gonococcal isolates with decreased ceftriaxone susceptibility and high-level azithromycin resistance may bring the threat of treatment failure in the United States with the current recommended dual therapy one step closer,” authors conclude based on a report of 7 patients in Hawaii (pp. 918–23). Over a period of less than 3 weeks in 2016, eight Neisseria gonorrhoeae isolates in these patients had elevated azithromycin minimum inhibitory concentrations (MICs) >256 mcg/mL and elevated ceftriaxone MICs (≥0.125 mcg/mL). Further study of the isolates and patient interviews showed the following: “All isolates had azithromycin MICs >16 µg/mL and 5 had ceftriaxone MICs = 0.125 µg/mL by agar dilution. All isolates were beta-lactamase positive and were resistant to penicillin, tetracycline, and ciprofloxacin. Genomic analysis revealed genetic relatedness. No patients reported recent travel or antibiotic use, and no male patients reported male sex partners. All patients were successfully treated.” (A. R. Katz, katz@hawaii.edu)
>>>Oncology Highlights
Source:
 Sept. 10 issue of the Journal of Clinical Oncology (2017; 35).
Arsenic & Anthracyclines in Acute Promyelocytic Leukemia: Arsenic trioxide (ATO) consolidation permitted significant reductions in cumulative anthracycline doses in pediatric patients with newly diagnosed acute promyelocytic leukemia (APL), Children’s Oncology Group AAML0631 investigators report (pp. 3021–9). With patients stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic white blood cell count, the phase 3 trial shows: “One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% (P = .003), and EFS was 95% versus 83% (P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients.” (M. A. Kutny, mkutny@peds.uab.edu)
>>>PNN NewsWatch
FDA yesterday granted accelerated approval and orphan designation to the kinase inhibitor copanlisib (Aliqopa, Bayer) for treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies.
* Amgen’s 
bevacizumab-awwb (Mvasi) was approved yesterday by FDA as a biosimilar to Avastin (Genentech) for treatment of several types of cancer. The first biosimilar approved with an oncologic indication and the first biosimilar to this agent, bevacizumab-awwb is indicated for the treatment of adults with five types of cancer, including in combination with chemotherapy for nonsquamous, nonsmall cell lung cancer, in combination with chemotherapy for metastatic colorectal cancer, glioblastoma, metastatic renal cell carcinoma in combination with interferon alfa, and in combination with chemotherapy for persistent, recurrent, or metastatic carcinoma of the cervix.

PNN Pharmacotherapy Line
Sept. 18, 2017 * Vol. 24, No. 179
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Sept. 16 issue of Lancet (2017; 390).
Global Burden of Disease Study 2016: In one of seven articles in this issue detailing results of the Global Burden of Disease Study 2016, authors examine worldwide mortality rates in young children and adults, age-specific mortality, and life expectancy, reaching this conclusion (pp. 1084–150): “Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age-specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled.” (C. J. L. Murray, cjlm@uw.edu)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Anxiety Relapse After Antidepressant Discontinuation: Used in treatment of patients with diverse anxiety disorders, antidepressants continue to provide benefits when continued for up to 1 year, a study shows (j3927). Systematic review and meta-analyses of relapse prevention trials showed these results for patients with anxiety disorders, obsessive–compulsive disorder, or posttraumatic stress disorder: “The meta-analysis included 28 studies (n = 5,233) examining relapse with a maximum follow-up of one year. Across studies, risk of bias was considered low. Discontinuation increased the odds of relapse compared with continuing antidepressants (summary odds ratio 3.11, 95% confidence interval 2.48 to 3.89). Subgroup analyses and meta-regression analyses showed no statistical significance. Time to relapse (n = 3,002) was shorter when antidepressants were discontinued (summary hazard ratio 3.63, 2.58 to 5.10; n = 11 studies). Summary relapse prevalences were 36.4% (30.8% to 42.1%; n = 28 studies) for the placebo group and 16.4% (12.6% to 20.1%; n = 28 studies) for the antidepressant group, but prevalence varied considerably across studies, most likely owing to differences in the length of follow-up. Dropout was higher in the placebo group (summary odds ratio 1.31, 1.06 to 1.63; n = 27 studies).” (N. Batelaan, n.batelaan@ggzingeest.nl)
Glaucoma & Intraocular Pressure: As a measure for detecting glaucoma, intraocular pressure (IOP) “is inaccurate and probably not viable,” researchers conclude (j3889). In the EPIC-Norfolk Eye Study, 8,623 participants aged 48 to 92 years who underwent ocular examination to identify glaucoma had these outcomes: “The mean IOP in 8,401 participants was 16.3 mm Hg (95% confidence interval 16.2 mm Hg to 16.3 mm Hg; SD 3.6 mm Hg). In 363 participants (4%), glaucoma was present in either eye; 314 (87%) had primary open angle glaucoma. In the remaining participants, glaucoma was suspected in 607 (7%), and 863 (10.0%) had ocular hypertension. Two thirds (242) of those with glaucoma had previously already received the diagnosis. In 76% of patients with newly diagnosed primary open angle glaucoma (83/107), the mean IOP was under the threshold for ocular hypertension (21 mm Hg). No one IOP threshold provided adequately high sensitivity and specificity for diagnosis of glaucoma.” (P. Foster, p.foster@ucl.ac.uk)
>>>PNN JournalWatch
* Evolving Insights Into the Epidemiology and Control of Clostridium difficile in Hospitals, in Clinical Infectious Diseases, 2017; 65: 1232–38. (M. Klompas, mklompas@partners.org
* Bezlotoxumab: A Novel Agent for the Prevention of Recurrent 
Clostridium difficile Infection, in Pharmacotherapy, 2017; 37: 10.1002/phar.1990. (L. M. Daniels, Lindsay.Daniels@unchealth.unc.edu
* Identifying Health Information Technology Needs of Oncologists to Facilitate the Adoption of Genomic Medicine: Recommendations From the 2016 American Society of Clinical Oncology Omics and Precision Oncology Workshop, in 
Journal of Clinical Oncology, 2017; 35: 3153–9. (J. L. Warner, jeremy.warner@vanderbilt.edu)

PNN Pharmacotherapy Line
Sept. 19, 2017 * Vol. 24, No. 180
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Sept. 19 issue of and early-release articles from the Annals of Internal Medicine (2017; 167).
Continuous Glucose Monitoring in Type 2 Diabetes: Patients on intensive glycemic therapy for type 2 diabetes more frequently use of continuous glucose monitoring (CGM), based on results of a study of adults conducted at 25 endocrinologic practices in North America (pp. 365–74). Among 158 patients randomized to CGM or usual care, these results were reported for glycemic control using multiple daily insulin injections over a 24-week period: “Mean HbA1c levels decreased to 7.7% in the CGM group and 8.0% in the control group at 24 weeks (adjusted difference in mean change, −0.3% [95% CI, −0.5% to 0.0%]; P = 0.022). The groups did not differ meaningfully in CGM-measured hypoglycemia or quality-of-life outcomes. The CGM group averaged 6.7 days (SD, 0.9) of CGM use per week.” (R. W. Beck, rbeck@jaeb.org)
Kidney, Cardiovascular Outcomes & Intensive SBP Control: While intensive control of systolic blood pressure (SBP) is connected to an increased risk of kidney disease, this is “outweighed by cardiovascular and all-cause mortality benefits,” SPRINT researchers report based on outcomes of 6,662 participants (pp. 375–83). A composite of all-cause death or cardiovascular event showed the following when analyzed along with changes in estimated glomerular filtration rates (eGFRs) and prespecified incident CKD: “The difference in adjusted mean eGFR between the intensive and standard groups was −3.32 mL/min/1.73 m2 (95% CI, −3.90 to −2.74 mL/min/1.73 m2) at 6 months, was −4.50 mL/min/1.73 m2 (CI, −5.16 to −3.85 mL/min/1.73 m2) at 18 months, and remained relatively stable thereafter. An incident CKD event occurred in 3.7% of participants in the intensive group and 1.0% in the standard group at 3-year follow-up, with a hazard ratio of 3.54 (CI, 2.50 to 5.02). The corresponding percentages for the composite of death or cardiovascular event were 4.9% and 7.1% at 3-year follow-up, with a hazard ratio of 0.71 (CI, 0.59 to 0.86).” (S. Beddhu, Srinivasan.beddhu@hsc.utah.edu)
Maraviroc-Containing Regimens for HIV Prophylaxis: For HIV preexposure prophylaxis (PrEP), the investigational drug maraviroc (MVC) was safe and well-tolerated compared with tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) (pp. 384–93). A phase 2 trial produced these results among 188 participants who were not initially infected with HIV despite condomless vaginal or anal intercourse with at least one man with HIV infection or unknown serostatus within 90 days: “Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC–FTC), 9 (MVC–TDF), and 8 (TDF–FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC–TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.” (R. M. Gulick, rgulick@med.cornell.edu)
ACP Reaffirms Opposition to Physician-Assisted Suicide: Citing ethical arguments and clinical, policy, legal, and other concerns, the American College of Physicians reaffirms its opposition to legalization of physician-assisted suicide in this issue of Annals, and also affirms a professional responsibility to improve the care of dying patients (10.7326/M17-0938). The update to a 2001 position paper discusses the role of palliative and hospice care, explores the nature of the patient–physician relationship and the critical distinction between refusal of life-sustaining treatment and physician-assisted suicide, and provides recommendations to physicians for responding to patient requests for physician-assisted suicide, recognizing that some individual cases will be medically and ethically challenging. The article notes that medical ethics and the law strongly support a patient’s right to refuse treatment, including life-sustaining treatment. The intent is to avoid or withdraw treatment judged by the patient as unduly burdensome and inconsistent with her health goals and preferences, ACP writes. Death follows naturally after the refusal due to underlying disease. Vigorous management of pain and symptoms such as nausea at the end of life is ethical and, indeed appropriate, even when the risk of shortening life is foreseeable, if the intent is to relieve those symptoms. (L. S. Sulmasy, lsnyder@acponline.org)

PNN Pharmacotherapy Line
Sept. 20, 2017 * Vol. 24, No. 181
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Sept. 19 issue of JAMA (2017; 318).
Adding Metronidazole to Post-Cesarean Prophylaxis in Obesity: Higher risks of surgical site infections (SSIs) in patients with obesity may necessitate addition of metronidazole to cephalosporin prophylaxis in women with higher body mass indices who have cesarean deliveries, researchers report (pp. 1026–34). Compared with placebo in women with prepregnancy body mass indices of 30 or more, metronidazole produced these outcomes in 2010–15 among women treated with I.V. cephalexin before surgery and oral cephalexin afterwards: “Among 403 randomized participants who were included (mean age, 28 [SD, 6] years; mean BMI, 39.7 [SD, 7.8]), 382 (94.6%) completed the trial. The overall rate of SSI was 10.9% (95% CI, 7.9%–14.0%). Surgical site infection was diagnosed in 13 women (6.4%) in the cephalexin–metronidazole group vs 31 women (15.4%) in the placebo group (difference, 9.0% [95% CI, 2.9%-15.0%]; relative risk, 0.41 [95% CI, 0.22–0.77]; P = .01). There were no serious adverse events, including allergic reaction, reported in either the antibiotic group or the placebo group.” (C. R. Warshak, eaglercr@ucmail.uc.edu)
“The results of this study suggest that a brief course of postoperative antimicrobial prophylaxis may significantly reduce the incidence of SSI among women with a prepregnancy body mass index of 30 or higher,” editorialists write (
pp. 1012–3). “Additional studies are needed to confirm these findings and to a determine if there are specific subpopulations within this group to whom the benefit is limited to avoid unnecessary antibiotic exposure and its associated risks among those unlikely to benefit. Furthermore, despite the apparent effectiveness of the intervention, the rate of SSI observed among women assigned to the postoperative antimicrobial prophylaxis group of the study was higher than that typically observed among nonobese women. This finding is important because it highlights that this strategy is not a panacea, that obese women remain at high risk of infectious complications, and that additional strategies to mitigate this risk are needed.” (D. P. Calfee, dpc9003@med.cornell.edu)
Managing Agitated Delirium During Palliative Care: In a preliminary study of 90 patients with advanced cancer who were hospitalized in an acute palliative care unit, addition of lorazepam to haloperidol resulted in better control of agitated delirium at 8 hours (pp. 1047–56). In 2014–16, lorazepam 3 mg I.V. or placebo produced these changes a primary outcome of change in Richmond Agitation-Sedation Scale (RASS) score in patients who also received haloperidol 2 mg I.V.: “Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95% CI, −2.8 to −0.9]; P <.001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95% CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]).” (D. Hui, dhui@mdanderson.org)
“In this fast-paced world of medicine, the challenge for clinicians is to show patience and balance in seeking to reduce distressing symptoms, such as those involving severe pain or hyperactive delirium,” two editorialists conclude (
pp. 1014–5). “Ultimately, as the study by Hui et al sought to demonstrate, it is essential for clinicians to focus on the humanness of medicine; to keep dying patients comfortable and as awake as they and their families would like them to be so they can make the last few hours or days of life meaningful; and to make reasonable efforts not to cloud their sensorium unless essential to alleviate patient pain or other severe symptoms.” (P. Pandharipande, pratik.pandharipande@vanderbilt.edu)

PNN Pharmacotherapy Line
Sept. 21, 2017 * Vol. 24, No. 182
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Sept. 21 New England Journal of Medicine (2017; 377).
Canakinumab for Atherosclerotic Disease: Acting independently of lipid levels, the anti-inflammatory agent canakinumab lowered the rate of recurrent cardiovascular events among 10,061 patients with previous myocardial infarction and high C-reactive protein, according to the CANTOS trial (pp. 1119–31). A primary efficacy end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death showed these outcomes with the interleukin-1-beta–targeting agent: “At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person–years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person–years in the 150-mg group, and 3.90 events per 100 person–years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31).” (P. M. Ridker, pridker@partners.org)
“CANTOS has helped move the inflammatory hypothesis of coronary artery disease forward scientifically,” an editorialist writes (
pp. 1197–8). “However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with previous myocardial infarction until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.” (R. A. Harrington)
Anticoagulation in STEMI/NSTEMI: Bivalirudin and heparin produced similar outcomes among more than 6,000 patients undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) (pp. 1132–42): “At 180 days, a primary end-point event [death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up] had occurred in 12.3% of the patients (369 of 3,004) in the bivalirudin group and in 12.8% (383 of 3,002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P = 0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P = 0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P = 0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P = 0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P = 0.76).” (D. Erlinge, david.erlinge@med.lu.se)
“Even after VALIDATE-SWEDEHEART, there is no definitive answer to the question of whether to use bivalirudin or heparin during PCI,” concludes an editorialist (
pp. 1198–200). “Detailed data from ongoing studies of more than 36,000 patients randomly assigned to bivalirudin or heparin should provide robust evidence to guide decisions regarding anticoagulation among patients with STEMI and NSTEMI according to various patient characteristics, procedures, and adjunct pharmacotherapies.” (G. W. Stone)
>>>PNN NewsWatch
* After further review, FDA says that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other CNS depressants.

PNN Pharmacotherapy Line
Sept. 22, 2017 * Vol. 24, No. 183
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Health Affairs Report
Source:
 Sept. issue and blogs of Health Affairs (2017; 36).
PBMs & Opioids: Sharing some of the details behind yesterday’s announcement of restrictions on opioid dispensing, CVS Health staff described in a blog the company’s respective roles as a pharmacy benefits manager and prescription dispenser (9/21/17 blog): “In the face of the opioid crisis…, we believe it is time to give greater weight to the CDC Guideline — based on patient care and safety. The CDC Guideline should become the default approach to prescribing opiates, a scenario in which physicians would have to seek exceptions for those patients who need more medication or longer duration of therapy. What is more, pharmacy benefit managers are better placed than others in the pharmacy supply chain to put this approach to the CDC Guideline into practice. Wholesalers have no real contact with patients or payers. Retail pharmacists have opportunities to provide patient counseling about opiates, and are required by the Controlled Substance Act to exercise a ‘corresponding responsibility’ as to whether a prescription was issued for legitimate medical purpose. But when faced with a valid prescription written by a medical professional, it is difficult, and often not appropriate, for retail pharmacists to take it upon themselves to limit prescribing.” (T. Brennan)
Preferred SNF Networks: “Establishing preferred provider networks of skilled nursing facilities (SNFs) is one approach hospital administrators are using to reduce excess thirty-day readmissions and avoid Medicare penalties or to reduce beneficiaries’ costs as part of value-based payment models,” write researchers who found reduced readmission rates among such networks (pp. 1591–8). “However, hospitals are also required to provide patients at discharge with a list of Medicare-eligible providers and cannot explicitly restrict patient choice. This requirement complicates the development of a SNF network. Furthermore, there is little evidence about the effectiveness of network development in reducing readmission rates. We used a concurrent mixed-methods approach, combining Medicare claims data for the period 2009–13 with qualitative data gathered from interviews during site visits to hospitals in eight US markets in March–October 2015, to examine changes in rehospitalization rates and differences in practices between hospitals that did and did not develop formal SNF networks. Four hospitals had developed formal SNF networks as part of their care management efforts. These hospitals saw a relative reduction from 2009 to 2013 in readmission rates for patients discharged to SNFs that was 4.5 percentage points greater than the reduction for hospitals without formal networks. Interviews revealed that those with networks expanded existing relationships with SNFs, effectively managed patient data, and exercised a looser interpretation of patient choice.” (J. P. McHugh, john.mchugh@columbia.edu)
>>>Medical Care Highlights
Source:
 Oct. issue of Medical Care (2017; 55).
Innovative Cancer Care Programs: Spending and resource utilization were reduced through use of the Community Oncology Medical Home (COME HOME) or Patient Care Connect Program (PCCP), researchers report (pp. 873–8). “In the adjusted models, both COME HOME and PCCP were associated with fewer [emergency department] visits than a comparison group (15 and 22 per 1,000 patients/quarter, respectively; P <0.01). In addition, COME HOME had lower spending ($675 per patient/quarter; P <0.01), and PCCP had fewer hospitalizations (11 per 1,000 patients/quarter; P <0.05), relative to the comparison group. Among patients undergoing chemotherapy, fewer COME HOME and PCCP patients had ED visits (18 and 28 per 1,000 patients/quarter, respectively; P <0.01) and fewer PCCP patients had hospitalizations (13 per 1,000 patients/quarter; P <0.05), than comparison patients.” (E. M. Colligan)
>>>PNN NewsWatch
FDA is warning that obeticholic acid (Ocaliva, Intercept Pharmaceuticals) is being incorrectly dosed in some patients with moderate to severe decreases in liver function, resulting in an increased risk of serious liver injury and death.
* Undeclared sildenafil and similar agents has prompted recalls of 
Vegetable Vigra (Natures Supplement) and Rhino 7, Papa Zen, Fifty Shades, and Grande X (Gadget Island).

PNN Pharmacotherapy Line
Sept. 25, 2017 * Vol. 24, No. 184
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Corticosteroids for Sore Throat: Pain associated with sore throat is relieved by single low doses of corticosteroids, conclude investigators who conducted a systematic review and meta-analysis of 10 trials of 1,426 patients (j3887): “Patients who received single low dose corticosteroids (the most common intervention was oral dexamethasone with a maximum dose of 10 mg) were twice as likely to experience pain relief after 24 hours (relative risk 2.2, 95% confidence interval 1.2 to 4.3; risk difference 12.4%; moderate quality evidence) and 1.5 times more likely to have no pain at 48 hours (1.5, 1.3 to 1.8; risk difference 18.3%; high quality). The mean time to onset of pain relief in patients treated with corticosteroids was 4.8 hours earlier (95% confidence interval −1.9 to −7.8; moderate quality) and the mean time to complete resolution of pain was 11.1 hours earlier (−0.4 to −21.8; low quality) than in those treated with placebo. The absolute pain reduction at 24 hours (visual analogue scale 0–10) was greater in patients treated with corticosteroids (mean difference 1.3, 95% confidence interval 0.7 to 1.9; moderate quality).” (B. Sadeghirad, sadeghb@mcmaster.ca)
Childhood IBD & Cancer Risk: Data from the Swedish national patient register for 1964–2014 indicate an association between childhood-onset inflammatory bowel disease (IBD) and increased risk of cancer, especially those involving the gastrointestinal tract, that has persisted over time (j3951). Children with ulcerative colitis, Crohn disease, or unclassified IBD had these cancer risk patterns: “During follow-up through adulthood (median age at end of follow-up 27 years), 497 (3.3 per 1,000 person years) people with childhood onset inflammatory bowel disease had first cancers, compared with 2,256 (1.5 per 1,000 person years) in the general population comparators (hazard ratio 2.2, 95% confidence interval 2.0 to 2.5). Hazard ratios for any cancer were 2.6 in ulcerative colitis (2.3 to 3.0) and 1.7 in Crohn’s disease (1.5 to 2.1). Patients also had an increased risk of cancer before their 18th birthday (2.7, 1.6 to 4.4; 20 cancers in 9,405 patients, 0.6 per 1,000 person years). Gastrointestinal cancers had the highest relative risks, with a hazard ratio of 18.0 (14.4 to 22.7) corresponding to 202 cancers in patients with inflammatory bowel disease.…” (O. Olén, ola.olen@ki.se)
>>>PNN NewsWatch
Aegerion Pharmaceuticals Inc. on Friday agreed to plead guilty in federal district court to two misdemeanor counts of violating the Federal Food, Drug, and Cosmetic Act involving the introduction of misbranded Juxtapid (lomitapide) into interstate commerce. The complaint charged that Juxtapid was misbranded because Aegerion failed to comply with the requirements of the Juxtapid Risk Evaluation and Mitigation Strategy program and because the drug’s labeling lacked adequate directions for all of Juxtapid’s intended uses, FDA said.
>>>PNN JournalWatch
* Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction, in Annals of Internal Medicine, 2017; 167: 394–409. (J. Papenburg, jesse.papenburg@mail.mcgill.ca)
* Emerging Treatment Models in Rheumatology: Antiphospholipid Syndrome and Pregnancy: Pathogenesis to Translation, in 
Arthritis & Rheumatology, 2017; 69: 1710–21. (J. E. Salmon, salmonj@hss.edu
* Emerging Treatment Models in Rheumatology: IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies, in 
Arthritis & Rheumatology, 2017; 69: 1722–32. (J. H. Stone, jhstone@mgh.harvard.edu
* Changing Trends in Opioid Use Among Patients With Rheumatoid Arthritis in the United States, in 
Arthritis & Rheumatology, 2017; 69: 1733–40. (J. R. Curtis, jcurtis@uab.edu)
* Polypharmacy and Gait Performance in Community-Dwelling Older Adults, in 
Journal of the American Geriatrics Society, 2017; 65: 2082–7. (C. George, clgeorge@montefiore.org)
* Advances in Asthma in 2016: Designing Individualized Approaches to Management, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 671–80. (S. J. Szefler, Stanley.Szefler@childrenscolorado.org)
* Therapeutic Pipeline for Atopic Dermatitis: End of the Drought?, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 633–43. (A. S. Paller, apaller@northwestern.edu)
* Psoriasis Pathogenesis and the Development of Novel Targeted Immune Therapies, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 645–53. (J. G. Krueger, kruegej@rockefeller.edu)

PNN Pharmacotherapy Line
Sept. 26, 2017 * Vol. 24, No. 185
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Geriatrics Report
Source:
 Sept. issue of the Journal of the American Geriatrics Society (2017; 65).
Long-Term Oral Bisphosphonate Therapy: Prolonged use of oral bisphosphonates among those in the Women’s Health Initiative adds to concerns about safety of the agents when taken for very long time periods (pp. 1924–31). The analysis includes 5,120 older women who reported at least 2 years of bisphosphonates in 2008–09. Annually determined outcomes were as follows during 3–5, 6–9, and 10–13 years of use: “On average participants were 80 years old and were followed for 3.7 ± 1.2 years. There were 127 hip, 159 wrist or forearm, 235 clinical vertebral, and 1,313 clinical fractures. In multivariate-adjusted analysis, 10 to 13 years of bisphosphonate use was associated with higher risk of any clinical fracture than 2 years of use (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.07–1.57). This association persisted in analyses limited to women with a prior fracture (HR = 1.30, 95% CI = 1.01–1.67) and women with no history of cancer (HR = 1.36, 95% CI = 1.10–1.68). The association of 10 to 13 years of use, compared with 2 years of use, was not statistically significant for hip (HR = 1.66, 95% CI = 0.81–3.40), clinical vertebral (HR = 1.65, 95% CI = 0.99–2.76), or wrist fracture (HR = 1.16, 95% CI = 0.67–2.00).” (R. L. Drieling, rdrieling@stanford.edu)
PPIs & Mild Cognitive Impairment and Dementia: Contrary to recent reports, an observational longitudinal study of Alzheimer disease (AD) centers found no relationship between self-reported PPI use and conversion to mild cognitive impairment, dementia, and specifically AD (pp. 1969–74; F. C. Goldstein, fgoldst@emory.edu).
Statin Use in Nursing Homes: In Ontario, statin prescribing was substantial for residents of nursing homes, including those who were frail, a study of 631 facilities shows (pp. 2044–51). Likelihood of statin prescribing varied substantially across physicians, the researchers add, noting these results for 2013–14: “Among 76,226 nursing home residents assigned to 1,919 physicians, 25,648 (33.6%) were statin users. There were 13,331 (30.1%) statin users among the 44,290 residents categorized as frail. In an adjusted mixed-effects logistic regression model, frail residents (adjusted odds ratio = 0.62, 95% confidence interval 0.58–0.65) were significantly less likely to be statin users compared with non-frail residents. After adjustment for resident characteristics, the intraclass correlation coefficient indicated that between-physician variability accounted for 9.1% of the residual unexplained variation in statin use (P < .001). Among the 894 physicians assigned 20 or more residents, funnel plots confirmed there were more low-outlying (17.4%) and high-outlying (12.0%) prescribers of statins than expected by chance. Physicians who were high-outlying prescribers had higher historical rates of statin prescribing.” (M. Campitelli, michael.campitelli@ices.on.ca)
Defining Delirium: At three Dutch medical centers, two experts evaluating a common set of data on 167 older adults varied widely on presence of delirium, researchers report (pp. 1932–8). Dutch Delirium Detection Study Group investigators found the following for 424 postoperative assessments performed by evaluators who viewed videos and reviewed clinical information: “The overall kappa was 0.61 (95% confidence interval = 0.53–0.68). There was no agreement between the experts for 89 (21.0%) assessments and a third delirium expert was needed for the final classification. Delirium screening that nurses performed detected 32% of the assessments that the experts diagnosed as (possibly) delirious.” (T. Numan, tiannenuman@gmail.com)
>>>PNN NewsWatch
* The post-hurricane situation in Puerto Rico is “a catastrophic event unlike many the United States has faced,” FDA Commissioner Scott Gottlieb, MD, said in a statement released yesterday. “At the FDA we are pushing beyond our normal processes to support the relief efforts in Puerto Rico – whether it’s working to prevent shortages of life-saving therapeutics, helping to coordinate plane landing rights between [the Dept. of Homeland Security] and pharmaceutical companies, ensuring ample blood supply or helping facilitate access to resources on the ground that our fellow citizens will need in their recovery efforts. We stand ready to use all our resources to help in these missions.”

PNN Pharmacotherapy Line
Sept. 27, 2017 * Vol. 24, No. 186
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>JAMA Report
Source:
 Sept. 26 issue of JAMA (2017; 318).
Genotype-Guided Warfarin Dosing: Tested in older adults undergoing hip or knee arthroplasty, genotype-guided warfarin dosing yielded significantly better clinical outcomes than clinically guided dosing, researchers report (pp. 1115–24). At six U.S. medical centers in the Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis, patients genotyped for VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M polymorphisms had these responses to warfarin therapy based on a primary end point of composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death: “Among 1,650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1,597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%–7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56–0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05–1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51–0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54–1.34), and there were no deaths.” (B. F. Gage, bgage@dom.wustl.edu)
“In addition to questions about the generalizability of the GIFT trial results, there are remaining questions about the cost-effectiveness of this strategy,” writes an editorialist (
pp. 1110–2). “Based on the GIFT trial composite primary outcome, 26 patients would need to be genotyped to prevent 1 ‘event’ (most commonly an INR ≥4). Although the cost of genotyping continues to decline, health insurers and publically funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy worthy of investment. This is despite modeling from [European Pharmacogenetics of Anticoagulant Therapy] trial data suggesting that from a Swedish or UK health system perspective, pharmacogenomic testing would be cost-effective for patients with atrial fibrillation initiating warfarin therapy. Ideally an updated meta-analysis of trial data should be applied to cost-effectiveness modeling to inform new policy.” (J. D. Emery, jon.emery@unimelb.edu.au)
Biotin Interference With Assays: Ingestion of biotin 10 mg/d for 7 days was associated with interference on immunoassays in a preliminary study of 6 healthy adults (pp. 1150–60): “Among the 2 women and 4 men (mean age, 38 years [range, 31–45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion–associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low.” (D. Li, dannili@umn.edu)
Delirium in Older Persons: Drug treatment of delirium in older adults remains controversial, according to authors who reviewed research studies of 11,616 patients and other published systematic reviews, meta-analyses, and articles of other types (pp. 1161–74): “Advances in diagnosis have included the development of brief screening tools with high sensitivity and specificity, such as the 3-Minute Diagnostic Assessment; 4 A’s Test; and proxy-based measures such as the Family Confusion Assessment Method. Measures of severity, such as the Confusion Assessment Method–Severity Score, can aid in monitoring response to treatment, risk stratification, and assessing prognosis. Nonpharmacologic approaches focused on risk factors such as immobility, functional decline, visual or hearing impairment, dehydration, and sleep deprivation are effective for delirium prevention and also are recommended for delirium treatment. Current recommendations for pharmacologic treatment of delirium, based on recent reviews of the evidence, recommend reserving use of antipsychotics and other sedating medications for treatment of severe agitation that poses risk to patient or staff safety or threatens interruption of essential medical therapies.” (E. S. Oh, eoh9@jhmi.edu)

PNN Pharmacotherapy Line
Sept. 28, 2017 * Vol. 24, No. 187
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Sept. 28 issue of the New England Journal of Medicine (2017; 377).
Anacetrapib in Atherosclerotic Vascular Disease: Addition of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib to intensive statin therapy lowered the incidence of major cardiovascular events among patients with atherosclerotic vascular disease by a significant but small amount, according to the HPS3/TIMI55–REVEAL Collaborative Group (pp. 1217–27). Results in 30,449 adults based on a primary outcome of first major coronary event (composite of coronary death, myocardial infarction, or coronary revascularization) were as follows: “During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1,640 of 15,225 patients [10.8%] vs. 1,803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P = 0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of −18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events.” (M. J. Landray, reveal@ndph.ox.ac.uk)
“Will the REVEAL findings sufficiently motivate the sponsor to file for approval from the Food and Drug Administration?” asks an editorialist (
pp. 1284–5). “Relevant factors include the relatively small beneficial effect and the possible need for a replication study, especially given the track record of CETP inhibitors. The clinical relevance of subtle changes in the creatine kinase level and the glomerular filtration rate, plus the propensity of anacetrapib to linger in adipose tissue for years, also need to be clarified. Nonetheless, the fact that CETP inhibition remains in play reinforces Yogi Berra’s adage, ‘It ain’t over till it’s over.’” (R. A. Hegele)
Once-Weekly Exenatide & Cardiovascular Outcomes: In 14,752 patients with type 2 diabetes, the incidence of major adverse cardiovascular events was unchanged when once-weekly exenatide was added to usual care (pp. 1228–39): “A primary composite outcome event [first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke] occurred in 839 of 7,356 patients (11.4%; 3.7 events per 100 person–years) in the exenatide group and in 905 of 7,396 patients (12.2%; 4.0 events per 100 person–years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P <0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P = 0.06 for superiority).…” (R. R. Holman, rury.holman@dtu.ox.ac.uk)
Rituximab in Mantle-Cell Lymphoma: In a phase 3 trial of 299 patients younger than 66 years who had mantle-cell lymphoma, use of rituximab maintenance therapy after autologous stem-cell transplantation significantly prolonged event-free survival, progression-free survival, and overall survival (pp. 1250–60): “Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P = 0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P <0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P = 0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P = 0.04).” (S. Le Gouill, steven.legouill@chu-nantes.fr)
>>>PNN NewsWatch
FDA yesterday approved the FreeStyle Libre Flash Glucose Monitoring System (Abbott), a continuous glucose monitoring system that does not require a fingerstick for calibration.

PNN Pharmacotherapy Line
Sept. 29, 2017 * Vol. 24, No. 188
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Diabetes Care Report
Source:
 Oct. issue of Diabetes Care (2017; 40).
Changing Tides of the Type 2 Diabetes Epidemic: In the Kelly West Award Lecture for 2016, the recipient notes that “rates of classic diabetes complications have declined in recent decades, representing a major success for people with diabetes as well as clinical and public health efforts that have driven these changes” (pp. 1289–97). “Despite these successes, several currents below the surface of the diabetes epidemic will present major challenges in the coming years. These currents include 1) the continued growth in the numbers of people with diabetes and continued increases in diabetes in youth, 2) a proportional shift in overall complications toward middle-aged adults, the relative persistence of microvascular disease, 3) diversification of diabetes-related morbidity following the reduction in [cardiovascular disease], 4) the continued high levels of diabetes complications in the overall population, and 5) the combined impact of increasing life span and high prevalence on the total years and cumulative morbidity burden in communities. These currents will all play major roles in the course of the diabetes epidemic in the future and will challenge all disciplines of epidemiology to continue to improve the monitoring and understanding of risk factors, risk stratification approaches, and the future prioritization of interventions.” (E. W. Gregg, edg7@cdc.gov)
Alpha-Cell Dysfunction in Chronic Pancreatitis: Results of glucose challenges in patients with diabetes caused by chronic pancreatitis showed similarities to findings in those with type 2 diabetes, researchers report, suggesting a common etiology (pp. 1314–22). A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) showed these results in 10 patients with diabetes secondary to chronic pancreatitis, 13 patients with type 2 diabetes, and 10 healthy control participants: “Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P <0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P <0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P <0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to beta-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis.” (J. J. Meier, juris.meier@rub.de)
Falling Insulin Requirements & Placental Dysfunction: In women with preexisting diabetes, falling insulin requirements during pregnancy should alert clinicians to check for underlying placental dysfunction, a study of 158 women shows (pp. 1323–30; S. Padmanabhan, suja_padman@yahoo.com.au).
>>>PNN NewsWatch
* Following a priority review of an agent with a “breakthrough” designation, FDA yesterday approved abemaciclib (Verzenio, Lilly) to treat adult patients who have hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer that has progressed after endocrine therapy. Abemaciclib is approved for use in combination with the endocrine agent fulvestrant following tumor progression while on endocrine therapy. The agent is also approved for single-agent therapy in patients previously treated with endocrine therapy and chemotherapy after metastasis.
FDA has launched a new user-friendly search tool that improves access to data on adverse events associated with drug and biologic products through the FDA’s Adverse Event Reporting System. The new dashboard enables users to search for and organize data by criteria such as drug/biological product, age of the patient, type of adverse event, year the adverse event occurred, or within a specific timeframe. In addition to making it easier for consumers to search for adverse events reported with drug or biologic products, FDA hopes the increased transparency will spur the submission of more detailed and complete reports from consumers, health care professionals and others, by making it easier for people to see other reports that the FDA receives, and search the database for similar observations.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN April–June 2017

PNN Pharmacotherapy Line
Apr. 3, 2017 * Vol. 24, No. 63
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 1 issue of Lancet (2017; 389).
Prophylactic Hydration With Iodinated Contrast Material: Prehydrating patients with compromised renal function before administration of iodinated contrast material may be of little clinical benefit despite extra costs, a study shows (pp. 1312–22). Concluding that “no prophylaxis [was] non-inferior and cost-saving in preventing contrast-induced nephropathy,” authors of the AMACING trial report these results in a comparison with hydration of high-risk adult patients: “Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n = 332) or intravenous hydration (n = 328). 2–6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2.6%) of 307 non-hydrated patients and in eight (2.7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was −0.10% (one-sided 95% CI −2.25 to 2.06; one-tailed p = 0.4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5.5%) of 328 patients had complications associated with intravenous hydration.” (E. C. Nijssen, estelle.nijssen@mumc.nl)
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Pump v. Syringe in Insulin Therapy: Providing insulin pumps to patients with poor glycemic control of type 1 diabetes is not justified until “the effects of training on participants’ level of engagement in intensive self management have been determined,” conclude investigator in the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial (j1285). At eight secondary care centers in England and Scotland, adults willing to begin intensive insulin treatment were assigned in clusters and pairs to pump or multiple daily injection therapy, with these results: “317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was −0.85% with pump treatment and −0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was −0.24% (−2.7 mmol/mol) in favour of pump users (95% confidence interval −0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24 months.” (S. Heller, s.heller@sheffield.ac.uk)
Antenatal Corticosteroids in Preterm Infants: A prospective cohort study at 300 U.S. neonatal intensive care units demonstrates lower mortality and morbidity among most preterm infants receiving antenatal corticosteroids (j1039): “Infants exposed to antenatal corticosteroids (n =81,832) had a significantly lower rate of death before discharge at each gestation 29 weeks or less, 31 weeks, and 33–34 weeks compared with infants without exposure (range of adjusted odds ratios 0.32 to 0.55). The number needed to treat with antenatal corticosteroids to prevent one death before discharge increased from six at 23 and 24 weeks’ gestation to 798 at 34 weeks’ gestation. The rate of survival without major hospital morbidity was higher among infants exposed to antenatal corticosteroids at the lowest gestations. Infants exposed to antenatal corticosteroids had lower rates of severe intracranial hemorrhage or death, necrotizing enterocolitis stage 2 or above or death, and severe retinopathy of prematurity or death compared with infants without exposure at all gestations less than 30 weeks and most gestations for infants born at 30 weeks’ gestation or later.” (W. A. Carlo, wcarlo@peds.uab.edu)
>>>PNN NewsWatch
* Citing a defective activation part,
Meridian Medical Technologies is voluntarily recalling 13 lots of Mylan’s EpiPen and EpiPen Jr (epinephrine injection) Auto-Injector. 
>>>PNN JournalWatch
* Maternal Immunization, in
New England J. Medicine, 2017; 376: 1256–67. (S. B. Omer, somer@emory.edu)

PNN Pharmacotherapy Line
Apr. 4, 2017 * Vol. 24, No. 64
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. 4 issue of the Annals of Internal Medicine (2017; 166).
Management of Low Back Pain: Clinical guidelines for managing low back pain are presented, along with supporting systematic reviews and an editorial.
“New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain,” authors of a pharmacologic review conclude (
pp. 480–92). “For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms,” the group adds. “Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective.” (R. Chou, chour@ohsu.edu)
Review of studies on nonpharmacologic options leads authors to this synthesis (
pp. 493–505): “New evidence indicates that tai chi (strength of evidence [SOE], low) and mindfulness-based stress reduction (SOE, moderate) are effective for chronic low back pain and strengthens previous findings regarding the effectiveness of yoga (SOE, moderate). Evidence continues to support the effectiveness of exercise, psychological therapies, multidisciplinary rehabilitation, spinal manipulation, massage, and acupuncture for chronic low back pain (SOE, low to moderate). Limited evidence shows that acupuncture is modestly effective for acute low back pain (SOE, low). The magnitude of pain benefits was small to moderate and generally short term; effects on function generally were smaller than effects on pain.” (R. Chou, chour@ohsu.edu)
Based on these findings, the American College of Physicians makes three recommendations (
pp. 514–30; A. Qaseem, aqaseem@acponline.org):
* Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants (moderate-quality evidence). (Grade: strong recommendation)
* For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation)
* In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence)
“If clinicians and their professional societies cannot demonstrate that their recommendations are improving the delivery of high-value services, what are the alternatives?” asks an editorialist (
pp. 533–4). “Likely what is needed is an ‘all-of-the-above’ approach: more pragmatic trials to evaluate proven therapies and their combinations in real-world settings; efforts to reduce the use of low-value services, such as payer coverage policies based on guideline recommendations; patient engagement through shared decision making; and pressure on insurers to cover nonpharmacologic, noninvasive therapies that have shown benefit. Nevertheless, rigorous reviews of existing evidence and their application in practice guidelines remain an underpinning that should drive efforts not only to decrease the use of therapies without demonstrated benefit but also to show that the therapies being used improve real-world outcomes for patients with low back pain.” (S. J. Atlas, satlas@mgh.harvard.edu)

PNN Pharmacotherapy Line
Apr. 5, 2017 * Vol. 24, No. 65
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 4 issue of JAMA (2017; 317).
2-Year Outcomes With Low-Dose Hydrocortisone in Extremely Preterm Neonates: Neurodevelopment at 2 years of age was not affected by early hydrocortisone therapy in the Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial (pp. 1329–37). Previous studies have associated dexamethasone treatment of extremely preterm neonates with neurodevelopmental impairment at 2 years, the investigators note, but their study identified these outcomes when neonates were randomized to low-dose hydrocortisone or placebo in 2010 through 2016: “Of 1,072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21–23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, −2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups.” (O. Baud, olivier.baud@rdb.aphp.fr)
“Early use of low-dose hydrocortisone holds promise as an intervention to prevent bronchopulmonary dysplasia,” an editorialist writes (
pp. 1317–8). “However, a systematic review found steroid-related short-term complications, including gastrointestinal bleeding and perforation, although those complications were not seen in the current trial. A reevaluation of early neonatal therapy is warranted. Other trial investigators should confirm the findings of the PREMILOC trial, using a very low dose of hydrocortisone and powering their studies to investigate safety outcomes. The PREMILOC investigators are planning later outcome studies when patients are aged 5 to 7 years. Until those and other trials are completed, the value of early hydrocortisone to safely prevent bronchopulmonary dysplasia appears promising but remains unclear.” (N. Marlow, n.marlow@ucl.ac.uk)
Dexmedetomidine in Mechanical Ventilation With Sepsis: The light sedative dexmedetomidine made no difference in mortality or ventilator-free days when compared with placebo in patients undergoing ventilation, researchers report (pp. 1321–8). Among 201 patients, dexmedetomidine or placebo showed these effects: “The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38–1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5–24] days; control group: median, 18 [interquartile range, 0.5–23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%–58% vs 20%–39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively.” (H. Yamamura, yamamura@hirosaki-u.ac.jp)
Treatment of Obsessive-Compulsive Disorder: “The dissemination of computer-based cognitive behavioral therapy and improved evidence supporting it represent a major advancement in treatment of” obsessive–compulsive disorder, a review article concludes (pp. 1358–67). SSRIs remain a preferred initial therapy, and “increasing evidence that supports the safety and efficacy of neuroleptics and neuromodulatory approaches in treatment-resistant cases provides alternatives for patients whose condition does not respond to first-line interventions.” (C. A. Mathews, carolmathews@ufl.edu)

PNN Pharmacotherapy Line
Apr. 6, 2017 * Vol. 24, No. 66
Providing news and information about medications and their proper use
>>>NEJM Report
Source:
Apr. 6 issue of the New England Journal of Medicine (2017; 376).
Immunomodulation + Transplantation for Myeloma: High-dose chemotherapy plus transplantation extended progression-free survival in patients with multiple myeloma, compared with chemotherapy alone, but researchers report that overall survival was not changed significantly (pp. 1311–20). In the IFM 2009 Study, 700 patients were assigned to induction therapy with three cycles of lenalidomide, bortezomib, and dexamethasone (RVD) and then consolidation therapy with either five additional cycles of RVD or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD, with these results: “Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P <0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P = 0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P <0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy.” (M. Attal, attal.michel@iuct-oncopole.fr)
Summarizing the findings of this trial and noting the $120,000 per year cost of lenalidomide, editorialists conclude, “Transplantation resulted in a deeper and longer initial treatment response than did a nontransplantation approach” (
pp. 1378–9). “However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative. While some questions about initial therapy remain unanswered, we owe a big ‘merci’ to the IFM investigators for the important issues addressed in this study.” (C. A. Schiffer)
Body Weight in Coronary Disease: Using data from the Treating to New Targets (TNT) trial, investigators find that fluctuations in body weight among patients with coronary artery disease “was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors” (pp. 1332–40). Data from the lipid-lowering trial showed these patterns for a primary outcome of any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina): “Among 9,509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2,091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P = 0.01), any cardiovascular event (2,727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P <0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P <0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models.” (S. Bangalore, sripalbangalore@gmail.com)
FDA on Medical-Device Clinical Trials: Successful introduction of medical devices in the U.S. requires robust data on the innovation’s benefit–risk profile, FDA authors write, and sometimes the needed data are beyond those that the agency can require in premarketing studies (pp. 1350–7). The authors call on the industry and practitioners to provide additional evidence through trials, registries, and data analyses. (O. Faris, owen.faris@fda.hhs.gov)

PNN Pharmacotherapy Line
Apr. 7, 2017 * Vol. 24, No. 67
Providing news and information about medications and their proper use
>>>Psychiatry Report
Source: Apr. issue of the American Journal of Psychiatry (2017; 174).
Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder: Swedish national registries demonstrate no association of methylphenidate use by patients with bipolar disorder who are receiving mood-stabilizing medications with treatment-emergent mania, researchers report (pp. 341–8). Data on 2,307 adults who began methylphenidate treatment in 2006 and 2014 show these patterns: “Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0–22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio = 0.6, 95% CI = 0.4–0.9). Comparable results were observed when only hospitalizations for mania were counted.” (A. Viktorin)
Computerized Cognitive Training for Dementia in Older Adults: Computerized cognitive training (CCT) is an effective intervention in patients with mild cognitive impairment or dementia that should be studied further in larger trials, according to results of a systematic review and meta-analysis (pp. 329–40): “The overall effect [of CCT] on cognition in mild cognitive impairment across 17 trials was moderate (Hedges’ g = 0.35, 95% CI = 0.20–0.51). There was no evidence of publication bias or difference between active- and passive-controlled trials. Small to moderate effects were found for global cognition, attention, working memory, learning, and memory, with the exception of nonverbal memory, and for psychosocial functioning, including depressive symptoms. In dementia, statistically significant effects were found on overall cognition (k = 11, g = 0.26, 95% CI = 0.01–0.52) and visuospatial skills, but these were driven by three trials of virtual reality or Nintendo Wii.” (N. T. M. Hill)
>>>Pediatrics Highlights
Source: Apr. issue of Pediatrics (2017; 139).
Antibiotic Prescribing for Community-Acquired Pneumonia: Antibiotics prescribed for pediatric patients with community-acquired pneumonia (CAP) varied widely in a retrospective cohort study and in ways “unlikely related to the microbiologic etiology of CAP” (10.1542/peds.2016-2331). Concluding that anti-infective stewardship efforts should be informed by “drivers of off-guideline prescribing,” investigators report these data from an outpatient pediatric primary care network in 2009–13: “Of 10,414 children, 4,239 (40.7%) received amoxicillin, 4,430 (42.5%) received macrolides and 1,745 (16.8%) received broad-spectrum antibiotics. The factors associated with an increased odds of receipt of macrolides compared with amoxicillin included patient age ≥5 years (adjusted odds ratio [aOR]: 6.18; 95% confidence interval [CI]: 5.53–6.91), previous antibiotic receipt (aOR: 1.79; 95% CI: 1.56–2.04), and private insurance (aOR: 1.47; 95% CI: 1.28–1.70). The predicted probability of a child being prescribed a macrolide ranged significantly between 0.22 and 0.83 across clinics. The nonclinical characteristics associated with an increased odds of receipt of broad-spectrum antibiotics compared with amoxicillin included suburban practice (aOR: 7.50; 95% CI: 4.16–13.55) and private insurance (aOR: 1.42; 95% CI: 1.18–1.71).” (L. K. Handy)
Impact of Pneumonia Treatment Guideline: Local implementation efforts were an important factor in adoption of antibiotic recommendations made in the 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America pneumonia guideline — more so than hospital organizational readiness to change — according to analysis of inpatient antibiotic prescribing in 28 children’s hospitals (10.1542/peds.2016-3231; D. J. Williams).
>>>PNN NewsWatch
*
FDA yesterday allowed the marketing of the 23andMe Personal Genome Service Genetic Health Risk tests for 10 diseases or conditions. These are the first direct-to-consumer tests authorized by FDA to provide information on an individual’s genetic predisposition to certain medical diseases or conditions.
*
Isomeric Pharmacy Solutions is voluntarily recalling all lots of sterile products it has compounded and packaged and that remain within expiry to the hospital/user level because of FDA concerns of a lack of sterility assurance.

PNN Pharmacotherapy Line
Apr. 10, 2017 * Vol. 24, No. 68
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 8 issue of Lancet (2017; 389).
Liraglutide in Prediabetes: Used for risk and weight reduction in patients with prediabetes and obesity, liraglutide 3 mg daily showed promising results in the SCALE Obesity and Prediabetes trial (pp. 1399–409). Among adults with body mass indices of 30 mg/sq m or more (or 27 kg/sq m with comorbidities), these results were generated over 3 years of treatment in the placebo-controlled study: “We randomly assigned 2,254 patients to receive liraglutide (n = 1,505) or placebo (n = 749). 1,128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1,472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2.7 times longer with liraglutide than with placebo (95% CI 1.9 to 3.9, p <0.0001), corresponding with a hazard ratio of 0.21 (95% CI 0.13–0.34). Liraglutide induced greater weight loss than placebo at week 160 (–6.1 [SD 7.3] vs −1.9% [6.3]; estimated treatment difference −4.3%, 95% CI −4.9 to −3.7, p <0.0001). Serious adverse events were reported by 227 (15%) of 1,501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group.” (C. W. le Roux, carel.leroux@ucd.ie)
>>>Circulation Report
Source: Apr. 4 issue of Circulation (2017; 135).
Genetic Variants in QT Prolongation Risk: A genetic QT score comprising 61 common genetic variants explains a significant proportion of QT prolongation and predicts risk of torsades de pointes, researchers report (pp. 1300–10). Concluding that larger studies are needed, the group reports these results from genetic analyses of 22 individuals who participated in a larger crossover trial of three QT-prolonging drugs with 15 time-matched QT/plasma drug concentration measurements: “The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55; 95% confidence interval, 0.09–0.81; P = 0.02), 23% in response to quinidine (r = 0.48; 95% confidence interval, −0.03 to 0.79; P = 0.06), and 27% in response to ranolazine (r = 0.52; 95% confidence interval, 0.05–0.80; P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2 = 12%, P = 1×10−7).” (D. G. Strauss, david.strauss@fda.hhs.gov)
>>>PNN NewsWatch
*
FDA on Friday approved supplemental applications for sofosbuvir (Sovaldi) and ledipasvir/sofosbuvir (Harvoni) to treat hepatitis C virus (HCV) infections in children ages 12 to 17 years. Both Gilead products were previously approved to treat HCV in adults.
>>>PNN JournalWatch
* Management of Ventricular Arrhythmias in Patients With Advanced Heart Failure, in
Journal of the American College of Cardiology, 2017; 69: 10.1016/j.jacc.2017.01.047. (P. Santangeli) 
* Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery, in
Journal of the American College of Cardiology, 2017; 69: 10.1016/j.jacc.2017.02.012. (S. Banerjee)
* Interstitial Lung Disease in the Elderly, in
Chest, 2017; 151: 838–44. (K. C. Patterson) 
* Use of Management Pathways or Algorithms in Children With Chronic Cough: CHEST Guideline and Expert Panel Report, in
Chest, 2017; 151: 875–83.
(A. B. Chang) 
* Management of Children With Chronic Wet Cough and Protracted Bacterial Bronchitis: CHEST Guideline and Expert Panel Report, in
Chest, 2017; 151: 884–90.
(A. B. Chang) 
* Urine Culture Follow-up and Antimicrobial Stewardship in a Pediatric Urgent Care Network, in
Pediatrics, 2017; 139: 10.1542/peds.2016-2103. (D. Saha) 
* Dinutuximab for Maintenance Therapy in Pediatric Neuroblastoma, in
American Journal of Health-System Pharmacy, 2017; 74: 563–7. (J. Kolesar, jill.kolesar@uky.edu)

PNN Pharmacotherapy Line
Apr. 11, 2017 * Vol. 24, No. 69
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. issue of JAMA Internal Medicine (2017; 177).
Antibiotic Selection for Clostridium difficile Infection: In a comparative effectiveness trial of patients with Clostridium difficile infection (CDI), vancomycin significantly reduced 30-day mortality rates  in severe cases, compared with metronidazole, researchers report (pp. 546–53). Retrospective data for VA patients with stool tests positive for C. difficile toxins showed these patterns when analyzed in this propensity-matched cohort study: “A total of 47,471 patients (mean [SD] age, 68.8 [13.3] years; 1,947 women [4.1%] and 45,524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47,147 eligible first treatment episodes, 2,068 (4.4%) were with vancomycin. Those 2,068 patients were matched to 8,069 patients in the metronidazole group for a total of 10,137 included patients. Subcohorts were constructed that comprised 5,452 patients with mild to moderate disease and 3,130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, –0.02; 95% CI, –0.03 to –0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, –0.04; 95% CI, –0.07 to –0.01).” (V. W. Stevens, vanessa.stevens@hsc.utah.edu)
Warfarin for Atrial Fibrillation After Head Bleeds: A nationwide observational cohort study from Denmark shows that resumption of warfarin in patients with atrial fibrillation (AF) may carry more risks in those who have had spontaneous hemorrhagic strokes than in those with traumatic intracranial hemorrhages (ICHs) (pp. 563–70). “Resumption of warfarin therapy after spontaneous hemorrhagic stroke in patients with AF was associated with a lower rate of ischemic events and a higher rate of recurrent ICH,” the authors conclude. “Among patients with a traumatic ICH, a similar lower rate of ischemic events was found; however, a lower relative risk for recurrent ICH despite resuming warfarin treatment was also revealed.” (P. Brønnum Nielsen, pbn@rn.dk)
Testosterone Replacement Therapy in Older Men: An editorialist (pp. 459–60; E. Orwoll, orwoll@ohsu.edu) reaches these conclusions in response to three research articles assessing the effects of testosterone replacement therapy (TRT) in older men on bone density and strength (pp. 471–9; P. J. Snyder, pjs@mail.med.upenn.edu), anemia (pp. 480–90; P. J. Snyder, pjs@mail.med.upenn.edu), and cardiovascular risks (pp. 491–9; T. C. Cheetham, tcraigcheetham@icloud.com):
* “Testosterone replacement may be sufficient to forestall the need for osteoporosis therapies in those with borderline [bone mineral densities] who will otherwise be treated with testosterone. The management of older men with hypogonadism and more severe osteoporosis is more challenging.”
* “In older men with unexplained anemia, or anemia of known etiology but without adequate response to therapy, an assessment of gonadal status would be warranted. If hypogonadism is present, testosterone replacement should be considered.”
* “At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement in older hypogonadal men have not been adequately resolved.”
CNS Polypharmacy Among Older Adults: Polypharmacy involving medications that affect the central nervous system (CNS) doubled between 2004 and 2013, an analysis of data from the National Ambulatory Medical Care Surveys shows (pp. 583–5). Patients aged 65 years or older who were taking three or more psychoactive drugs from the Beers list accounted for 1.4% of outpatient visits in 2013, compared with 0.6% in 2004. The largest increase in CNS polypharmacy was observed in rural areas, and women were disproportionately receiving CNS polypharmacy. (D. T. Maust, maustd@umich.edu)

PNN Pharmacotherapy Line
Apr. 12, 2017 * Vol. 24, No. 70
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 11 issue of JAMA (2017; 317).
Norepinephrine Shortage & Septic Shock Mortality: Mortality rates were higher among patients hospitalized for septic shock during the 2011 shortage of first-line agent norepinephrine, according to an analysis of the Premier Healthcare Database (pp. 1433–42). A retrospective cohort study of 26 hospitals shows phenylephrine was the most commonly administered alternative vasopressor, leading to these results: “Among 27,835 patients (median age, 69 years [interquartile range, 57–79 years]; 47.0% women) with septic shock in 26 hospitals that demonstrated at least 1 quarter of norepinephrine shortage in 2011, norepinephrine use among cohort patients declined from 77.0% (95% CI, 76.2%–77.8%) of patients before the shortage to a low of 55.7% (95% CI, 52.0%–58.4%) in the second quarter of 2011; phenylephrine was the most frequently used alternative vasopressor during this time (baseline, 36.2% [95% CI, 35.3%–37.1%]; maximum, 54.4% [95% CI, 51.8%–57.2%]). Compared with hospital admission with septic shock during quarters of normal use, hospital admission during quarters of shortage was associated with an increased rate of in-hospital mortality (9,283 of 25,874 patients [35.9%] vs 777 of 1,961 patients [39.6%], respectively; absolute risk increase = 3.7% [95% CI, 1.5%–6.0%]; adjusted odds ratio = 1.15 [95% CI, 1.01–1.30]; P = .03).” (H. Wunsch, hannah.wunsch@sunnybrook.ca)
“This precarious situation did not arise by design, but rather through a complicated set of actions and unintended consequences,” editorialists write (
pp. 1415–7). “In 1984, the Drug Price Competition and Patent Term Restoration Act (also known as the Hatch–Waxman Act) introduced a new approval mechanism to incentivize pharmaceutical companies to manufacture generic drugs. The principal burden for approval under the Hatch–Waxman Act is to demonstrate bioequivalence. Consequently, the only differentiating feature among generic drugs is price. The Hatch–Waxman Act worked extremely well, with generic drugs increasing from 18.6% of prescriptions in 1984 to 85.4% of prescriptions in 2016, driven by payers negotiating for lower prices and generating substantial savings for patients. However, for generic sterile injectable drugs, the market does not recognize quality differences in production, which inadvertently incentivizes manufacturers to adopt a reactive approach to quality management.” (J. M. Donohue, jdonohue@pitt.edu)
Universal Health Coverage Without Single-Payer System: Requirements that Americans purchase insurance “are as old as the Republic,” according to Viewpoint authors (pp. 1409–10). “In 1790, President George Washington required that ship owners purchase medical insurance for their seamen, and Medicare has long assessed penalties on healthy people who do not enroll by age 65 years,” the group writes, adding these observations about countries that have achieved universal coverage without use of a single-payer system: “Health insurance models in Switzerland, Singapore, and Germany suggest that an individual mandate, with adequate subsidies, can achieve affordable universal coverage. But the recipe for their success also includes firm penalties. They also suggest that the [Affordable Care Act’s] individual mandate failed to pool risk adequately, in large part because its penalties were too weak. In 2014, approximately 7.5 million individuals paid the penalty rather than purchasing insurance, and of the approximately 15 million uninsured people who were ineligible for Medicaid, an estimated 7.1 million would pay a penalty lower than the cost of the least expensive plan.… ” (R. J. Boxer, rboxer@mednet.ucla.edu)
>>>PNN NewsWatch
*
FDA has approved valbenazine (Ingrezza, Neurocrine Biosciences) to treat adults with tardive dyskinesia. This is the first drug approved for this common drug adverse effect.In a clinical trial of 234 participants, valbenazine improved the severity of abnormal involuntary movements to a significantly greater degree than did placebo. Valbenazine can cause serious side effects including sleepiness and QT prolongation. Its use should be avoided in patients with congenital long QT syndrome or with abnormal heartbeats associated with a prolonged QT interval. Those taking valbenazine should not drive, operate heavy machinery, or perform other dangerous tasks until it is known how the drug affects them.

PNN Pharmacotherapy Line
Apr. 13, 2017 * Vol. 24, No. 71
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 13 issue of the New England Journal of Medicine (2017; 376).
Trends in Mortality, Incidence of Diabetes: In two research articles and an editorial, authors examine trends in diabetes and their implications.
From Sweden come data showing a declining incidence of cardiovascular outcomes in people with diabetes but less so for fatal outcomes among those with the type 2 condition (
pp. 1407–18). The national registry showed significant declines in 1998 through 2014 for all-cause mortality, cardiovascular mortality, coronary heart disease mortality, and hospitalizations for cardiovascular disease in patients with diabetes. “Patients with type 1 diabetes had roughly 40% greater reduction in cardiovascular outcomes than controls, and patients with type 2 diabetes had roughly 20% greater reduction than controls,” the authors add. “Reductions in fatal outcomes were similar in patients with type 1 diabetes and controls, whereas patients with type 2 diabetes had smaller reductions in fatal outcomes than controls.” (A. Rawshani, aidin.rawshani@gu.se)
American youth — particularly those in minority ethnic and racial groups — had significantly increased incidence of diabetes in 2012 than in 2002, researchers report (
pp. 1419–29). Figures from five U.S. study centers combined with census data show the following: “A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2,846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002–2003 to 21.7 cases per 100,000 youths per year in 2011–2012, P = 0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non-Hispanic whites (4.2% vs. 1.2%, P <0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002–2003 to 12.5 cases per 100,000 youths per year in 2011–2012, P <0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non-Hispanic whites (0.6%) was lower than that among non-Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P <0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P = 0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P <0.001) and that of type 2 diabetes was 4.8% (P <0.001).” (E. J. Mayer-Davis, ejmayer-davis@unc.edu)
“What do the marked increase in the incidence of diabetes and more people at risk imply about therapy?” editorialists ask (
pp. 1473–4). “Over the past several decades, there have been important studies focusing on the treatment of type 1 and type 2 diabetes. For example, the Diabetes Control and Complications Trial (DCCT) showed that intensive glycemic control improved outcomes in persons with type 1 diabetes mellitus, as did the United Kingdom Prospective Diabetes Study (UKPDS) in persons with type 2 diabetes. Despite a growing understanding about the pathogenesis of each condition, knowledge about how best to lower the number of new cases and how best to treat problems in persons with diabetes, once they arise, has been elusive.
“It is clear that we are far from controlling the negative effects of diabetes on health worldwide. As the prevalence increases, we clearly need new approaches to reduce the burden of this disease on public health.” (J. R. Ingelfinger)
Inclisiran for Elevated LDL Cholesterol: A small interfering RNA that targets PCSK9 messenger RNA, inclisiran lowered PCSK9 and LDL cholesterol levels among 501 patients with high cardiovascular risks and elevated LDL cholesterol levels, a phase 2 study shows (pp. 1430–40). “The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180,” the investigators write. “At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens.” (K. K. Ray, k.ray@imperial.ac.uk)

PNN Pharmacotherapy Line
Apr. 14, 2017 * Vol. 24, No. 72
Providing news and information about medications and their proper use
>>>Infectious Diseases Report
Source: Apr 15 issue of Clinical Infectious Diseases (2017; 64).
Relapse After HCV Treatment in Patients With HIV: Used for treating acute hepatitis C virus (HCV) genotype-1 infection in patients who also have HIV-1 infection, sofosbuvir–ribavirin has a high relapse rate, according to an open-label, two-cohort, 12-week clinical trial of safety and efficacy (pp. 1035–42): “Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2,280,000 IU/mL (interquartile range, 272,000–4,230,000). Ten participants (59%) achieved the primary outcome of [sustained viral response at 12 weeks (SVR12)] (90% confidence interval, 36%–78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment.” (S. Naggie, susanna.naggie@duke.edu)
Risk of Eardrum Perforation With Quinolone Ear Drops in Children With Tubes: Analysis of Medicaid data for children with tympanostomy tube (TT) placement in 29 U.S. states shows that exposure to quinolone ear drops is associated with increased risk of eardrum perforations requiring tympanoplasty, researchers report (pp. 1052–8). The data, from 1999 to 2006, also show that the risk is exacerbated by corticosteroids: “A total of 96,595 children entered the study cohort. Patients exposed to quinolone ear drops had a higher risk of perforation, with an adjusted hazard ratio of 1.61 (95% confidence interval [CI], 1.15–2.26). The adjusted hazard ratios were 1.49 (95% CI, 1.05–2.09) for ofloxacin, 1.94 (95% CI, 1.32–2.85) for ciprofloxacin plus hydrocortisone, and 2.00 (95% CI, 1.18–3.41) for ciprofloxacin plus dexamethasone.” (A. Alrwisan)
>>>Oncology Highlights
Source: Apr. issue of the Journal of Clinical Oncology (2017; 35).
Cholesterol-Lowering Drugs & Reduced Breast Cancer Recurrence: Observational associations of reduced breast cancer recurrence in women taking cholesterol-lowering medications (CLMs) should be explored in prospective randomized trials, investigators write (pp. 1179–88). In the Breast International Group (BIG) phase 3 trial BIG 1-98, postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer (n = 8,010) had these outcomes in 1998–2003 while being treated with tamoxifen: “Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen–letrozole (n = 189), letrozole–tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer–free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence–free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03).” (S. Borgquist, signe.borgquist@med.lu.se)
>>>PNN NewsWatch
* Standard Homeopathic Company this week agreed to a recall of
Hyland’s Baby Teething Tablets and Hyland’s Baby Nighttime Teething Tablets, as requested in January after FDA found inconsistent amounts of belladonna in the products.
*
Illicitly manufactured fentanyl, an important factor in a 150% increase in opioid overdose deaths in Massachusetts in 2012–15, often causes death within seconds to minutes after the person injects or insufflates the drug, an article in this week’s MMWR reports. Based on an analysis of factors surrounding 196 opioid overdose deaths, the authors conclude, “The high percentage of fatal overdoses occurring at home with no naloxone present, coupled with the rapid onset of overdose symptoms after using fentanyl through injection or insufflation, underscores the urgent need to expand initiatives to link persons at high risk for overdose (such as persons using heroin, persons with past overdoses, or persons recently released from incarceration) to harm reduction services and evidence-based treatment.”

PNN Pharmacotherapy Line
Apr. 17, 2017 * Vol. 24, No. 73
Providing news and information about medications and their proper use
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Short-Term Oral Corticosteroids: The use and adverse effects of short-term courses of oral corticosteroids in the U.S. is quantified through analysis of commercial insurance claims, with researchers reporting that 1 in 5 Americans receive the agents in a 3-year period (j1415). Adverse effects are common, as detailed in these results for the initial 30 days and the 31–90-day risk period after prescription: “Of 1,548,945 adults, 327,452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P <0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31–90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P <0.001).” (A. K. Waljee, awaljee@med.umich.edu)
>>>Allergy/Immunology Report
Source: Apr. issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Mepolizumab in Severe Eosinophilic Asthma: Compared with placebo in four studies of 1,388 patients with severe eosinophilic asthma, mepolizumab reduced exacerbations and emergency department visits by one-half, a meta-analysis shows (pp. 1167–.75e2): “Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30–0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33–0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively.” (S. W. Yancey, steve.w.yancey@gsk.com)
Microbiota in Asthma & Allergic Disease: Authors of two review articles examine evidence of the effects of microbiota on development of asthma and allergies.
“Microbiota in the gut and lungs can influence both the inception and progress of asthma,” writes an author (
pp. 1071–81). “In babies and infants the presence of pathogenic bacteria in the lungs and gut has been associated with subsequent development of allergic sensitization and asthma. Lung microbiota are present in the airways of healthy subjects but are dysregulated in adults with asthma, with a reduced diversity and community composition that has been linked to severity and inflammatory phenotypes. Causality between certain gut microbiota and the development of allergic asthma has been shown in experiments conducted in neonatal mice. Manipulation of the airway microbiome, particularly in early life, might be a strategy to prevent or treat asthma, although the results of studies of probiotics used together with prebiotics have been overall negative. A better understanding of the regulation of both the lung and gut microbiota to derive appropriate targets for prevention or treatment of asthma is needed.” (K. F. Chung, f.chung@imperial.ac.uk)
PRACTALL 2017 — an initiative of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology — “is focused on what has been established regarding the role of the microbiome in patients with asthma, atopic dermatitis, and food allergy,” authors write (
pp. 1099–110). “This is complemented by outlining important knowledge gaps regarding its role in allergic disease and delineating strategies necessary to fill these gaps.” (T. A. Fleisher, tfleishe@mail.nih.gov)
>>>PNN JournalWatch
* Eight Habits of Highly Effective Antimicrobial Stewardship Programs to Meet the Joint Commission Standards for Hospitals, in
Clinical Infectious Diseases, 2017; 64: 1134–9. (D. A. Goff) 
* Somatic
BRCA1/2 Recovery as a Resistance Mechanism After Exceptional Response to Poly (ADP-ribose) Polymerase Inhibition, in Journal of Clinical Oncology, 2017; 35: 1240–9. (A. M. Oza, amit.oza@uhn.ca)
PNNInfo@mac.com www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Apr. 18, 2017 * Vol. 24, No. 74
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. 18 issue of the Annals of Internal Medicine (2017; 166).
Glucocorticoid Injections in Chronic Low Back Pain: At three tertiary care centers in France, a single glucocorticoid intradiscal injection (GC IDI) in patients with chronic low back pain (LBP) provided relief at month 1 but not 12, researchers report (pp. 547–56). Comparing prednisolone acetate 25 mg with no intervention during discography, investigators identified these differences: “At 1 month after the intervention, the percentage of responders (LBP intensity <40 [on an 11-point scale from 0 to 100]) was higher in the GC IDI group (36 of 65 [55.4%]) than the control group (21 of 63 [33.3%]) (absolute risk difference, 22.1 percentage points [95% CI, 5.5 to 38.7 percentage points]; P = 0.009). The groups did not differ in LBP intensity at 12 months and in most secondary outcomes at 1 and 12 months.” (S. Poiraudeau, serge.poiraudeau@aphp.fr)
 “In patients with an acute pain episode that coincides with Modic 1 changes on magnetic resonance imaging, [GC IDI] may be an option for short-term pain relief,” editorialists write (
pp. 601–2). “However, in patients with chronic pain, glucocorticoid injection clearly is not effective over the long term. The question then arises about the utility of using an invasive treatment for short-term relief in the setting of an acute condition with a favorable natural history or for an acute flare of a chronic condition.” (D. J. Kennedy, djkenned@stanford.edu)
Anakinra in Chronic Fatigue Syndrome: Symptoms of chronic fatigue syndrome (CFS) were not improved by 4 weeks of subcutaneous anakinra therapy, researchers report in a previously released manuscript (see PNN, Mar. 7; pp. 557–64). Cytokine inhibition was tested in 50 women aged 18–59 years of age with CFS and severe fatigue, with these results during 4 weeks of treatment and 20 weeks of follow-up: “At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in … fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).” (M. E. Roerink, Megan.Roerink@radboudumc.nl)
Synopsis of 2017 ADA Standards for Medical Care of Diabetes: Pharmacologic management of type 2 diabetes based on this year’s guidelines from the American Diabetes Association are summarized in a Clinical Guidelines article (pp. 572–8): “Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes (A rating). Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in patients treated with metformin, especially those with anemia or peripheral neuropathy (B rating). Providers should consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic, have a hemoglobin A1c (HbA1c) level of 10% or greater, or have a blood glucose level of 16.7 mmol/L (300 mg/dL) or greater (E rating). If noninsulin monotherapy at the maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months, adding a second oral agent, a glucagon-like peptide-1–receptor agonist, or basal insulin should be considered (A rating). For patients with type 2 diabetes who are not achieving glycemic goals, insulin therapy should be instituted without delay (B rating). A patient-centered approach should be used to guide the choice of pharmacologic agents (E rating).” (J. J. Chamberlain, jimchammd@yahoo.com)
Canadian Survival Advantage in Cystic Fibrosis: Reacting to a cohort study showing that Canadians with cystic fibrosis live a median of 10 years longer than Americans (pp. 537–46; A. L. Stephenson, stephensona@smh.ca), editorialists propose that the difference might be the result of lack of health care services among impoverished people in the U.S. (pp. 599–600; P. A. Flume, flumepa@musc.edu).

PNN Pharmacotherapy Line
Apr. 19, 2017 * Vol. 24, No. 75
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 18 issue of JAMA (2017; 317).
Maternal Depression, Prenatal Antidepressant Use & Autism: Two research articles and an editorial attempt to clarify the relationship among development of autism and maternal depression and use of antidepressants during pregnancy.
Contrary to prior studies —including a
JAMA Pediatrics analysis from Quebec republished in this issue (pp. 1568–9; B. H. King, bryan.king@ucsf.edu) — a retrospective cohort study of public prescription drugs dispensed in Ontario to pregnant women shows no increased risk of autism spectrum disorder associated with prenatal use of serotonergic antidepressants (pp. 1544–52). Among 35,906 singleton births with mean gestational age of 38.7 weeks, 2.0% of 2,837 children exposed in utero to antidepressants developed autism spectrum disorder. “The incidence of autism spectrum disorder was 4.51 per 1,000 person–years among children exposed to antidepressants vs 2.03 per 1,000 person–years among unexposed children (between-group difference, 2.48 [95% CI, 2.33–2.62] per 1,000 person–years; hazard ratio [HR], 2.16 [95% CI, 1.64–2.86]; adjusted HR, 1.59 [95% CI, 1.17–2.17]). After inverse probability of treatment weighting based on the high-dimensional propensity score, the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]).” (S. N. Vigod, simone.vigod@wchospital.ca)
Among Swedish children born in 1996–2012, those exposed to antidepressants during the first trimester had “a small increased risk of preterm birth but no increased risk [after data adjustment] of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder,” researchers report (
pp. 1553–62). The study, which included 1.6 million births to nearly 950,000 mothers, found these relationships among first-trimester antidepressant use and adverse outcomes: “6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years.” (B. M. D’Onofrio, bmdonofr@indiana.edu)
“[These studies] serve as a reminder that regardless of antidepressant treatment, children of mothers with depression remain at increased risk for developmental disturbances (
pp. 1533–4). “Although maternal depression (both prenatal and postnatal) remains a key determinant of child development, its effect is far from simple and may not be directly related to maternal behavior or decision making about treatment. Identifying how maternal mood and related genetic and environmental factors shape developmental risk is needed, moving away from a focus on antidepressant medications alone and toward whether some mothers and their children might actually benefit from prenatal maternal antidepressant treatment.” (T. F. Oberlander, toberlander@bcchr.ca)
Oral Dexamethasone for Acute Sore Throat: Two days after administration, a single oral dose of dexamethasone 10 mg relieved symptoms of sore throat among 565 acutely ill adults, a study shows (pp. 1535–43). At 42 family practices in England, patients with acute sore throat not requiring antibiotics had these outcomes when randomized to dexamethasone or placebo: “At 24 hours, 65 participants (22.6%) in the dexamethasone group and 49 (17.7%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 4.7% (95% CI, −1.8% to 11.2%) and a relative risk of 1.28 (95% CI; 0.92 to 1.78; P = .14). At 24 hours, participants receiving dexamethasone were not more likely than those receiving placebo to have complete symptom resolution. At 48 hours, 102 participants (35.4%) in the dexamethasone group vs 75 (27.1%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 8.7% (95% CI, 1.2% to 16.2%) and a relative risk of 1.31 (95% CI, 1.02 to 1.68; P = .03). This difference also was observed in participants not offered delayed antibiotic prescription, for a risk difference of 10.3% (95% CI, 0.6% to 20.1%) and a relative risk of 1.37 (95% CI, 1.01 to 1.87; P = .046). There were no significant differences in any other secondary outcomes.” (G. N. Hayward, gail.hayward@phc.ox.ac.uk)
PNNInfo@mac.com www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Apr. 20, 2017 * Vol. 24, No. 76
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 20 issue of the New England Journal of Medicine (2017; 376).
Risks & Benefits of Bococizumab: A humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), bococizumab is used to reduce elevated LDL cholesterol levels. Two research articles and a letter examine pharmacotherapy with this agent.
Problems with development of antidrug antibodies and wide variations in cholesterol reduction even in patients without the antibodies are evident in data from six large clinical trials, researchers report (
pp. 1517–26). Among 4,300 patients with hyperlipidemia, these outcomes were recorded with bococizumab 150 mg or placebo subcutaneously every 2 weeks for up to 12 months: “At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, −55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P <0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P = 0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person–years).” (P. M. Ridker, jean-claude.tardif@icm-mhi.org)
Significantly improved outcomes occurred in two randomized trials of bococizumab only for patients with higher risks, an analysis shows (
pp. 1527–39). The trials had 27,438 participants and showed these results based on a primary end point of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death: “In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08)…” (P. M. Ridker, pridker@partners.org)
Differing views on antibodies to and efficacy of bococizumab are provided in a letter to the editor from companies developing the investigational drug (
pp. 1589–90). Despite those benefits though, “immunogenicity led to the discontinuation of clinical development of bococizumab,” the authors write. (E. M. Roth, eroth@sterlingresearch.org)
Eltrombopag for Aplastic Anemia: Compared with a historical cohort, the synthetic thrombopoietin-receptor agonist eltrombopag produced higher rates of hematologic response among patients with severe aplastic anemia, a 92-patient, a phase 1-2 study shows (pp. 1540–50; D. M. Townsley, townsleydm@nhlbi.nih.gov).
Risankizumab for Plaque Psoriasis: Risankizumab was superior to ustekinumab for symptom relief in a phase 2 trial of 166 patients with moderate-to-severe plaque psoriasis (pp. 1551–60). Week 12 results showed 77% of patients on risankizumab had a reduction of 90% or more on a standard scale, compared with 40% of those on ustekinumab. (K. A. Papp, kapapp@probitymedical.com)
>>>PNN NewsWatch
*
Organic Herbal Supply is recalling several products following FDA analyses showing presence of tadalafil or flibanserin, FDA said.
PNN Pharmacotherapy Line
Apr. 21, 2017 * Vol. 24, No. 77
Providing news and information about medications and their proper use
>>>Geriatrics Report
Source: Apr. Journal of the American Geriatrics Society (2017; 65).
Natriuretic Peptides in Heart Failure: In addition to ejection fraction (EF) and comorbidities, N-terminal pro b-type natriuretic peptide (NT-proBNP) was associated with significantly poorer prognoses in 279 older adults hospitalized for decompensation of chronic established heart failure in two Italian facilities (pp. 822–6). Study participants, all older than 75 years of age, had these mortality outcomes: “In-hospital, 12-month and 5-year mortality were, respectively, 10%, 36%, and 77%. NT-proBNP, [estimated glomerular filtration rate], hemoglobin, diabetes, systolic blood pressure, and moderate to severe tricuspid regurgitation were independently associated with long-term prognosis and were entered into a multivariate model, with a C-index of 0.765 for the determination of high-risk patients. The C-index for NT-proBNP to predict mortality at 2 and 12 months was 0.740 and 0.756, respectively. The optimal cutoff point[s] for predicting mortality at 2 and 12 months [were] 8,444 pg/mL (hazard ratio 5.33) and 8,275 pg/mL (hazard ratio 6.03), respectively.” (A. Passantino, andrea.passantino@fsm.it)
“The role of natriuretic peptides in mortality risk stratification in older [heart failure (HF)] patients seems clear,” editorialists write (
pp. 691–2). “We need more information about natriuretic peptides and cardiovascular and non-cardiovascular cause of death, and information on the use of natriuretic peptides to risk stratify for rehospitalization or advanced therapies such as cardiac resynchronization devices, implantable cardioverter defibrillators (ICDs), and mechanical circulatory support. Finally, the role of natriuretic peptides in end of life decision making warrants consideration. For example, the decision to turn off an ICD may be informed by a natriuretic peptide level which indicates very high short term morality regardless of a defibrillator shock. As the population ages, managing the HF epidemic will place continued demands on the healthcare system so continued efforts to clarify the use of natriuretic peptides to inform that care and improve the lives of older patients with HF will be crucial.” (A. Sharma)
>>>PNN NewsWatch
*
FDA is restricting the use of codeine and tramadol medicines in children by requiring several changes to the labels of all prescription medicines containing these drugs. These new actions further limit the use of these medicines beyond the 2013 FDA restriction of codeine use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids. Specifically, FDA has added (1) a contraindication to the drug labels of codeine and tramadol alerting that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 years; (2) a new contraindication to the tramadol label warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids; (3) a warning to the drug labels of codeine and tramadol to recommend against their use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems; and (4) a strengthened warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants such as excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.
*
CDC has released the General Best Practice Guidelines for Immunization as an online report. It helps vaccination providers to assess vaccine benefits and risks, use recommended administration practices, understand the most effective strategies for ensuring that vaccination coverage in the population remains high, and communicate the importance of vaccination to reduce the effects of vaccine-preventable disease.
* Moving beyond medication reconciliation to the
“correct medication list” is the topic of a JAMA Viewpoint article released online in advance of print publication. “Achieving this list would involve multiple levels of reconciliation,” the authors write, adding that it is inappropriate to continue listing medications the patient cannot afford or does not want, that some drugs need to be discontinued, and that the burden of adherence should be addressed.
PNN Pharmacotherapy Line
Apr. 24, 2017 * Vol. 24, No. 78
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 22 issue of Lancet (2017; 389).
Doxycycline for Bullous Pemphigoid: Compared with oral prednisolone, doxycycline is noninferior “for short-term blister control in bullous pemphigoid and significantly safer in the long-term,” authors of a pragmatic study conclude (pp. 1630–8). Adult patients with the potentially fatal blistering-skin disorder had these outcomes: “Between March 1, 2009, and Oct. 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 U.K. and seven German dermatology centres. Mean age was 77.7 years (SD 9.7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18.6% (90% CI 11.1–26.1) favouring prednisolone (upper limit of 90% CI, 26.1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19.0% (95% CI 7.9–30.1), p = 0.001.” (H. C. Williams, hywel.williams@nottingham.ac.uk)
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Dexamethasone in Gastrointestinal Surgery: In a U.K. trial of patients undergoing large or small bowel surgery, addition of an intravenous dose of dexamethasone 8 mg at the induction of anesthesia significantly reduced the incidence of postoperative nausea and vomiting at 24 hours and the need for rescue antiemetics for up to 72 hours (j1455). Among 1,350 patients, the pragmatic, parallel-group trial yielded these results: “Vomiting within 24 hours of surgery occurred in 172 (25.5%) participants in the dexamethasone arm and 223 (33.0%) allocated standard care (number needed to treat (NNT) 13, 95% confidence interval 5 to 22; P = 0.003). Additional postoperative antiemetics were given (on demand) to 265 (39.3%) participants allocated dexamethasone and 351 (51.9%) allocated standard care (NNT 8, 5 to 11; P <0.001). Reduction in on demand antiemetics remained up to 72 hours. There was no increase in complications.” (L. Magill, e.l.magill@bham.ac.uk)
Active Commuting & Morbidity/Mortality: People who cycle or walk to work have improved health outcomes, a study shows, including lower risk of cardiovascular disease (CVD), cancer, and all-cause mortality with cycling, according to a prospective, population-based study (j1456). U.K. Biobank data from 22 sites showed these associations: “2,430 participants died (496 were related to CVD and 1,126 to cancer) over a median of 5.0 years (interquartile range 4.3–5.5) follow-up. There were 3,748 cancer and 1,110 CVD events. In maximally adjusted models, commuting by cycle and by mixed mode including cycling were associated with lower risk of all cause mortality (cycling hazard ratio 0.59, 95% confidence interval 0.42 to 0.83, P = 0.002; mixed mode cycling 0.76, 0.58 to 1.00, P <0.05), cancer incidence (cycling 0.55, 0.44 to 0.69, P <0.001; mixed mode cycling 0.64, 0.45 to 0.91, P = 0.01), and cancer mortality (cycling 0.60, 0.40 to 0.90, P = 0.01; mixed mode cycling 0.68, 0.57 to 0.81, P <0.001). Commuting by cycling and walking were associated with a lower risk of CVD incidence (cycling 0.54, 0.33 to 0.88, P = 0.01; walking 0.73, 0.54 to 0.99, P = 0.04) and CVD mortality (cycling 0.48, 0.25 to 0.92, P = 0.03; walking 0.64, 0.45 to 0.91, P = 0.01).…” (J. M. R. Gill, jason.gill@glasgow.ac.uk)
>>>PNN NewsWatch
* Moving beyond its traditional electronics business, Samsung on Friday received FDA approval for a
biosimilar for Remicade (infliximab) , the Wall Street Journal reports. This second follow-on product for the rheumatoid arthritis agent has the trade name Renflexis.
* Lot 70952A of
Phenobarbital Tablets, USP, 15 mg, has been recalled by C. O. Truxton because of a confirmed customer complaint of a bottle containing 30-mg tablets.
>>>PNN JournalWatch
* Rheumatoid Arthritis and Risk of Malignant Lymphoma: Is the Risk Still Increased?, in
Arthritis & Rheumatology, 2017; 69: 700–8. (K. Hellgren, karin.hellgren@karolinska.se)
* States With Prescription Drug Monitoring Mandates Saw a Reduction in Opioids Prescribed to Medicaid Enrollees, in
Health Affairs, 2017; 36: 733–41. (Y. Bao, yub2003@med.cornell.edu)
PNN Pharmacotherapy Line
Apr. 25, 2017 * Vol. 24, No. 79
Providing news and information about medications and their proper use
>>>Diabetes Report
Source: May issue of Diabetes Care (2017; 40).
Sulfonylureas & Cardiovascular Outcomes: Despite dozens of studies of sulfonylureas’ effects on cardiovascular outcomes, a careful look at the methodological strength of observational data shows that more accurate measures of cardiovascular safety are needed (pp. 706–14). Only 6 of 19 studies had no major design-related biases, the authors report. In those trials, “sulfonylureas were associated with an increased risk of cardiovascular events and mortality in the majority of studies with no major design-related biases,” the authors write. “Among studies with important biases, the association varied significantly with respect to the comparator, the outcome, and the type of bias. With the introduction of new antidiabetic drugs, the use of appropriate design and analytical tools will provide their more accurate cardiovascular safety assessment in the real-world setting.” (L. Azoulay, laurent.azoulay@mcgill.ca)
“Metaphorically, the jury is still deliberating as to whether all sulfonylureas are unsafe based on worrisome evidence from studies of tolbutamide and glyburide,” editorialists conclude (
pp. 629–31). “Gliclazide, glipizide, and glimepiride are reliably effective in lowering glucose, but are they too dangerous to use? As suggested by Azoulay and Suissa, more skillful analysis of observational data are possible, and some randomized trial experience is soon to be reported. If new evidence supports a not guilty verdict, the modern sulfonylureas should regain respect and continue to be an important option for controlling glucose.” (M. C. Riddle, riddlem@ohsu.edu)
Canagliflozin & Phentermine for Weight Management: The combination of canagliflozin (CANA) plus phentermine (PHEN) “produced meaningful reductions in body weight and was generally well tolerated in individuals who were overweight or obese without type 2 diabetes,” a study shows (pp. 632–9). A 26-week, phase 2a trial produced these outcomes among 335 participants who received the drug combination, the drugs separately, or placebo (PBO): “CANA/PHEN provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference –6.9% [95% CI –8.6 to –5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss ≥5% and reduction in systolic blood pressure compared with PBO. CANA/PHEN was generally well tolerated, with a safety and tolerability profile consistent with that of the individual components.” (P. Hollander, priscilh@baylorhealth.edu)
Pancreas Safety During Dulaglutide Development: During phase 2/3 trials of the glucagon-like peptide 1 receptor agonist dulaglutide, acute pancreatitis occurred at a rate similar to that in patients on placebo, researchers report (pp. 647–54). Among 6,005 patients with type 2 diabetes receiving dulaglutide, active comparators, or placebo, these outcomes were identified: “Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient–years, placebo group 3.52 patients/1,000 patient–years, sitagliptin group 4.71 patients/1,000 patient–years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with [adverse events].” (Z. Milicevic, milicevic_zvonko@lilly.com)
>>>PNN NewsWatch
* Hospira is voluntarily recalling one lot (58382EV) of
25% Dextrose Injection, USP, (Infant) prefilled syringe to the hospital/user level due to the presence of particulate matter, identified as human hair, found within an internal sample syringe, FDA reports.
* Pharmacists’ expanding role in self-care is the subject of
a new FIP report. “Pharmacy as a gateway to care: Helping people towards better health” reviews consumer interest in health care, presents a collection of evidence of pharmacy services related to self-care and the value pharmacists bring to health systems, and lays out drivers of self-care and “profound” changes in the way health systems operate. 
PNN Pharmacotherapy Line
Apr. 26, 2017 * Vol. 24, No. 80
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 25 issue of JAMA (2017; 317).
Dosing Schedule for Quadrivalent HPV Vaccine: While waning of vaccine effectiveness is evident by 3 years after immunization, data from a study of dosing of quadrivalent human papillomavirus (HPV) vaccine support shifting from three to two doses (pp. 1687–8). The CDC Advisory Committee on Immunization Practices made that recommendation last year for all three formulations of HPV vaccines available in the U.S. In the current report, a post hoc analysis of data from a phase 3 postlicensure, noninferiority immunogenicity trial at three Canadian centers in 2007–08 shows the following: “Of 520 girls originally randomized, 101 provided serum samples at 60 months (50 receiving 2 doses and 51 receiving 3 doses). Seropositivity at 60 months for both 2 doses and 3 doses was above 95% for all genotypes except HPV 18. At 60 months, responses for HPV 6, HPV 11, and HPV 16 were all noninferior in the 2-dose vs 3-dose groups. Between 36 and 60 months, there was a significant reduction in [geometric mean titers (GMTs)] across all HPV types for both the 2-dose and 3-dose groups based on paired sample t test. However, there was no significant difference in the reduction between groups. For all 4 types in both groups, there was a decline in GMT titers to 60 months, but there was no difference (P >.05) between the trend in decline between 2 and 3 doses.” (G. Ogilvie, gina.ogilvie@cw.bc.ca)
OTC Mechanical Nasal Dilators: In an article reprinted from JAMA Facial Plastic Surgery, authors of a systematic review conclude that external nasal dilator strips available over the counter are an effective alternative to surgical intervention for internal nasal valve obstruction for some patients (pp. 1684–5). Published data on 33 available OTC mechanical dilators showed these results: “An analysis of each product’s mechanism revealed 4 broad classes: external nasal dilator strips, nasal stents, nasal clips, and septal stimulators. A review demonstrated 5 studies supporting the use of external nasal dilator strips, 4 studies supporting the use of nasal clips, 1 study supporting the use of nasal stents, and no studies supporting the use of septal stimulators.” (S. S. Pawar, spawar@mcw.edu)
Trends in Infective Endocarditis: While the overall incidence of infective endocarditis is stable, etiologies shifted in 1998–2013 to more nonnosocomial sources of health-care-associated conditions, according to epidemiologic data from California and New York state (pp. 1652–60). Sources of nonnosocomial health-care-associated infections are intravenous therapies (including chemotherapy), specialized nursing facilities, hemodialysis, or hospitalization for 2 days or more in the 90 days before admission of infective endocarditis. Also, the proportion of patients with native-valve endocarditis decreased (from 74.5% to 68.4%), while prosthetic-valve endocarditis and cardiac device–related endocarditis increased (from 12.0% to 13.8% and from 1.3% to 4.1%, respectively). (J. Chikwe, joanna.chikwe@mountsinai.org)
Lack of Evidence Guiding Marijuana Therapy: After taking an 8-hour course required in Florida before physicians can recommend medical marijuana to their patients, an internist practicing in Key West found that he had little evidence to make him comfortable with this intervention, according to a news article (pp. 1611–3). “‘The course has no dosing data. You go to the smallest amount possible and then work your way up,’ Norris explained. ‘It’s like trying to prescribe St John’s wort instead of Prozac.’ The lack of clear dosing guidelines also makes it difficult to determine whether a patient is misusing medical marijuana.…
“Norris, who has a sign hanging in his waiting room stating ‘this is not a pain clinic,’ is unmoved by callers claiming that since their state approved an amendment legalizing medical marijuana, it is now their constitutional right to get it. ‘They think I’m supposed to just go ahead and write the scripts, and I’m not doing that.’” (R. Rubin)
>>>PNN NewsWatch
*
FDA yesterday posted online warning letters to 14 U.S.-based companies that it said were illegally selling more than 65 products that fraudulently claim to prevent, diagnose, treat, or cure cancer. The products are marketed and sold without FDA approval, most commonly on websites and social media platforms, the agency said.
PNN Pharmacotherapy Line
Apr. 27, 2017 * Vol. 24, No. 81
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 27 issue of the New England Journal of Medicine (2017; 376).
Cytokine BAFF Overexpression & Autoimmunity Risk: Patients with a DNA variant had higher risks of developing multiple sclerosis and systemic lupus erythematosus (SLE) in a genomewide-association, case–control study from Sardinia, Italy (pp. 1615–26): “A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT [to] A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.” (F. Cucca, fcucca@uniss.it)
“It will be a challenge for the future to assess whether the insertion–deletion variant of
TNFSF13B can be used to stratify patients for a specific therapy,” editorialists write (pp. 1680–1). “Although the data from the current study clearly point in this direction, the discriminatory power of this solitary [single-nucleotide polymorphism] may not be sufficient for clinical decision making. However, it seems reasonable to study whether stratification of patients according to the variant of TNFSF13B could be useful for clinical trials that assess B-cell–directed therapies.” (T. Korn)
Uninterrupted Dabigatran in Atrial Fibrillation Ablation: Compared with uninterrupted warfarin in patients undergoing ablation for atrial fibrillation, continued dabigatran produced significantly fewer bleeding episodes, researchers report (pp. 1627–36). In a randomized, open-label trial with blinded adjudicated end-point assessments, dabigatran 150 mg twice daily or warfarin titrated to INRs of 2.0 to 3.0 produced these results based on bleeding in the 8 weeks after ablation: “The trial enrolled 704 patients across 104 sites; 635 patients underwent ablation. Baseline characteristics were balanced between treatment groups. The incidence of major bleeding events during and up to 8 weeks after ablation was lower with dabigatran than with warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk difference, −5.3 percentage points; 95% confidence interval, −8.4 to −2.2; P <0.001). Dabigatran was associated with fewer periprocedural pericardial tamponades and groin hematomas than warfarin. The two treatment groups had a similar incidence of minor bleeding events. One thromboembolic event occurred in the warfarin group.” (H. Calkins, hcalkins@jhmi.edu)
Adalimumab/Methotrexate for Uveitis in Juvenile Idiopathic Arthritis: In a study of children and adolescents with active juvenile idiopathic arthritis (JIA)–associated uveitis, adalimumab provided better control of inflammation when added to methotrexate, but the anti-TNF agent also produced a much higher incidence of adverse effects, including serious ones (pp. 1637–46). Based on a primary end point of time to treatment failure, the study showed: “The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P <0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient–year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient–year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient–year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient–year [95% CI, 0.00 to 0.40]).” (A. V. Ramanan, avramanan@hotmail.com)
>>>PNN NewsWatch
*
Correction: Yesterday’s PNN incorrectly stated that vaccine effectiveness waned in the JAMA study of two versus three doses of HPV vaccine. While geometric mean titers indicated declining antibodies to the four HPV types, breakthrough cases of cervical cancer or other HPV diseases were not observed; studies of long-term vaccine efficacy are pending.
PNN Pharmacotherapy Line
Apr. 28, 2017 * Vol. 24, No. 82
Providing news and information about medications and their proper use
>>>Nephrology Report
Source: May issue of the American J. Kidney Diseases (2017; 69).
Self-Managed Sodium Restriction in CKD: At four Dutch hospitals, patients with moderately decreased renal function who were randomized to regular care plus self-management of sodium restriction had modestly improved outcomes over those managed with regular care alone (pp. 576–86). The intervention — education, motivational interviewing, coaching, and self-monitoring of blood pressure (BP) and sodium — yielded these results: “At baseline, mean sodium excretion rate was 163.6 ± 64.9 (SD) mmol/24 h; mean estimated glomerular filtration rate was 49.7 ± 25.6 mL/min/1.73 m2; median protein excretion rate was 0.8 (IQR, 0.4–1.7) g/24 h; and mean 24-hour ambulatory systolic and diastolic BPs were 129 ± 15 and 76 ± 9 mm Hg, respectively. Compared to regular care only (n = 71), at 3 months, the intervention group (n = 67) showed reduced sodium excretion rate (mean change, −30.3 [95% CI, −54.7 to −5.9] mmol/24 h), daytime ambulatory diastolic BP (mean change, −3.4 [95% CI, −6.3 to −0.6] mm Hg), diastolic office BP (mean change, −5.2 [95% CI, −8.4 to −2.1] mm Hg), protein excretion (mean change, −0.4 [95% CI, −0.7 to −0.1] g/24h), and improved self-efficacy (mean change, 0.5 [95% CI, 0.1 to 0.9]). At 6 months, differences in sodium excretion rates and ambulatory BPs between the groups were not significant, but differences were detected in systolic and diastolic office BPs (mean changes of −7.3 [95% CI, −12.7 to −1.9] and −3.8 [95% CI, −6.9 to −0.6] mm Hg, respectively), protein excretion (mean changes, −0.3 [95% CI, −0.6 to −0.1] g/24h), and self-efficacy (mean change, 0.5 [95% CI, 0.0 to 0.9]). No differences in kidney function, medication, and health-related quality of life were observed.” (Y. Meuleman, meulemany@fsw.leidenuniv.nl)
Belatacept in Kidney Transplant Recipients: Phase 2 trial participants with kidney transplants who were switched from a calcineurin inhibitor (CNI) to belatacept had acceptable safety outcomes at 36 months posttransplantation, researchers report (pp. 587–94). Medications were changed between 6 and 36 months after transplant; a previous study showed improved kidney function at 12 months postconversion. Safety data at 36 months for 173 patients were as follows: “Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure−adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person–years) and malignancies (3.01 vs 3.41 per 100 person–years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person–years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07 mL/min/1.73 m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65–9.65; P = 0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14–7.07; P = 0.9).” (Josep M. Grinyó, jgrinyo@ub.edu)
>>>PNN NewsWatch
* In its first liver-cancer indication approval in almost a decade,
FDA yesterday expanded the approved use of regorafinib (Stivarga, Bayer) to include treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
*
FDA also approved cerliponase alfa (Brineura, BioMarin Pharmaceutical) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2, also known as tripeptidyl peptidase-1 deficiency.
* Label changes for
general anesthetics and sedatives in children younger than 3 years of age have been approved by FDA. A new warning states that exposure to these medicines for lengthy periods of time or over multiple surgeries or procedures may negatively affect brain development in children younger than 3 years, and the pregnancy and pediatric use sections of the label now cautions of widespread neuronal damage in young animals and pregnant animals exposed to the drugs for more than 3 hours.

PNN Pharmacotherapy Line
May 1, 2017 * Vol. 24, No. 83
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 29 issue of Lancet (2017; 389).
Risankizumab Induction Therapy in Crohn’s disease: Blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in moderate-to-severe Crohn’s disease, according to findings of a short-term study of risankizumab (pp. 1699–709). In an international phase 2 study, patients with moderate-to-severe Crohn’s disease had these outcomes after randomization to placebo or risankizumab 200 or 600 mg: “Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15.0%, 95% CI 0.1 to 30.1; p = 0.0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9.0%, −8.3 to 26.2; p = 0.31) and 15 (37%) of 41 who received the 600 mg dose (20.9%, 2.6 to 39.2; p = 0.0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn’s disease. No deaths occurred.” (B. G. Feagan, brian.feagan@robartsinc.com)
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Mortality Risk of Opioid Substitution Treatment: A systematic review and meta-analysis of 19 cohorts in published studies of 122,885 people taking methadone over 1.3–13.9 years and 15,831 people treated with buprenorphine for 1.1–4.5 years reached this conclusion (j1550): “Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.” (G. Barrio, gbarrio@isciii.es)
>>>PNN NewsWatch
*
FDA on Friday approved midostaurin (Rydapt, Novartis) for treatment of adults with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation, FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies), which is used to detect the FLT3 mutation in patients with AML. Midostaurin is also approved for treatment of adults with advanced systemic mastocytosis, which includes aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, and mast cell leukemia.
>>>PNN JournalWatch
* Inappropriate Medication in Non-Hospitalized Patients With Renal Insufficiency: A Systematic Review, in
Journal of the American Geriatrics Society, 2017; 65: 853–62. (M. Dörks, michael.doerks@uni-oldenburg.de
* Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients, in
American Journal of Kidney Diseases, 2017; 69: 595–601. (C. R. Lenihan, clenihan@stanford.edu
* E-Prescribing and Adverse Drug Events: An Observational Study of the Medicare Part D Population With Diabetes, in
Medical Care, 2017; 55: 456–62. (M. H. Gabriel) 
* Chronic Health Outcomes and Prescription Drug Copayments in Medicaid, in
Medical Care, 2017; 55: 520–7. (D. Kostova) 
* Antibiotic Prophylaxis for Urinary Tract Infection–Related Renal Scarring: A Systematic Review, in
Pediatrics, 2017; 139: 0.1542/peds.2016-3145. (I. K. Hewitt)
* Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-4317. (H. S. Fischer)
PNN Pharmacotherapy Line
May 2, 2017 * Vol. 24, No. 84
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: May 2 issue of the Annals of Internal Medicine (2017; 166).
Oral Direct-Acting Agent Therapy for Hepatitis C Virus: FDA-approved oral direct-acting antiviral (DAA) regimens produce high sustained virologic response (SVR) rates for all six hepatitis C virus (HCV) genotypes and for patient populations historically considered difficult to cure, conclude authors of a systematic review article (pp. 637–48). These details reflect data from 43 English-language studies of trials lasting at least 8 weeks of interferon-free regimens for HCV in adults: “Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.” (O. Falade-Nwulia, ofalade1@jhmi.edu)
“These findings provide hope that HCV infection is now a fully treatable condition that, with sufficient efforts, can be eliminated as an important medical problem in the United States,” an editorialist writes (
pp. 675–6). “Amid the optimism about HCV therapy, however, a few caveats need to be mentioned.” The  caveats include concerns that the response rates were close to, but not equal to, 100%; many persons remain unaware of their infection until cirrhosis or end-stage liver disease arises; rare but serious adverse events have been reported; and the word “cure” may imply that further concern or follow-up is not needed. (J. H. Hoofnagle)
Benefits & Harms of Osteoporosis Medications in Chronic Kidney Disease: “Effects of osteoporosis medications on [bone mineral density (BMD)], fracture risk, and safety among patients with [chronic kidney disease (CKD)] are not clearly established,” conclude authors of a systematic review and meta-analysis article (pp. 649–58): “There were 13 trials (n = 9,850) that included kidney transplant recipients (6 trials), patients who had stage 3 to 5 CKD or were receiving dialysis (3 trials), or postmenopausal women with CKD (4 trials). Evidence showed that bisphosphonates may slow loss of BMD among transplant recipients (moderate [strength of evidence (SOE)]), but their effects on fractures and safety in transplant recipients and others with CKD are unclear. Raloxifene may prevent vertebral fractures but may not improve BMD (low SOE). Effects of teriparatide and denosumab on BMD and fractures are unclear (very low SOE), and these medications may increase risk for some safety outcomes.” (L. M. Wilson, lisawilson@jhmi.edu)
Administrative Tasks in Health Care: An American College of Physicians (ACP) position paper presents seven recommendations on how to assess administrative requirements and tasks that affect physician time, practice, and system cost, and patient care (pp. 659–61). ACP first calls on “stakeholders external to the physician practice or health care clinician environment who develop or implement administrative tasks (such as payers, governmental and other oversight organizations, vendors and suppliers, and others) to provide financial, time, and quality-of-care impact statements for public review and comment” for all existing and new administrative tasks. “Administrative tasks that cannot be eliminated from the health care system must be regularly reviewed, revised, aligned, and/or streamlined in a transparent manner, with the goal of minimizing burden, by all stakeholders involved,” the authors continue. “Stakeholders, including public and private payers, must collaborate with professional societies, frontline clinicians, patients, and electronic health record vendors to aim for performance measures that minimize unnecessary clinician burden, maximize patient and family centeredness, and integrate the measurement of and reporting on performance with quality improvement and care delivery.” Other recommendations call for efficiency and research on the effects of administrative tasks. (S. M. Erickson, serickson@acponline.org)
PNN Pharmacotherapy Line
May 3, 2017 * Vol. 24, No. 85
Providing news and information about medications and their proper use
>>>JAMA Report
Source: May 2 issue of JAMA, a theme issue on conflicts of interest (2017; 317).
Conflicts of Interest: In one of numerous Viewpoints on conflicts of interest in medicine, health care, education, research, and publication, a writer asks, “Why does it matter?” (pp. 1717–8): “Physicians, like others, have many types of possible financial interests. As clinicians, their basic income may be salary, capitation, or fee-for-service. A surgeon paid fee-for-service clearly has a financial stake in whether a patient agrees to surgery. This is transparent to the patient and may be readily balanced by seeking a second opinion from a disinterested expert. Consultant fees, honoraria, and other financial interests may arise in relation to other professional roles. Authors of a published article, for example, may disclose an institutional affiliation, sources of other relevant income, and funders of the research. What is acceptable for an author and remedied by disclosure may differ from more lax standards required for a reviewer who is merely advising the editors and from more stringent standards for selecting an editorialist who will interpret the meaning of the research for clinical practitioners. Standards for disclosure and inclusion may be even more stringent for experts chosen to develop professional guidelines or regulations that can directly affect practice.…
“The Gallup poll reports that nurses, pharmacists, and physicians are among the professions most trusted by the US public. Especially at a time when the place of science is challenged in public policy and decision making, it is incumbent on the health professions to champion their reliance on evidence and disinterested expertise. Adherence to carefully considered, transparent, and evenhanded policies on conflict of interest can help physicians earn and maintain their trusted place in the minds of the public and policy makers.” (H. V. Fineberg,
harvey.fineberg@moore.org)
Trying to distinguish between “potential or perceived” and “true or actual” COIs are misguided, argue authors of a second article (
pp. 1721–2): “Distinctions between potential and actual COI are rooted in a basic misunderstanding of the concept of a COI and its ethical significance. These invidious distinctions should be avoided. A COI exists when a secondary interest has the potential to bias a physician’s or a researcher’s primary interest in pursuing patient well-being and generalizable knowledge. Physicians and others must use clear and consistent terms to describe the severity of a COI, the policies that are used to manage a COI, and the standards for identifying a COI. Achieving greater conceptual clarity is essential to develop policies that effectively regulate COIs without unduly limiting financial interactions that do not constitute COIs. Only in this way can the integrity of medical research and practice be protected.” (M. S. McCoy, mmcco@mail.med.upenn.edu)
>>>Pediatrics Report
Source: May issue of Pediatrics (2017; 139).
Support for Vaccinations: Three articles provide useful information and insights regarding pediatric immunizations.
Vaccinating children against influenza saves lives, report authors who assessed the risk reduction using a case–cohort analysis of U.S. data for 2010–14 (
10.1542/peds.2016-4244). “Overall [vaccine effectiveness (VE)] against death was 65% (95% CI, 54% to 74%). Among 153 deaths in children with underlying high-risk medical conditions, 47 (31%) were vaccinated. VE among children with high-risk conditions was 51% (95% CI, 31% to 67%), compared with 65% (95% CI, 47% to 78%) among children without high-risk conditions.” (B. Flannery)
A retrospective study from Kaiser Northern California “strongly supports the United States’ current recommendation to administer Tdap during each pregnancy” (
10.1542/peds.2016-4091). “Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life,” the investigators conclude. “Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life.” (R. Baxter)
Adults who get vaccinated are more likely to have their children immunized, according to data from the Oregon ALERT Immunization Information System (
10.1542/peds.2016-2883). The authors conclude that “encouraging parental immunization is a potential tool for increasing children’s immunization rates.” (S. G. Robison)
PNN Pharmacotherapy Line
May 4, 2017 * Vol. 24, No. 86
Providing news and information about medications and their proper use
>>>NEJM Report
Source: May 4 issue of the New England Journal of Medicine (2017; 376).
Cardiovascular Outcomes With Evolocumab: In a trial of 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/mL or more who were receiving statin therapy, addition of the PCKS9 inhibitor evolocumab lowered LDL cholesterol levels to a median of 30 mg/dL, researchers report (pp. 1713–22). In the FOURIER trial, subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly produced these outcomes: “At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P <0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary [efficacy] end point (1,344 patients [9.8%] vs. 1,563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P <0.001) and the key secondary [efficacy] end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P <0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).” (M. S. Sabatine, msabatine@partners.org)
“It is anticipated that the results of the FOURIER trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs,” an editorialist writes (
pp. 1790–1). “The FOURIER trial is a landmark trial providing formal evidence that treatment targeted at PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved by lipid-lowering treatment alone. However, in this trial, the duration of evolocumab treatment was rather short. The efficacy, with regard to atherosclerotic cardiovascular disease, of PCSK9 inhibition treatment that is started shortly after an acute event still needs to be determined, as does the efficacy of the treatment in other categories of high-risk patients. End-point studies of alirocumab and other monoclonal antibodies against PCSK9 (bococizumab and LY3015014) are under way, and an RNA interference therapeutic agent that inhibits PCSK9 synthesis and lowers plasma LDL cholesterol levels has been tested in a phase 1 study.” (R. P. F. Dullaart)
Tofacitinib in Ulcerative Colitis: The oral small-molecule Janus kinase inhibitor tofacitinib produced significant improvements as induction and maintenance treatment of ulcerative colitis in 3 placebo-controlled, phase 3 trials (pp. 1723–36). The OCTAVE Induction 1 and 2 trials and the OCTAVE Sustain trial included 598, 541, and 593 patients, respectively, and produced these results: “In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P = 0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P <0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P <0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.” (W. J. Sandborn, wsandborn@ucsd.edu)
“Regardless of its eventual place in the treatment algorithm for ulcerative colitis, tofacitinib is a new class of therapy that has efficacy” and a “promising step forward,” an editorialist writes (
pp. 1792–3; S. Friedman).
PNN Pharmacotherapy Line
May 5, 2017 * Vol. 24, No. 87
Providing news and information about medications and their proper use
>>>Psychiatry Report
Source: May issue of the American Journal of Psychiatry (2017; 174).
Pediatric Antidepressant Efficacy: Studies funded by the National Institute of Mental Health support antidepressant efficacy in children and adolescents for a variety of pediatric internalizing conditions, concludes the author of a review article (pp. 430–7). In contrast, industry-funded research has a number of flaws that limit applicability of the results, as noted in this summary: “In this review, the author discusses several scientific and clinical complexities that are important to understand in reviewing the antidepressant literature: the strengths and weaknesses of meta-analyses; the scientific and regulatory context for the large number of antidepressant trials in the late 1990s and early 2000s; and the distinction between a negative trial, where the treatment does not demonstrate efficacy, and a failed trial, where methodological problems make it impossible to draw any conclusion about efficacy. It is the premise of this review that meta-analyses that include the large number of industry-sponsored antidepressant trials distort the picture of antidepressant efficacy for teen depression. Industry-sponsored child and adolescent depression trials suffer from a number of implementation challenges and should be considered failed trials that are largely uninformative and not eligible to be included in efficacy meta-analyses. In contrast to the industry-sponsored trials, depression trials funded by the National Institute of Mental Health (NIMH) (N = 2) are characterized by many methodological strengths, lower placebo response rates (30%−35%), and meaningful between-group differences (25%−30%) that support antidepressant efficacy. The NIMH-funded trials, taken together with the demonstrated efficacy of the serotonin reuptake inhibitors for childhood-onset obsessive-compulsive disorder and the anxiety disorders, suggest a broad and important role for antidepressant medications in pediatric internalizing conditions.” (J. T. Walkup, jtw9001@med.cornell.edu)
“One can understand the controversy surrounding SSRIs by noting the context from which it arose,” editorialists write (
pp. 407–8). “When considering this context, it is also important to remember the large burden to patients, families, and communities associated with pediatric mental disorders. Most importantly, when clinicians look beyond controversy to their patients’ clinical burden, Walkup’s perspective helps us carefully evaluate the efficacy data to choose the best treatment for children and adolescents with major depression, anxiety disorders, and OCD, and in particular, to consider the SSRIs as a reasonable therapeutic option for many of our patients.” (D. S. Pine, daniel.pine@nih.gov)
Overdoses/Poisonings With Antidepressants: Data from the National Poison Data System for 2000–14 show a large increase in overdoses with and nonintentional exposures to drugs used to treat depression, researchers report (pp. 438–50): “During this 15-year period, there were 962,222 single substance exposures to the 48 medications studied. Serious outcomes rose 2.26-fold and in linear fashion over the 15 years. While tricyclic and monoamine oxidase inhibitor medications were associated with high morbidity and mortality, several newer agents also appeared hazardous. Lithium, quetiapine, olanzapine, bupropion, and carbamazepine were associated with high morbidity indices. Lithium, venlafaxine, bupropion, quetiapine, olanzapine, ziprasidone, valproic acid, carbamazepine, and citalopram were associated with higher mortality indices.” (J. C. Nelson, craig.nelson@ucsf.edu)
>>>PNN NewsWatch
* “Insurers and markets, rather than government, should be empowered to find ways to provide health insurance to a broad set of people at affordable prices,” writes a
Wall Street Journal reporter in analyzing yesterday’s Obamacare repeal-and-replace vote in the U.S. House of Representatives. “Republicans are betting that these changes will engender competition, draw healthier people into the insurance pool and cut premium prices overall. Democrats, who uniformly opposed the bill Thursday, said many participants and providers in the health system will face higher costs and be worse off than under [Obamacare].”
* May is
Lyme Disease Awareness Month and the beginning of the period through July when people will get more tick bites and tick-borne diseases than any other time of year in the U.S., says CDC.
PNN Pharmacotherapy Line
May 8, 2017 * Vol. 24, No. 88
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: May 6 issue of Lancet (2017; 389).
Antithrombotic Treatment After ACS: Combined with a P2Y12 inhibitor, low-dose rivaroxaban versus low-dose aspirin produced similar risks of clinically significant bleeding in patients with acute coronary syndromes, researchers report (pp. 1799–808). Participants at 371 clinical centers in 21 countries were randomized to rivaroxaban 2.5 mg or aspirin 100 mg daily; investigators chose between clopidogrel or ticagrelor for P2Y12 therapy. Results showed: “Between April 22, 2015, and Oct 14, 2016, 3,037 patients with acute coronary syndromes were randomly assigned; 1,518 to receive aspirin and 1,519 to receive rivaroxaban. 1,704 patients (56%) were in the ticagrelor and 1,333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239–354). [Thrombolysis in myocardial infarction] non–[coronary artery bypass grafting] clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1,519 vs 74 participants [5%] of 1,518; HR 1.09 [95% CI 0.80–1.50]; p = 0.5840).” Based on these findings, the authors conclude, “A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.” (E. M. Ohman, ohman001@mc.duke.edu)
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Postapproval Drug Studies: For 117 new drugs approved by FDA in 2005–12 based on a single pivotal trial and/or surrogate markers, controlled studies published later often did not support the evidence relied on for the initial approval, a systematic review shows (j1680): “We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4–8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0–2) for indications approved on the basis of a single pivotal trial, 3 (1–8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0–2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0–509), 533 (122–3633), and 38 (0–666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.” (J. S. Ross, joseph.ross@yale.edu)
>>>PNN NewsWatch
*
FDA on Friday approved edaravone (Radicava, Mitsubishi Tanabe Pharma America) to treat patients with amyotrophic lateral sclerosis (Lou Gehrig’s disease). 
>>>PNN JournalWatch
* Acute Kidney Injury in Patients with Cancer, in
New England Journal of Medicine, 2017; 376: 1770–81. (M. H. Rosner, mhr9r@virginia.edu
* Antiphospholipid Syndrome: Role of Vascular Endothelial Cells and Implications for Risk Stratification and Targeted Therapeutics, in
Journal of the American College of Cardiology, 2017; 69: 2317–30. (M. T. Corban) 
* Shift Work and Shift Work Sleep Disorder: Clinical and Organizational Perspectives, in
Chest, 2017; 151: 1156–72. (E. Wickwire) 
* Is Rapid Health Improvement Possible? Lessons From the Million Hearts Initiative, in
Circulation, 2017; 135: 1677–80. (J. S. Wright, janet.wright@cms.hhs.gov
* First-Trimester Artemisinin Derivatives and Quinine Treatments and the Risk of Adverse Pregnancy Outcomes in Africa And Asia: A Meta-analysis of Observational Studies, in
PLOS Med, 2017; 14(5): e1002290. (A. Stergachis, stergach@uw.edu)
PNN Pharmacotherapy Line
May 9, 2017 * Vol. 24, No. 89
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: May issue of JAMA Internal Medicine (2017; 177).
Thiazolidinediones in Nonalcoholic Steatohepatitis: The thiazolidinedione pioglitazone has shown indications of improving advanced fibrosis in nonalcoholic steatohepatitis (NASH), even in patients without diabetes, authors of a meta-analysis report (pp. 633–40): “This study analyzed 8 [randomized controlled trials (RCTs)] (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25–7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12–2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17–4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04–10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02–3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95–5.93; P < .001; I2= 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%–4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy.” (G. Musso, giovanni_musso@yahoo.it)
Until more data are available, “it may make sense to consider the use of pioglitazone in patients with type 2 diabetes who have NASH and evidence of advanced fibrosis,” editorialists write (
pp. 640–1). “Treating such patients would not incur any incremental risk of adverse events because they might already be taking pioglitazone as part of the management of their diabetes, while potentially benefiting from its putative benefits in NASH. For most patients with NASH, prior guidance to reduce weight, exercise, and refrain from heavy consumption of alcohol would seem prudent until we have data showing therapies that improve clinical outcomes.” (H. F. Yee, Jr., hal.yee@ucsf.edu)
Suicidality & Depression With 5-Alpha-Reductase Inhibitors: Administrative medication use data from Ontario show that men using 5-alpha reductase inhibitors are not at increased risk of suicide, but they do have increase rates of self-harm and depression, researchers report (pp. 683–91). In a retrospective, matched-cohort study of 93,197 men aged 66 years or older, those receiving new prescriptions for agents in this drug class had the following outcomes: “Men who used 5-alpha-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53–1.45). Risk of self-harm was significantly increased during the initial 18 months after 5-alpha-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34–2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5-alpha-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73–2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08–1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100,000 patient–years and 237 per 100,000 patient–years, respectively. The type of 5-alpha-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression.” (B. Welk, bkwelk@gmail.com)
Magnesium Oxide & Nocturnal Leg Cramps: Compared with placebo in a randomized controlled trial of older adults, supplements of magnesium oxide were not significantly better for prevention of nocturnal leg cramps (NLCs) (pp. 617–23). “The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC,” the authors conclude. (U. Milman, uzimy@netvision.net)
>>>PNN NewsWatch
* Following FDA analysis showing presence of anabolic steroids and steroid like substances, all lots of
GEC Laxoplex dietary supplement capsules distributed between Feb. 2, 2015 and May 2, 2017, have been recalled by Genetic Edge Compounds to the retail and consumer levels, the agency said.
PNN Pharmacotherapy Line
May 10, 2017 * Vol. 24, No. 90
Providing news and information about medications and their proper use
>>>JAMA Report
Source: May 9 issue of JAMA (2017; 317).
Selumetinib in Non–Small Cell Lung Cancer: The mitogen-activated protein kinase (MEK) inhibitor selumetinib provided no additional benefit when paired with docetaxel in a trial of 510 patients with advanced KRAS-mutant non–small cell lung cancer (NSCLC), researchers report (pp. 1844–53). In 2013–16, participants in a multinational clinical trial with this type of neoplasm were randomized to docetaxel plus placebo or both active drugs, with these results: “At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5–5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4–5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77–1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6–16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8–20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85–1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00–2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7–4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8–5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%).” (P. A. Jänne, pasi_janne@dfci.harvard.edu)
Characterizing these results as “the end of the beginning for targeted therapies,” editorialists write that such agents are “are critical to the future management of patients with
KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations” (pp. 1835–7): “Molecular testing is rapidly evolving and circulating tumor DNA testing will facilitate tumor testing and may allow for serial monitoring and use of surrogate end points for drug development. The next generation of targeted therapies will likely focus on the primary oncogenic molecular event and the acquired resistance mechanisms, and will be more potent and specific for the oncogenic driver. This will ideally improve efficacy and reduce off-target toxicities.” (T. E. Stinchcombe, thomas.stinchcombe@duke.edu)
Quinine Exposure & All-Cause Mortality: Long-term exposure to quinine — either as a treatment for leg cramps or as an ingredient in drinks such as bitter lemon or tonic water — is associated with increased risk of death, a study shows, especially from sudden cardiac death (pp. 1907–9). A U.K. primary care database, The Health Improvement Network (THIN), shows these outcomes among adults who received quinine salt prescriptions for at least 1 year in 1990–2014: “Exposed persons received a median 203 mg/d (interquartile range, 163–252) of quinine. There were 11,598 deaths (4.2 per 100 person–years) among the 44,699 exposed individuals vs 26,753 (3.2 per 100 person–years) among the 130,496 unexposed individuals (adjusted hazard ratio [HR], 1.24 [95% CI, 1.21–1.27]). The increase in the risk of death was more pronounced in those younger than 50 years (adjusted HR, 3.06 [95% CI, 2.51–3.73]), whatever the indication for prescription. A dose-effect was found for exposure of 200 to 299 mg/d (adjusted HR, 1.25 [95% CI, 1.20–1.30]), 300 to 399 mg/d (adjusted HR, 1.83 [95% CI, 1.72–1.94]), and 400 mg/d or more (adjusted HR, 2.24 [95% CI, 1.95–2.58]) compared with less than 200 mg/d (P value for trend, <.001).” (L. Fardet, laurence.fardet@aphp.fr)

* A pro-industry approach is expected from the new Commissioner of Food and Drugs, Scott Gottlieb, MD, who was confirmed by the Senate yesterday 57–42. His support of faster approvals of generic drugs and looser restrictions on off-label marketing could become a factor in the drug-pricing discussion, and he supports “more widespread use of expedited approval reviews for brand-name drugs, the Wall Street Journal reports. The “veteran health-care investor and physician” has opposed importation of drugs by consumers from Canada and other countries.
PNN Pharmacotherapy Line
May 11, 2017 * Vol. 24, No. 91
Providing news and information about medications and their proper use
>>>Pharmacotherapy Report
Source: Early-release articles from Pharmacotherapy (2017; 37).
Postoperative Naloxone Nausea/Vomiting Prophylaxis: Based on a meta-analysis of nine randomized controlled trials, investigators conclude that low-dose naloxone “plays no role in preventing [postoperative nausea and vomiting (PONV)]” (10.1002/phar.1930). The drug reduces postoperative nausea, the authors note, but this does not “translate into decreases in postoperative vomiting,” as explained in this summary of data on 946 adult and pediatric patients: “Naloxone demonstrated a reduced risk of postoperative nausea (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.67–0.95, p = 0.01) in a pooled analysis of eight of the nine studies. However, naloxone did not decrease the risk of postoperative vomiting in a collective assessment of all nine trials (RR 0.83, 95% CI 0.63–1.09, p = 0.18). Subgroup analysis of continuous-infusion naloxone found further reductions in nausea and vomiting, but these findings were limited to 186 of the 946 patients. Three studies recorded antiemetic doses and found an overall dose reduction (RR 0.64, 95% CI 0.42–0.96, p = 0.03). Compared with controls, naloxone prophylaxis of PONV did not significantly change cumulative postoperative opioid needs (mean difference 0.29 mg, 95% CI −3.55 to 4.13 mg, p = 0.88) among five trials, nor visual analog scale pain scores (mean difference −0.11, 95% CI −0.26 to 0.05, p = 0.18) in six studies.” (R. W. Barrons, rbarrons@wingate.edu)
Benzalkonium Chloride in Albuterol Nebulizer Solutions: Authors advise against use of a bronchoconstricting preservative in pharmacy-prepared continuous albuterol nebulizer solutions (10.1002/phar.1929): “For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.” (L. Hendeles, lhendeles@gmail.com)
Drug Polymorphisms in Renal Transplant Recipients: Single nucleotide polymorphisms (SNPs) affect genes for metabolizing enzymes and transporters, a 148-patient study from Brazil shows, and this affects dose and dose-adjusted trough blood concentrations (CLaugh ratio) (10.1002/phar.1928): “ABCC2 c.−24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.−76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus CLaugh values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus CLaugh values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.−76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49–18.79, p <0.05).” (F. D. V. Genvigir, fdallavecchia@yahoo.com.br)
>>>PNN NewsWatch
* The
U.S. Senate Committee on Health, Education, Labor & Pensions this morning continues its consideration of S. 934, the Food and Drug Administration Reauthorization Act. The legislation is being fast-tracked by Congressional leadership and has become a vehicle for other health-related bills, including one that would create a category of OTC hearing aids for use in patients with mild or moderate deficits. Biosimilars, generic drugs, complex nonbiologic bioequivalence, and orphan drugs are other topics in the bill, according to RAPS and National Law Review reports.
PNN Pharmacotherapy Line
May 12, 2017 * Vol. 24, No. 92
Providing news and information about medications and their proper use
>>>Chest Highlights
Source: May issue of Chest (2017; 151).
Combination Therapy of H3N2 Influenza: Among adult patients hospitalized for influenza A(H3N2) infections in early 2015, treatment with a clarithromycin–naproxen–oseltamivir combination reduced 30- and 90-day mortality rates and hospital length of stay, investigators from Hong Kong write of a phase 2b/3 trial (pp. 1069–80). Compared with oseltamivir without placebo for 5 days in the open-label trial, 2 days of the drug combination followed by 3 days of oseltamivir produced these results: “Among the 217 patients with influenza A(H3N2) enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years, and 53.5% were men. Adverse events were uncommon. Ten patients died during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P = .01), less frequent high dependency unit admission (P = .009), and shorter hospital stay (P < .0001). The virus titer and [pneumonia severity index] (days 1–3; P < .01) and the [serial nasopharyngeal aspirate] specimens with [percentage of neuraminidase-inhibitor-resistant A(H3N2) virus] quasispecies ≥ 5% (days 1–2; P < .01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (OR, 0.06; 95% CI, 0.004–0.94; P = .04).” (K-Y Yuen)
Prophylactic Corticosteroids Before Elective Extubation: In critical care settings, postextubation airway events and reintubation were reduced by administration of prophylactic corticosteroids before elective extubations in mechanically ventilated patients (pp. 1002–10). A systematic review and meta-analysis found these outcomes in 11 trials of 2,472 patients: “Use of prophylactic corticosteroids was associated with a reduced incidence of postextubation airway events (risk ratio [RR], 0.43; 95% CI, 0.29–0.66) and reintubation (RR, 0.42; 95% CI, 0.25–0.71) compared with placebo or no treatment. This association was prominent in participants at high risk for the development of postextubation airway complications, defined using the cuff-leak test, with a reduced incidence of postextubation airway events (RR, 0.34; 95% CI, 0.24–0.48) and reintubation (RR, 0.35; 95% CI, 0.20–0.64). This association was not found in trials with unselected participants. Adverse events were rare.” (A. Kuriyama)
>>>Cardiology Report
Source: May issue of the Journal of the American College of Cardiology (2017; 69).
Ambulatory Hemodynamic Monitoring in Heart Failure: “Real-world” effectiveness of ambulatory hemodynamic monitoring of patients with heart failure (HF) is supported by CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association Functional Class III Heart Failure Patients) trial data (10.1016/j.jacc.2017.03.009). The retrospective cohort analysis of U.S. Medicare data shows a reduction in heart failure hospitalization (HFH) and HF costs with monitoring of patients undergoing pulmonary artery pressure sensor implantation in 2014–15: “Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001).” (A. S. Desai)
>>>PNN NewsWatch
*
Cholera vaccine recommendations for travelers to areas with active cholera transmission are published in yesterday’s MMWR.
* The number of
new hepatitis C virus infections reported to the CDC has tripled over the past 5 years, the agency reported yesterday. While many baby boomers continue to harbor undetected, asymptomatic virus, new infections are more common among those 20–29 years of age and are the result of the U.S. opioid epidemic.

PNN Pharmacotherapy Line
May 15, 2017 * Vol. 24, No. 93
Providing news and information about medications and their proper use
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Acute Myocardial Infarction With NSAIDs in Real-World Use: Patients taking any traditional or selective NSAID, including celecoxib and naproxen, are at increased risk of acute myocardial infarction, according to a systematic review and meta-analysis (j1909). “Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDs and was lower than for rofecoxib,” the authors conclude. “Risk was greatest during the first month of NSAID use and with higher doses.” (M. Bally, michele.bally.chum@ssss.gouv.qc.ca)
Diet & Risk of Gout in Men: Compared with a Western diet (high intake of red and processed meats, French fries, refined grains, sweets, and desserts), the DASH (Dietary Approaches to Stop Hypertension) diet is associated with a lower risk of gout in men, researchers report (j1794). Data for 44,444 men in the Health Professionals Follow-up Study show these benefits for those with high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats: “During 26 years of follow-up, 1,731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P = 0.005).” (H. K. Choi, hchoi@partners.org)
Genetic Risks of Early-Onset Hypertension: Heritable factors appear important when parents had early-onset hypertension, according to an analysis of data from the Framingham Heart Study (j1949). Patients with parental onset of hypertension before age 55 years had twice the risk of hypertension, leading to this conclusion: “Early onset and not late onset hypertension in parents was strongly associated with hypertension in offspring. In turn, early onset compared with late onset hypertension was associated with greater odds of cardiovascular, and particularly coronary, death. These findings suggest it may be important to distinguish between early onset and late onset hypertension as a familial trait when assessing an individual’s risk for hypertension, and as a specific type of blood pressure trait when estimating risk for cardiovascular outcomes in adults with established hypertension.” (T. J. Niiranen, teemu.niiranen@thl.fi)
>>>Lancet Highlights
Source:
 May 13 issue of Lancet (2017; 389).
Extrafine Triple Therapy in COPD: Single-inhaler extrafine therapy using three drugs was more effective for relieving symptoms of chronic obstructive pulmonary disease than tiotropium alone, the TRINITY study shows (pp. 1919–29). Participants received either tiotropium alone, fixed triple therapy with beclomethasone, formoterol fumarate, and glycopyrronium bromide as a single-dose, extrafine inhaler (fixed) or as individual inhalers (open), with these results: “Between Jan 21, 2014, and March 18, 2016, 2,691 patients received fixed triple (n = 1,078), tiotropium (n = 1,075), or open triple (n = 538). Moderate-to-severe exacerbation rates were 0.46 (95% CI 0.41–0.51) for fixed triple, 0.57 (0.52–0.63) for tiotropium, and 0.45 (0.39–0.52) for open triple; fixed triple was superior to tiotropium (rate ratio 0.80 [95% CI 0.69–0.92]; p = 0.0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0.061 L [0.037 to 0.086]; p <0.0001) and non-inferior to open triple (−0.003L [–0.033 to 0.027]; p = 0.85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple.” (J. Vestbo, jorgen.vestbo@manchester.ac.uk)
>>>PNN JournalWatch
* Mortality From Different Causes Associated With Meat, Heme Iron, Nitrates, and Nitrites in the NIH–AARP Diet And Health Study: Population Based Cohort Study, in BMJ, 2017; 357: j1957. (A. Etemadi, arash.etemadi@nih.gov
* Biologics in Patients With Skin Diseases, in 
Journal of Allergy and Clinical Immunology, 2017; 139: 1423–30. (N. H. Shear, neil.shear@sunnybrook.ca
* Charting the Future of Infectious Disease: Anticipating and Addressing the Supply and Demand Mismatch , in 
Clinical Infectious Diseases, 2017; 64: 1299–301. (R. P. Walensky, rwalensky@partners.org)

PNN Pharmacotherapy Line
May 16, 2017 * Vol. 24, No. 94
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 May 16 issue of the Annals of Internal Medicine (2017; 166).
Prevention and Treatment of Substance Use Disorders: In a position paper, the American College of Physicians advocates for management of substance use disorder involving illicit or prescription drugs as a chronic medical condition and supports “removing or reducing criminal penalties for nonviolent offenses involving illicit drugs” (pp. 733–6): “Substance use disorders have been regarded as a moral failing for centuries, a mindset that has helped establish a harmful and persistent stigma that affects how the medical community confronts addiction. We now know more about the nature of addiction and its effects on brain function, which has led to broader acceptance of the concept that substance use disorder is a disease, like diabetes, that can be treated. Communities across the country are confronting an opioid epidemic that has taken tens of thousands of lives, leading physicians to take a more active role in managing the condition and spurring policymakers to reassess the nation’s drug control policy. Physicians can help guide their patients toward recovery by becoming educated about substance use disorders, proper prescribing practices, consulting prescription drug monitoring programs to reduce opioid misuse, and assisting patients in their treatment. Policymakers can mitigate the effects of drug use by permitting harm reduction strategies, such as syringe exchange programs, supporting initiatives to increase the behavioral health workforce, testing evidence-based prevention and stigma-reduction programs, and encouraging treatment of substance use disorders among incarcerated persons and diversion programs for those with nonviolent drug arrests.” (R. A. Crowley, RCrowley@mail.acponline.org)
HEART Score for ED Chest Pain: Use of the HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score in patients presenting to emergency departments with chest pain is safe for identification of short-term risks of major adverse cardiac events (MACEs), Dutch researchers report, but clinicians often are reluctant to follow its management recommendations (pp. 689–97). At nine hospitals in the Netherlands, unselected patients with chest pain presenting in 2013–14 were managed with either usual care or, in one hospital every 6 weeks, with “HEART care,” producing these results in a stepped-wedge, cluster randomized trial: “A total of 3,648 patients were included (1,827 receiving usual care and 1,821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed.” (J. M. Poldervaart, j.poldervaart@umcutrecht.nl)
Cardiac Troponin T for Rapid Rule-out of AMI: Combined with a nonischemic electrocardiogram (ECG), a single high-sensitivity cardiac troponin T assay below detectable limits can be used to quickly rule out acute myocardial infarction (AMI), according to a collaborative meta-analysis (pp. 715–24). Investigators of studies provided data on the number of low-risk patients and the number who had AMI during hospitalization. Results were as follows: “Of 9,241 patients in 11 cohort studies, 2,825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day major adverse cardiac events ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died.” (M. Than, martinthan@xtra.co.nz)
>>>PNN NewsWatch
ASHP yesterday urged the U.S. Senate to “safeguard public health through the provision of robust coverage including access to health care services, affordable medications, and pharmacist patient care services” as it drafts health care reform legislation. As part of a six-point listing of its top priorities, the Society called for preserving the integrity of 340B drug pricing programs and recognizing pharmacists as full providers of care in team-based delivery models.

PNN Pharmacotherapy Line
May 17, 2017 * Vol. 24, No. 95
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 May 16 issue of JAMA (2017; 317).
Oral Iron Repletion in Heart Failure: In patients with heart failure with reduced left ventricular ejection fraction (HFrEF), exercise capacity was unchanged after 16 weeks of high doses of oral iron polysaccharide, researchers report (pp. 1958–66). Iron deficiency occurs in about 50% of these patients. Based on a primary end point of change in peak oxygen uptake (Vo2), effects of oral iron polysaccharide 150 mg twice daily or placebo were as follows: “Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak Vo2 was 1196 mL/min (interquartile range [IQR], 887–1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887–1449 mL/min) in the placebo group. The primary end point … did not significantly differ between the oral iron and placebo groups (+23 mL/min vs −2 mL/min; difference, 21 mL/min [95% CI, −34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), [plasma N-terminal pro-B-type natriuretic peptide] levels (159; 95% CI, −280 to 599 pg/mL), or [Kansas City Cardiomyopathy Questionnaire] score (1; 95% CI, −2.4 to 4.4), all P >.05.” (G. D. Lewis, glewis@partners.org)
Intra-articular Triamcinolone in Knee Osteoarthritis: Two years of steroid injections into the knees of patients with osteoarthritis produced significantly worse outcomes than saline injections, a study shows (pp. 1967–75). Intra-articular triamcinolone or saline every 12 weeks produced these changes in cartilage volume measured with annual magnetic resonance imaging: “Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm (between-group difference, −0.11 mm; 95% CI, −0.20 to −0.03 mm); and no significant difference in pain (−1.2 vs −1.9; between-group difference, −0.6; 95% CI, −1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels (between-group difference, −0.2%; 95% CI, −0.5% to −0.007%).” (T. E. McAlindon, tmcalindon@tuftsmedicalcenter.org)
Intravitreous Fluocinolone Implants in Uveitis: A common cause of noninfectious intraocular inflammation leading to visual impairment, uveitis is better treated with systemic therapy than implants of fluocinolone acetonide, according to 7-year follow-up results of participants in a randomized trial (pp. 1993–2005). Based on minimal clinically important differences of 7 letters in visual acuity testing, results for surgically placed implants and systemic corticosteroids supplemented by immunosuppression were as follows for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy): “Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1–12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).” (J. H. Kempen, john_kempen@meei.harvard.edu)
Postoperative Opioid Prescribing & Pain Scores: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) pain scores in Michigan hospitals did not correlate with opioid prescribing after surgery, a study shows, supporting less opioid use in these patients (pp. 2013–5; J. F. Waljee, filip@med.umich.edu).
>>>PNN NewsWatch
FDA has added a boxed warning to the labeling of canagliflozin (Invokana, Invokamet, Invokamet XR; Janssen) cautioning of an increased risk of leg and foot amputations with the antidiabetic drug.

PNN Pharmacotherapy Line
May 18, 2017 * Vol. 24, No. 96
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 May 18 issue of the New England Journal of Medicine (2017; 376).
Imatinib in Severe Refractory Asthma: A 24-week trial of imatinib in patients with poorly controlled severe asthma indicates involvement of KIT-dependent processes and mast cells in the pathophysiology of the disease, researchers report (pp. 1911–20). Participants had airway hyperresponsiveness despite maximal medical therapy when imatinib or placebo produced these results: “Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (± SD) of 1.73 ± 0.60 doubling doses in the imatinib group, as compared with 1.07 ± 0.60 doubling doses in the placebo group (P = 0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02 ± 2.32 vs. 0.56 ± 1.39 ng per milliliter, P = 0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.” (E. Israel, eisrael@partners.org)
“In those unfortunate people in whom the functions of mast cells can be strongly implicated as contributing to disease, suppressing their function or reducing their numbers may indeed confer more benefit than harm, particularly if these cells can be targeted locally at sites of disease,” an editorialist writes (
pp. 1983–4). “It should go without saying that if agents were to be devised that can more specifically target mast cells than do drugs such as imatinib, and can do so safely, then testing such agents in the clinic will be of particular interest.” (S. J. Galli)
Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: The anti–interleukin-5 monoclonal antibody mepolizumab produced significantly more weeks in remission among patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis and enabled less use of glucorticoids, a study shows, but only about one-half of patients benefited from the intervention (pp. 1921–32). Subcutaneous mepolizumab or placebo every 4 weeks over 52 weeks yielded these outcomes in 136 participants: “Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P <0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P <0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P <0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P <0.001). The safety profile of mepolizumab was similar to that observed in previous studies.” (M. E. Wechsler, mikewechsler@gmail.com)
“After this proof-of-concept study, additional research is needed to identify biomarkers that inform success and failure of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis and to elucidate the fate of tissue eosinophils, especially in vasculitic lesions,” according to editorialists (
pp. 1985–6). “Further studies may discover previously unknown pro-eosinophilic mechanisms or identify eosinophil-independent mechanisms in eosinophilic granulomatosis with polyangiitis. Future trials will also need not only to establish the appropriate dosing of mepolizumab but also to include participants with life-threatening eosinophilic granulomatosis with polyangiitis who were not included in this trial and possibly to evaluate synergy with immunosuppressants such as azathioprine and cyclophosphamide.” (R. Djukanovic)
>>>PNN NewsWatch
FDA yesterday expanded the approved use of ivacaftor (Kalydeco, Vertex Pharmaceuticals) for treating cystic fibrosis, tripling the number of rare gene mutations that the drug can now treat and expanding the indication from the treatment of 10 to 33 mutations.

PNN Pharmacotherapy Line
May 19, 2017 * Vol. 24, No. 97
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Infectious Diseases Report
Source:
 June 1 issue of Clinical Infectious Diseases (2017; 64).
Repeated Influenza Vaccinations & Hospitalizations: A study provides supportive data for people receiving annual influenza vaccinations, with higher vaccine effectiveness (VE) against hospitalization for influenza in those immunized during both current and prior seasons, compared with those immunized only in a single season (pp. 1564–72). Some studies have shown lower VE after multiple influenza vaccinations. In this study, data from the Australian Influenza Complications Alert Network (FluCAN) provide more reassuring data: “Over 2010–2015, 6,223 cases and 6,505 controls were hospitalized with confirmed influenza and influenza test–negative acute respiratory illness, respectively. Following stratification by quintile of propensity score, site, and year, VE was estimated to be 43% (95% confidence interval [CI], 37%–49%) overall. VE was estimated to be 51% (95% CI, 45%–57%) in those vaccinated in both the current and previous season, compared with 33% (95% CI, 17%–47%) vaccinated in the current season only and 35% (95% CI, 21%–46%) in the previous season only. Similar results were observed for influenza A/H1N1, influenza A/H3N2, and influenza B strains.” (A. C. Cheng)
Phage Lysis for Pathogenic E. coli: In an in vitro microscope study, therapeutically relevant bacteriophages were noninferior to beta-lactams in their cidal effects on pathogenic Escherichia coli, researchers report (pp. 1582–8). Comparing two phages and four antibiotics in two bacterial strains, investigators assessed kill rates and levels of associated endotoxin release (ER): “While beta-lactams have a relatively slow effect, both tested phages, as well as amikacin, were able to rapidly abolish the bacterial growth. Even when considering the fastest phage (cell lysis in 9 minutes), the concentrations of phage-induced ER never reached the highest values, which were recorded with antibiotic treatments. Cumulative concentrations of endotoxin over time in phage-treated conditions were lower than those observed with beta-lactams and close to those observed with amikacin. Whereas beta-lactams were responsible for strong cell morphology changes (spheroplast with imipenem, filamentous cells with cefoxitin and ceftriaxone), amikacin and phages did not modify cell shape but produced intracellular inclusion bodies.” (L. Debarbieux, laurent.debarbieux@pasteur.fr)
>>>Oncology Highlights
Source:
 May 10 issue of the Journal of Clinical Oncology (2017; 35).
Pravastatin in Small-Cell Lung Cancer: Combined with standard therapy for small-cell lung cancer (SCLC), pravastatin was safe but failed to demonstrate benefits among 846 patients (pp. 1506–14). Observational studies have shown possible statin benefits, but this randomized, placebo-controlled trial of pravastatin 40 mg daily during six chemotherapy cycles produced these results: “The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 [progression-free survival (PFS)] events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year [overall survival (OS)] rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups.” (M. J. Seckl, m.seckl@imperial.ac.uk)
“On the basis of these and other prospective trial data and given the resources required, additional prospective trials of statins to improve survival in other cancers are likely not justified,” an editorialist writes (
pp. 1497–8). “These data also fire another loud warning shot for cancer therapy repurposing, given the negative outcomes for thalidomide, topical nitroglycerin, and dalteparin. Moreover, for SCLC, where multiple trials have previously failed to deliver new systemic therapies despite encouraging retrospective or preclinical evidence, the systemic therapeutics future now eagerly anticipates late-phase development of immune-checkpoint inhibitors and antibody drug conjugates….” (S. Popat, sanjay.popat@rmh.nhs.uk)

PNN Pharmacotherapy Line
May 22, 2017 * Vol. 24, No. 98
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 May 20 issue of Lancet (2017; 389).
Rituximab & Short-Term Prednisone in Pemphigus: Compared with prednisone alone, first-line rituximab plus short-term prednisone proved more effective for patients with pemiphigus and produced fewer adverse events, researchers report (pp. 2031–40). At 25 French dermatology hospital departments, 90 adults newly diagnosed with pemphigus had these treatment responses: “At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38.4–71.7; p <0.0001. This difference corresponded to a relative risk of success of 2.61 (95% CI 1.71–3.99, p <0.0001), corresponding to 1.82 patients (95% CI 1.39–2.60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1.20 [SD 1.25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0.59 [1.15]; p = 0.0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]).” (J. Pascal, Pascal.Joly@chu-rouen.fr)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Medical Abortion & Online Telemedicine: Self-sourced medical abortion supported by online telemedicine services produces outcomes similar to those obtained in clinics, a study from Ireland and Northern Ireland shows (j2011). “Women are able to self identify the symptoms of potentially serious complications, and most report seeking medical attention when advised,” the authors conclude based on these results: “In 2010-12, abortion medications (mifepristone and misoprostol) were sent to 1,636 women and follow-up information was obtained for 1,158 (71%). Among these, 1,023 women confirmed use of the medications, and follow-up information was available for 1,000. At the time women requested help from [Women on Web], 781 (78%) were <7 weeks pregnant and 219 (22%) were 7–9 weeks pregnant. Overall, 94.7% (95% confidence interval 93.1% to 96.0%) reported successfully ending their pregnancy without surgical intervention. Seven women (0.7%, 0.3% to 1.5%) reported receiving a blood transfusion, and 26 (2.6%, 1.7% to 3.8%) reported receiving antibiotics (route of administration (IV or oral) could not be determined). No deaths resulting from the intervention were reported by family, friends, the authorities, or the media. Ninety three women (9.3%, 7.6% to 11.3%) reported experiencing any symptom for which they were advised to seek medical advice, and, of these, 87 (95%, 87.8% to 98.2%) sought attention. None of the five women who did not seek medical attention reported experiencing an adverse outcome.” (A. Aiken, araa2@utexas.edu)
Physician Age & Outcomes in Hospitalized Older Americans: Older adults treated in U.S. hospitals have poorer outcomes when treated by older physicians, according to analysis of a 20% sample of Medicare fee-for-service beneficiaries in 2011–14 (j1797): “Patients’ adjusted 30 day mortality rates were 10.8% for physicians aged <40 (95% confidence interval 10.7% to 10.9%), 11.1% for physicians aged 40-49 (11.0% to 11.3%), 11.3% for physicians aged 50–59 (11.1% to 11.5%), and 12.1% for physicians aged ≥60 (11.6% to 12.5%). Among physicians with a high volume of patients, however, there was no association between physician age and patient mortality. ” (Y. Tsugawa, ytsugawa@hsph.harvard.edu)
>>>PNN JournalWatch
* An Appraisal of the Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-analysis of the Age-Stratified Disease Occurrence, in Clinical Infectious Diseases, 2017; 64: 1604–11. (C. Britto, carl.britto@paediatrics.ox.ac.uk)
* Creation of an Interprofessional Teledementia Clinic for Rural Veterans: Preliminary Data, in 
Journal of the American Geriatrics Society, 2017; 65: 1092–9. (B. B. Powers, powersb3@uthscsa.edu
* Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups, in 
J. Gerontology, Series A, 2017; 72: 838–45. (M. A. Espeland, mespelan@wakehealth.edu)

PNN Pharmacotherapy Line
May 23, 2017 * Vol. 24, No. 99
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Rheumatology Report
Source:
 May issue of Arthritis & Rheumatology (2017; 69).
Risk Stratification Needed for Rheumatoid Arthritis Prevention: Among 110 participants in the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial, methotrexate administered for 1 year delayed and prevented development of rheumatoid arthritis (RA) in those at high risk who had undifferentiated arthritis (UA), researchers report (pp. 926–31). Reinvestigation of the methotrexate’s effects during 5 years of follow-up showed these results: “Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm (P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P <0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm (P = 0.031). These beneficial effects of MTX were observed both in anti–citrullinated protein antibody (ACPA)–positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score.” (L. E. Burgers, l.e.burgers@lumc.nl)
>>>Neurology Highlights
Source:
 May issue of Neurology (2017; 88).
Alcohol & ICH Risk: In the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, rare and moderate use of alcohol decreased participants’ risk of intracranial hemorrhage (ICH), while heavy alcohol consumption was linked to increased risk, particularly in black and Hispanic patients (pp. 2043–51). The case–control study recruited 1,000 patients with ICH in each of three racial-ethnic groupings and determined their risk based on alcohol use. With no-alcohol as the reference group, results showed: “Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p <0.0001), moderate (OR 0.65, p <0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p < 0.0001). A similar association was not found in white participants.” (S. Koch, skoch@med.miami.edu)
>>>PNN NewsWatch
FDA approval of an additional indication for subcutaneous tocilizumab (Actemra, Roche) provides the first therapy specific for giant cell arteritis. The agent was previously approved for subcutaneous treatment of moderate to severely active rheumatoid arthritis and intravenous treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis.
* Consumers should stop using the dietary supplement product 
Tri-Ton immediately and discard it in accordance in state and local ordinances, FDA said yesterday. Analysis of Tri-Ton indicated the presence of the selective anabolic androgen receptor modulators andarine and ostarine, the agency explained. All lots of the products are being recalled.
FDA announced yesterday that its review to date has identified no adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. While GBCAs may be associated with some gadolinium retention in the brain and other body tissues, lack of evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time, the agency said. FDA will continue to assess the safety of GBCAs and plans to have a public meeting to discuss this issue.

PNN Pharmacotherapy Line
May 24, 2017 * Vol. 24, No. 100
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 May 23/30 issue of JAMA (2017; 317).
Bevacizumab in Macular Edema: Among 362 patients with macular edema caused by central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept based on visual acuity after 6 months of treatment, SCORE2 researchers report (pp. 2072–87). Every-4-week injections of the drugs produced these outcomes with a noninferiority margin of 5 letters on visual acuity tests: “At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, −0.14; 97.5% CI, −3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure.” (P. C. VanVeldhuisen, score2@emmes.com)
“These results are welcome news for the treatment of common global eye care problems like retinal vein occlusions, given the priority that people place on avoiding blindness,” an editorialist writes (
pp. 2067–9). “The noninferior efficacy findings for visual acuity, the comparable rates of adverse ocular events, and the lower cost for bevacizumab from the 6-month primary outcome from SCORE2 are an excellent start. However, given the long-term need for anti-VEGF therapy in many eyes with macular edema from a central retinal or hemiretinal vein occlusion, additional data will be needed to guide further therapy. Continued follow-up results from SCORE2 are anticipated to compare outcomes between these anti-VEGF agents when other than fixed-monthly dosing schedules are used after 6 months. The primary outcome and subsequent results then can be weighed by patients with physician guidance in deciding which anti-VEGF agent to consider when treating macular edema from a central retinal or hemiretinal vein occlusion.” (N. M. Bressler, nbressler@jhmi.edu)
“The effort to compare efficacy and safety of treatments is increasingly critical when therapeutic options differ in cost, either to the individual consumer or to society as a whole,” writes the author of an invited 
JAMA Ophthalmology commentary (10.1001/jamaophthalmol.2017.1142). “Although studies including SCORE2 and Protocol T have been successful at collaborating with industry partners to provide partial support, the availability of resources independent of these companies through federal funding is essential for such endeavors. Both real and perceived conflicts of interest must be carefully managed with respect to industry involvement in studies. Future leveraging of available clinical trial infrastructure through existing networks and collaborations also would promote efficient implementation of such efforts.” (J. K. Sun, jennifer.sun@joslin.harvard.edu)
Antibiotics for Uncomplicated Cellulitis: “Among [496]patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim–sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis,” investigators conclude based on findings of a multicenter U.S. trial (pp. 2088–96). Relying on a primary outcome of clinical cure as evidenced by absence of signs of clinical failure, the group adds: “However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.” (G. J. Moran, idnet@ucla.edu)
>>>PNN NewsWatch
FDA yesterday granted accelerated approval to pembrolizumab (Keytruda, Merck) for treatment of adult and pediatric patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic solid tumors. This is the first agent approved for use in patients with a specific genetic biomarker without regard to location of the tumor.

PNN Pharmacotherapy Line
May 25, 2017 * Vol. 24, No. 101
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Early-release article from and the May 25 New England Journal of Medicine (2017; 376).
Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome: Among 120 children and young adults with the Dravet syndrome and drug-resistant seizures, cannabidiol reduced convulsive-seizure frequency more than placebo but was associated with higher rates of adverse events (pp. 2011–20). Dosed as an oral solution, cannabidiol 20 mg/kg/d produced these results in combination with standard antiepileptic therapy: “The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P = 0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P = 0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P = 0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P = 0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P = 0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.” (O. Devinsky, od4@nyu.edu)
While requiring replication, “this trial represents the beginning of solid evidence for the use of cannabinoids in epilepsy,” an editorialist writes (
pp. 2075–6). “Future trials may answer further questions about the applicability of cannabinoids to the many other syndromes of childhood epilepsy and to treatment in adults. After an era dominated by anecdote and obfuscated by medicolegal issues and emotionally infused debate, more scientific studies are under way. Much more research is needed to understand the basic science, benefits, and risks of cannabinoids in epilepsy.” (S. F. Berkovic)
Benralizumab in Severe Asthma: The interleukin-5-alpha receptor inhibitor benralizumab performed significantly better than placebo in a 28-week trial of 220 patients with severe asthma (10.1056/NEJMoa1703501). As presented at an American Thoracic Society meeting, the study showed reduced glucocorticoid use and exacerbation rates with the agent, as evident in these results: “The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P <0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P = 0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P <0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.” (P. Nair, parames@mcmaster.ca)
>>>PNN NewsWatch
* Pharmacies with substantial numbers of patients on Medicaid would be affected by the large decrease in enrollments under the American Health Care Act, if yesterday’s figures from the Congressional Budget Office prove accurate. Decreases in numbers of Medicaid beneficiaries would be 4.2 million by 2018, and this would climb to 14.4 million in 2026.

PNN Pharmacotherapy Line
May 26, 2017 * Vol. 24, No. 102
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Geriatrics Report
Source:
 May issue of the Journal of the American Geriatrics Society (2017; 65).
B12 Levels & Long-term Metformin Therapy: Among veterans in 2002–12, long-term use of metformin was associated with reduced serum levels of vitamin B12, researchers report, and these should be monitored and replaced based on clinical guidelines (pp. 1061–6). At a single Veterans Affairs Medical Center (VAMC), those aged 50 years or older with type 2 diabetes and taking long-term metformin showed these associations: “Only 37% of older adults with diabetes receiving metformin were tested for vitamin B12 status after long-term metformin prescription. The mean B12 concentration was significantly lower in the metformin-exposed group (439.2 pg/dL) compared to those without diabetes (522.4 pg/dL) (P = .0015). About 7% of persons with diabetes receiving metformin were vitamin B12 deficient (<170 pg/dL) compared to 3% of persons without diabetes or metformin use (P = .0001). Depending on their age, metformin users were two to three times more likely not to receive vitamin B12 testing compared to those without metformin exposure, after adjusting for sex, race and ethnicity, body mass index, and number of years treated at the VAMC.” (C. P. Vaughan, camille.vaughan@emory.edu)
Outcomes in Treated Hypertension at Age 80 or Older: Unplanned dips in systolic blood pressure (SBP) to levels below 135 mm Hg were associated with the highest levels of mortality in a study of patients aged 80 years or older who were being treated for hypertension at U.K. primary practices (pp. 995–1003). This could be a useful clinical sign of poor prognosis, the authors conclude, “perhaps requiring clinical review of overall care.” Assessment of SBPs in increments of 10 mm Hg from 125 to 185 mm Hg yielded these findings: “Myocardial infarction hazards increased linearly with increasing SBP, and stroke hazards increased for SBP of 145 mmHg or greater, although lowest mortality was in individuals with SBP of 135 to 154 mmHg. Mortality of the 13.1% of patients with SBP less than 135 mm Hg was higher than that of the reference group (Cox hazard ratio = 1.25, 95% confidence interval = 1.19–1.31; equating to one extra death per 12.6 participants). This difference in mortality was consistent over short- and long-term follow-up; adjusting for diastolic [blood pressure] did not change the risk. Incident heart failure rates were higher in those with SBP less than 125 mm Hg than in the reference group.” (D. Melzer, d.melzer@exeter.ac.uk)
>>>Diabetes Highlights
Source:
 June issue of Diabetes Care (2017; 40).
Renal Handling of Ketones With SGLT-2 Inhibitors: Glycosuria and other metabolic effects of sodium–glucose cotransporter 2 (SGLT-2) inhibitors lead to increased excretion of beta-hydroxybutyrate (beta-HB) and sodium, according to a study of 66 patients with type 2 diabetes and preserved renal function (pp. 771–6). These changes were positively related to glycosuria, the authors report, with smaller changes in those without diabetes than among controls. The group adds: “We conclude that the [SGLT-2] inhibitor–induced increase in beta-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.” (E. Ferrannini, ferranni@ifc.cnr.it)
>>>PNN NewsWatch
* Older age, obesity, and lower socioeconomic status are among the factors believed involved in a higher incidence of arthritis among rural U.S. residents. In this week’s MMWR, investigators report that 1 in 3 adults has arthritis, and about one-half of affected patients report arthritis-attributable activity limitations (2017; 66(20): 527–32; M. A. Boring, MBoring@cdc.gov): “Health care providers can help their patients manage their arthritis by recommending physical activity and self-management education programs. Adults with arthritis are more likely to attend a self-management education program when it is recommended by a health care provider.”
PNN will not be published on Mon., May 29, Memorial Day.

PNN Pharmacotherapy Line
May 30, 2017 * Vol. 24, No. 103
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 May 27 issue of Lancet (2017; 389).
Early Tranexamic Acid in Postpartum Hemorrhage: In the WOMAN trial, early administration of tranexamic acid reduced death from bleeding in women with postpartum hemorrhage, researchers report, with no adverse effects (pp. 2105–16). “When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset,” the authors conclude, based on these results at 193 hospitals in 21 countries: “Between March, 2010, and April, 2016, 20,060 women were enrolled and randomly assigned to receive tranexamic acid (n = 10,051) or placebo (n = 10,009), of whom 10,036 and 9,985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1.5%] of 10,036 patients vs 191 [1.9%] of 9,985 in the placebo group, risk ratio [RR] 0.81, 95% CI 0.65–1.00; p = 0.045), especially in women given treatment within 3 h of giving birth (89 [1.2%] in the tranexamic acid group vs 127 [1.7%] in the placebo group, RR 0.69, 95% CI 0.52–0.91; p = 0.008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3.6%] patients in the tranexamic acid group vs 351 [3.5%] in the placebo group, RR 1.02, 95% CI 0.88–1.07; p = 0.84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5.3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5.5%] in the placebo group, RR 0.97, 95% CI 0.87-1.09; p = 0.65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.” (Clinical Trials Unit, thewomantrial@LSHTM.AC.UK)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 356).
Antibiotic Rx Strategies in Lower Respiratory Tract Infections: In a prospective study of adolescents and adults with lower respiratory tract infections at U.K. general practices, delayed antibiotic prescriptions appeared preferable over immediate treatment, producing statistically similar numbers of hospitalizations and fewer subsequent consultations for worsening illness within 30 days (j2148). Multivariate analysis based on primary outcomes of reconsultations, hospital admissions, or death showed these results: “Of the 28,883 participants, 104 (0.4%) were referred to hospital for radiographic investigation or admission, or both on the day of the index consultation, or were admitted with cancer. Of the remaining 28,779, subsequent hospital admission or death occurred in 26/7,332 (0.3%) after no antibiotic prescription, 156/17,628 (0.9%) after prescription for immediate antibiotics, and 14/3,819 (0.4%) after a prescription for delayed antibiotics. Multivariable analysis documented no reduction in hospital admission and death after immediate antibiotics (multivariable risk ratio 1.06, 95% confidence interval 0.63 to 1.81, P = 0.84) and a non-significant reduction with delayed antibiotics (0.81, 0.41 to 1.64, P = 0.61). Reconsultation for new, worsening, or non-resolving symptoms was common (1,443/7,332 (19.7%), 4,455/17,628 (25.3%), and 538/3,819 (14.1%), respectively) and was significantly reduced by delayed antibiotics (multivariable risk ratio 0.64, 0.57 to 0.72, P <0.001) but not by immediate antibiotics (0.98, 0.90 to 1.07, P = 0.66).” (P. Little, p.little@soton.ac.uk)
>>>PNN NewsWatch
AstraZeneca is recalling one lot of professional sample bottles containing eight tablets of Brilinta (ticagrelor) 90 mg tablets (#JB5047) because of a report of one bottle also containing the company’s Zurampic (lesinurad) 200 mg tablets.
* Because of a rotation of blister packaging, 
Lupin Pharmaceuticals Inc. has recalled lot L600518 (exp. 05/18) of Mibelas 24 Fe (norethindrone acetate and ethinyl estradiol 1 mg/0.02 mg chewable and ferrous fumarate 75 mg) tablets to the consumer level.
>>>PNN JournalWatch
* Targeted-Release Budesonide Versus Placebo in Patients With IgA Nephropathy (NEFIGAN): A Double-Blind, Randomised, Placebo-Controlled Phase 2b Trial, in Lancet, 2017; 389: 2117–27. (B. C. Fellström, bengt.fellstrom@medsci.uu.se)
* Considerations and Controversies in Managing Chronic Kidney Disease: An Update, in 
American Journal of Health-System Pharmacy, 2017; 74: 795–810. (L. Prasad-Reddy, lprasad@csu.edu)

PNN Pharmacotherapy Line
May 31, 2017 * Vol. 24, No. 104
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Medical Care Report
Source:
 June issue of Medical Care (2017; 55).
ROI for ADR Surveillance: Pharmacovigilance programs that use active surveillance systems could generate large returns on investment (ROIs), authors conclude after analyzing public health and economic benefits in three case examples during which early signals of safety hazards were not recognized (pp. 545–51). Rofecoxib, cerivastatin, and troglitazone were eventually pulled from the U.S. market, but not until these costs — estimated using individual patient simulation model and the health care system perspective — were incurred: “We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773–$884 million for rofecoxib, $3–$10 million for cerivastatin, and $38–$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present.” (K. F. Huybrechts, khuybrechts@bwh.harvard.edu)
“We all … [bear] the financial return from public investment in a modern surveillance system for adverse drug effects,” an editorialist writes (
pp. 543–4). “Politics, for better or for worse, plays a critical role in public health financing decisions. Sustained public investment in a robust national pharmacovigilance system is warranted economically and because it provides the public health safety-net necessary in an era of faster drug approvals. It should be noted, however, that a robust pharmacovigilance system requires more than data and analytics alone. It requires rapid and transparent risk communication and regulatory decision-making processes. It also requires the ability to monitor the impact of regulatory decisions on health care utilization and health outcomes so that risk management strategies can be modified on the basis of evidence and not conjecture. Only then will we gain from our investment.” (E. H. Morrato, elaine.morrato@ucdenver.edu)
Cost-effectiveness of Antihypertensive Medications: Treatment of hypertension is cost-saving in white and black adults, a study concludes, with particularly marked effects on costs of care among black men and women (pp. 552–60). Using a State Transition Model to assess costs and quality-adjusted life–years (QALYs) and treatment data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study and published literature, researchers report these results in 2012 dollars for cardiovascular disease (CVD) events and health states such as stroke, coronary heart disease, heart failure, chronic kidney disease, and end-stage renal disease: “Antihypertensive medication treatment was cost-saving and increased QALYs compared with no-treatment for white men ($7,387; 1.14 QALYs), white women ($7,796; 0.89 QALYs), black men ($8,400; 1.66 QALYs), and black women ($10,249; 1.79 QALYs).” (G. S. Tajeu, gtajeu@uab.edu)
Quality of Midlevel Practitioner Primary Care: In community health centers in 2006–10, quality of care provided by nurse practitioners (NPs) and physician assistants (PAs) was “largely comparable” to that of primary care physicians (PCMDs), an analysis shows (pp. 615–22). National Ambulatory Medical Care Survey data for 23,704 patient visits to 1,139 practitioners showed these patterns in a multivariate regression analysis based on nine patient-level outcomes (three quality indicators, four service utilization measures, and two referral pattern measures): “On 7 of the 9 outcomes studied, no statistically significant differences were detected in NP or PA care compared with PCMD care. On the remaining outcomes, visits to NPs were more likely to receive recommended smoking cessation counseling and more health education/counseling services than visits to PCMDs (P ≤0.05). Visits to PAs also received more health education/counseling services than visits to PCMDs (P ≤0.01; design-based model only).” (E. T. Kurtzman, etk@gwu.edu)
>>>PNN NewsWatch
* Released early by the Annals of Internal Medicine, an article shows that switching directly to biologic therapy when methotrexate fails in rheumatoid arthritis is not cost-effective. Triple therapy with sulfasalazine, hydroxychloroquine, and methotrexate should be tried first, the results indicate.

PNN Pharmacotherapy Line
June 1, 2017 * Vol. 24, No. 105
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 1 New England Journal of Medicine (2017; 376).
Non–Small-Cell Lung Cancer Evolution: Chromosome instability is an important prognostic predictor in non–small-cell lung cancer (NSCLC), according to a study of intratumor heterogeneity and cancer genome evolution (pp. 2109–21). Multiregion whole-exome sequencing of 100 early-stage NSCLC tumors showed these results in the prospective cohort TRACERx study: “We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P = 4.4×10−4), which remained significant in multivariate analysis.” (C. Swanton, charles.swanton@crick.ac.uk)
“It is hoped that TRACERx is not just a candle at the end of the heterogeneity tunnel but a headlight on a train of similar initiatives that can carry cancer researchers out of the darkness,” editorialists write (
pp. 2190–1). “TRACERx is a proof of concept that longitudinal sampling can uncover novel pathways for tumor evolution, heterogeneity, and resistance to therapy. This report will no doubt be followed by more such efforts that will apply these principles to untangling the phylogenetic complexity of other types of cancers.” (A. I. Robles)
Strategies for Previously Treated HCV: In the POLARIS-1 and POLARIS-4 trials, 12 weeks of sofosbuvir–velpatasvir–voxilaprevir provided high rates of sustained virologic response among patients with several genotypes of hepatitis C virus (HCV) infection for whom treatment with direct-acting antiviral agents had previously failed (pp. 2134–46). POLARIS-1 included 300 patients with HCV genotype 1 infection and 114 patients with other genotypes; 314 patients with HCV genotype 1, 2, or 3 infection and 19 patients with HCV genotype 4 infection participated in POLARIS-4. Sofosbuvir–velpatasvir–voxilaprevir produced these compartative outcomes: “In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.” (M. Bourlière, mbourliere@hopital-saint-joseph.fr)
Adjuvant Capecitabine for Breast Cancer: Among 910 patients with HER2-negative breast cancer who had residual invasive disease, addition of adjuvant capecitabine therapy to standard neoadjuvant chemotherapy was safe and effective, researchers report, prolonging disease-free and overall survival (pp. 2147–59): “The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P = 0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P = 0.01).…” (M. Toi, toi@kuhp.kyoto-u.ac.jp)
>>>PNN NewsWatch
Jeff A. Goad, PharmD, MPH, of Chapman U. School of Pharmacy has received the 2017 Ronald P. Bangasser, MD, Immunization Leadership Award from the California Immunization Coalition. Goad has maintained an active travel health clinic for 15 years and was president of CIC in 2012–14.

PNN Pharmacotherapy Line
June 2, 2017 * Vol. 24, No. 106
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Pediatrics Report
Source:
 June issue of Pediatrics (2017; 139).
Safety of Cough & Cold Medications: Countering concerns about adverse events (AEs) with cough and cold medication (CCM) use in pediatric patients, a study shows low rates of reactions and no deaths with therapeutic doses among cases with experiences recorded in five data sources (10.1542/peds.2016-3070). Reports with AEs following ingestion of at least one CCM (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) in children younger than 12 years of age were assessed by an expert panel, with these results: “Of the 4,202 cases reviewed, 3,251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553–0.593) or 1 case per 1.75 million units.” (J. L. Green)
Aspirin Dose in Kawasaki Disease: Administered concomitantly with intravenous immunoglobulin to children aged 0 to 10 years of age with acute Kawasaki disease (KD), low-dose aspirin was noninferior to higher doses of acetylsalicylic acid (ASA), researchers report (10.1542/peds.2017-0098). At two institutions that routinely used low-dose ASA (3–5 mg/kg/d) and three institutions using high-dose ASA (80 mg/kg/d) in 2004–15, these results were recorded: “There were 1,213 subjects included, 848 in the high-dose and 365 in the low-dose ASA group. There was no difference in the risk of [coronary artery (CA)] abnormalities in the low-dose compared with the high-dose ASA group (22.2% vs 20.5%). The risk difference adjusted for potential confounders was 0.3% (95% confidence interval [CI]: −4.5% to 5.0%). The adjusted risk difference for CA abnormalities persisting at the 6-week follow-up was −1.9% (95% CI: −5.3% to 1.5%). The 95% CI of the risk difference of CA abnormalities adjusted for confounders was within the prespecified 5% margin considered to be noninferior.” (F. Dallaire)
Evidence-Based Asthma Interventions: “Evidence-based interventions can be successfully adapted into primary care settings that serve impoverished, high-risk populations, reducing the morbidity of asthma in these high-need populations,” conclude investigators who studied 590 children aged 5–12 years with moderate to severe asthma (10.1542/peds.2016-4221). In the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) study, these results were noted at three intervention and three control sites in Arizona, Michigan, and Puerto Rico: “Allergen sensitivity testing (96%) and home environmental assessments (89%) were performed on the majority of intervention children. Overall study activity completion (eg, intervention visits, clinical assessments) was 70%. Overall and individual site participant symptom days in the previous 4 weeks were significantly reduced compared with control findings (control, change of −2.28; intervention, change of −3.27; difference, −0.99; P < .001), and this result was consistent with changes found in the rigorous evidence-based interventions.” (S. Kennedy)
Disparities in ADHD Treatment Quality: Care of Medicaid-enrolled youth with attention-deficit/hyperactivity disorder (ADHD) is poor overall, with minorities having higher rates of medication discontinuation, a study shows (10.1542/peds.2016-2444). Based on data from nine state programs, the authors conclude that these disparities “translate into higher rates of treatment disengagement because most youth discontinuing medication receive no psychotherapy.” (J. R. Cummings)
>>>PNN NewsWatch
FDA yesterday approved the first generic versions of Strattera (atomoxetine) to treat attention-deficit/hyperactivity disorder in pediatric and adult patients.

PNN Pharmacotherapy Line
June 5, 2017 * Vol. 24, No. 107
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 357).
ADHD Risk & Prenatal Antidepressant Use: Data from Hong Kong indicate that if there is a causal association between maternal use of antidepressants during pregnancy and offspring development of attention-deficit/hyperactivity disorder (ADHD), a confounding factor related to drug indication partially explains the relationship and “the size of the effect is probably smaller than that reported previously” (j2350). Analysis of 190,618 children and 1,252 mothers who used prenatal antidepressants yielded these results: “5,659 children (3.0%) were given a diagnosis of ADHD or received treatment for ADHD. The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P <0.01) compared with non-use. After adjustment for potential confounding factors, including maternal psychiatric disorders and use of other psychiatric drugs, the adjusted hazard ratio was reduced to 1.39 (95% confidence interval 1.07 to 1.82, P = 0.01). Likewise, similar results were observed when comparing children of mothers who had used antidepressants before pregnancy with those who were never users (1.76, 1.36 to 2.30, P <0.01). The risk of ADHD in the children of mothers with psychiatric disorders was higher compared with the children of mothers without psychiatric disorders even if the mothers had never used antidepressants (1.84, 1.54 to 2.18, P <0.01). All sensitivity analyses yielded similar results. Sibling matched analysis identified no significant difference in risk of ADHD in siblings exposed to antidepressants during gestation and those not exposed during gestation (0.54, 0.17 to 1.74, P = 0.30).” (I. C. K. Wong, i.wong@ucl.ac.uk)
“Decision models that incorporate the risks of maternal depression and drugs and also take into account individual factors, including genetic traits, would be helpful,” an editorialist writes, adding, “Such models will require more research on the importance of these factors, and greater collaboration to reach sample sizes big enough to generate answers to these important questions.” (
j2544). The author adds this advice for clinicians: “Future care of pregnant women with depression should ideally consider detailed clinical and background information, including type of treatment and pharmacogenetic traits. Importantly, the nature and severity of maternal mental illness must be taken into account. Because the uncertainties around many of the risks statistically associated with antidepressants cannot be disregarded, pregnant women with mild depression may benefit from non-drug treatment. However, pregnant women with severe depression need effective treatment that will in most cases include antidepressants.” (L. H. Pedersen, LHP@clin.au.dk)
>>>PNN NewsWatch
ASHP’s House of Delegates yesterday adopted a policy of “studied neutrality” on the issue of pharmacist participation in medical aid in dying, leaving the choice to individual pharmacists based on their own conscience. The policy is similar to that of APhA, which avoids “a particular moral stance on the issue of physician-assisted suicide.” Other policy topics adopted by the ASHP House during its first meeting at the Society’s Summer Meetings in Minneapolis included expansion of federal and state laws and regulations on collaborative drug therapy management by pharmacists, multimodal pain therapy, increased competition among generic and biosimilar products, transgender care, and controlled substance diversion prevention programs. The ASHP election slate was also announced; presidential candidates are Philip J. Schneider of Kansas and Kelly M. Smith of Kentucky.
>>>PNN JournalWatch
* The Impact of Pediatric-Specific Vancomycin Dosing Guidelines: A Quality Improvement Initiative, in Pediatrics, 2017; 139: 10.1542/peds.2016-2423. (M. Miloslavsky) 
* Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review, in 
Pediatrics, 2017; 139: 10.1542/peds.2016-4131. (J. N. Lind) 
* Nutritional and Dietary Interventions for Autism Spectrum Disorder: A Systematic Review, in 
Pediatrics, 2017; 139: 10.1542/peds.2017-0346. (N. Sathe) 
* Irritability in Youths: A Translational Model, in 
American Journal of Psychiatry, 2017; 174: 520–32. (M. A. Brotman)
* Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD, in 
American Journal of Kidney Diseases, 2017; 69: 815–26. (J. B. Wish, jaywish@earthlink.net)

PNN Pharmacotherapy Line
June 6, 2017 * Vol. 24, No. 108
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June 6 issue of the Annals of Internal Medicine (2017; 166).
Antibiotics for Nonbacterial AURIs in Older Adults: Physician descriptors can be used to identify likely prescribers of antibiotics for older adults with nonbacterial acute upper respiratory infections (AURIs), a study shows (pp. 765–74). Among primary care practices in Ontario in 2012, mid- or late-career physicians with high patient volumes were more likely to give antibiotic prescriptions for nonbacterial AURIs, as were physicians trained outside of Canada or the U.S. The low-risk patient population, all aged 66 years or older, had these outcomes during encounters for nonbacterial AURIs: “The cohort included 8,990 primary care physicians and 185,014 patients who presented with a nonbacterial AURI, including the common cold (53.4%), acute bronchitis (31.3%), acute sinusitis (13.6%), or acute laryngitis (1.6%). Forty-six percent of patients received an antibiotic prescription; most prescriptions were for broad-spectrum agents (69.9% [95% CI, 69.6% to 70.2%]). Patients were more likely to receive prescriptions from mid- and late-career physicians than early-career physicians (rate difference, 5.1 percentage points [CI, 3.9 to 6.4 percentage points] and 4.6 percentage points [CI, 3.3 to 5.8 percentage points], respectively), from physicians trained outside of Canada or the United States (3.6 percentage points [CI, 2.5 to 4.6 percentage points]), and from physicians who saw 25 to 44 patients per day or 45 or more patients per day than those who saw fewer than 25 patients per day (3.1 percentage points [CI, 2.1 to 4.0 percentage points] and 4.1 percentage points [CI, 2.7 to 5.5 percentage points], respectively).” (M. F. Silverman, michael.silverman@sjhc.london.on.ca)
“We should be optimistic that the current state of affairs is amenable to large-scale improvement,” an editorialist writes (
pp. 844–5). “Durable reductions in antibiotic prescribing have been observed in countries where rigorous local and national campaigns were launched. In the United States, we have substantially decreased antibiotic use in young children. Outpatient stewardship is an expanding feature of antibiotic stewardship programs associated with health systems, which heretofore focused on the inpatient setting. Further research will improve our understanding of the cognitive and motivational processes that drive clinical behaviors and how clinicians share information, attitudes, and practice norms to shape prescribing patterns. Studies of behavioral interventions that target modifiable risk factors, can be integrated into clinician workflow, and promote sustainable change are needed. The tipping point to a culture of judicious antibiotic use is within reach, with clinicians at the forefront of change. Preservation of the benefits of the ‘wonder drugs’ depends on us.” (B. E. Jones, barbara.jones@hsc.utah.edu)
HBV Reactivation During HCV Therapy: In patients being treated with direct-acting agents for hepatitis C virus (HCV) infection, reactivation of hepatitis B virus (HBV) is “a newly identified safety concern” (pp. 792–8). Clinical monitoring is needed in patients with a history of HBV infection, researchers conclude, based on these cases reported in the FDA Adverse Event Reporting System: “The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom [HBV reactivation (HBV-R)] developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others.” (S. Bersoff-Matcha, Susan.Bersoff-Matcha@fda.hhs.gov)
Osteoporosis Guideline: A practice guideline from the American College of Physicians recommends treatment of women with osteoporosis for 5 years with alendronate, risedronate, zoledronic acid, or denosumab (pp. 818–39). Men with clinically recognized osteoporosis should be treated with bisphosphonates, the guideline states, but no duration of therapy is specified. (A. Qaseem, aqaseem@acponline.org)

PNN Pharmacotherapy Line
June 7, 2017 * Vol. 24, No. 109
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 6 issue of JAMA (2017; 317).
Obstacles to Biosimilar Adoption: Noting the need for pharmacists to be able to substitute biosimilars, authors of a Viewpoint article outlined obstacles to the agents’ adoption for chronic diseases (pp. 2163–4): “Several policy solutions may help ensure that savings from biosimilars can be realized, assuming that biosimilars are less expensive and are priced lower than branded biologics. The US biosimilars pathway allows the FDA to designate biosimilar products as ‘interchangeable,’ a higher standard than ‘biosimilarity.’ However, since 2013, only 21 states have passed laws allowing substitution by a pharmacist based on interchangeability. Moreover, the FDA released draft regulatory guidance in January 2017 outlining a case-by-case approach for determining whether a biosimilar could be designated as interchangeable, considering biocharacterization, analytical similarity, switching studies, and postmarketing data. With this guidance in place, automatic substitution laws in all states based on interchangeability could bolster competition, lower prices, and increase biosimilar availability for patients.” (J. S. Ross, joseph.ross@yale.edu)
Trends in Medicare Annual Wellness Visits: Use of annual wellness visits (AWVs) by Medicare beneficiaries has remained “modest” since their introduction as part of the Affordable Care Act in 2010, researchers report (pp. 2233–5). A 20% sample of Medicare claims indicated these patterns among nearly 6 million eligible patients for each year from 2011 to 2014, which showed an increase from 7.5% of beneficiaries in 2011 to 15.6% in 2014: “White individuals, urban residents, and those from higher-income areas and with 1 or 2 comorbidities were more likely to receive an AWV, as were beneficiaries who received an AWV in the previous year (53.4% receiving an AWV in the previous year vs 10.4% not receiving an AWV in the previous year; P <.001) or belonged to an [accountable care organization (ACO)] (25.9% belonged to an ACO vs 17.6% did not belong to an ACO; P <.001). Among all AWVs, 44.4% (95% CI, 44.3%–44.5%) had a concurrent problem-based visit.
“Regional AWV rates in 2014 varied from 3.0% (95% CI, 2.5%–3.5%) in San Angelo, Texas, to 34.3% (95% CI, 33.0%–35.8%) in Appleton, Wisconsin. Rates were not correlated with Medicare spending (Pearson coefficient, 0.01; P = .85).” (I. Ganguli, 
iganguli@partners.org)
>>>PNN NewsWatch
* Three quarters of patients with Legionnaire’s disease acquired the pathogen from health care facilities, CDC said yesterday. Referring to data from 21 U.S. juridictions, CDC Acting Director Anne Schuchat said, “Legionnaires’ disease in hospitals is widespread, deadly, and preventable. These data are especially important for health care facility leaders, doctors, and facility managers because it reminds them to think about the risks of Legionella in their facility and to take action. Controlling these bacteria in water systems can be challenging, but it is essential to protect patients.”
Max L. (Mick) Hunt last night received the 2017 Harvey A. K. Whitney Award at the ASHP Summer Meetings in Minneapolis. Hunt, associate professor emeritus at the Northeast Ohio Medical U. College practiced during his career at Novation (now Vizient), U. Kentucky Hosp., Lutheran General Hosp. in Park Ridge, IL, and St. Marys Hosp. in Rochester, MN.
* Reporting yesterday to the ASHP House of Delegates at its second meeting, 
Lisa M. Gersema of St. Paul, MN, reviewed her year as the Society’s president by reviewing the components of “Pharmacy’s True North,” the theme of her presidential year: Accountability, Collaboration, Excellence, and Leadership. The new ASHP president is Paul W. Bush of Durham, NC.
* Attendance at the ASHP Midyear Clinical Meeting last year in Las Vegas reached a record 25,483, said 
ASHP CEO Paul W. Abramowitz. Former First Lady Michelle Obama will keynote this year’s Midyear, scheduled for Dec. 3–7 in Orlando. The ASHP budget continues to grow, from $40.5 million in 2012 to a projected $50.7 million in 2018, he added. ASHP — celebrating its 75th anniversary this year — recently sold its building as part of transportation and redevelopment activities in downtown Bethesda, MD, and has now settled into a state-of-the-art facility a few blocks away. The new facility was dedicated last month as the Joseph A. Oddis Global Headquarters of ASHP.

PNN Pharmacotherapy Line
June 8, 2017 * Vol. 24, No. 110
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 8 issue of the New England Journal of Medicine (2017; 376).
Cardiac Malformations With Lithium Use in Pregnancy: A study supports previous observations of a link between heart defects and maternal use of lithium in the first trimester of pregnancy but finds a smaller magnitude of effect than “previously postulated” (pp. 2245–54). In a cohort study of 1.3 million pregnancies in Medicaid-enrolled women, infants born alive between 2000 and 2010 had these heart problems: “Cardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1,945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group.” (E. Patorno, epatorno@bwh.harvard.edu)
Early, Goal-Directed Therapy for Septic Shock: A patient-level meta-analysis shows lack of better mortality outcomes and higher costs with early, goal-directed therapy (EGDT) in those with septic shock (pp. 2223–34). PRISM investigators report these results when data from the ProCESS, ARISE, and ProMISe trials were pooled: “We studied 3,723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1,852 patients [24.9%]) and usual care (475 of 1,871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P = 0.68). EGDT was associated with greater mean (± SD) use of intensive care (5.3 ± 7.1 vs. 4.9 ± 7.0 days, P = 0.04) and cardiovascular support (1.9 ± 3.7 vs. 1.6 ± 2.9 days, P = 0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation.” (PRISM Investigators, kathy.rowan@icnarc.org)
Mortality With Mandated Emergency Care for Sepsis: The times to treatment for sepsis care and antibiotic initiation — but not the time to initiation of intravenous fluids — are associated with lower risk-adjusted in-hospital mortality, a study shows (pp. 2235–44). Based on data reported to the New York State Department of Health from Apr. 1, 2014, to June 30, 2016, investigators found these outcomes among patients who had a sepsis protocol initiated within 6 hours of arrival in the emergency department and had all items in a 3-hour bundle of care completed within 12 hours: “Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P <0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P <0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P = 0.21).” (C. W. Seymour, seymourcw@upmc.edu)
>>>PNN NewsWatch
Brad Tice, PharmD, MBA, FAPhA, of Thompsons Station, TN, is the 2018–19 APhA president-elect, the Association announced this week. Elected to 3-year terms as trustees were Magaly Rodriguez de Bittner, PharmD, FAPhA, of U. Maryland and Theresa Tolle, BPharm, FAPhA, of Sebastian, FL.

PNN Pharmacotherapy Line
June 9, 2017 * Vol. 24, No. 111
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Chest Highlights
Source:
 June issue of Chest (2017; 151).
Hydrocortisone, Vitamin C, & Thiamine for Severe Sepsis: In a retrospective before–after clinical study of patients with severe sepsis and septic shock, intravenous vitamin C, given with corticosteroids and thiamine, prevented progressive organ dysfunction — including acute kidney injury — and reduced mortality, researchers report (pp. 1229–38). Compared with a control group of 47 patients treated in an intensive care unit during the previous 7 months, 47 patients given the triple therapy during the ensuing 7-month period had these outcomes: “The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P <.001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04–0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P <.001).” (P. E. Marik)
“The pathophysiology of sepsis reminds us that high-dose IV vitamin C should probably be limited to the very early phase of severe sepsis or septic shock because in the long run, low levels of [reactive oxygen species] are crucial for intracellular signaling,” editorialists write (
pp. 1199–200). “To avoid the Linus Pauling trap [considering megadoses of vitamin C a panacea for cancer], pragmatic multicenter trials are needed to confirm this benefit and to exclude unforeseen harm as was seen in previous sepsis trials using promising drugs. Studies should also determine optimal dose and treatment duration, whether normal or temporarily supernormal plasma concentrations should be obtained, whether intermittent (high peak concentrations) or continuous dosing (less renal excretion of vitamin C and oxalate) performs better, whether coadministration of thiamine reduces oxalate excretion, and finally whether the combination with hydrocortisone acts synergistically.” (H. M. Oudemans–van Straaten)
>>>Cardiology Report
Source:
 June 13 issue of the Journal of the American College of Cardiology (2017; 69).
Non–Vitamin K Antagonist Oral Anticoagulant Dosing in AF With Renal Dysfunction: Non–vitamin K antagonist oral anticoagulants (NOACs) are often dosed outside product labeling, a study shows, compromising safety without greater effectiveness of the drugs in patients with atrial fibrillation (AF) (10.1016/j.jacc.2017.03.600). Analysis of a large U.S. administrative database identified 14,865 patients with AF who were taking apixaban, dabigatran, or rivaroxaban in 2010–15 showed these outcomes with standard doses in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication was not present (potential underdosing): “Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.” (X. Yao)
>>>PNN NewsWatch
FDA yesterday requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market. In a statement, FDA said, “After careful consideration, the agency is seeking removal based on its concern that the benefits of the drug may no longer outweigh its risks. This is the first time the agency has taken steps to remove a currently marketed opioid pain medication from sale due to the public health consequences of abuse.”

PNN Pharmacotherapy Line
June 12, 2017 * Vol. 24, No. 112
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Incretin-Based Treatments & Mortality: Claims that incretin-based treatment of patients with type 2 diabetes is associated with increased mortality are not supported in a systematic review and meta-analysis (j2499). The authors conclude that further study of the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is needed, based on these findings: “189 randomised controlled trials (n = 155,145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3,888 deaths among 151,614 patients. Meta-analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1,925/84,136 v 1,963/67,478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2 = 0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1,000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.” (X. Sun, sunx26@gmail.com)
Alcohol Intake & Cognition: Britain’s cancer-based recommendations for lower alcohol intake are supported by results of an observational cohort study of 550 men and women who had adverse brain outcomes with moderate consumption, researchers conclude (j2353). Screening questionnaires and magnetic resonance imaging showed the following: “Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P ≤0.001), even those drinking moderately (14–21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P = 0.007). There was no protective effect of light drinking (1–<7 units/week) over abstinence. Higher alcohol use was also associated with differences in corpus callosum microstructure and faster decline in lexical fluency. No association was found with cross sectional cognitive performance or longitudinal changes in semantic fluency or word recall.” (A. Topiwala, anya.topiwala@psych.ox.ac.uk)
>>>Lancet Highlights
Source:
 June 10 issue of Lancet (2017; 389).
Infliximab-to-Biosimilar Switches: In the Norwegian noninferiority NOR-SWITCH trial, efficacy, safety, and immunogenicity outcomes were similar among patients treated with the infliximab originator product and a biosimilar, CT-P13 (pp. 2304–16). The phase 4 trial was conducted in 2014–15, and the adult patients had one of several diseases for which the agent is used. Based on a primary end point of disease worsening during 52-week follow-up and a noninferiority margin of 15% (assuming 30% disease worsening), results showed: “155 (32%) patients in the full analysis set had Crohn’s disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4.4%, 95% CI −12.7 to 3.9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively).” (T. K. Kvien, t.k.kvien@medisin.uio.no)
>>>PNN JournalWatch
* LOX-1 in Atherosclerosis and Myocardial Ischemia : Biology, Genetics, and Modulation, in Journal of the American College of Cardiology, 2017; 69: 2759–68. (N. V. K. Pothineni) 
* Sleep and Neurodegeneration: A Critical Appraisal, in 
Chest, 2017; 151: 1375–86. (J. A. Pillai) 
* A Randomized Clinical Trial Comparing the Effects of Antitussive Agents on Respiratory Center Output in Patients With Chronic Cough, in 
Chest, 2017; 151: 1288–94. (G. Fontana) 
* Composite End Points in Clinical Research: A Time for Reappraisal, in 
Circulation, 2017; 135: 2299–307. (P. W. Armstrong)
PNN Pharmacotherapy Line
June 13, 2017 * Vol. 24, No. 113
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June issue of JAMA Internal Medicine (2017; 177).
Preventing CMV Reactivation in Critically Ill Patients: Reactivation of cytomegalovirus (CMV) during critical illness can be blocked through prophylaxis with valacyclovir or low-dose valganciclovir, researchers report (pp. 774–83). Occurring in up to one third of critically ill patients, reactivation of latent CMV infections is associated with a 2-fold increase in mortality. In 124 CMV-seropositive patients who had mechanical ventilation for at least 24 hours in a British intensive care unit, these outcomes were noted in a 28-day, proof-of-principle study: “Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04–0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm.” (N. J Cowley, nicholascowley@nhs.net)
Acid Suppression & Recurrent Clostridium difficile Infection: Patients on long-term proton pump inhibitors or histamine-2 blockers may be at greater risk of recurrent primary Clostridium difficile infection (CDI), according to a systematic review and meta-analysis (pp. 784–91). “These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies,” the authors conclude. “It may be reasonable to re-evaluate the need for these medications in patients with CDI.” In 16 observational studies of 7,703 patients with CDI, including 1,525 individuals with recurrent cases, these associations were evident: “The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4,038 patients) compared with 17.3% (633 of 3,665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20–1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08–1.76; P = .02).” (S. Khanna, khanna.sahil@mayo.edu)
“An unbiased assessment without the risk of unmeasured confounding would require randomized clinical trials of gastric acid suppressant continuation vs withdrawal among patients with 
C difficile colitis who are also using chronic gastric acid suppressants,” editorialists write (p. 791). “In the meantime, these findings support a strategy of withholding gastric acid suppression therapy in the setting of active or recent C difficile infection.” (S. R. Bauer)
Reducing Antipsychotic Use Through Communication Training: In 93 Massachusetts nursing homes, antipsychotic use declined during implementation of an OASIS train-the-trainer communication intervention (pp. 846–53). Decreases did not continue during the maintenance phase of the intervention, but the authors concluded that their “study adds evidence for nonpharmacological programs to treat behavioral and psychological symptoms of dementia.” (J. Tjia, jennifer.tjia@umassmed.edu)
Polypharmacy Among Older Adults: In a “Teachable Moment” contribution, authors use the case of an 83-year-old woman on unnecessary digoxin and atorvastatin to examine principles of polypharmacy and utility of the Beers and STOPP criteria (p. 871): “Optimizing an individual’s medication takes into account more than just practice guidelines but also patient preferences. Correctly assessing the unique preferences of the patient allows for tailoring medication regimens to each patient’s individual circumstances, including affordability, tolerability, and goals of care. In this case, the patient’s priorities were to minimize pill burden, improve affordability, and avoid hospitalization if at all possible.” (C. Carroll, casey.carroll@ucdenver.edu)
>>>PNN NewsWatch
* The 2018 print and online editions of the CDC’s travel-health Yellow Book are now available.

PNN Pharmacotherapy Line
June 14, 2017 * Vol. 24, No. 114
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 13 issue of JAMA (2017; 317).
Iron Products for Nutritional Iron-Deficiency Anemia: In a study of infants and young children with nutritional iron-deficiency anemia (IDA), ferrous sulfate produced a greater increase in hemoglobin concentration at 12 weeks than iron polysaccharide complex, researchers report (pp. 2297–304). Doses of elemental iron 3 mg/kg using products with the two iron sources produced these results at a U.S. tertiary care hospital among participants aged 9–48 months: “Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P <.001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P <.001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 μg/dL (ferrous sulfate) vs 506 to 417 μg/dL (iron complex) (a greater difference of −50 μg/dL [95% CI, −86 to −14 μg/dL] with ferrous sulfate; P <.001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04).” (J. M. Powers, jacquelyn.powers@bcm.edu)
NSAIDs for Chronic Low Back Pain: NSAIDs are of limited value in treatment of patients with chronic low back pain, according to authors of a JAMA Clinical Evidence Synopsis (pp. 2327–8). Results of 13 randomized clinical trials that included 4,807 participants led to this bottom line: “Compared with placebo, NSAIDs are associated with a small but significant improvement in pain and disability in patients with chronic low back pain, although this difference became nonsignificant when studies with high risk for bias were excluded. The associated benefits were smaller than the minimal clinically important difference.” (W. T. M. Enthoven, w.enthoven@erasmusmc.nl)
Brain Amyloid & Cognitive Function: Elevated brain amyloid levels in cognitively normal people are a troublesome prognostic indicator, a study shows (pp. 2305–16). Over a median follow-up period of 3.1 years in 445 study participants, those with elevated amyloid levels had a higher likelihood of cognitive decline than did those with normal levels. (M. C. Donohue, mdonohue@usc.edu)
“Together with the findings reported from other independent cohorts, [this study] clearly indicates that amyloid pathology in cognitively normal older persons is not a benign phenomenon of normal aging but part of a progressive neurodegenerative disease,” editorialists write (
pp. 2285–7). “These findings pave the way for the development of preventive strategies that ultimately may enable persons with [Alzheimer disease] to live without dementia.” (P. J. Visser, pj.visser@maastrichtuniversity.nl)
>>>PNN NewsWatch
* Announcing plans for a July 10–11 meeting to assess opioid formulations with abuse-deterrent properties, FDA Commissioner Scott Gottlieb, MD, said in a statement posted on the FDA website, “Opioid formulations with properties designed to deter abuse are not abuse-proof or addiction-proof. These drugs can still be abused, particularly orally, and their use can still lead to new addiction. Nonetheless, these new formulations may hold promise as one part of a broad effort to reduce the rates of misuse and abuse. One thing is clear: we need better scientific information to understand how to optimize our assessment of abuse deterrent formulations; and I look forward to a productive discussion on how to best tackle this challenge.” FDA released an issues paper outlining existing regulatory and public health challenges regarding these products.
* Bristol-Myers Squibb is voluntarily recalling one lot (HN0063) of 
Eliquis (apixaban) 5 mg tablets to the consumer level because of a consumer complaint of a bottle labeled as 5 mg that contained 2.5 mg tablets, FDA said yesterday.

PNN Pharmacotherapy Line
June 15, 2017 * Vol. 24, No. 115
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 15 issue of the New England Journal of Medicine (2017; 376).
Buprenorphine for Neonatal Abstinence Syndrome: Compared with oral morphine, sublingual doses of buprenorphine produced better efficacy and equivalent safety outcomes in 63 term infants with neonatal abstinence syndrome, a study shows (pp. 2341–8). Infants exposed to opioids in utero and with signs of the syndrome were randomized to one of the treatments, with these results based on a primary end point of duration of treatment for symptoms of neonatal opioid withdrawal: “The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P <0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P = 0.36). Rates of adverse events were similar in the two groups.” (W. K. Kraft, walter.kraft@jefferson.edu)
Treatment of HIV-Associated Talaromycosis: Amphotericin produced significantly better outcomes in treating infections of the dimorphic fungus Talaromyces (previously Penicilliummarneffei in patients with HIV infections than the oral agent itraconazole, researchers report (pp. 2329–40). The infections are a major source of mortality in patients with HIV in South and Southeast Asia. Based a primary outcome of all-cause mortality at week 24, investigators report the following results in 440 adult patients with HIV and talaromycosis at five Vietnamese hospitals: “The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], −3.9 to 5.6; P <0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P = 0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and [immune reconstitution inflammatory syndrome] than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.” (T. Le, thuyl@oucru.org)
Effects of Hospital Value-Based Purchasing on Quality: In the 4 years since being mandated under provisions of the Affordable Care Act, hospital value-based purchasing (HVBP) “has resulted in little tangible benefit,” authors conclude, adding, “It may be useful for the Centers for Medicare and Medicaid Services to continue to experiment with other value-based payment models, including the [Hospital Readmissions Reduction Program], accountable care organization programs, and bundled payment programs, in an effort to improve the value of hospital spending” (pp. 2358–66). The HVBP program incentivizes acute-care hospitals for quality performance-based adjustments of up to 1% of Medicare reimbursements. Comparing acute-care hospitals with a control group of critical access hospitals, which were not exposed to HVBP, the authors found that “HVBP was not associated with improvements in measures of clinical process or patient experience and was not associated with significant reductions in two of three mortality measures” (mortality among patients admitted for acute myocardial infarction or heart failure was unchanged, while mortality among those admitted for pneumonia declined). (A. M. Ryan, amryan@umich.edu)
>>>PNN NewsWatch
Biosimilars scored a victory in the U.S. Supreme Court this week when Sandoz prevailed in a case against Amgen. The result should be accelerated marketing of biosimilars, as the Court ruled that a required 180-day notification need not begin after FDA approval; the biosimilars company can notify the originator company of its intent at the time of application submission to FDA, according to SCOTUSblog.
* Consumers, distributors, and retailers with any lot of several 
Phillips Company products should stop using and return unused, unexpired products to the manufacturer, FDA said yesterday. This recall affects Tetrastem, Diabecline, Tetracycline-ABC, VenomX, Acneen, StaphWash, StringMed, NoPain, and LidoMed.

PNN Pharmacotherapy Line
June 16, 2017 * Vol. 24, No. 116
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Infectious Diseases Report
Source:
 June 15 issue of Clinical Infectious Diseases (2017; 64).
Hospitalization & Pediatric Pneumococcal Vaccine: At eight U.S. children’s hospitals, pneumococcal pneumonia (PP) requiring hospitalization declined after introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 (pp. 1699–704). In 2006–14, these annual pneumococcal pneumonia hospitalization rates per 100,000 admissions were identified: “A total of 377 patients with PP requiring hospitalization were identified. Hospitalization rates of PP decreased from 53.6 to 23.3 per 100,000 admissions post PCV13 (P <.0001). Complicated PP rates also decreased (P <.0001). Need for intensive care, mechanical ventilation, and invasive procedure remained unchanged after the introduction of PCV13. Comorbidities were more common among children with uncomplicated than complicated pneumonia (52.2% vs. 22.5%, P <.001). Overall, PCV13 serotypes 19A, 3, 7F, and 1 caused 80% of PP. Hospitalization rates of PCV13 serotype pneumonia decreased from 47.2 to 15.7 per 100,000 admissions post PCV13. In 2014, the most common serotypes were 3, 19A and 35B.” (L. Olarte)
Efficacy of All-Oral HCV/HIV Regimens: Oral treatment of patients coinfected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) produced high sustained virologic response (SVR) rates in those with genotype-1 (GT1) HCV, researchers report (pp. 1711–20). An observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry led to this conclusion for 12 weeks of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV: “African American race or [proton pump inhibitor] use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with [tenofovir disoproxil fumarate].” (D. Bhattacharya)
Short-Course Adjunctive Gentamicin in Severe Sepsis: In two Dutch intensive care units, short courses of empirical gentamicin “in patients with sepsis was associated with an increased incidence of renal failure but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance,” a study of 648 patients shows (pp. 1731–6). One of the units used a protocol that recommended empirical gentamicin as add-on therapy; logistic regression analysis of outcomes showed the following: “The adjusted odds ratios associated with gentamicin use were 1.39 (95% confidence interval [CI], 1.00–1.94) for renal failure, 1.34 (95% CI, 0.96–1.86) for shock duration, and 1.41 (95% CI, 0.94–2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (P = .62).” (D. S. Y. Ong)
>>>Oncology Highlights
Source:
 June issue of the Journal of Clinical Oncology (2017; 35).
Adjuvant Bisphosphonates in Breast Cancer: Zolendrate or clodronate are preferred agents in adjuvant therapy of postmenopausal women with breast cancer, according to a guideline from Cancer Care Ontario and the American Society of Clinical Oncology (pp. 2062–81): “Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations.” (S. Dhesy-Thind)
>>>PNN NewsWatch
* Advanced Pharma, Inc. (Avella of Houston) is voluntarily recalling all unexpired lots of nitroglycerin admixtures produced between Mar. 3 and May 31 to the hospital/user level, FDA said yesterday. The agency also said Teva is recalling to the consumer/user level Actavis-labeled paliperidone extended-release tablets, 3 mg, 90 count bottles, lot 1160682A, because of failure of the dissolution test.

PNN Pharmacotherapy Line
June 19, 2017 * Vol. 24, No. 117
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 June 17 issue of Lancet (2017; 389).
NSAID Selection in Patients with CVD, GI Risks: In the CONCERN trial of patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib was safer than naproxen for reducing the risk of recurrent upper gastrointestinal bleeding, researchers report (pp. 2375–82). Both drugs were administered in combination with PPIs, and study participants all were taking aspirin for cardiovascular prophylaxis. The cyclooxygenase-2–selective NSAID celecoxib, administered in doses of 100 mg twice daily, produced these outcomes in comparison with naproxen 500 mg twice daily: “Between May 24, 2005, and Nov. 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5.6% (95% CI 3.3–9.2) in the celecoxib group and 12.3% (8.8–17.1) in the naproxen group (p = 0.008; crude hazard ratio 0.44, 95% CI 0.23–0.82; p = 0.010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study.” (F. K. L. Chan, fklchan@cuhk.edu.hk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 356).
Congenital Malformations With Maternal Overweight, Obesity: Women with body mass indices (BMIs) above the normal range should attempt to lose weight before becoming pregnant, based on results of a study of major congenital malformations among 1.2 million singletons (j2563). Assessing data from Swedish national registries in 2001–14, investigators found these relationships in a cohort study: “A total of 43,550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20,074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.” (M. Persson, Martina.Persson@ki.se)
>>>PNN NewsWatch
* Alvogen is voluntarily recalling seven lots of Hospira’s Clindamycin Injection USP ADD-Vantage Vials to the hospital/retail level due to microbial growth detected during a routine simulation of the manufacturing process, FDA said on Friday.
FDA also announced that Hospira is voluntarily recalling 42 lots of 8.4% Sodium Bicarbonate Injection, USP, 50 mL vials, 5 lots of Neut (sodium bicarbonate 4% additive solution) 5 mL vials, 5 lots of Quelicin (Succinylcholine Chloride Injection, USP) 200 mg/10 mL vials and 7 lots of Potassium Phosphates Injection, USP, 45 mM vials to the hospital/retail level, also because of microbial growth detected during a routine simulation of the manufacturing process.
>>>PNN JournalWatch
* Phenotypic and Genetic Aspects of Epithelial Barrier Function in Asthmatic Patients, in Journal of Allergy and Clinical Immunology, 2017; 139: 1736–51. (Donna E. Davies, donnad@soton.ac.uk
* Benefits, Pitfalls, and Future Design of Population-Based Registers in Neurodegenerative Disease, in 
Neurology, 2017; 88: 2321–9. (J. P .K. Rooney, jrooney@rcsi.ie)

PNN Pharmacotherapy Line
June 20, 2017 * Vol. 24, No. 118
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June 20 issue of the Annals of Internal Medicine (2017; 166).
Lipid Screening & Cardiovascular Risks in Young Adults: Among American adults aged 30–49 years, prevalence of increased atherosclerotic cardiovascular disease (ASCVD) was low among women younger than 50 and men younger than 40 if they had no ASCVD risk factors, researchers report (pp. 876–82). Data from the National Health and Nutrition Examination Survey 1999 to 2000 through 2011 to 2012 for those without known ASCVD or diabetes showed the following: “Overall, 9,608 NHANES participants representing 67.9 million adults were included, with approximately half (47.12%, representing 32 million adults) in low-prevalence subgroups. In the absence of smoking or hypertension, 0.09% (95% CI, 0.02% to 0.35%) of adult men younger than 40 years and 0.04% (CI, 0.0% to 0.26%) of adult women younger than 50 years had an elevated risk. Among other subgroups, 0% to 75.9% of participants had an increased risk. Overall, 2.9% (CI, 2.3% to 3.5%) had an LDL-C level of 4.92 mmol/L (190 mg/dL) or greater.” (K. K. Patel, patelkris@umkc.edu)
This analysis excluded those already on statins and those with known hypercholesterolemia in youth, editorialists point out (
pp. 901–2). These and other limitations of the study led editorialists to this conclusion: “Absence of evidence is not evidence of absence. We disagree with the [U.S Preventive Services Task Force] recommendation to delay lipid screening until mid-adulthood simply because clinical trial evidence is not available in younger persons. Rather, we believe that at least 1-time LDL-C screening should be universally recommended for all patients in their late teen or early adult years. If anything, we support the principled biologic approach promoted by the American Academy of Pediatrics, which recommends that all children be screened for high cholesterol levels at least once between the ages of 9 and 11 years, and again between ages 17 and 21 years.” (P. M. Ridker, pridker@partners.org)
>>>Allergy/Immunology Report
Source:
 June issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Intradermal Grass Pollen Immunotherapy: While “intradermal allergen immunotherapy suppressed skin late-phase responses,” investigators conclude that the intervention “was not clinically effective and resulted in worsening of respiratory allergic symptoms” in 93 adult participants with grass pollen–induced allergic rhinitis (pp. 1830–9.e13). Seven preseason intradermal allergen injections or a histamine control produced these outcomes based on a primary end point of daily combined symptom–medication scores during the 2013 pollen season: “There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, −172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, −11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense–specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03).” (S. J. Till, stephen.till@kcl.ac.uk)
>>>PNN NewsWatch
* FDA yesterday approved the fluoroquinolone delafloxacin (Baxdela, Melinta Therapeutics) for treatment of adults with acute bacterial skin and skin-structure infections caused by susceptible bacteria. The agent has activity against both gram-positive and gram-negative pathogens, including methicillin-resistant Staphylococcus aureus. It will be available in intravenous and oral formulations. As with other fluoroquinolones, delafloxacin labeling includes a boxed warning of serious adverse reactions, including tendinitis, tendon rupture, peripheral neuropathy, CNS effects, and exacerbation of myasthenia gravis.

PNN Pharmacotherapy Line
June 21, 2017 * Vol. 24, No. 119
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 20 issue of JAMA (2017; 317).
Combination Regimens for Advanced Colorectal Cancer: For treating patients with KRAS wild-type (wt) untreated advanced or metastatic colorectal cancer, addition of cetuximab or bevacizumab to the mFOLFOX6 or FOLFIRI chemotherapy regimen produced statistically similar outcomes, a study shows (pp. 2392–401). In 2005–12, adults at National Clinical Trials Network centers in the U.S. and Canada had these outcomes: “Among 1,137 patients (median age, 59 years; 440 [39%] women), 1,074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0–110.7 months), and 82% of patients (938 of 1,137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab–chemotherapy group and 29.0 months in the bevacizumab–chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77–1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab–chemotherapy group and 10.6 months in the bevacizumab–chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84–1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%–9.0%, P = .13).” (A. Venook, alan.venook@ucsf.edu)
“No difference” does not mean “not the same,” editorialists counter (
pp. 2376–8): “Taking the results at face value, it may appear that it would be reasonable to treat advanced, unresectable RAS wt colorectal cancer with either FOLFOX or FOLFIRI in combination with either cetuximab or bevacizumab given that there were no significant differences between the regimens for overall survival or progression-free survival. However, with emerging data from several trials regarding right- vs left-sided colon cancer, the most recent National Comprehensive Cancer Network Guidelines for colon cancer now recommend consideration of [epidermal growth factor-receptor (EGFR)] therapy [cetuximab] for patients with RAS wt and left-sided tumors only in the first-line therapy setting. What cannot be determined from the study by Venook et al is the effect of subsequent therapy or if EGFR inhibitors can be effectively used in RAS wt right-sided colon cancer for second-line treatment and beyond.” (W. A. Messersmith, wells.messersmith@ucdenver.edu)
Screening for Pediatric Obesity: Updating its 2010 recommendation, the U.S. Preventive Services Task Force (USPSTF) advises clinicians to “screen for obesity in children and adolescents 6 years and older and offer or refer them to comprehensive, intensive behavioral interventions to promote improvements in weight status” (pp. 2417–26). The “B” recommendation is based on these findings from an evidence review: “Comprehensive, intensive behavioral interventions (≥26 contact hours) in children and adolescents 6 years and older who have obesity can result in improvements in weight status for up to 12 months; there is inadequate evidence regarding the effectiveness of less intensive interventions. The harms of behavioral interventions can be bounded as small to none, and the harms of screening are minimal. Therefore, the USPSTF concluded with moderate certainty that screening for obesity in children and adolescents 6 years and older is of moderate net benefit.” (D. C. Grossman, chair@uspstf.net)
“The USPSTF recommendation should provide an impetus to redouble efforts to invest in practice, community, policy, and multilevel intervention research focused on achieving primary prevention and sustained improvements in health and health trajectories for children and adolescents and their families,” editorialists write (
pp. 2378–80). “Such a focus is critical for reversing the obesity epidemic.” (R. L. J. Thornton, rjohns21@jhmi.edu)
Chronic Pain Therapies: “The primary change in approach to the treatment of chronic pain is the use of nonpharmacological therapies,” write Viewpoint authors (pp. 2367–8). “A wide range of psychological, self-management, educational, and complementary and alternative therapies are available but are often underutilized.” These include structured educational programs, cognitive behavioral and other psychologic therapies, mindfulness meditation, and increased activity through structured exercise programs (usually walking). (T. L. Schwenk, tschwenk@med.unr.edu)

PNN Pharmacotherapy Line
June 22, 2017 * Vol. 24, No. 120
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 22 issue of the New England Journal of Medicine (2017; 376).
First-Line Nivolumab in Non–Small-Cell Lung Cancer: In an open-label phase 3 trial of 423 patients with previously untreated stage IV or recurrent non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) expression level of 5% or more, overall survival was similar with first-line nivolumab or platinum-based chemotherapy (pp. 2415–26). With crossover to nivolumab allowed in patients with disease progression, the trial investigators found these results: “The median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P = 0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.” (D. P. Carbone, david.carbone@osumc.edu)
“In light of these data, the presence of PD-L1 expression in at least 50% of tumor cells versus in less than 50% of tumor cells should be determined in patients with newly diagnosed, advanced NSCLC with the use of the assay associated with pembrolizumab efficacy until a prospectively evaluated alternative biomarker shows similar predictive value,” an editorialist writes (
pp. 2483–5). “The exploratory biomarker of the tumor-mutation burden that is proposed by Carbone et al. is intriguing, but it is akin to an algorithm developed today that predicts last season’s World Series victory by the Cubs. Although potentially meritorious, its ability to pick this season’s champion is unclear. If subtly different PD-L1–enhancement strategies can distinguish a strongly positive study from a clearly negative one, it will be important to evaluate consistency among pathologists. If the strategies for the selection of patients in clinical practice differ significantly from proven approaches, the data suggest that our patients may not derive the same benefits as have been seen in clinical trials.” (E. B. Garon)
Recombinant Influenza Vaccine in Adults Aged 50 Years or More: In 8,855 adults aged 50 years or older, a quadrivalent, recombinant influenza vaccine (RIV4) provided better protection than a standard-dose, egg-grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2-predominant 2014–15 influenza season, researchers report (pp. 2427–36). The RIV4 formulation had 3 times as much hemagglutinin (HA) per strain (45 mcg versus 15 mcg of HA per strain in the IIV4 product). Based on occurrence of reverse-transcriptase polymerase-chain-reaction (RT-PCR)–confirmed, protocol-defined, influenza-like illness, results showed the following: “Among RIV4 recipients, the RT-PCR–confirmed influenza attack rate was 2.2% (96 cases among 4,303 participants) in the modified per-protocol population and 2.2% (96 cases among 4,427 participants) in the modified intention-to-treat population. Among IIV4 recipients, the attack rate was 3.2% (138 cases among 4,301 participants) in the modified per-protocol population and 3.1% (138 cases among 4,428 participants) in the modified intention-to-treat population. A total of 181 cases of influenza A/H3N2, 47 cases of influenza B, and 6 cases of nonsubtypeable influenza A were detected. The probability of influenza-like illness was 30% lower with RIV4 than with IIV4 (95% confidence interval, 10 to 47; P = 0.006) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4. The safety profiles of the vaccines were similar.” (L. M. Dunkle, ldunkle@proteinsciences.com)
Benralizumab in Severe Asthma: The interleukin-5-alpha receptor inhibitor benralizumab was oral glucocorticoid–sparing in a trial of 220 patients with severe asthma (pp. 2448–58). Over 28 weeks of randomized treatment, exacerbation rates were lower with the monoclonal antibody than with placebo, and median steroid doses were 75% lower. (P. Nair, parames@mcmaster.ca)

PNN Pharmacotherapy Line
June 23, 2017 * Vol. 24, No. 121
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Health Affairs Report
Source:
 June issue of Health Affairs, a theme issue on Pursuing Health Equity (2017; 36).
Impacts of Obamacare: As the U.S. Senate takes up a bill to repeal and replace the Affordable Care Act (ACA), researchers report the 3-year impacts of ACA in two expansion (AR and KY) states and one nonexpansion (TX) state (pp. 1119–28): “By the end of 2016 the uninsurance rate in the two expansion states had dropped by more than 20 percentage points relative to the nonexpansion state. For uninsured people gaining coverage, this change was associated with a 41-percentage-point increase in having a usual source of care, a $337 reduction in annual out-of-pocket spending, significant increases in preventive health visits and glucose testing, and a 23-percentage-point increase in ‘excellent’ self-reported health. Among adults with chronic conditions, we found improvements in affordability of care, regular care for those conditions, medication adherence, and self-reported health.” (B. D. Sommers, bsommers@hsph.harvard.edu)
U.S. Trends That Could Exacerbate Health Inequities: Trends in U.S. health care that could worsen health inequities are reviewed (pp. 992–8): “Health inequities among people of different races and ethnicities, geographical locations, and social classes are not a new phenomenon, although the size of the inequities has changed since researchers first began documenting them. While interventions to improve the health of targeted disadvantaged groups may help combat disparities, broader trends that disproportionately benefit privileged groups or harm vulnerable populations can eclipse the progress made through isolated interventions. These trends threaten equity in health and health care in the United States either through direct effects on health or through impacts on the distribution of resources, risks, and power. We highlight trends in four domains: health care technologies, health reform policies, widening socioeconomic inequality, and environmental hazards. We suggest ways of countering the effects of these trends to promote health equity, focusing on strategies that promise co-benefits across multiple sectors.” (M. C. Arcaya, marcaya@mit.edu)
Income-Related Differences in Perception About Health Care: Large differences in the ways Americans view health care relate to income, a study shows, and the gaps are much larger than in other countries (pp. 1032–40). In 32 middle- and high-income countries, income gaps and perceptions in 2011–13 showed these trends: “While high-income respondents were generally more positive about their health and health care in most countries, the gap between them and low-income respondents was much bigger in some than in others. The United States has among the largest income-related differences in each of the measures we studied, which assessed both respondents’ past experiences and their confidence about accessing needed health care in the future. Relatively low levels of moral discomfort over income-based health care disparities despite broad awareness of unmet need indicate more public tolerance for health care inequalities in the United States than elsewhere. Nonetheless, over half of Americans felt that income-based health care inequalities are unfair, and these respondents were significantly more likely than their compatriots to support major health system reform—differences that reflect the country’s political divisions. Given the many provisions in the Affordable Care Act that seek to reduce disparities, any replacement would also require attention to disparities or risk taking a step backward in an area where the United States is in sore need of improvement.” (J. O. Hero, hero@fas.harvard.edu)
>>>PNN NewsWatch
FDA has approved Haegarda, the first C1 esterase inhibitor (human) for subcutaneous administration to prevent attacks of the orphan disease hereditary angioedema (HAE) in adolescent and adult patients. The CSL Behring product is a human plasma–derived, purified, pasteurized, lyophilized concentrate prepared from large pools of human plasma from U.S. donors. It is indicated for routine prophylaxis to prevent but not treat acute HAE attacks.
* Following Hospira’s recent recall (
see PNN, June 19), Advanced Pharma, Inc. d/b/a Avella of Houston, is conducting a limited recall of specific lots of repackaged or compounded potassium phosphate and succinylcholine chloride.

PNN Pharmacotherapy Line
June 26, 2017 * Vol. 24, No. 122
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 June 24 issue of Lancet (2017; 389).