Dec 2016

PNN October–December 2016

PNN Pharmacotherapy Line
Oct. 3, 2016 * Vol. 23, No. 191
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Mortality With Concomitant Tamoxifen Plus SSRIs: Use of SSRIs that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) was not associated with increased mortality during tamoxifen therapy, a population-based cohort study concludes (i5014). Two cohorts of women were constructed using five U.S. databases; those in cohort 1 began SSRI treatment while taking tamoxifen, and women in cohort 2 were taking an SSRI when tamoxifen therapy began. Based on all-cause mortality in each cohort for women taking CYP2D6 inhibitors (paroxetine, fluoxetine) versus other SSRIs, the investigators found: “There were 6,067 and 8,465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1,014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9–4.5) and 2.0 (0.8–3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1,000 person years) compared with other SSRIs (rate 57.9/1,000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses.” (J. J. Gagne, jgagne1@partners.org)
NSAIDs & Heart Failure: In a nested case–control study, use of several but not all NSAIDs was associated with increased risk of hospitalization for heart failure, researchers report (i4857). The effect was dose dependent, the group noted, adding these details of analysis of five population-based health databases: “Current use of any NSAID (use in preceding 14 days) was found to be associated with a 19% increase of risk of hospital admission for heart failure (adjusted odds ratio 1.19; 95% confidence interval 1.17 to 1.22), compared with past use of any NSAIDs (use >183 days in the past). Risk of admission for heart failure increased for seven traditional NSAIDs (diclofenac, ibuprofen, indomethacin, ketorolac, naproxen, nimesulide, and piroxicam) and two COX 2 inhibitors (etoricoxib and rofecoxib). Odds ratios ranged from 1.16 (95% confidence interval 1.07 to 1.27) for naproxen to 1.83 (1.66 to 2.02) for ketorolac. Risk of heart failure doubled for diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib used at very high doses (≥2 defined daily dose equivalents), although some confidence intervals were wide. Even medium doses (0.9-1.2 defined daily dose equivalents) of indomethacin and etoricoxib were associated with increased risk. There was no evidence that celecoxib increased the risk of admission for heart failure at commonly used doses.” (G. Corrao, giovanni.corrao@unimib.it)
Bivalirudin or Unfractionated Heparin in ACS: Compared with heparin with or without glycoprotein IIb/IIIa inhibitors, bivalirudin monotherapy did not reduce major adverse cardiovascular events or net adverse clinical events in patients with acute coronary syndrome (ACS) with or without ST-segment elevation (i4935). The open-label trial included 7,213 patients with ACS undergoing planned percutaneous coronary intervention: “In patients with ST segment elevation, major adverse cardiovascular events occurred in 118 (5.9%) assigned to bivalirudin and 129 (6.5%) assigned to heparin (rate ratio 0.90, 95% confidence interval 0.70 to 1.16; P = 0.43), whereas net adverse clinical events occurred in 139 (7.0%) patients assigned to bivalirudin and 163 (8.2%) assigned to heparin (0.84, 0.67 to 1.05; P = 0.13). In patients without ST segment elevation, major adverse cardiovascular events occurred in 253 (15.9%) assigned to bivalirudin and 262 (16.4%) assigned to heparin (0.97, 0.80 to 1.17; P = 0.74), whereas net adverse clinical events occurred in 262 (16.5%) patients assigned to bivalirudin and 281 (17.6%) assigned to heparin (0.93, 0.77 to 1.12; P = 0.43).” (M. Valgimigli, marco.valgimigli@insel.ch)

>>>PNN NewsWatch
* FDA on Friday warned consumers against the use of homeopathic teething tablets and gels, saying they may pose a risk to infants and children, including seizures in infants and children.

>>>PNN JournalWatch
* Codeine: Time to Say “No,” in
Pediatrics, 2016; 138: 10.1542/peds.2016-2396. (J. D. Tobias)
* The Role of Cognitive Bias in Suboptimal HPV Vaccine Uptake, in
Pediatrics, 2016; 138: 10.1542/peds.2016-1537. (L. M. Niccolai)

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 © 2016, 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 Pharmacotherapy Line
Oct. 4, 2016 * Vol. 23, No. 192
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 4 issue of the Annals of Internal Medicine (2016; 165).
Treatment-Related Antifracture Effects: Among 6,629 women on medications for osteoporosis, treatment-related increases in total bone mineral density (BMD) resulted in a reduced risk of fracture, researchers report (pp. 465–72). While the outcome had been projected, this registry-based cohort study provides evidence of efficacy for reducing fractures. Women in the study were aged 40 years or older living in Manitoba. Results of two dual-energy x-ray absorptiometry scans combined with registry data showed the following: “During a mean of 9.2 years, 910 (13.7%) women developed incident fractures, including 198 with hip fractures. After adjustment for baseline fracture probability, women with a detectable decrease in total hip BMD compared with stable BMD had an absolute increase of 2.9% (95% CI, 1.5% to 4.4%) and 5.5% (CI, 2.8% to 8.1%) in the 5- and 10-year cumulative incidence of any fracture, respectively. In contrast, risk for any fracture in women with a detectable increase in total hip BMD was 1.3% (CI, 0.4% to 2.2%) and 2.6% (CI, 0.7% to 4.5%) lower after 5 and 10 years, respectively. Consistent results were seen for change in femoral neck and lumbar spine BMD and across a range of subgroup analyses.” (W. D. Leslie, bleslie@sbgh.mb.ca)
U.S. Trends in Prevalence of Chronic Kidney Disease: The prevalence of chronic kidney disease (CKD), rising in recent decades, stabilized over the past 10 years, a study shows (pp. 473–81). Defining stage 3 or 4 CKD as an estimated glomerular filtration rate (eGFR) of 15–59 mL/min/1.73 sq m, investigators found these patterns in data from the NHANES (National Health and Nutrition Examination Survey) for 1988–94 and 1999–2012: “The unadjusted prevalence of stage 3 and 4 CKD increased from the late 1990s to the early 2000s. Since 2003 to 2004, however, the overall prevalence has largely stabilized (for example, 6.9% prevalence in 2003 to 2004 and in 2011 to 2012). There was little difference in adjusted prevalence of stage 3 and 4 CKD overall in 2003 to 2004 versus 2011 to 2012 after age, sex, race/ethnicity, and diabetes mellitus status were controlled for (P = 0.26). Lack of increase in CKD prevalence since the early 2000s was observed in most subgroups and with an expanded definition of CKD that included persons with higher eGFRs and albuminuria.” (C. Hsu, hsuchi@medicine.ucsf.edu)
Improved pharmacotherapy of at-risk patients may account for this decrease in CKD prevalence, editorialists write (
pp. 521–2): “Although the data showing stabilization in CKD prevalence are cause for optimism, the underlying reason for the bending of the CKD prevalence curve is uncertain. One can speculate that it is related to improvements in blood pressure and glycemic control among high-risk persons and increased use of medications blocking the renin–angiotensin system in patients with proteinuria. If so, this would support intensified efforts to increase awareness and treatment of persons with CKD.” (P. M. Palevsky, palevsky@pitt.edu)
Mortality & the Mediterranean Diet: Consumed with no restriction on fat intake, the Mediterranean diet lowers patients’ risk of cardiovascular events, breast cancer, and type 2 diabetes but fails to lower mortality, according to a systematic review and meta-analysis (pp. 491–500): “Two primary prevention trials found no difference in all-cause mortality between diet groups. One large primary prevention trial found that a Mediterranean diet resulted in a lower incidence of major cardiovascular events (hazard ratio [HR], 0.71 [95% CI, 0.56 to 0.90]), breast cancer (HR, 0.43 [CI, 0.21 to 0.88]), and diabetes (HR, 0.70 [CI, 0.54 to 0.92]). Pooled analyses of primary prevention cohort studies showed that compared with the lowest quantile, the highest quantile of adherence to a Mediterranean diet was associated with a reduction in total cancer mortality (risk ratio [RR], 0.86 [CI, 0.82 to 0.91]; 13 studies) and in the incidence of total (RR, 0.96 [CI, 0.95 to 0.97]; 3 studies) and colorectal (RR, 0.91 [CI, 0.84 to 0.98; 9 studies]) cancer.” (H. E. Bloomfield, Hanna.Bloomfield@va.gov)

>>>PNN NewsWatch
* All unexpired lots of Baxter 50-mm 0.2 micron filters (product code H93835, expiration 6/27/2016–6/27/2019) are being recalled because of a possible missing filter support membrane and for potential presence of particulate matter, FDA said yesterday.

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 © 2016, 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 Pharmacotherapy Line
Oct. 5, 2016 * Vol. 23, No. 193
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Oct. 4 issue of JAMA (2016; 316).
OnabotulinumtoxinA in Urgency Urinary Incontinence: In the Refractory Overactive Bladder: Sacral Neuromodulation vs Botulinum Toxin Assessment (ROSETTA) trial, significant improvements in refractory urgency urinary incontinence resulted from onabotulinumtoxinA treatment compared with sacral neuromodulation (pp. 1366–74). Urinary tract infections and the need for transient self-catheterizations also increased with drug therapy, the investigators report, and the symptom improvements were of “uncertain clinical importance.” Among 381 women with the condition, cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA or sacral neuromodulation produced these intention-to-treat results: “190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group (−3.9 vs −3.3 episodes per day; mean difference, 0.63; 95% CI, 0.13 to 1.14; P = .01). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Questionnaire SF for symptom bother (−46.7 vs −38.6; mean difference, 8.1; 95% CI, 3.0 to 13.3; P = .002); treatment satisfaction (67.7 vs 59.8; mean difference, 7.8; 95% CI, 1.6 to 14.1; P = .01) and treatment endorsement (78.1 vs 67.6; mean difference; 10.4, 95% CI, 4.3 to 16.5; P < .001) than treatment with sacral neuromodulation. There were no differences in convenience (67.6 vs 70.2; mean difference, −2.5; 95% CI, −8.1 to 3.0; P = .36), adverse effects (88.4 vs 85.1; mean difference, 3.3; 95% CI, −1.9 to 8.5; P = .22), and treatment preference (92.% vs 89%; risk difference, −3%; 95% CI, −16% to 10%; P = .49). Urinary tract infections were more frequent in the onabotulinumtoxinA group (35% vs 11%; risk difference, −23%; 95% CI, −33% to −13%; P < .001). The need for self-catheterization was 8% and 2% at 1 and 6 months in the onabotulinumtoxinA group. Neuromodulation device revisions and removals occurred in 3%.” (C. L. Amundsen, cindy.amundsen@duke.edu)
LDL-C–Lowering Genetic Variants & Diabetes Risk: Potential adverse effects of LDL cholesterol (LDL-C)–lowering therapies are uncovered in a study showing increased risk of type 2 diabetes among patients with certain genetic variants (pp. 1383–91). In a meta-analysis of genetic association studies, the regions in and around genes encoding for the molecular targets of ezetimibe and statins (NPC1L1 and HMGCR, respectively) were assessed for genetic variants affecting LDL-C levels, with these results: “Low-density lipoprotein cholesterol–lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42–0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70–3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02–1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles.” (N. J. Wareham, nick.wareham@mrc-epid.cam.ac.uk)
In Addiction, Words Matter: Substance use disorders can be treated effectively, but the stigma of terms associated with the condition “isolates people,” authors of a Viewpoint article write, “[discouraging them] from coming forward for treatment, and [leading] some clinicians, knowingly or unknowingly, to resist delivering evidence-based treatment services” (pp. 1361–2; H. K. Koh, hkoh@hsph.harvard.edu).

>>>PNN NewsWatch
* FDA is adding a boxed warning to the labeling of direct-acting antiviral (DAA) medications about the risk of hepatitis B virus (HBV) reactivation during treatment for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death. HBV reactivation usually occurred within 4–8 weeks, FDA said based on 24 cases reported to the agency or published in the literature over a 31-month period ending in July 2016.

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 © 2016, 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 Pharmacotherapy Line
Oct. 6, 2016 * Vol. 23, No. 194
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Oct. 6 New England Journal of Medicine (2016; 375).
Daratumumab for Multiple Myeloma: In a phase 3 trial, “addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma,” researchers report (pp. 1319–31). The 569 participants received prior therapy before randomization to lenalidomide and dexamethasone with or without daratumumab, with these results: “At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P <0.001 by stratified log-rank test). The Kaplan–Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P <0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P <0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P <0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.” (M. A. Dimopoulos, mdimop@med.uoa.gr)
Calling the drug a “monoclonal breakthrough,” editorialists write that “daratumumab represents a landmark advance in the treatment of myeloma” (
pp. 1390–2): “It is likely to be incorporated into the treatment of all stages of the disease over the next several years. The challenge will be to prevent unnecessary use, since it will be hard to isolate the effect of daratumumab when it is combined with multiple other active agents. It will be important for future randomized trials to compare the various triplet regimens so that we can make more informed decisions.” (S. V. Rajkumar)
Closing “Immunity Gaps”: Referring to a report of a measles outbreak in an underimmunized Amish community (pp. 1343–54; P. A. Gastañaduy, vid7@cdc.gov), an editorialist comments, “[This] outbreak… highlights the challenge posed by unimmunized or partially immunized young adult travelers who visit areas in which measles is still endemic and subsequently return home with the virus” (pp. 1392–3). “Every death from measles is a tragedy that should have been prevented. Effective tools to achieve the elimination of measles are already available, and even more effective delivery methods, such as the use of microarray patches, are on the horizon. Every immunity gap should be filled. Because the measles virus has an uncanny ability to expose these immunity gaps, we should capitalize on this phenomenon and allow a careful understanding of measles outbreaks to be our guide as we progress toward the ultimate goal of measles eradication.” (D. N. Durrheim)
A related Perspective article explores “the limits of public health persuasion and coercion” (
pp. 1316–7; J. Colgrove).
Explosions of E-Cigarette Batteries: Authors of a letter report 15 cases of injuries caused by explosions of the lithium-ion battery component of electronic cigarettes over a 9-month period (pp. 1400–2). Patients presented with flame burns (80%), chemical burns (33%), and blast injuries (27%) to the face (20%), hands (33%), and thigh or groin (53%). These injuries “add to growing evidence that e-cigarettes are a public safety concern that demands increased regulation as well as design changes to improve safety,” the group writes. (E. G. Brownson, elishag@uw.edu)

>>>PNN NewsWatch
* Nurse Assist has announced a voluntary recall of all unexpired lots of I.V. Flush Syringes due to a potential link to Burkholderia cepacia bloodstream infections with the product, FDA said yesterday.

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 © 2016, 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 Pharmacotherapy Line
Oct. 7, 2016 * Vol. 23, No. 195
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Oct. issue of Pediatrics (2016; 138).
Liquid Medication Errors & Dosing Tools: Oral syringes should be preferred over cups for home measurement of liquid medications for children, according to authors who tested three dosing tools in parents of children at five urban pediatric clinics (10.1542/peds.2016-0357). A total or 2,110 English- and Spanish-speaking parents measured 2.5, 5, and 7.5 mL of medication using a medication cup and two oral syringes (one in 0.2-mL increments and another in 0-5-mL increments). Dosing error was defined as a deviation of more than 20% from the target dose; a large error was defined as a dose of more than 2 times the target dose. Results showed: “A total of 84.4% of parents made ≥1 dosing error (21.0% ≥1 large error). More errors were seen with cups than syringes (adjusted odds ratio = 4.6; 95% confidence interval, 4.2–5.1) across health literacy and language groups (P < .001 for interactions), especially for smaller doses. No differences in error rates were seen between the 2 syringe types. Use of a teaspoon-only label (with a milliliter and teaspoon tool) was associated with more errors than when milliliter-only labels and tools were used (adjusted odds ratio = 1.2; 95% confidence interval, 1.01–1.4).” (H. S. Yin)
Oral Propranolol in Infantile Hemangioma: Assessing the safety of propranolol in infantile hemangioma (IH), authors of a review article conclude that the common off-label use is relatively safe “if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment” (10.1542/peds.2016-0353). In 83 published reports of 3,766 propranolol-treated patients, these indications of safety were identified: “The most frequently reported [adverse events (AEs)] included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review.” (C. Léaute-Labrèze)

>>>Psychiatry Report
Source:
Oct. issue of the American Journal of Psychiatry (2016; 173).
Conditioning & Extinction Learning in Male Cocaine Users: Results of a 91-man study support “the postulated role of altered aversive conditioning in cocaine use disorder,” researchers report, adding that the findings “may be an important step in understanding the role of aversive learning in the pathology of cocaine use disorder” (pp. 1033–42). During functional MRIs, 40 cocaine users and 51 control participants underwent a fear conditioning and extinction protocol, with these effects on brain function and skin conductance response: “Cocaine users showed hyperresponsiveness of the amygdala and insula during fear conditioning, as well as hyporesponsiveness of the dorsomedial prefrontal cortex during extinction learning. In cocaine users, but not in control subjects, skin conductance responses were positively correlated with responsiveness of the insula, amygdala, and dorsomedial prefrontal cortex during fear conditioning but negatively correlated with responsiveness of the ventromedial prefrontal cortex during extinction learning.” (A. M. Kaag)

>>>PNN NewsWatch
* Vaccination rates remain high among kindergartners and children aged 19–35 months, according to articles in this week’s MMWR. There is still room for improvement, though, with 2% of kindergartners neither vaccinated nor exempt at the time of provisional enrollment. Younger children had lower coverage for vaccines recommended in the second year of life.
*
CDC has awarded more than $14 million to fund new approaches to combat antibiotic resistance, including research on how microorganisms naturally present in the human microbiome can be used to predict and prevent infections caused by drug-resistant organisms. The awards, mostly to universities, support activities in the CDC Antibiotic Resistance Solutions Initiative.
*
PNN will not be published on Mon., Oct. 10, Columbus Day.

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 © 2016, 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 Pharmacotherapy Line
Oct. 11, 2016 * Vol. 23, No. 196
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 8 issue of Lancet (2016; 388).
Global Burden of Disease 2015: People in sub-Saharan Africa can expect much greater lifespans now than 10 years ago, according to 2015 figures from the Global Burden of Diseases investigators (pp. 1459–544). The survival increase in that region resulted from a “[rebound] from an era of exceedingly high loss of life due to HIV/AIDS,” the authors report. “At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11.3 years (3.7–17.4), to 62.6 years (56.5–70.2).” (GBD 2015 Mortality and Causes of Death Collaborators)

>>>Internal Medicine Report
Source:
Oct. issue of JAMA Internal Medicine (2016; 176).
Folic Acid & Progression of Chronic Kidney Disease: Adding folic acid to enalapril therapy can significantly slow the progression of chronic kidney disease (CKD) among patients with mild-to-moderate CKD, according to a study of Chinese adults with hypertension (pp. 1443–50). In a substudy of China Stroke Primary Prevention Trial (CSPPT), participants with estimated glomerular filtration rates (eGFRs) of 30 mL/min/1.73 sq m or greater, including 1,671 patients with CKD, had these outcomes from enalapril 10 mg alone or with folic acid 0.8 mg daily: “Overall, 15,104 Chinese adults with a mean (range) age of 60 (45–75) years were recruited; median follow-up was 4.4 years. There were 164 and 132 primary events in the enalapril group and the enalapril–folic acid group, respectively. Compared with the enalapril group, the enalapril–folic acid group had a 21% reduction in the odds of the primary event (odds ratio [OR], 0.79; 95% CI, 0.62–1.00) and a slower rate of eGFR decline (1.28% vs 1.42% per year; P = .02). Among the participants with CKD at baseline, folic acid therapy resulted in a significant reduction in the risks for the primary event (OR, 0.44; 95% CI, 0.26–0.75), rapid decline in renal function (OR, 0.67; 95% CI, 0.47–0.96) and the composite event (OR, 0.62; 95% CI, 0.43–0.90), and a 44% slower decline in renal function (0.96% vs 1.72% per year, P < .001). Among those without CKD at baseline, there was no between-group difference in the primary end point.” (F. F. Hou, ffhouguangzhou@163.com)
“Currently for adults in the United States, median daily intake of folic acid from fortification is estimated to be less than half the level administered in CSPPT,” editorialists note (
pp. 1451–2). “Clinical conditions that are known to alter nutritional status indicators include diseases and states of chronic inflammation, cancer and chronic use of certain pharmaceuticals. This study spotlights the need to better understand the effect of nutrients on disease prevention and disease management.” (P. J. Stover, pjs13@cornell.edu)
Prescription Drug Use & Fragility Fracture: Reducing patients’ exposure to prescription medications associated with fragility fractures is a “missed opportunity,” according to authors of a retrospective cohort study of Medicare beneficiaries (pp. 1531–8). Analysis of prescription drug use by 168,133 patients surviving fractures of the hip, shoulder, or wrist led the authors to this conclusion: “Exposure to prescription drugs associated with fracture risk is infrequently reduced following fragility fracture occurrence. While some patients eliminate their exposure to drugs associated with fracture, an equal number initiate new high-risk drugs.” (J. C. Munson, jeffrey.c.munson@hitchcock.org)

>>>PNN JournalWatch
* Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review, in
JAMA, 2016; 316: 1392–401. (C. McParlin, catherine.mcparlin@ncl.ac.uk)
* The Health Effects of Electronic Cigarettes, in
New England Journal of Medicine, 2016; 375: 1372–81. (G. T. O’Connor, goconnor@bu.edu)
* Medical Training to Achieve Competency in Lifestyle Counseling: An Essential Foundation for Prevention and Treatment of Cardiovascular Diseases and Other Chronic Medical Conditions: A Scientific Statement From the American Heart Association, in
Circulation, 2016; 134: e308–27. (M-F Hivert)
* Opioids and Sleep-Disordered Breathing, in
Chest, 2016; 150: 934–44. (N. A. Antic)
* A Critical Review of the Quality of Cough Clinical Practice Guidelines, in
Chest, 2016; 150: 777–88. (K-f Lai)

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 © 2016, 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 Pharmacotherapy Line
Oct. 12, 2016 * Vol. 23, No. 197
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Oct. 11 issue of JAMA (2016; 316).
Trends in Dietary Supplement Use: Use of multivitamins/multiminerals (MVMMs) by Americans declined between 1990 and 2012, a study shows, while use of other dietary supplements varied according to product category (pp. 1464–74). Overall use of supplements was stable, according to these data from the National Health and Nutrition Examination Surveys (NHANES) conducted every 2 years during that time: “A total of 37,958 adults were included in the study (weighted mean age, 46.4 years; women, 52.0% ), with an overall response rate of 74%. Overall, the use of supplements remained stable between 1999 and 2012, with 52% of US adults reporting use of any supplements in 2011–2012 (P for trend = .19). This trend varied by population subgroup. Use of MVMM decreased, with 37% reporting use of MVMM in 1999–2000 and 31% reporting use in 2011–2012 (difference, −5.7% [95% CI, −8.6% to −2.7%], P for trend <.001). Vitamin D supplementation from sources other than MVMM increased from 5.1% to 19% (difference, 14% [95% CI, 12% to 17%], P for trend  <.001) and use of fish oil supplements increased from 1.3% to 12% (difference, 11% [95% CI, 9.1% to 12%], P for trend <.001) over the study period, whereas use of a number of other supplements decreased.” (E. D. Kantor, kantore@mskcc.org)
“Funders and legislators [should] reconsider their priorities with respect to supplements” in view of Americans’ continued use of supplements that have been shown to be no better than placebo, an editorialist writes (
pp. 1453–4). “Given the current regulatory framework, even high-quality research appears to have only modest effects on supplement use. Future efforts should focus on developing regulatory reforms that provide consumers with accurate information about the efficacy and safety of supplements and on improving mechanisms for identifying products that are causing more harm than good.” (P. A. Cohen, pcohen@challiance.org)
Probiotics & Prevention of Antibiotic-Associated Diarrhea: “Moderate-quality evidence suggests that probiotics are associated with lower rates of antibiotic-associated diarrhea in children (aged 1 month to 18 years) without an increase in adverse events,” advise authors of a JAMA Clinical Evidence Synopsis (pp. 1484–5). “Among 23 studies comparing probiotics with control for the prevention of antibiotic-associated diarrhea, probiotics were associated with lower rates of diarrhea and were not associated with higher rates of adverse events,” the group writes. “No trials reported serious adverse events attributable to probiotics.” (B. C. Johnston, bradley.johnston@sickkids.ca)
Medicaid Expansion & U.S. Hospital Finances: Compared with hospitals in the 25 states have not expanded Medicaid using federal monies made available through the Affordable Care Act, hospitals in the 19 states with Medicaid expansion had significantly increased Medicaid revenue, decreased uncompensated care costs, and improvements in profit margins in 2014, researchers report (pp. 1475–83). Observational data for nonfederal medical or surgical hospitals in fiscal years 2011 through 2014 were assessed for uncompensated care, uncompensated care as a percentage of total hospital expenses, Medicaid revenue, Medicaid as a percentage of total revenue, operating margins, and excess margins, with these results: “The sample included between 1,200 and 1,400 hospitals per fiscal year in 19 states with Medicaid expansion and between 2,200 and 2,400 hospitals per fiscal year in 25 states without Medicaid expansion (with sample size varying depending on the outcome measured). Expansion of Medicaid was associated with a decline of $2.8 million (95% CI, −$4.1 to −$1.6 million; P < .001) in mean annual uncompensated care costs per hospital. Hospitals in states with Medicaid expansion experienced a $3.2 million increase (95% CI, $0.9 to $5.6 million; P = .008) in mean annual Medicaid revenue per hospital, relative to hospitals in states without Medicaid expansion. Medicaid expansion was also significantly associated with improved excess margins (1.1 percentage points [95% CI, 0.1 to 2.0 percentage points]; P = .04), but not improved operating margins (1.1 percentage points [95% CI, −0.1 to 2.3 percentage points]; P = .06).” (F. Blavin, fblavin@urban.org)

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 © 2016, 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 Pharmacotherapy Line
Oct. 13, 2016 * Vol. 23, No. 198
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Oct. 13 New England Journal of Medicine (2016; 375).
Monoclonal Cocktail for Ebola Virus Infection: ZMapp, a triple monoclonal antibody cocktail, showed beneficial effects in a trial of 72 patients with Ebola virus disease (EVD) but failed to meet prespecified efficacy criteria, PREVAIL II investigators report (pp. 1448–56). Compared with standard of care EVD therapy, ZMapp 50 mg/kg every third day produced these results based on a primary end point of 28-day mortality: “A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, −15 percentage points; 95% confidence interval, −36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups.” (R. T. Davey, Jr., rdavey@niaid.nih.gov)
Cardiovascular Toxic Effects of Targeted Cancer Therapies: The new field of cardio-oncology is explored in a review article of cardiovascular toxicities linked to targeted cancer therapies (pp. 1457–67): “The intersection between cancer and cardiovascular disease extends beyond toxicology. Tumors themselves may adversely affect the cardiovascular and metabolic systems or may arise from cardiovascular tissue. In addition, emerging data suggest that common genetic and traditional risk factors may predispose patients to both cancer and cardiovascular and metabolic diseases. For example, somatic or inherited mutations in select genes not only may predispose patients to various cancers but also may lead to an increased risk of cardiovascular disease or cardiovascular risk factors, such as insulin sensitivity. Obesity and hyperlipidemia, which are established risk factors for cardiovascular disease, may also predispose patients to certain cancers, such as estrogen-receptor–positive breast cancer. The recent discovery of a cholesterol metabolite that activates the estrogen receptor and stimulates tumor growth lends biologic plausibility to these observations. Lowering cholesterol levels through lifestyle modifications, pharmacologic intervention, or exercise — all factors that have been known to be cardioprotective — may also reduce the risk of breast cancer or slow tumor growth. If true, this concept would have enormous public health implications and directly affect the care of patients with cancer and subsequent survivors.” (J. J. Moslehi, javid.moslehi@vanderbilt.edu)
Management of Early Prostate Cancer: Reflecting on two studies of treatment versus monitoring of early prostate cancer (pp. 1415–24, F. C. Hamdy, mailto:freddie.hamdy@nds.ox.ac.uk; pp. 1425–37; J. L. Donovan, jenny.donovan@bristol.ac.uk), an editorialist reaches this conclusion about the choices of active monitoring, radiotherapy with neoadjuvant androgen-deprivation therapy for 3 to 6 months, and surgery (pp. 1482–3): “For today, we can conclude on the basis of level 1 evidence that [prostate-specific antigen] monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis. Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment, monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study. In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk prostate cancer should feel free to select a treatment approach using the data on health-related quality of life and without fear of possibly selecting a less effective cancer therapy.” (A. V. D’Amico)

>>>PNN NewsWatch
* The price tag for Americans who don’t receive the 10 adult vaccines is $9 billion annually, a Health Affairs study estimates. “These results not only indicate the potential economic benefit of increasing adult immunization uptake but also highlight the value of vaccines,” the authors write.

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 © 2016, 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 Pharmacotherapy Line
Oct. 14, 2016 * Vol. 23, No. 199
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Nov. 1 issue of Clinical Infectious Diseases (2016; 63).
End-Stage Liver Disease in HIV–Viral Hepatitis Coinfected Persons: The risk of end-stage liver disease (ESLD) has not been reduced in patients who are coinfected by HIV and hepatitis B (HBV) and C (HCV) viruses despite the introduction of antiretroviral agents into practice over the past 15 years, a study shows (pp. 1160–7). In 12 cohorts derived from participants in the North American AIDS Cohort Collaboration on Research and Design, ESLD events from 1996 to 2010 showed these patterns: “Among 34,119 HIV-infected adults followed for 129,818 person–years, 380 incident ESLD outcomes occurred. ESLD incidence (per 1,000 person–years) was highest in triply infected (11.57) followed by HBV- (8.72) and HCV- (6.10) coinfected vs 1.27 in HIV-monoinfected patients. Adjusted incidence rate ratios (95% confidence intervals) comparing the modern to the early antiretroviral era were 0.95 (.61–1.47) for HCV, 0.95 (.40–2.26) for HBV, and 1.52 (.46–5.02) for triply infected patients. Use of antiretrovirals dually activity against HBV increased over time. However, in the modern era, 35% of HBV-coinfected patients were not receiving tenofovir. There was little use of HCV therapy.” (M. B. Klein, marina.klein@mcgill.ca)
“Klein et al’s findings firmly show that the risk of ESLD in HIV-infected patients, especially in those coinfected with HCV or HBV, is important,” an editorialist writes (
pp. 1168–70). “Others have clearly shown that liver-related disease is a major underlying cause of death in HIV-infected patients and that people coinfected with HCV or HBV and HIV are at significantly higher risk for mortality, especially those with advanced liver disease. Potent anti-HBV treatments exist. In addition, HCV has become a modifiable risk factor with the advent of highly efficacious direct-acting antivirals (DAAs). Thus, future studies will need to assess the effect of broader use of DAAs in HCV-HIV–coinfected patients on the risk on ESLD. Close follow-up on the effect of [combination antiretroviral therapy (cART)], including drugs active against both HIV and HBV in HBV-HIV–coinfected patients, is needed to confirm a reduced risk of hepatic decompensation in these patients. Specific cohorts (ie, post-sustained virological response cohorts for HCV-HIV–coinfected patients and on active cART for both HBV and HIV cohorts for HBV-HIV–coinfected patients) or cohort collaborations with long-term follow-up are needed for comprehensive analysis in order to better understand factors associated with liver and nonliver–related disease progression in both HCV-HIV and HBV-HIV coinfected patients.” (L. Wittkop, linda.wittkop@isped.u-bordeaux2.fr)

>>>Oncology Highlights
Source:
Oct. 20 issue of the Journal of Clinical Oncology (2016; 34).
New Standard of Care in Multiple Myeloma: In patients with multiple myeloma (MM) who are not eligible for stem-cell transplantation, results of the phase 3 FIRST Trial support lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) as a new standard of care (pp. 3609–17). Among 1,623 patients with untreated unsymptomatic MM (35% of patients were older than 75 years), Rd continuous, Rd for 18 cycles (Rd18), or melphalan, prednisone, and thalidomide (MPT) for 18 cycles (72 weeks) produced these changes in a primary end point of progression-free survival: “Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P <.001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P <.001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous–treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions.” (T. Facon, thierry.facon@chru-lille.fr)

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 © 2016, 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 Pharmacotherapy Line
Oct. 17, 2016 * Vol. 23, No. 200
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 15 issue of Lancet (2016; 388).
Gemcitabine in Nasopharyngeal Carcinoma: Phase 3 study results “establish gemcitabine plus cisplatin as the standard first-line treatment option” in patients with recurrent or metastatic nasopharyngeal carcinoma, investigators conclude (pp. 1883–92). Median progression-free survival was 7.0 months in those receiving this drug combination, significantly greater than the 5.6 months with fluorouracil/cisplatin. (L. Zhang, zhangli6@mail.sysu.edu.cn)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 353).
Vaccines & Childhood Mortality: Administered to children younger than 5 years of age, Bacillus Calmette-Guérin (BCG) and standard-titer measles-containing vaccines (MCV) reduce mortality more than would be expected, but diphtheria–tetanus–pertussis (DTP) vaccine is associated with a nonsignificantly increased risk in mortality, according to a systematic review, bias assessment, and meta-analysis (i5170). Noting that the DTP vaccine is “almost always” administered with oral polio vaccine, the writers conclude that “randomised trials are needed to compare the effects of different [administration] sequences.” Evaluation of available data showed the following: “Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV.” (J. Higgins, julian.higgins@bristol.ac.uk)
Nonspecific Immunologic Effects of Childhood Vaccines: A second systematic review reaches these conclusions about nonspecific immunologic effects after childhood BCG, measles, and DTP vaccines (i5225): “The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-gamma responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the clinical importance of the findings.” (R. Kandasamy, rama.kandasamy@paediatrics.ox.ac.uk)

>>>PNN JournalWatch
* Sex-Differential Non-Vaccine-Specific Immunological Effects of Diphtheria–Tetanus–Pertussis and Measles Vaccination, in
Clinical Infectious Diseases, 2016; 63: 1213–26. (K. L. Flanagan, katie.flanagan@ths.tas.gov.au)
* Adherence to Antiretroviral Therapy During and After Pregnancy: Cohort Study on Women Receiving Care in Malawi’s Option B+ Program, in
Clinical Infectious Diseases, 2016; 63: 1227–35. (A. D. Haas, andreas.haas@ispm.unibe.ch)
* Optimizing Treatment for Elderly Patients With Newly Diagnosed Multiple Myeloma: A Personalized Approach, in
Journal of Clinical Oncology, 2016; 34: 3600–4. (A. Palumbo, appalumbo@yahoo.com)
* Patient Navigation in Breast Cancer Treatment and Survivorship: A Systematic Review, in
Journal of Clinical Oncology, 2016; 34: 3686–96. (K. J. Wells, kwells@mail.sdsu.edu)
* Antenatal Corticosteroids for Maturity of Term or Near Term Fetuses: Systematic Review and Meta-analysis of Randomized Controlled Trials, in
BMJ, 2016; 355: i5044. (V. Berghella, vincenzo.berghella@jefferson.edu)

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 © 2016, 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 Pharmacotherapy Line
Oct. 18, 2016 * Vol. 23, No. 201
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 18 issue of the Annals of Internal Medicine (2016; 165).
Bioequivalence of Biosimilar TNF-Alpha Inhibitors: Available evidence indicates that follow-on tumor necrosis inhibitor–alpha inhibitors and reference products are biosimilar and interchangeable, a systematic review concludes (pp. 565–74): “Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes.” (G. C. Alexander, galexand@jhsph.edu)
After addressing “principles [that] will undoubtedly underpin any regulatory guidance in the evolving area of biosimilars,” editorialists write that “terminology is also important” (
pp. 595–6): “[These authors] use the term ‘bioequivalence’ as a sort of all-encompassing comparability term. We agree that it is important to adequately convey to various stakeholders when a ‘follow-on’ biologic is highly similar to an originator biologic such that no clinical differences between the biosimilar and reference are expected. It is easy to conflate concepts of bioequivalence, biosimilarity, interchangeability, and therapeutic equivalence because these are generally terms of art established under regulatory and legal frameworks. We encourage further exploration of mechanisms to ensure common understanding of these concepts among the drug development, regulatory, clinical practice, patient, and payer communities.” (I. Zineh, issam.zineh@fda.hhs.gov)

>>>Nephrology Highlights
Source:
Oct. issue of the American Journal of Kidney Diseases (2016; 68).
Mineralocorticoid Receptor Antagonists in Dialysis: Large, high-quality trials of mineralocorticoid receptor antagonists (MRAs) are needed to resolve uncertainty about the relative efficacy and safety of the drugs when used in patients on dialysis, according to authors of a systematic review and meta-analysis (pp. 591–8). Based on findings of 9 trials with 829 patients (8 trials of spironolactone and 1 of eplerenone), the authors report: “The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results.” (M. Walsh, lastwalsh1975@gmail.com)
“For too long, patients treated with dialysis have lived with unacceptably high risks for [cardiovascular] morbidity and mortality,” an editorialist concludes (
pp. 512–4). “[This] meta-analysis … nicely highlights the potential for mineralocorticoid receptor antagonists to decrease morbidity and mortality in our most vulnerable patients and to change the paradigm of early death for dialysis patients, which many of us have grown too used to. It is now up to the nephrology community to take up the challenge and shoulder the burden of conducting multiple large high-quality trials to determine whether we can make this old therapy new again.” (D. M. Charytan, dcharytan@partners.org)

>>>PNN NewsWatch
* FDA yesterday announced that it has awarded 21 new clinical trial research grants totaling more than $23 million over the next 4 years to boost clinical development of drugs, biologics, medical devices, or medical foods for use in rare diseases. Consistent with Vice President Joe Biden’s “cancer moonshot” initiative, 24% of grants focus on oncology.

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 © 2016, 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 Pharmacotherapy Line
Oct. 19, 2016 * Vol. 23, No. 202
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Oct. 18 issue of JAMA (2016; 316).
Empirical Micafungin Treatment of Critically Ill Patients: Used empirically, antifungal therapy did not significantly improve fungal infection–free survival at day 28 in 260 nonneutropenic, nontransplanted, critically ill patients with ICU-acquired sepsis, multiple Candida colonization, multiple organ failure, and exposed to broad-spectrum antibacterial agents (pp. 1555–64). The EMPIRICUS study, conducted in 19 French ICUs, compared placebo with micafungin doses of 100 mg once daily for 14 days, with these results: “Among 260 patients (mean age 63 years; 91 [35%] women), 251 (128, micafungin group; 123, placebo group) were included in the modified intent-to-treat analysis. Median values were 8 for Sequential Organ Failure Assessment (SOFA) score, 3 for number of Candida-colonized sites, and 99 pg/mL for level of (1-3)-beta-D-glucan. On day 28, there were 82 (68%) patients in the micafungin group vs 79 (60.2%) in the placebo group who were alive and [invasive fungal infection (IF)] free (hazard ratio [HR], 1.35 [95% CI, 0.87–2.08]). Results were similar among patients with a (1-3)-beta-D-glucan level of greater than 80 pg/mL (n = 175; HR, 1.41 [95% CI, 0.85–2.33]). Day-28 IFI–free survival in patients with a high SOFA score (>8) was not significantly different when compared between the micafungin vs placebo groups (HR, 1.69 [95% CI, 0.96–2.94]). Use of empirical micafungin decreased the rate of new invasive fungal infection in 4 of 128 patients (3%) in the micafungin group vs placebo (15/123 patients [12%]) (P = .008).” (J-F Timsit, jean-francois.timsit@bch.aphp.fr)
Noting mixed results and lack of conclusively demonstrated mortality benefits with empirical antifungal therapy in these patients, editorialists write (
pp. 1549–50): “The aim of the EMPIRICUS study was to answer whether empirical antifungal therapy among a high-risk colonized population would result in mortality benefits. Better efficacy profiles and decreased toxicity of newer antifungal agents have most likely contributed to increased use of these agents for empirical treatment. These newer agents inevitably result in increased cost of care and raise concern about the potential of antifungal resistance. In light of these findings, guidelines concerning empirical treatment and surveillance should be revisited. Ultimately, like other prophylactic interventions, future studies will need to weigh the risks and potential benefits of empirical echinocandin therapy for critically ill, immune-competent patients in the ICU. Novel biomarkers or clinical risk assessment algorithms may help in identifying those patients who are at highest risk of infection-related morbidity and mortality and would benefit most from targeted preventive therapies.” (W. Checkley, wcheckl1@jhmi.edu)
Reassessing Compendial Use in Off-Label Oncology Drug Coverage: Use of AHFS and other compendia to determine coverage for off-label use of oncology drugs is an “outdated system,” write authors of a Viewpoint article (pp. 1541–2). “The current compendia-based approach for coverage decisions in oncology has lacked oversight and is not suitable for making safe recommendations or coverage decisions for cancer drugs,” the article states. “Toward the future, this function would be most appropriately performed under the direct oversight of the FDA, perhaps within the new FDA Oncology Center of Excellence, or alternatively by a new entity supported by a consortium of public and private payers with enforced policies to limit relationships with industry. Under such a model, new indications for existing therapies could be nominated along with accompanying evidence for impartial review and decision making through a consistent, rigorous, and transparent review process. Evidence standards might differ from full regulatory approval, with a likely role for real-world evidence. Although this work would entail substantial effort, it would undoubtedly be less than the current compendia efforts and would likely lead to more rigorous indications. This approach also could alleviate concerns about conflicts of interest among current compendia contributors and would likely engender greater transparency.” (E. M. Basch, ebasch@med.unc.edu)
Pharmacogenomics in the Clinic: Helping physicians understand and use genotype-guided prescribing is needed for pharmacogenomics to be more widely adopted in clinics, according to a news article (pp. 1533–5). Lack of reimbursement is also delaying adoption, the writers note. (J. Abbasi)

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 © 2016, 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 Pharmacotherapy Line
Oct. 20, 2016 * Vol. 23, No. 203
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Oct. 20 issue of the New England Journal of Medicine (2016; 375).
Romosozumab in Postmenopausal Women with Osteoporosis: Compared with placebo, monthly doses of the sclerostin-binding monoclonal antibody romosozumab produced a lower risk of vertebral fracture among 7,180 postmenopausal women, researchers report (pp. 1532–43). The study used coprimary end points of cumulative incidences of new vertebral fractures at 12 months and 24 months in identifying these effects of the new drug: “At 12 months, new vertebral fractures had occurred in 16 of 3,321 patients (0.5%) in the romosozumab group, as compared with 59 of 3,322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P <0.001). Clinical fractures had occurred in 58 of 3,589 patients (1.6%) in the romosozumab group, as compared with 90 of 3,591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P = 0.008). Nonvertebral fractures had occurred in 56 of 3,589 patients (1.6%) in the romosozumab group and in 75 of 3,591 (2.1%) in the placebo group (P = 0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3,325 patients] in the romosozumab group vs. 2.5% [84 of 3,327] in the placebo group, a 75% lower risk with romosozumab; P <0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group.” (F. Cosman, cosmanf@helenhayeshosp.org)
“The results of the present trial can be viewed as either meeting [high] expectations [of biologists and clinicians] or falling short,” editorialists write (
pp. 1583–4). “The changes in bone mineral density are remarkable, and the lower risks of vertebral fracture and clinical fracture with romosozumab are considerable, yet the findings regarding the risk of nonvertebral fracture, although lower with romosozumab than with placebo, were not significant, despite a magnitude of difference that was similar to that observed with other therapies. There are at least three possibilities to explain this last observation — first, therapy was administered for only 1 year; second, the overall risk of fractures in the enrolled cohort may not have been as high as in other trials; and third, as the authors suggest, geographic heterogeneity may have played a role. Notably, the trial was powered a priori for a 3.5% incidence of nonvertebral fracture in the placebo group, but the incidence in this group was only 2.1% overall and a mere 1.2% in Latin America.” (C. J. Rosen)
Guillain–Barré Syndrome With Zika Virus: In Colombia, 66 of 68 patients with Guillain–Barré syndrome developed symptoms following infections of Zika virus, a study shows (pp. 1513–23). The observation “lends support to the role of [Zika virus] infection in the development of the Guillain–Barré syndrome,” the authors conclude. (C. A. Pardo, cpardov1@jhmi.edu)

>>>PNN NewsWatch
* The CDC’s Advisory Committee on Immunization Practices (ACIP) voted yesterday to recommend a 2-dose human papillomavirus (HPV) vaccine schedule for young adolescents. CDC Director Tom Frieden, MD, MPH, approved the committee’s recommendations shortly after the vote. The new guidance calls for 11- to 12-year-olds to receive two doses of HPV vaccine at least 6 months apart rather than the previously recommended three doses to protect against cancers caused by HPV infections. Teens and young adults who start the series later, at ages 15 through 26 years, will continue to need three doses of HPV vaccine to protect against cancer-causing HPV infection. ACIP also voted to recommend vaccination of all newborns within 24 hours of birth with monovalent hepatitis B vaccine.
*
FDA yesterday granted accelerated approval for use of olaratumab (Lartruvo, Lilly) with doxorubicin to treat adults with soft tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. The approval is based on results of the phase 2 JGDG trial; a phase 3 trial, ANNOUNCE, is fully enrolled.

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 © 2016, 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 Pharmacotherapy Line
Oct. 21, 2016 * Vol. 23, No. 204
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Oct. issue of the Journal of Allergy and Clinical Immunology (2016; 138).
Pharmacogenomics & Adverse Drug Reactions: The clinical usefulness of pharmacogenomic tests in preventing adverse drug reactions (ADRs) is assessed by authors of a review article (pp. 943–55): “Pharmacogenetics and, more recently, pharmacogenomics have been applied to the field of ADRs for both predictable ADRs and hypersensitivity drug reactions. Evaluations for glucose-6-phosphate dehydrogenase and thiopurine S-methyltransferase are commonplace clinical tests to reduce hematologic problems associated with drugs, such as dapsone and azathioprine, respectively. Numerous pharmacogenetic associations have been discovered for immediate hypersensitivity reactions to beta-lactams, aspirin, and nonsteroidal anti-inflammatory drugs; however, the clinical utility of testing for these genetic associations has not been established. In contrast, pharmacogenetic testing for HLA-B*1502 before carbamazepine in patients of certain Asian ethnicities and testing for HLA-B*5701 before abacavir treatment are recommended.” (D. A. Khan, dave.khan@utsouthwestern.edu)
Breathomics in Asthma & COPD: Noninvasive testing of the exhaled breath for any of the “thousands of volatile organic compounds that reflect the metabolic process occurring in the host both locally in the airways and systemically” is reviewed (pp. 970–6): “Comprehensive analysis of breath volatile organic compounds (breathomics) provides opportunities for noninvasive biomarker discovery and novel mechanistic insights. Applications in patients with obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease, include not only diagnostics (especially in children and other challenging diagnostic areas) but also identification of clinical treatable traits, such as airway eosinophilia and risk of infection/exacerbation, that are not specific to diagnostic labels. Although many aspects of breath sampling and analysis are challenging, proof-of-concept studies with mass spectrometry and electronic nose technologies have provided independent studies with moderate-to-good diagnostic and phenotypic accuracies. The present review evaluates the data obtained by using breathomics in (1) predicting the inception of asthma or chronic obstructive pulmonary disease, (2) inflammatory phenotyping, (3) exacerbation prediction, and (4) treatment stratification. The current findings merit the current efforts of large multicenter studies using standardized sampling, shared analytic methods, and databases, including external validation cohorts. This will position this noninvasive technology in the clinical assessment and monitoring of chronic airways diseases.” (L. D. Bos, l.d.bos@amc.nl)

>>>Health Affairs Highlights
Source:
Oct. issue of Health Affairs (2016; 35).
Opioid Prescribing Policies: State laws and policies intended to reduce opioid prescribing are effective but should be analyzed further for unintended consequences such as increasing heroin overdose deaths, researchers conclude (pp. 1876–83). Using the IMS Health National Prescription Audit data from 2006–13, the group finds: “Combined implementation of mandated provider review of state-run prescription drug monitoring program data and pain clinic laws reduced opioid amounts prescribed by 8 percent and prescription opioid overdose death rates by 12 percent. We also observed relatively large but statistically insignificant reductions in heroin overdose death rates after implementation of these policies. This combination of policies was effective, but broader approaches to address these coincident epidemics are needed.” (D. Dowell, gdo7@cdc.gov)
Controlled Substance Lock-In Programs: A second report shows that restricting high-risk Medicaid patients to a single provider for opioid prescriptions is associated with a 4-fold increase in out-of-pocket controlled substance fills (pp. 1884–92; A. W. Roberts, drewroberts1@creighton.edu).

>>>PNN NewsWatch
* The U.S. Dept. of Health and Human Services is calling for comments on a national action plan for preventing adverse drug events, according to a Federal Register notice. The plan proposes that 2014 figures be used as a baseline for most measures and calls for targets to be achieved by 2020.

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 © 2016, 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 Pharmacotherapy Line
Oct. 24, 2016 * Vol. 23, No. 205
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 22 issue of Lancet (2016; 388).
Edoxaban in Atrial Fibrillation Cardioversion: In the ENSURE-AF trial, edoxaban and edoxaban–warfarin were similarly effective when used during cardioversion of patients with atrial fibrillation, and rates of major and clinically relevant nonmajor (CRNM) bleeding were similar (pp. 1995–2003). At 239 sites in 19 countries, edoxaban 30–60 mg/d with or without warfarin produced these results: “Between March 25, 2014, and Oct 28, 2015, 2,199 patients were enrolled and randomly assigned to receive edoxaban (n = 1,095) or enoxaparin–warfarin (n = 1,104). The mean age was 64 years (SD 10.54) and mean CHA2DS2-VASc score was 2.6 (SD 1.4). Mean time in therapeutic range on warfarin was 70.8% (SD 27.4). The primary efficacy endpoint [of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality] occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin–warfarin group (odds ratio [OR] 0.46, 95% CI 0.12–1.43). The primary safety endpoint [of CRNM] occurred in 16 (1%) of 1,067 patients given edoxaban versus 11 (1%) of 1,082 patients given enoxaparin–warfarin (OR 1.48, 95% CI 0.64–3.55). The results were independent of the [transoesophageal echocardiography]-guided strategy and anticoagulation status.” (A. Goette, andreas.goette@vincenz.de)
Dexamethasone/Radiotherapy in Metastatic NSCLC: Compared with dexamethasone plus optimal supportive care (OSC), whole brain radiotherapy (WBRT) plus dexamethasone provided “little additional clinically significant benefit” in 538 patients with brain metastases from nonsmall-cell lung cancer (NSCLC) (pp. 2004–14). Treating patients whose brain tumors were nonresectable and unsuitable for stereotactic radiotherapy, investigators found these results with WBRT and dexamethasone: “Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups. There was no evidence of a difference in overall survival (hazard ratio 1.06, 95% CI 0.90–1.26), overall quality of life, or dexamethasone use between the two groups. The difference between the mean [quality-adjusted life–years (QALYs)] was 4.7 days (46.4 QALY days for the OSC plus WBRT group vs 41.7 QALY days for the OSC group), with two-sided 90% CI of −12.7 to 3.3.” (R. E. Langley, ruth.langley@ucl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 353).
Antidiabetic Drugs & Breast Cancer: In a population-based cohort study, use of glucagon-like peptide-1 (GLP-1) analogs was not associated with an overall increase in risk of breast cancer among middle-aged and older women, researchers report in a comparison with dipeptidylpeptidase-4 (DPP-4) inhibitors (i5340). A transient increase in breast cancer was observed as duration of therapy increased, making it impossible to “rule out a tumour promoter effect,” the group concludes based on these findings for 44,984 women at least 40 years of age and receiving new treatment with the drugs: “The cohort was followed for a mean of 3.5 years (standard deviation 2.2), with 549 incident events of breast cancer recorded (crude incidence 3.5 (95% confidence interval 3.3 to 3.8) per 1,000 person years). Overall, compared with use of DPP-4 inhibitors, use of GLP-1 analogues was not associated with an increased risk of breast cancer (incidence 4.4 v 3.4 per 1,000 person years; hazard ratio 1.40 (95% confidence interval 0.91 to 2.16)). Hazard ratios gradually increased with longer durations of use, with a peak between two to three years of GLP-1 use (2.66 (95% confidence interval 1.32 to 5.38)), and returned closer to the null after more than three years of use (0.98 (0.24 to 4.03)). A similar pattern was observed with time since initiation of GLP-1 analogues.” (L. Azoulay, laurent.azoulay@mcgill.ca)

>>>PNN JournalWatch
* Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement, in
Arthritis & Rheumatism, 2016; 68: 2361–71. (K. M. Sullivan, keith.sullivan@duke.edu)
* Rethinking Thirty-Day Hospital Readmissions: Shorter Intervals Might Be Better Indicators Of Quality Of Care, in
Health Affairs, 2016; 35: 1867–75. (D. L. Chin; dlchin@ucdavis.edu)

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 © 2016, 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 Pharmacotherapy Line
Oct. 25, 2016 * Vol. 23, No. 206
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source:
Oct. issue of the Journal of the American Geriatrics Society (2016; 64).
GFR v. CrCL in Dosing Direct Oral Anticoagulants: In determining doses of direct oral anticoagulants (DOACs), substituting glomerular filtration rates (GFRs) for Cockroft–Gault estimation of creatinine clearance (CrCL-CG) can lead clinicians to fail to recognize the need to lower doses, causing bleeding, a study shows (pp. 1996–2002). Using simulation and retrospective data from the 2011–12 National Health and Nutrition Examination Survey (NHANES) (n = 4,687) and 208 medically stable research participants (25–105 years old), the author reports: “Renal clearance estimates according to all methods were highly correlated (P< .001), although at lower clearances, substitution of GFR estimates for CrCL-CG resulted in failure to recognize needs for dose reductions of rivaroxaban or edoxaban in 28% of NHANES subjects and 47% to 56% of research subjects. At a CrCL-CG of less than 30 mL/min, GFR estimates missed indicated dosage reductions for dabigatran in 18% to 21% of NHANES subjects and 57% to 86% of research subjects. Age and weight contributed to differences between renal clearance estimates (P< .001), but correction of GFR for body surface area (BSA) did not reduce dosing errors. At a CrCL-CG greater than 95 mL/min, edoxaban is not recommended, and GFR estimates misclassified 24% of NHANES and 39% of research subjects. Correction for BSA reduced misclassification to 7% for NHANES and 14% in research subjects.” (J. B. Schwartz, Janice.schwartz@ucsf.edu)
Intensive Chemotherapy in Acute Myeloid Leukemia: Physical function declines during induction chemotherapy in older adults with acute myeloid leukemia (AML), researchers report, and “depressive symptoms before and during chemotherapy may be linked to potentially modifiable physical function declines” (pp. 1988–95). The 49-patient study conducted geriatric assessments using the Pepper Assessment Tool for Disability (activity of daily living, instrumental activity of daily living [IADL], mobility questions), Short Physical Performance Battery (SPPB), and other tests. Results at baseline and during 8 weeks after induction chemotherapy showed: “After chemotherapy, IADL dependence worsened (mean 1.4 baseline vs 2.1 follow-up, P< .001), as did mean SPPB scores (7.5 vs 5.9, P = .02 for total). Grip strength also declined (38.9 ± 7.7 vs 34.2 ± 10.3 kg, P < .001 for men; 24.5 ± 4.8 vs 21.8 ± 4.7 kg, P = .007 for women). No significant changes in cognitive function (mean 84.7 vs 85.1, P = .72) or depressive symptoms (14.0 vs. 11.3, P = .11) were detected, but symptoms of distress declined (5.0 vs 3.2, P < .001). Participants with depressive symptoms at baseline and follow-up had greater declines in SPPB scores [than] those without at both time points.” (H. D. Klepin, hklepin@wakehealth.edu)
Constitutional Symptoms & Antibiotic Prescribing in NHs: Among 162 residents of six Michigan nursing homes (NHs) with urinary or enteral feeding tubes, changes in constitutional symptoms such as function or mentation often lead to diagnostic testing and, regardless of test outcome, prescribing of antibiotics (pp. 1975–80). Clinical and demographic data obtained at study enrollment, on day 14, and monthly for 1 year showed the following: “One hundred (62%) NH residents had an incident infection requiring antibiotics, with substantial variations between NHs. In addition to presence of infection-specific symptoms, change in function was a significant predictor of ordering a chest X-ray to detect pneumonia (odds ratio (OR) = 1.7, P = .01). Similarly, change in mentation was a significant predictor of ordering a urinalysis (OR = 1.9, P = .02), chest X-ray (OR = 3.3, P< .001), and blood culture (OR = 2.3, P = .02). Antibiotics were used empirically, before laboratory results were available, in 50 of 233 suspected cases of UTI (21.5%) and 16 of 53 (30.2%) suspected cases of pneumonia. Antibiotics were used in 17% of visits without documented clinical or laboratory evidence of infection.” (L. Mody, lonamody@umich.edu)

>>>PNN NewsWatch
* Patient- and family-centered care were center stage on Sunday morning at the ACCP Annual Meeting in Hollywood, FL. Christine Bechtel, principal with a firm that focuses on implementing advanced, patient-centered policies in practice, shared her perspectives during the keynote address along with Hala Durrah, who provided care to a daughter with a congenital rare liver disease.

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 © 2016, 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 Pharmacotherapy Line
Oct. 26, 2016 * Vol. 23, No. 207
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Oct. 25 issue of JAMA, a special issue with reports from working groups of the Vital Directions for Health & Health Care initiative of the National Academy of Medicine (2016; 316).
Achieving “Complete Well-being” Through Improvements in Health, Health Care: Summarizing five overarching themes in the 19 areas covered by the Vital Directions reports, an editorialist makes these comments (pp. 1679–81; H. K. Koh, hkoh@hsph.harvard.edu):
* Respecting the Social Determinants of Health—“Beyond biology, health arises where people live, labor, learn, play, and pray.… Future social determinants approaches to improve health and also reduce inequalities could include, for example, housing quality and safety strategies and home visiting programs for disadvantaged families.”
* Advancing Wellness and Prevention—“Some people need health care some of the time, but all people need health and wellness all the time. Nevertheless, disease prevention and wellness efforts remain chronically overlooked, underappreciated, and underfunded.”
* Strengthening Systems of Care—“Through the 2010 Affordable Care Act (ACA), about 20 million additional individuals in the United States now have access to health insurance. Increasing the number of insured people will require improvements in access to health exchanges and Medicaid. In addition, strengthening health systems will require coordination and integration of previously fragmented services. As a major commitment to health system redesign, the US Department of Health and Human Services is shifting from traditional Medicare fee-for-service toward a 2018 goal of 50% payment through alternative payment models (APMs). McClellan and Leavitt [
pp. 1655–6; M. B. McClellan, mark.mcclellan@duke.edu] note that moving from volume to value involves implementation and evaluation of APMs including accountable care organizations (ACOs) (currently reaching 28 million individuals nationally), fixed bundled payments for episodes of care, and primary care medical homes with shared savings.”
* Fostering a 21st-Century Workforce— “To realize a person-centered and population-centered future, Lipstein and Kellermann [
pp. 1665–6; S. H. Lipstein, shl8635@bjc.org] posit that the 21st-century health workforce must stretch far beyond traditional roles. Health professionals must support all those who, in navigating today’s health landscape, encounter barriers such as finding the right care at the right time, paying for costly medications, and fully comprehending the nuances of medical information. Furthermore, entire communities trying to address these challenges, including minorities by race/ethnicity, sexual orientation, and disability level, incur substantial health disparities. Tang and Smith [pp. 1663–4; P. C. Tang, paultang@stanford.edu] urge ‘democratization of health care’ because people who are better partners in their own health gain more trust in the system, with concomitant improvements in informed consent, patient safety, and health literacy. Through multidisciplinary teams, the 21st-century workforce can also serve diverse populations (across many stages of health and life) by offering culturally and linguistically appropriate services.”
* Monitoring Outcomes for Continuous Improvement—“How best to monitor progress in health remains a simple, yet profound, question.… [In addition to APM competencies, measures, and benchmarks, and other ideas], assessment of broader health progress can emerge from other resources including Healthy People, a national stakeholder-driven process that spans 4 decades and focuses on 26 Leading Health Indicators; County Health Rankings that identify, and generate support for, communities most in need of health improvements, and Vital Signs, a set of 15 measures tracking national, state, community, and institutional performance. Rallying around a unified core set of validated metrics could foster quality improvement and continuous learning in both the clinic and community.”

>>>PNN NewsWatch
* Purdue Pharma “thwarted” a West Virginia state plan in 2001 to limit access to OxyContin by paying Merck Medco (now a part of Express Scripts) “to make the drug available without prior authorization and with low copayments,” according to an investigative article on the STAT website. STAT is produced by Boston Globe Media.

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 © 2016, 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 Pharmacotherapy Line
Oct. 27, 2016 * Vol. 23, No. 208
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Oct. 27 issue of the New England Journal of Medicine (2016; 375).
Levosimendan for Preventing Acute Organ Dysfunction in Sepsis: In adults with sepsis, addition of the calcium-sensitizing inotrope levosimendan was not beneficial for preventing organ failure, weaning patients from mechanical ventilation, or other outcomes, and use of the drug was associated with a higher risk of supraventricular tachyarrhythmia, researchers report (pp. 1638–48). A 516-patient trial compared levosimendan with placebo using a primary outcome of mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (higher scores are worse symptoms), with these results: “There was no significant difference in the mean (± SD) SOFA score between the levosimendan group and the placebo group (6.68 ± 3.96 vs. 6.06 ± 3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29; P = 0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to 11.7; P = 0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P = 0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P = 0.04).” (A. C. Gordon, anthony.gordon@imperial.ac.uk)
Hepatic Encephalopathy: Initial therapy, second-line treatments, and intensive care of patients with hepatic encephalopathy are reviewed (pp. 1660–70). Noting the variations in management based on presence of cirrhosis and other modulators of pathology, authors recommend this approach to pharmacotherapy in the two forms of acute encephalopathy: “Lactulose or rifaximin can be beneficial for the treatment of gradual-onset encephalopathy in patients with prior cirrhosis, but additional, aggressive treatment of brain edema with osmotic diuretics is required in new, fulminant forms to prevent secondary, permanent brain-stem damage and to sustain patients through liver transplantation.” (E. F. M. Wijdicks, wijde@mayo.edu)
Voters’ Views on Health Care: In an analysis of Americans’ views on health care policies during the current election season, authors conclude that bipartisan action is likely on pharmaceutical prices, with new policies perhaps “related to price review, negotiation, and faster Food and Drug Administration drug-review procedures” (e37): “The public ranks pharmaceutical companies as most responsible for high health care costs. A large majority (73%) of likely voters believe that Medicare should use its bargaining power to negotiate lower drug prices from pharmaceutical companies, a view shared by both Democratic voters (80%) and Republican voters (68%). Less than one in five (19%) think Medicare should continue to rely on market competition to establish prescription-drug prices. Nearly two thirds (64%) of likely voters believe the federal government should have the authority to limit how much pharmaceutical companies can increase prescription-drug prices. More than three fourths of Democratic voters (79%) think the federal government should have this authority. A slight majority (52%) of Republican voters believe it should.” (R. J. Blendon, rblendon@hsph.harvard.edu)

>>>PNN NewsWatch
* FDA on Tuesday approved classwide labeling changes for all prescription testosterone products, adding a new warning and updating the abuse and dependence section to include new safety information from published literature and case reports regarding the risks associated with abuse and dependence of testosterone and other anabolic androgenic steroids. Reported serious adverse outcomes include heart attack, heart failure, stroke, depression, hostility, aggression, liver toxicity, and male infertility. Individuals abusing high doses of testosterone have also reported withdrawal symptoms, such as depression, fatigue, irritability, loss of appetite, decreased libido, and insomnia, FDA said.

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 © 2016, 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 Pharmacotherapy Line
Oct. 28, 2016 * Vol. 23, No. 209
Providing news and information about medications and their proper use

>>>Diabetes Care Report
Source:
Nov. issue of Diabetes Care, with a focus on precision medicine (2016; 39).
Precision Medicine in Diabetes: Referring to the NIH goal of constructing a research cohort of 1 million people as part of the President’s Precision Medicine Initiative, journal editors introduce readers to issue contents that “focus specifically on a translational theme related to implementing the principles of precision medicine, which are often nested in basic science, into the realm of clinical practice” (pp. 1854–7): “In addition, [articles in this issue] provide insight into the many challenges in refining the diagnostic and therapeutic pathways for optimal management of the individual with diabetes, given the individual diversity in genomic profile and environmental exposures. Even with 1 million volunteers, the number with a specific disease may be large, yet when partitioned into specific subgroups, it becomes small. Thus, the promise of precision medicine in general, and the Precision Medicine Initiative specifically, will reside in implementing a comprehensive translational approach enlisting the efforts of those in basic science, clinical science, and population science working in partnership.” (S. S. Rich, ssr4n@virginia.edu)
Barriers to Genomics in Diabetes: Authors describe “the potential application of genomics to the prediction, prevention, and treatment of diabetes [using] examples from other areas of medicine to illustrate some of the challenges involved in conducting genomics research in human populations and implementing findings in practice” (pp. 1858–69): “At this time, a major barrier to the application of genomics in diabetes care is the lack of actionable genomic findings. Whether genomic information should be used in clinical practice requires a framework for evaluating the validity and clinical utility of this approach, an improved integration of genomic data into electronic health records, and the clinical decision support and educational resources for clinicians to use these data. Efforts to identify optimal approaches in all of these domains are in progress and may help to bring diabetes into the era of genomic medicine.” (J. S. Floyd, jfloyd@uw.edu)
Precision Medicine, Genomics & Public Health: Deciding which advances in genomics to incorporate into routine clinical practice is nothing new, authors write, as questions were recognized two decades ago (pp. 1870–3): “As advances in molecular genetics have marched steadily forward and genetic epidemiologists have attempted to generate useful public health knowledge, paradigms have meanwhile shifted and developing disciplines (e.g., epigenetics, metabolomics) now contribute substantively to the conversation. The challenges faced by public health practitioners in this context have stemmed from the shifting landscape upon which the discipline is built.” (D. K. Arnett, donna.arnett@uky.edu)
Precision Medicine, Diabetes & FDA: In an article that provides “an overview of the regulatory expectations and challenges in realizing a future where the therapeutics for [diabetes mellitus (DM)] are informed by precise knowledge of a patient’s genetics and specific phenotype,” an author writes (pp. 1874–8): “FDA has long sought to achieve the broader use of personalized medicine, which is better targeting of FDA-approved therapies through incorporating precise knowledge of a patient’s underlying condition to therapies optimally chosen to match those needs. While some strides have been made in precision medicine—particularly in oncology and rare genetic diseases—most of the standard general medicine indications have yet to realize the benefits of precision-guided therapies. This includes those for DM, both type 1 and type 2. Although the scientific and regulatory considerations needed to move to a more ‘precise’ future of DM prevention and treatment differ between the two disease subsets, scientific advances in both must occur before the FDA can incorporate precision medicine into its oversight of DM drug development and approval.” (R. J. Meyer, rjm7cd@virginia.edu)

>>>PNN NewsWatch
* The Commission for Certification in Geriatric Pharmacy has reached an agreement with the Board of Pharmacy Specialties to move the Certified Geriatric Pharmacist credential under the BPS portfolio of pharmacist certifications, APhA and ASCP announced this week. The credential name will be changed to Board Certified Geriatric Pharmacist.

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 © 2016, 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 Pharmacotherapy Line
Oct. 31, 2016 * Vol. 23, No. 210
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 29 issue of Lancet (2016; 388).
Benralizumab in Severe Asthma: Three articles examine use of benralizumab in patients with severe, refractory asthma.
In the phase 3 SIROCCO trial, benralizumab was safe and effective in patients with severe asthma and elevated eosinophils uncontrolled by high-dosage inhaled corticosteroids and long-acting beta-2-agonists (ICS plus LABA) (
pp. 2115–27). At 374 sites in 17 countries, participants aged 12 to 75 years received benralizumab 30 mg every 4 or 8 weeks (Q4W or Q8W), with these placebo-controlled results: “2,681 patients were enrolled, 1,205 of whom met the study criteria and were randomly assigned: 407 to placebo, 400 to benralizumab 30 mg Q4W, and 398 to benralizumab 30 mg Q8W. 267 patients in the placebo group, 275 in the benralizumab 30 mg Q4W group, and 267 in the benralizumab 30 mg Q8W group had blood eosinophil counts at least 300 cells per µL and were included in the primary analysis population. Compared with placebo, benralizumab reduced the annual asthma exacerbation rate over 48 weeks when given Q4W (rate ratio 0.55, 95% CI 0.42–0.71; p <0.0001) or Q8W (0.49, 0.37–0.64; p <0.0001). Both benralizumab dosing regimens significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo (least-squares mean change from baseline: Q4W group 0.106 L, 95% CI 0.016–0.196; Q8W group 0.159 L, 0.068–0.249). Compared with placebo, asthma symptoms were improved by the Q8W regimen (least-squares mean difference −0.25, 95% CI −0.45 to −0.06), but not the Q4W regimen (−0.08, −0.27 to 0.12). The most common adverse events were worsening asthma (105 [13%] of 797 benralizumab-treated patients vs 78 [19%] of 407 placebo-treated patients) and nasopharyngitis (93 [12%] vs 47 [12%]).” (E. R. Bleecker, ebleec@wakehealth.edu)
“Benralizumab significantly reduced annual exacerbation rates and was generally well tolerated for patients with severe, uncontrolled asthma with blood eosinophils 300 cells per µL or greater,” phase 3 CALIMA investigators report (
pp. 2128–41). Based on methodology similar to the above trial, results showed: “2,505 patients were enrolled, of whom 1,306 patients were randomised; 425 patients were randomly assigned to and received benralizumab 30 mg Q4W, 441 to benralizumab 30 mg Q8W, and 440 to placebo. 728 patients were included in the primary analysis population. Benralizumab resulted in significantly lower annual exacerbation rates with the Q4W regimen (rate 0.60 [95% CI 0.48–0.74], rate ratio 0.64 [95% CI 0.49–0.85], p = 0.0018, n = 241) and Q8W regimen (rate 0.66 [95% CI 0.54–0.82], rate ratio 0.72 [95% CI 0.54–0.95], p = 0.0188, n = 239) compared with placebo (rate 0.93 [95% CI 0.77–1.12], n = 248). Benralizumab also significantly improved pre-bronchodilator FEV1 (Q4W and Q8W) and total asthma symptom score (Q8W only) in these patients. The most common adverse events were nasopharyngitis (90 [21%] in the Q4W group, 79 [18%] in the Q8W group, and 92 [21%] in the placebo group) and worsening asthma (61 [14%] in the Q4W group, 47 [11%] in the Q8W group, and 68 [15%] in the group).” (J. M. FitzGerald, mark.fitzgerald@vch.ca)
“The age of precision medicine has arrived for the subset of severe asthma patients with an eosinophilic driven phenotype using anti-interleukin-5 pathway therapies with mepolizumab, reslizumab, and now benralizumab,” editorialists conclude (
pp. 2059–60). “All three of these antibodies have now established efficacy in these select severe eosinophilic asthma patients with excellent safety profiles. Additional studies are needed using anti-interleukin-5 pathway therapies in school age children (aged 6 years and older) and in patients with other eosinophilic driven diseases such as chronic rhinosinusitis, nasal polyposis, eosinophilic esophagitis, atopic dermatitis, and eosinophilic granulomatosis with polyangitis.” (M. Castro, castrom@dom.wustl.edu)

>>>PNN JournalWatch
* Type 2 Diabetes: The Pathologic Basis of Reversible Beta-Cell Dysfunction, in
Diabetes Care, 2016; 39: 2080–8. (R. Taylor, roy.taylor@ncl.ac.uk)
* Potentially Inappropriate Drug Prescribing and the ‘Never Change a Winning Team’ Principle, in
Journals of Gerontology Series A, 2016; 71: 1531–2. (G. Onder, graziano.onder@unicatt.it)
* The Impact of Medication Reviews by Community Pharmacists, in
Journal of the American Pharmacists Association, 2016; 56: 513–20.e1. (M. R. Law, michael.law@ubc.ca)

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 © 2016, 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 Pharmacotherapy Line
Nov. 1, 2016 * Vol. 23, No. 211
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Nov. 1 issue of the Annals of Internal Medicine (2016; 165).
Treating Hepatitis C Virus in Injection Drug Users: Continued drug use should not be a barrier to instituting interferon-free treatment of hepatitis C virus (HCV) in persons who inject drugs (PWID), authors conclude (pp. 625–34). Based on a primary outcome of sustained virologic response at 12 weeks (SVR12), 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT) responded as follows to immediate (ITG) or deferred (DTG) treatment with elbasvir–grazoprevir for 12 or 24 weeks: “The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.” (G. J. Dore, gdore@kirby.unsw.edu.au)
Diagnosis & Management of Gout: Systematic reviews and clinical practice guidelines are presented for diagnosis and management of gout.
Following a review of diagnostic approaches that recommends multidimensional algorithms that require further validation in primary care settings (
10.7326/M16-0462; S. J. Newberry, sydnen@rand.org), a systematic review of management of gout reports the following (10.7326/M16-0461): “High-strength evidence from 28 trials (only 3 of which were placebo-controlled) shows that colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids reduce pain in patients with acute gout. Moderate-strength evidence suggests that low-dose colchicine is as effective as high-dose colchicine and causes fewer gastrointestinal adverse events. Moderate-strength evidence suggests that urate-lowering therapy (allopurinol or febuxostat) reduces long-term risk for acute gout attacks after 1 year or more. High-strength evidence shows that prophylaxis with daily colchicine or NSAIDs reduces the risk for acute gout attacks by at least half in patients starting urate-lowering therapy, and moderate-strength evidence indicates that duration of prophylaxis should be longer than 8 weeks. Although lower urate levels reduce risk for recurrent acute attacks, treatment to a specific target level has not been tested.” (P. G. Shekelle, shekelle@rand.org)
The American College of Physicians advises in a clinical practice guideline that “clinicians use synovial fluid analysis synovial fluid analysis when clinical judgment indicates that diagnostic testing is necessary in patients with possible acute gout” but notes the recommendation is a “weak” one because it is based on low-quality evidence (
10.7326/M16-0569; A. Qaseem, aqaseem@acponline.org). For managing gout, ACP recommends(10.7326/M16-0570; A. Qaseem, aqaseem@acponline.org):
* That clinicians choose corticosteroids, NSAIDs, or colchicine to treat patients with acute gout. (Grade: strong recommendation, high-quality evidence)
* That clinicians use low-dose colchicine when using colchicine to treat acute gout. (Grade: strong recommendation, moderate-quality evidence)
* Against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks. (Grade: strong recommendation, moderate-quality evidence)
* That clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate-lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence)
Noting that these ACP documents “have some distinct differences from the 2012 American College of Rheumatology guidelines,” an editorialist concludes that guidelines must clearly state for clinicians the basis on which recommendations are made (
10.7326/M16-2426): “As we try to provide our patients with the best possible care, we must be clear about when the best clinical decision is defined by high-quality evidence and when it is suggested by consensus.” (R. M. McLean, robert.mclean@ynhh.org)

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 © 2016, 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 Pharmacotherapy Line
Nov. 2, 2016 * Vol. 23, No. 212
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Nov. 1 issue of JAMA (2016; 316).
Hydrocortisone & Shock in Severe Sepsis: Results of the HYPRESS trial do not support hydrocortisone use in adult patients with severe sepsis (pp. 1775–85). Rates of septic shock within 14 days were similar in those given low-dose hydrocortisone and placebo, as reflected in these results: “The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, −1.8%; 95% CI, −10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, −5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, −5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, −4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia.” (D. Keh, didier.keh@charite.de)
“Glucocorticoids are clearly immunomodulatory during sepsis, and they are inexpensive,” editorialists write (
pp. 1769–71) “Research has failed to demonstrate unequivocal efficacy for patients with sepsis, and larger trials should help address outstanding questions. However, if past is prologue, it may be time to change direction and consider alternative trial designs to identify glucocorticoid-responsive subtypes and enable greater precision in current intensive care unit practice.” (S. Yende, yendes@upmc.edu)
Psychotropic Use in Violent Reoffenders: In Sweden, people being released from prison committed fewer subsequent violent offenses when they were dispensed evidence-based antipsychotics, psychostimulants, and drugs for addictive disorders, researchers report (pp. 1798–807). In a cohort study of all released prisoners from July 1, 2005 through the end of 2010 (n = 22,275; mean age, 38 years; 91.9% male), these findings were recorded during periods with and without dispensed prescriptions of psychotropic medications: “During follow-up (median, 4.6 years; interquartile range, 3.0–6.4 years), 4,031 individuals (18.1%) had 5,653 violent reoffenses. The within-individual hazard ratio (HR) associated with dispensed antipsychotics was 0.58 (95% CI, 0.39–0.88), based on 100 events in 1,596 person–years during medicated periods and 1,044 events in 11,026 person–years during nonmedicated periods, equating to a risk difference of 39.7 (95% CI, 11.3–57.7) fewer violent reoffenses per 1,000 person–years. The within-individual HR associated with dispensed psychostimulants was 0.62 (95% CI, 0.40–0.98), based on 94 events in 1,648 person–years during medicated periods and 513 events in 4,553 person–years during nonmedicated periods, equating to a risk difference of 42.8 (95% CI, 2.2–67.6) fewer violent reoffenses per 1,000 person–years. The within-individual HR associated with dispensed drugs for addictive disorders was 0.48 (95% CI, 0.23–0.97), based on 46 events in 1,168 person–years during medicated periods and 1,103 events in 15,725 person–years during nonmedicated periods, equating to a risk difference of 36.4 (95% CI, 2.1–54.0) fewer violent reoffenses per 1,000 person–years.” (S. Fazel, seena.fazel@psych.ox.ac.uk)
Translating these findings for the U.S., an editorialist writes that “may be other countries should try to be more like Sweden” (
pp. 1771–2). “There are a few effective reentry programs in the United States that incorporate social context. These programs tend to consider risk of crime largely as a feature of the neighborhoods and social networks to which prisoners return, and they understand the priority of addressing basic needs for safe housing and income support. In Sweden, the social context of successful rehabilitation for ex-prisoners is already inherent in society, and when people with mental illnesses commit violent crimes, perhaps the underlying cause is more often primarily related to brain disorders—treatable with medication—rather than social-environmental factors.” (J. Swanson, jeffrey.swanson@duke.edu)

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 © 2016, 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 Pharmacotherapy Line
Nov. 3, 2016 * Vol. 23, No. 213
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Nov. 3 issue of the New England Journal of Medicine (2016; 375).
Neurologic Toxicity With Endocannabinoid: In a phase 1 trial of the endocannabinoid BIA 10-2474, unexpected neurologic disorders occurred in 3 of 4 participants who agreed for clinical findings to be reported, and death in a fifth individual (pp. 1717–25). BIA 10-2474, an orally administered reversible fatty acid amide hydrolase inhibitor, was administered to 84 healthy volunteers without severe adverse events. Two participants were then assigned to placebo and 6 to BIA 10-2474 50 mg for 5 days. Among the 4 participants who agreed to have findings included, these results were noted: “An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.” (G. Edan, gilles.edan@chu-rennes.fr)
Writing of the inherent risks of first-in-human drug trials, editorialists conclude that “clinical trials are still the best tool for providing the evidence needed for drug approval and appropriate clinical practice” (
pp. 1788–9). “Phase 1 trials are generally safe; there have been only two trials with very severe adverse events affecting several volunteers among the 14,700 studies (3,100 first-in-human studies) involving 305,000 participants that have been conducted in the EU since 2005. It is hoped that the revised [European Medicines Agency] guidelines, when available, will enhance strategies to identify and minimize risks for trial participants and to ensure that first-in-human trials throughout the EU member states are conducted in a safe, efficient, transparent, and harmonized manner for the benefit of human health.” (S. Bonini)
Antiretroviral Therapy for Perinatal HIV Prevention: While antenatal use of antiretroviral therapy (ART) reduces rates of early HIV transmission beyond those provided by zidovudine prophylaxis, authors write that the benefit comes at the cost of higher risks of adverse maternal and neonatal outcomes (pp. 1726–37). In a randomized trial of 3,490 HIV-infected women at 14 or more weeks’ gestation and CD4 counts of 350 cells/cu mm or more, outcomes were as follows with zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum “tail” of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir–ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir–ritonavir (tenofovir-based ART): “The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, −1.3 percentage points; repeated confidence interval, −2.1 to −0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P = 0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P= 0.03). Adverse events did not differ significantly between the ART groups (P >0.99). A birth weight of less than 2,500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P <0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P = 0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P <0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P = 0.04) and early infant death (4.4% vs. 0.6%, P =0 .001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P = 0.10 and P = 0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART.” (M. G. Fowler, mgfowler@mujhu.org)

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 © 2016, 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 Pharmacotherapy Line
Nov. 4, 2016 * Vol. 23, No. 214
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Early-online article from Health Affairs (2016; 35).
Cost of a Hepatitis C Virus Cure: “The cost of a cure—in this case for hepatitis C—has served as an important wake-up call after several years of low spending growth for prescription drugs,” write authors of a blog posted yesterday (Nov. 3). Based on analysis of data released by CMS in August, the group calculates 2014 individual and population costs, reaching this conclusion: “Although spending for hepatitis C drugs is expected to decline over the next few years, the cost of new specialty drugs will likely be a major driver of Medicare spending in the coming years, raising tough questions for policymakers as they explore how best to balance the need for medicines that improve our health with the need to keep spending under control.” (J. Hoadley)

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (2016; 138).
Influenza Vaccine Use Among Children Using CAM: Among 9,000 children, those exposed to complementary and alternative medicine (CAM) practitioners “are vulnerable to lower annual uptake of influenza vaccination,” a study shows (10.1542/peds.2015-4664). Records in the Child Complementary and Alternative Medicine File of the 2012 National Health Interview Survey showed these outcomes based on ever-use of acupuncture and other forms of alternative medical systems (AMS), herbal and other biological-based therapies, multivitamins/multiminerals, chiropractic manipulation and other forms of manipulative and body-based therapies (MBBT), and mind–body therapies such as yoga: “Influenza vaccination uptake was lower among children ever (versus never) using AMS (33% vs 43%; P = .008) or MBBT (35% vs 43%; P = .002) but higher by using multivitamins/multiminerals (45% vs 39%; P < .001). In multivariate analyses, multivitamin/multimineral use lost significance, but children ever (versus never) using any AMS or MBBT had lower uptake (respective odds ratios: 0.61 [95% confidence interval: 0.44–0.85]; and 0.74 [0.58–0.94]).” (R. BeLue, rzb10@psu.edu)
School-Located Influenza Vaccinations: In an upstate New York county, seasonal influenza vaccination rates were higher when school-located influenza vaccinations (SLIV) were available, and data show some substitution for primary care vaccinations in urban but not suburban areas (10.1542/peds.2016-1746). The cluster-randomized trial, conducted in 2014–15, included 44 elementary schools that were allocated in pairs to SLIV or usual care, with these results: “The 44 schools served 19,776 eligible children in 2014–2015. Children in SLIV schools had higher influenza vaccination rates than children in control schools county-wide (54.1% vs 47.4%, P < .001) and in suburban (61.9% vs 53.6%, P < .001) and urban schools (43.9% vs 39.2%; P < .001). Multivariate analyses (controlling for age, grade, vaccination in previous season) confirmed bivariate findings. Among parents who consented for SLIV, nearly half of those notified by backpack fliers and four-fifths of those notified by e-mail consented online. In suburban districts, SLIV did not substitute for primary care influenza vaccination. In urban schools, some substitution occurred.” (P. G. Szilagyi, pszilagyi@mednet.ucla.edu)
Neonatal Morbidity After Antidepressants During Pregnancy: Increased neonatal morbidity and a higher rate of admissions to neonatal intensive care units (NICUs) was found in an analysis of the Swedish Neonatal Quality Registry for 2006–12 (10.1542/peds.2016-0181). Absolute risk for severe disease was low, the authors note, among those neonates born to mothers who used SSRIs during pregnancy: “After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval: 1.4–1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5% compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6 [95% confidence interval: 1.5–1.8]). Respiratory and central nervous system disorders and hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary hypertension (number needed to harm: 285).” (U. Nörby, ulrika.norby@sll.se)

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 © 2016, 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 Pharmacotherapy Line
Nov. 7, 2016 * Vol. 23, No. 215
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 5 issue of Lancet (2016; 388).
Antisense Oligonucleotides for Raised Lp(a): In a phase 2 trial from Canada and Europe, the ligand-conjugated antisense oligonucleotide IONIS-APO(a)-LRx was tolerable and potent in 64 participants with raised lipoprotein(a) (Lp[a]) concentrations, researchers report (pp. 2239–53). The new agents “might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis,” the authors add in reporting these results: “Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30. In the multidose groups, IONIS-APO(a)-LRx resulted in mean reductions in Lp(a) of 66% (SD 21.8) in the 10 mg group, 80% (SD 13.7%) in the 20 mg group, and 92% (6.5) in the 40 mg group (p = 0.0007 for all vs placebo) at day 36.…” (S. Tsimikas, stsimikas@ucsd.edu)
Glucose-Sensing Technology & Hypoglycemia in Type 1 Diabetes: Compared with self-monitoring of blood glucose with capillary strips, a “novel flash glucose testing reduced the time adults with well controlled type 1 diabetes spent in hypoglycaemia,” a study shows (pp. 2254–63). In 328 participants at 23 European diabetes centers, these results were recorded with the two systems: “Mean time in hypoglycaemia changed from 3.38 h/day at baseline to 2.03 h/day at 6 months (baseline adjusted mean change −1.39) in the intervention group, and from 3.44 h/day to 3.27 h/day in the control group (−0.14); with the between-group difference of −1.24 (SE 0.239; p <0.0001), equating to a 38% reduction in time in hypoglycaemia in the intervention group. No device-related hypoglycaemia or safety issues were reported. 13 adverse events were reported by ten participants related to the sensor—four of allergy events (one severe, three moderate); one itching (mild); one rash (mild); four insertion-site symptom (severe); two erythema (one severe, one mild); and one oedema (moderate). There were ten serious adverse events (five in each group) reported by nine participants; none were related to the device.” (J. Bolinder, jan.bolinder@ki.se)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 353).
Diabetes & Duration of Dual Antiplatelet Therapy After Stent Placement: Six months of dual antiplatelet therapy (DAPT) is optimal following implantation of a drug-eluting stent, according to authors of systematic review and meta-analysis of 6 trials of 11,473 people (i5483): “3,681 (32.1%) [participants] had diabetes and 7,708 (67.2%) did not (mean age 63.7 (SD 9.9) and 62.8 (SD 10.1), respectively), and in 84 (0.7%) the information was missing. Diabetes was an independent predictor of [major adverse cardiac events (MACE)] (hazard ratio 2.30, 95% confidence interval 1.01 to 5.27; P = 0.048). At one year follow-up, long term DAPT was not associated with a decreased risk of MACE compared with short term DAPT in patients with (1.05, 0.62 to 1.76; P =0.86) or without (0.97, 0.67 to 1.39; P = 0.85) diabetes (P = 0.33 for interaction). The risk of myocardial infarction did not differ between the two DAPT regimens (0.95, 0.58 to 1.54; P = 0.82; for those with diabetes and 1.15, 0.68 to 1.94; P = 0.60; for those without diabetes (P = 0.84 for interaction). There was a lower risk of definite/probable stent thrombosis with long term DAPT among patients with (0.26, 0.09 to 0.80; P = 0.02) than without (1.42, 0.68 to 2.98; P = 0.35) diabetes, with positive interaction testing (P = 0.04 for interaction), although the landmark analysis showed a trend towards benefit in both groups. Long term DAPT was associated with higher rates of major or minor bleeding, irrespective of diabetes (P = 0.37 for interaction).” (M. Valgimigli, marco.valgimigli@insel.ch)

>>>PNN JournalWatch
* Perinatal Substance Abuse: At the Clinical Crossroads of Policy and Practice, in
American Journal of Psychiatry, 2016; 173: 1077–80. (S. J. House)
* Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework, in
American Journal of Psychiatry, 2016; 173: 1083–93. (J. E. LeDoux)
* The Use of Systemic and Topical Fluoroquinolones, in
Pediatrics, 2016; 138: 10.1542/peds.2016-2706. (M. A. Jackson)
* Handoffs: Transitions of Care for Children in the Emergency Department, in
Pediatrics, 2016; 138: 10.1542/peds.2016-2680. (American Academy of Pediatrics Committee on Pediatric Emergency Medicine et al.)

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 © 2016, 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 Pharmacotherapy Line
Nov. 8, 2016 * Vol. 23, No. 216
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. issue of JAMA Internal Medicine (2016; 176).
Postelection Health Care Reform: “Regardless of the outcome, the federal elections in November 2016 matter, and are likely to have long-term consequences for the future of the [Affordable Care Act (ACA)] and related health reform proposals,” Viewpoint authors write (pp. 1595–6). “A Republican victory that includes that party’s control of the White House, Senate, and House of Representatives would likely augur huge shifts in national health policy. A Democratic victory that included the White House and a Senate majority would likely further embed the ACA into state and federal health policy, and perhaps lead to further expansion and reforms. More than 6 years after President Barack Obama signed the legislation into law in 2010, the ACA has yet to become settled policy.” (J. E. McDonough, jmcdonough@hsph.harvard.edu)
Azithromycin in Asthma Exacerbations: Outcomes in the Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) trial were statistically and clinically similar among adults with acute asthma exacerbations with azithromycin or placebo (pp. 1630–7). Based on a primary outcome of diary card symptom score 10 days after randomization, investigators in the U.K.-based study report: “Of 4,582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2,044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14–28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, −0.166; 95% CI, −0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.” (S. L. Johnston, s.johnston@imperial.ac.uk)
“The most striking finding of the study is the [prerandomization] overuse of antibiotics in patients with asthma attacks,” editorialists write (
pp. 1637–8). “To tackle this problem, at least 4 strategies need to be combined: (1) raising awareness among health care professionals and patients; (2) implementing the recommendations of asthma guidelines not to use antibiotics routinely in asthma exacerbations; (3) performing large trials in primary and secondary care to investigate which patients with asthma attacks might benefit from antibiotic treatment, and (4) validating known biomarkers (C-reactive protein, procalcitonin) and developing novel biomarkers for guiding targeted antibiotic therapy.” (G. Brusselle, guy.brusselle@ugent.be)
Antibiotic Use in U.S. Hospitals: Overuse of broad-specturm antibiotics in U.S. hospitals is worrisome, authors conclude (pp. 1639–48). Data from the Truven Health MarketScan Hospital Drug Database (HDD) show that overall duration of therapy (DOT) did not change significantly in 2006–12, the group concludes: “However, the mean change (95% CI) for the following antibiotic classes increased significantly: third- and fourth-generation cephalosporins, 10.3 (3.1–17.5); macrolides, 4.8 (2.0–7.6); glycopeptides, 22.4 (17.5–27.3); beta-lactam/beta-lactamase inhibitor combinations, 18.0 (13.3–22.6); carbapenems, 7.4 (4.6–10.2); and tetracyclines, 3.3 (2.0–4.7).” (J. Baggs, jbaggs@cdc.gov)
Individual and geographic differences in antibiotic prescribing also point toward opportunities for improvement, editorialists conclude (
pp. 1649–50): “The dramatic variation in antibiotic prescribing across individual clinicians, regions in the United States, and internationally indicates great potential for improvement. In a single health system, physicians’ antibiotic prescribing rates for some conditions vary more than 2-fold. In the article by Baggs et al, inpatient antibiotic prescribing in some regions of the United States is roughly 20% lower than other regions. On a per capita basis, Swedes consume less than half the antibiotics per capita than Americans.” (A. Mehrotra, Mehrotra@hcp.med.harvard.edu)

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 © 2016, 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 Pharmacotherapy Line
Nov. 9, 2016 * Vol. 23, No. 217
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Nov. 8 issue of JAMA (2016; 316).
Cranberry for UTIs: Compared with placebo in 185 older women residing in 21 nursing homes in the New Haven, CT, area, cranberry capsules had no effect on rates of bacteriuria or pyuria over a 1-year period (pp. 1879–87). Participants assigned to the intervention group received two oral cranberry capsules containing proanthocyanidin 72 mg (equivalent to 20 ounces of cranberry juice) once daily, with these results: “Unadjusted results showed the presence of bacteriuria plus pyuria in 25.5% (95% CI, 18.6%–33.9%) of the treatment group and in 29.5% (95% CI, 22.2%–37.9%) of the control group. The adjusted generalized estimating equations model that accounted for missing data and covariates showed no significant difference in the presence of bacteriuria plus pyuria between the treatment group vs the control group (29.1% vs 29.0%; OR, 1.01; 95% CI, 0.61–1.66; P = .98). There were no significant differences in number of symptomatic UTIs (10 episodes in the treatment group vs 12 in the control group), rates of death (17 vs 16 deaths; 20.4 vs 19.1 deaths/100 person–years; rate ratio [RR], 1.07; 95% CI, 0.54–2.12), hospitalization (33 vs 50 admissions; 39.7 vs 59.6 hospitalizations/100 person–years; RR, 0.67; 95% CI, 0.32–1.40), bacteriuria associated with multidrug-resistant gram-negative bacilli (9 vs 24 episodes; 10.8 vs 28.6 episodes/100 person–years; RR, 0.38; 95% CI, 0.10–1.46), antibiotics administered for suspected UTIs (692 vs 909 antibiotic days; 8.3 vs 10.8 antibiotic days/person–year; RR, 0.77; 95% CI, 0.44–1.33), or total antimicrobial utilization (1,415 vs 1,883 antimicrobial days; 17.0 vs 22.4 antimicrobial days/person–year; RR, 0.76; 95% CI, 0.46–1.25).” (M. Juthani-Mehta, manisha.juthani@yale.edu)
It’s “time to move on” from advocating cranberry products for urinary tract infections (UTIs), an editorialist writes (
pp. 1873–4): “Clinicians should not be promoting cranberry use by suggesting that there is proven, or even possible, benefit. Clinicians who encourage such use are doing their patients a disservice. Recurrent UTI is a common problem that is distressing to patients and because it is so frequent and costly for the health care system. It is time to identify other potential approaches for management. This certainly must include a wiser use of antimicrobial therapy for syndromes of recurrent UTI in women in long-term care facilities. Other possible interventions to explore in this and other populations may include, among other approaches, adherence inhibitors or immunologic interventions. Intellectual discussions and clinical trial activity should be redirected to identify and evaluate other innovative antimicrobial and nonantimicrobial approaches. It is time to move on from cranberries.” (L. E. Nicolle, LNicolle@exchange.hsc.mb.ca)

>>>PNN NewsWatch
* How do you repeal and replace a law undergirding an industry that is one sixth of the national gross domestic product? With Republicans taking control of the White House and retaining majorities in both houses of Congress, we will find out soon. In a blog posted to the Health Affairs website in advance of yesterday’s election, an author explored the health care views of President-elect Donald Trump and (current) House speaker Paul Ryan’s intentions with regard to the Affordable Care Act: “After early teasing about his admiration for the Canadian and Scottish single-payer systems, Trump embraced standard Republican orthodoxy on ObamaCare, most recently announcing his intention to call a special Congressional session as soon as possible to repeal the law.… Speaker Ryan announced in September his intention—if Republicans control both houses of Congress and the White House in January—to expedite budget reconciliation legislation that would repeal as much of ObamaCare as possible. Though Ryan’s plan is more ambitious than Trump’s, of the latter’s seven health policy planks, five also show up on the Speaker’s agenda.” With health care legislation in play on Capitol Hill, the door opens for organized pharmacy to push for federal recognition of pharmacists’ patient care services as espoused by the Patient Access to Pharmacists’ Care Coalition, with 37 national and dozens of state pharmacy and health-system pharmacy organizations, or the ACCP Medicare Benefit Initiative, which is also supported by the College of Psychiatric and Neurologic Pharmacists.

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 © 2016, 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 Pharmacotherapy Line
Nov. 10, 2016 * Vol. 23, No. 218
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Nov. 10 New England Journal of Medicine (2016; 375).
Pembrolizumab for Non–Small-Cell Lung Cancer: Compared with platinum-based chemotherapy, pembrolizumab produced significantly longer progression-free survival and overall survival in an open-label, phase 3 trial of 305 patients with advanced non–small-cell lung cancer with increased activity in tumors that express programmed death ligand 1 (PD-L1) (pp. 1823–33). With crossover from the chemotherapy group permitted in cases of disease progression, study results showed: “Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P <0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P = 0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).” (J. R. Brahmer)
“Immunotherapy with checkpoint inhibitors will displace chemotherapy in yet another subset of patients with lung cancer,” an editorialist notes (
pp. 1892–3). “Oncologists may work with diagnostics laboratories to get appropriate, timely testing for PD-L1 expression in order to make determinations about the initial treatment of their patients with lung cancer. We await the results of long-term follow-up of large cohorts of patients who were treated with another checkpoint inhibitor, nivolumab, to see whether the initial survival advantage in the population translates to survival of 20% or greater at 3 years and beyond.” (B. E. Johnson)
Semaglutide in Type 2 Diabetes: Semaglutide produced significantly lower rates of major cardiovascular events than did placebo among patients with type 2 diabetes and high cardiovascular risk, researchers report (pp. 1834–44). In a noninferiority trial of 3,297 patients who received once-weekly semaglutide or placebo for 104 weeks, these outcomes were found based on a noninferiority margin of 1.8 for the upper 95% CI of the hazard ratio: “At baseline, 2,735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary [noninferiority] outcome occurred in 108 of 1,648 patients (6.6%) in the semaglutide group and in 146 of 1,649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P <0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P = 0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P = 0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P = 0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.” (S. P. Marso, smarso@gmail.com)
Vitamin D Deficiency: Counseling of adults regarding vitamin D intake should rely on the IOM Recommended Dietary Allowance (RDA) “as a guidepost,” Perspective authors write (pp. 1817–20). “Although clinical judgment and customized interventions can be used with individual patients, avoidance of overscreening and overprescribing of supplemental vitamin D remains important.” (J. E. Manson)

>>>PNN NewsWatch
* Skinny Bee Diet 500 mg is being recalled by Love My Tru Body because of undeclared sibutramine, desmethylsibutramine, and/phenolphthalein found in the product, FDA said.

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 © 2016, 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 Pharmacotherapy Line
Nov. 11, 2016 * Vol. 23, No. 219
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Nov. issue of Chest (2016; 150).
Long-term Rivaroxaban in Recurrent VTE: Rivaroxaban anticoagulation, continued past the initial 6–12 months after acute deep-vein thrombosis (DVT) or pulmonary embolism (PE) provides “a clinically important benefit and a favorable benefit-risk profile,” according to results of the EINSTEIN-Extension trial (pp. 1059–68). Comparing continued rivaroxaban with placebo in 1,197 patients with symptomatic DVT or PE who had completed 6 to 12 months of anticoagulation, investigators found: “Recurrent VTE occurred in eight recipients of rivaroxaban and 42 patients receiving placebo. In a population of 10,000 patients treated for 1 year, rivaroxaban treatment would have resulted in 665 (95% CI, 246-1,084) fewer recurrent VTEs than would placebo (number needed to treat = 15). Major bleeding occurred in four (0.7%) and zero patients, respectively. Rivaroxaban treatment would have resulted in 68 (95% CI, 2–134) more major bleeding events than would placebo (number needed to harm = 147). Kaplan–Meier analysis showed early recurrent VTE reduction with rivaroxaban that continued to improve throughout treatment; major bleeding increased gradually, plateauing at approximately 100 days.” (P. S. Wells)
Viruses in Nonventilated Hospital-Acquired Pneumonia: Respiratory viruses were an important cause of nonventilated hospital-acquired pneumonia (NVHAP) in a case–control study at a St. Louis hospital in 2014, researchers report (pp. 1008–14). NVHAP was associated with “significant increases in mortality, the use of intensive care and mechanical ventilation, and hospital length of stay,” the authors conclude based on these findings for 174 consecutive patients with NVHAP and 696 matched control patients: “NVHAP was pathogen-negative in 98 cases (56.3%). Respiratory viruses were identified in 42 patients (24.1%), gram-negative bacteria were seen in 25 patients (14.4%), and gram-positive bacteria were identified in 20 patients (11.5%). Individuals in whom NVHAP developed were more likely to die (15.5% vs 1.6%; P <0.01), to require intensive care (56.3% vs 22.8%; P <0.01) or mechanical ventilation (19.0% vs 3.9%; P < 0.01), and to have a longer hospital length of stay (15.9 days [range, 9.8–26.3 days] vs 4.4 days [range, 2.9–7.3 days]; P < 0.01). This case–control study identified a strong association between hospital mortality and NVHAP, with patients who acquired NVHAP having an 8.4 times greater odds of death (95% CI, 5.6–12.5).” (S. T. Micek)
These results “not only provide important information about the outcomes related to NVHAP, they also point to potential ways for practicing clinicians to improve the care of their patients,” editorialists write (
pp. 991–2): “Because antibiotics will not help those suffering from a viral infection, the search for (and potential identification of) a viral cause will facilitate antibiotic de-escalation and stewardship. In many situations, culture negative NVHAP patients receive a 7- to 10-day course of antibiotics. By limiting exposure to such agents because a virus has been identified, we can help prevent the emergence of further resistance as well as individual consequences of unnecessary antibiotic exposure, such as gut dysbiosis and Clostridium difficile infection. Finally, as rapid diagnostic tools are being developed for pneumonia, the manufacturers of these tests need to ensure that they include means not only for identifying bacteria, but also for determining if a viral pathogen is present.” (A. F. Shorr)

>>>PNN NewsWatch
* While more than 1 million tobacco-related cancer deaths have been avoided since 1990, tobacco use remains the leading preventable cause of cancer and cancer deaths in the U.S., according to an article in yesterday’s MMWR (2016; 65: 1205–11) and the November CDC Vital Signs report. Current cigarette smoking among U.S. adults declined from 20.9% (45.1 million) in 2005 to 15.1% (36.5 million) in 2015. During 2014–15 alone, there was a 1.7 percentage point decline, resulting in the lowest prevalence of adult cigarette smoking since the CDC’s National Health Interview Survey began collecting such data in 1965. Each year between 2009 and 2013, about 660,000 people in the U.S. were diagnosed with, and about 343,000 people died from, a cancer related to tobacco use. Three in ten cancer deaths were due to cigarette smoking, but progress has been made, CDC said.

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 © 2016, 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 Pharmacotherapy Line
Nov. 14, 2016 * Vol. 23, No. 220
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from JAMA (2016; 316).
Statins in Primary Prevention of Cardiovascular Disease: Statin therapy should be considered for primary prevention in all adults 40 through 75 years of age, according to revised guidelines from the U.S. Preventive Services Task Force (USPSTF), but starting the drugs for primary prevention in those aged 76 or older is not supported by currently available evidence (10.1001/jama.2016.15450). Based on information from the below systematic review, the USPSTF makes these recommendations (K. Bibbins-Domingo, chair@uspstf.net):
* Initiation of use of low- to moderate-dose statins in adults aged 40 to 75 years without a history of [cardiovascular disease (CVD)] who have 1 or more CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and a calculated 10-year CVD event risk of 10% or greater (B recommendation).
* Selectively offering low- to moderate-dose statins to adults aged 40 to 75 years without a history of CVD who have 1 or more CVD risk factors and a calculated 10-year CVD event risk of 7.5% to 10% (C recommendation).
* Current evidence is insufficient to assess the balance of benefits and harms of initiating statin use in adults 76 years and older (I statement).
These recommendations flow from findings in the evidence report and systematic review (
10.1001/jama.2015.15629): “Statin therapy was associated with decreased risk of all-cause mortality (risk ratio [RR], 0.86 [95% CI, 0.80 to 0.93]; I2 = 0%; absolute risk difference [ARD], −0.40% [95% CI, −0.64% to −0.17%]), cardiovascular mortality (RR, 0.69 [95% CI, 0.54 to 0.88]; I2 = 54%; ARD, −0.43% [95% CI, −0.75% to −0.11%]), stroke (RR, 0.71 [95% CI, 0.62 to 0.82]; I2 = 0; ARD, −0.38% [95% CI, −0.53% to −0.23%]), myocardial infarction (RR, 0.64 [95% CI, 0.57 to 0.71]; I2 = 0%; ARD, −0.81% [95% CI, −1.19 to −0.43%]), and composite cardiovascular outcomes (RR, 0.70 [95% CI, 0.63 to 0.78]; I2 = 36%; ARD, −1.39% [95% CI, −1.79 to −0.99%]). Relative benefits appeared consistent in demographic and clinical subgroups, including populations without marked hyperlipidemia (total cholesterol level <200 mg/dL); absolute benefits were higher in subgroups at higher baseline risk. Statins were not associated with increased risk of serious adverse events (RR, 0.99 [95% CI, 0.94 to 1.04]), myalgias (RR, 0.96 [95% CI, 0.79 to 1.16]), or liver-related harms (RR, 1.10 [95% CI, 0.90 to 1.35]). In pooled analysis, statins were not associated with increased risk of diabetes (RR, 1.05 [95% CI, 0.91 to 1.20]), although statistical heterogeneity was present (I2 = 52%), and 1 trial found high-intensity statins associated with increased risk (RR, 1.25 [95% CI, 1.05 to 1.49]). No trial directly compared titrated vs fixed-dose statins, and there were no clear differences based on statin intensity.” (R. Chou, chour@ohsu.edu)

>>>Lancet Highlights
Source:
Nov. 12 issue of Lancet (2016; 388).
First-Line Treatment of Helicobacter pylori: Rising clarithromycin resistance with Helicobacter pylori is making bismuth quadruple therapy preferable to 14-day triple therapy, according to investigators in a 5,454-patient trial in Taiwan (pp. 2355–65): “The eradication frequencies were 90.4% (488/540 [95% CI 87.6–92.6]) for 10-day bismuth quadruple therapy, 85.9% (464/540 [82.7–88.6]) for 10-day concomitant therapy, and 83.7% (452/540 [80.4–86.6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6.7% [95% CI 2.7–10.7, p = 0.001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy.” Respective rates of adverse events were 67%, 58%, and 47%. (M-S Wu, mingshiang@ntu.edu.tw)

>>>PNN JournalWatch
* Statins Are Associated With Reduced Mortality in Multiple Myeloma, in
Journal of Clinical Oncology, 2016; 34: 4008–14. (K. M. Sanfilippo, ksanfilippo@wustl.edu)
* Economic Incentives for Antibacterial Drug Development: Literature Review and Considerations From the Transatlantic Task Force on Antimicrobial Resistance, in
Clinical Infectious Diseases, 2016; 63: 1470–4. (J. Larsen, joseph.larsen@hhs.gov)
* Management of Myositis-Related Interstitial Lung Disease, in
Chest, 2016; 150: 1118–28. (J. S. Lee)

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 © 2016, 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 Pharmacotherapy Line
Nov. 15, 2016 * Vol. 23, No. 221
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 15 issue of the Annals of Internal Medicine (2016; 165).
Cost-Effectiveness of Sacubitril–Valsartan in HF/Reduced Ejection Fraction: In patients with New York Heart Association (NYHA) class II to IV heart failure, sacubitril–valsartan combination therapy yielded benefits at a reasonable cost, according to investigators who conducted a cost-effectiveness analysis (pp. 681–9). Using a Markov decision model to evaluate data from clinical trials, observational studies, and CMS, the authors determined: “The sacubitril–valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional [quality-adjusted life–year (QALY)], and $29,203 in incremental costs, equating to a cost per QALY gained of $47,053. The cost per QALY gained was $44,531 in patients with NYHA class II heart failure and $58,194 in those with class III or IV heart failure.” The sensitivity analysis showed: “Sacubitril–valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120,623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100,000 per QALY gained.” (A. T. Sandhu, ats114@stanford.edu)
Editorialists hope that this article will move the needle on the number of physicians prescribing this drug combination, despite “the plethora of articles and P values concerning sacubitril–valsartan published over the past 3 years [having] had minimal impact on prescribing behaviors” (
pp. 735–6): “This experience has important lessons for those who believe that publishing numerous articles will meaningfully influence clinical practice. Many physicians are too busy caring for patients to spend time reading research reports on new and unfamiliar drugs. Furthermore, even if physicians were to read the findings of a new study, they are likely to encounter data that are presented in an opaque and unpersuasive manner. For many, publications are simply a way that researchers talk to each other rather than communicating with physicians who are responsible for the care of most patients. This is a lesson the academic clinical community needs to hear and take to heart.” (M. Packer, milton.packer@baylorhealth.edu)
TAPS Tool for Substance Use Screening: The Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS) tool “detected clinically relevant problem substance use” among 2,000 adult patients seen at five adult primary care clinics, researchers report (pp. 690–9). Compared with the modified World Mental Health Composite International Diagnostic Interview (CIDI), the TAPS tool yielded these results regarding problem use and substance use disorder (SUD): “Interviewer- and self-administered versions of the TAPS tool had similar diagnostic characteristics. For identifying problem use (at a cutoff of 1+), the TAPS tool had a sensitivity of 0.93 (95% CI, 0.90 to 0.95) and specificity of 0.87 (CI, 0.85 to 0.89) for tobacco and a sensitivity of 0.74 (CI, 0.70 to 0.78) and specificity of 0.79 (CI, 0.76 to 0.81) for alcohol. For problem use of illicit and prescription drugs, sensitivity ranged from 0.82 (CI, 0.76 to 0.87) for marijuana to 0.63 (CI, 0.47 to 0.78) for sedatives; specificity was 0.93 or higher. For identifying any SUD (at a cutoff of 2+), sensitivity was lower.” (J. McNeely, Jennifer.McNeely@nyumc.org)
Guidelines for Cardiovascular Risk Assessment: An assessment of cardiovascular screening guidelines from Western national and international medical organizations shows that “considerable discrepancies … still exist, with no consensus on optimum screening strategies or treatment threshold” (pp. 713–22). Systematic review of guidelines by two individuals who looked at the rigor of guideline development using the Appraisal of Guidelines for Research and Evaluation II instrument yielded these findings: “Of the 21 guidelines, 17 showed considerable rigor of development. These recommendations address assessment of total cardiovascular risk (5 guidelines), dysglycemia (7 guidelines), dyslipidemia (2 guidelines), and hypertension (3 guidelines). All but 1 recommendation advocates for screening, and most include prediction models integrating several relatively simple risk factors for either deciding on further screening or guiding subsequent management. No consensus on the strategy for screening, recommended target population, screening tests, or treatment thresholds exists.” (M. G. M. Hunink, m.hunink@erasmusmc.nl)

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 © 2016, 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 Pharmacotherapy Line
Nov. 16, 2016 * Vol. 23, No. 222
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Early-release article from and Nov. 15 issue of JAMA (2016; 316).
Evolocumab in Statin-Treated Patients: In the GLAGOV trial, addition of evolocumab to statin therapy further lowered LDL cholesterol levels and reduced atheroma, researchers report (10.1001/jama.2016.16951). At 197 academic and community hospitals around the world, monthly evolocumab 420 mg or placebo administered subcutaneously produced these changes in percent atheroma volume (PAV) and total atheroma volume (TAV): “Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P <.001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, −1.0% [95% CI, −1.8% to −0.64%]; P <.001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, −4.9 mm3 [95% CI, −7.3 to −2.5]; P <.001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P <.001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P <.001 for TAV).” (S. J. Nicholls, stephen.nicholls@sahmri.com)
Managing Cholesterol: In the wake of release of the new cholesterol guideline (see PNN, Nov. 14), authors of Viewpoint articles discuss aspects of statin management of cholesterol.
“Managing statin-associated muscle symptoms is not evidenced based but requires reassuring the patient, reassessing the need for statin therapy, determining if statins may be responsible for the symptoms, eliminating possible contributors to the process, and developing alternative treatment plans,” an author writes. (
pp. 1969–70). “Other medications (especially gemfibrozil) and conditions (hypothyroidism and vitamin D deficiency) can increase muscle symptoms. Vitamin D deficiency alone can produce myopathy, but evidence that vitamin D supplementation reduces statin-associated muscle symptoms is limited. Coenzyme Q10 supplementation has not been effective in reducing symptoms in a meta-analysis of 10 studies, although some patients and clinicians are convinced this agent works perhaps via a placebo effect. Coenzyme Q10 can be tried after informing the patients that it has not been effective in clinical trials but has been useful in some patients.” (P. D. Thompson, paul.thompson@hhchealth.org)
Addressing the use of statins for primary prevention in those older than 75 years, authors conclude, “In the absence of clear evidence of net benefit for statins for primary prevention in adults older than 75 years and uncertainty about the risks of therapy, clinicians might reasonably follow a shared decision-making approach in discussing the use of statins for this indication with older patients” (
pp. 1971–2). “However, lack of evidence substantially challenges efforts to reach optimal health decisions for the aging population. Trends in prescription drug use, even before the 2013 ACC/AHA guideline, suggest that increasing numbers of individuals older than 75 years will likely be treated with statins for primary prevention in the absence of adequate information on benefits and risks. Furthermore, large numbers of persons aged 65 to 75 years who are currently receiving ‘evidence-based’ treatment with statins are aging into non–evidence-based territory. To address the substantial knowledge gaps about statins for primary prevention in persons older than 75 years, a randomized placebo-controlled trial is required—one that addresses a full range of outcomes, including health-related quality of life, function, and symptom burden related to statin therapy. Given the increasing use of statin therapy in older persons, the imperative for such a trial has never been greater, and the window to pursue it is closing fast.” (J. H. Gurwitz, jgurwitz@meyersprimary.org)

>>>PNN NewsWatch
* It’s Get Smart About Antibiotics Week, CDC’s annual opportunity to raise awareness of the threat of antibiotic resistance and emphasize the importance of appropriate antibiotic use across all health care settings.

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 © 2016, 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 Pharmacotherapy Line
Nov. 17, 2016 * Vol. 23, No. 223
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Nov. 17 issue of the New England Journal of Medicine (2016; 375).
Palbociclib in Advanced Breast Cancer: Positive results in a study of 666 postmenopausal women with ER-positive, HER2-negative breast cancer supports a role in cancer therapy for inhibitors of the cyclin D–dependent kinases CDK4 and CDK6, researchers and editorialists write (pp. 1925–36). In a phase 2 trial, addition of palbociclib to letrozole resulted in significantly longer progression-free survival, albeit with greater myelocytoxic effects: “The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib–letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo–letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P <0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib–letrozole group vs. 1.4% in the placebo–letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group and in none of the patients in the placebo–letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib–letrozole group and in 13 patients (5.9%) in the placebo–letrozole group.” (R. S. Finn, rfinn@mednet.ucla.edu)
These PALOMA-2 (Palbociclib: Ongoing Trials in the Management of Breast Cancer–2) results portend “a new standard” in breast cancer therapy, an editorialist writes (
pp. 1993–4). Combined with results from an interim analysis of the MONALEESA-2 (Mammary Oncology Assessment of LEE011’s [Ribociclib’s] Efficacy and Safety–2) trial, PALOMA-2 outcomes “suggest a drug class–specific effect,” the author writes. “CDK4 and CDK6 inhibition in combination with antiestrogens is clearly a new standard for the treatment of advanced ER-positive breast cancer. However, palbociclib [already approved in the U.S.] is costly and has some toxic effects. Some patients derive strong clinical benefit with antiestrogens alone as first-line therapy, and we must learn to identify those patients so that we can apply CDK4 and CDK6 inhibition in those who will benefit the most.” (A. C. Wolff)
“Orally available drugs that potently and specifically inhibit the activities of the cyclin D–dependent kinases CDK4 and CDK6 represent paradigm-shifting antineoplastic agents,” an author of a Perspectives article adds (
pp. 1920–3). “A caveat is that checkpoint inhibitors that reactivate the adaptive immune response to cancer cells would be antagonized by CDK4–CDK6 inhibitors that block cyclin D2– and cyclin D3–dependent G1-phase progression and T-cell expansion.… In short, CDK4–CDK6 inhibitors, while having limited value as monotherapeutic antineoplastic agents, offer greater promise when combined with other targeted therapies. This requirement for combinatorial therapy slowed the application of these agents, and despite the existence of more than 30 ongoing clinical trials supported by the National Cancer Institute, long-term results are unavailable for indications other than breast cancer. Indeed, though many years have passed since the foundational work was initiated, these are still early days.” (C.J. Sherr)

>>>PNN NewsWatch
* Instead of an expected focus on drug prices under a Clinton administration, the pharmaceutical industry may have an opportunity to advocate for looser approval procedures at FDA with Rep. Tom Price (R–GA) at the helm at the Dept. of Health and Human Services, according to media reports. Language on the Trump campaign website was modified after the election, with this sentence appearing, “Reform the Food and Drug Administration, to put greater focus on the need of patients for new and innovative medical products,” reports the Washington Post. An LA Times article asks, “Will the Trump presidency mean the end of FDA drug regulation?” while exploring libertarian and conservative ideas on drug regulation. Price, an orthopedic surgeon, is a supporter of value-based care as embodied in the MACRA legislation and parts of the Affordable Care Act. In addition to Price, Politico reports that former Louisiana Gov. Bobby Jindal is the running for HHS Secretary.

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 © 2016, 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 Pharmacotherapy Line
Nov. 18, 2016 * Vol. 23, No. 224
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Dec. 1 issue of Clinical Infectious Diseases (2016; 63).
Acute Demyelinating Events Following Vaccines: The risk of transverse myelitis (TM) is not increased by vaccines, according to a large case-centered analysis, and the risk of acute disseminated encephalomyelitis (ADEM) is possibly associated with one vaccine at a very low level (pp. 1456–62). Investigators calculated the risk difference or excess risk of acute demyelinating events based on cases of TM and ADEM in the Vaccine Safety Datalink population and matched persons in a study population who received the same type of vaccine. Results showed: “Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5–28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5–28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2–471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, −.04 to 1.16) cases per million doses.” (R. Baxter, roger.baxter@kp.org)
Corticosteroids for Pulmonary Tuberculosis With Respiratory Failure: In 124 patients with pulmonary tuberculosis who became critically ill because of acute respiratory failure (ARF), treatment with corticosteroids reduced 90-day mortality rates, researchers report (pp. 1449–55). Retrospective analysis of those cared for at a South Korean tertiary referral center in 1989–2014 had these outcomes: “The mean patient age was 62 years, and the 90-day mortality rate was 49.2% (61/124). Adjuvant steroids were used in 70 (56.5%) patients. The 90-day mortality rate was similar irrespective of corticosteroid use (48.6%, steroid group; 50.0%, nonsteroid group). The use of adjuvant steroids was not associated with the unadjusted 90-day mortality (odds ratio [OR], 0.94; 95% confidence interval [CI], .46–1.92; P = .875). In a comparison using an adjusted [inverse probability of treatment weighted] approach of the 90-day mortality between the 2 groups, we found that corticosteroid use was independently associated with reduced 90-day mortality (OR, 0.47; 95% CI, .22–.98; P = .049).” (K.-W. Jo, heathcliff6800@hanmail.net)
Treating HCV During Opioid Substitution Therapy: Opioid substitution therapy (OST) and drug use during treatment for hepatitis C virus (HCV) genotype 1 infection did not affect outcomes in the phase 3 ION studies, an analysis shows (pp. 1405–11): “Among 1,952 patients enrolled in the ION studies, 4% (n = 70) were receiving OST. Among those receiving (n = 70) and not receiving OST (n = 1,882), there was no difference in treatment completion (97% vs 98%; P = .40), ≥80% adherence (93% vs 92%; P = 1.00), [sustained virologic response (SVR12)] (94% vs 97%; P = .28), and serious adverse events (4% vs 3%; P = .43), respectively. Among participants in the ION-1 trial, 23% (n = 196) used illicit drugs during therapy (15% cannabinoids alone; 8% other illicit drugs ± cannabinoids). There was no difference in treatment completion, ≥80% adherence, SVR12, or serious AEs in those with no drug use during treatment compared with those who used cannabinoids and/or other illicit drugs. No cases of HCV reinfection were observed in the 24 weeks following treatment.” (J. Grebely, jgrebely@kirby.unsw.edu.au)

>>>PNN NewsWatch
* Prasterone (Intrarosa, Endoceutics)—chemically dehydroepiandrosterone (DHEA)—has been approved by FDA for treatment of women experiencing moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause. In a placebo-controlled trial, the once-daily vaginal insert relieved the severity of pain experienced during sexual intercourse among 406 healthy postmenopausal women, 40–80 years of age, who identified moderate to severe pain during sexual intercourse as their most bothersome symptom of VVA.
*
FDA said yesterday that it has developed a mouse model with potential utility in development of a vaccine against the Zika virus. In an article published in PLoS Pathogens, FDA scientists reported that neonatal C57BL/6 mice are susceptible to the Zika virus and develop neurologic symptoms 12 days after infection.

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 © 2016, 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 Pharmacotherapy Line
Nov. 21, 2016 * Vol. 23, No. 225
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source: Early-release articles from BMJ (2016; 353).
PPIs & CAP: An association found between use of PPIs and risk of developing community-acquired pneumonia is likely the result of confounding factors, researchers report (i5813). Patient experiences in 1990–2013 recorded in the U.K. Clinical Practice Research Datalink show these relationships among patient factors, medication use, and disease for adults with new PPI prescriptions: “160,000 new PPI users were examined. The adjusted Cox regression showed a risk of community acquired pneumonia 1.67 (95% confidence interval 1.55 to 1.79) times higher for patients exposed to PPI than for controls. In the self controlled case series, among 48,451 PPI exposed patients with a record of community acquired pneumonia, the incidence rate ratio was 1.19 (95% confidence interval 1.14 to 1.25) in the 30 days after PPI prescription but was higher in the 30 days before a PPI prescription (1.92, 1.84 to 2.00). The Cox regressions for prior event rate ratio similarly showed a greater increase in community acquired pneumonia in the year before than the year after PPI prescription, such that the analysis showed a reduced relative risk of pneumonia associated with PPI use (prior event rate ratio 0.91, 95% confidence interval 0.83 to 0.99).” (F. Othman, msxfo1@nottingham.ac.uk)

>>>Lancet Highlights
Source: Nov. 19 issue of Lancet (2016; 388).
Screening & Brief Intervention for Obesity: At 137 English primary care practices, screenings of adults for obesity and “a behaviourally informed, very brief, physician-delivered opportunistic intervention [was] acceptable to patients and an effective way to reduce population mean weight,” a study shows (pp. 2492–500). For those meeting obesity thresholds, physicians offered either referral to a weight-management group (active intervention) or advised the patient of the benefits of weight loss (control intervention). Changes in the primary outcome of weight change at 12 months were as follows: “Between June 4, 2013, and Dec 23, 2014, we screened 8,403 patients, of whom 2,728 (32%) were obese. Of these obese patients, 2,256 (83%) agreed to participate and 1,882 were eligible, enrolled, and included in the intention-to-treat analysis, with 940 individuals in the support group and 942 individuals in the advice group. 722 (77%) individuals assigned to the support intervention agreed to attend the weight management group and 379 (40%) of these individuals attended, compared with 82 (9%) participants who were allocated the advice intervention. In the entire study population, mean weight change at 12 months was 2.43 kg with the support intervention and 1.04 kg with the advice intervention, giving an adjusted difference of 1.43 kg (95% CI 0.89–1.97). The reactions of the patients to the general practitioners’ brief interventions did not differ significantly between the study groups in terms of appropriateness (adjusted odds ratio 0.89, 95% CI 0.75–1.07, p = 0.21) or helpfulness (1.05, 0.89–1.26, p = 0.54); overall, four (<1%) patients thought their intervention was inappropriate and unhelpful and 1,530 (81%) patients thought it was appropriate and helpful.” (P. Aveyard, paul.aveyard@phc.ox.ac.uk)

>>>PNN NewsWatch
*
FDA said on Friday that Nutra Manufacturing, Inc. has announced a nationwide, voluntary recall of one lot of GNC Women’s Ultra Mega Time Release dietary supplement product sold in 180 count containers UPC 048107158910, lot number 3044FQ2024, with an expiration date of June 2018 because the product may contain an undeclared major food allergen, milk. 

>>>PNN JournalWatch
* Advances in Rhinitis and Rhinosinusitis in 2015, in
Journal of Allergy and Clinical Immunology, 2016; 138: 1277–83. (C. Bachert, Claus.Bachert@ugent.be
* Advances in Allergen Immunotherapy in 2015, in
Journal of Allergy and Clinical Immunology, 2016; 138: 1284–91. (R. K. Bush, rkb@medicine.wisc.edu
* Knowledge Gaps in Cardiovascular Care of Older Adults: A Scientific Statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society: Executive Summary, in
Journal of the American Geriatrics Society, 2016; 64: 2185–92. (M. W. Rich, mrich@wustl.edu)
* Relationships Between Caffeine Intake and Risk for Probable Dementia or Global Cognitive Impairment: The Women’s Health Initiative Memory Study, in
J Gerontology A, 2016; 71: 1596–602. (I. Driscoll, driscoli@uwm.edu)

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 © 2016, 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 Pharmacotherapy Line
Nov. 22, 2016 * Vol. 23, No. 226
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from JAMA Internal Medicine (2016; 176).
Fracture Risks With Antihypertensive Medications: Compared with ACE inhibitors and calcium-channel blockers, thiazide diuretics reduce rates of hip or pelvic fracture in older patients being treated for hypertension, researchers report (10.1001/jamainternmed.2016.6821). The analysis used VA and Medicare claims data to examine fractures reported among participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, finding the following for those on chlorthalidone, lisinopril, or amlodipine: “A total of 22,180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16,622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63–0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58–0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63–1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74–1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up.” (J. I. Barzilay, joshua.barzilay@kp.org)
“Is the dual benefit of thiazides a happy coincidence or related to a common underlying mechanism of action in vascular tissue and bone?” editorialists ask (
10.1001/jamainternmed.2016.7040). “The science here is thin, and additional studies examining the overlap between cardiovascular disease and metabolic bone disease may help us develop other pleiotropic agents with a beneficial effect on both systems. Although we have avoided complexity in the case of choosing antihypertensive medications, we have yet to reach genius-level understanding that explains the complex interactions among bone, vascular disease, and the drugs that treat them.” (C. S. Colón-Emeric, colon001@mc.duke.edu)

>>>Geriatrics Highlights
Source: Nov. issue of the Journal of the American Geriatrics Society (2016; 64).
Depression Care Management: Used by nurses during regular home health care visits of older adults with depression symptoms before hospital discharge, the Depression CARE for PATients at Home (CAREPATH) model reduced rehospitalizations by 35% within 30 days and 28% within 60 days, a study shows (pp. 2196–203; M. L. Bruce, mbruce@dartmouth.edu).
Caring for Older Adults With HIV Infection: Clinicians need to begin addressing age-related differences in care of patients living with HIV, review authors argue, given that “more than 50% of individuals with HIV in the United States are aged 50 and older” (pp. 2322–9): “Part of this group consists of individuals who have aged with chronic HIV infection, but a large proportion also results from new HIV diagnosis, with approximately 17% of new HIV diagnoses in 2013 occurring in individuals aged 50 and older. Although many of the recommendations on management of HIV infection are not age-specific, individuals with HIV aged 50 and older differ from their younger counterparts in many aspects, including immune response to antiretroviral therapy, multimorbidity, antiretroviral toxicities, and diagnostic considerations. This article outlines these differences, offers a strategy on how to care for this unique population, and provides special considerations for problem-based management of individuals with HIV aged 50 and older.” (J. S. Appelbaum, Jonathan.appelbaum@med.fsu.edu)

>>>PNN NewsWatch
* Lack of sterility assurance has prompted product recalls by
Tri-Coast Pharmacy and Cantrell Drug Company, FDA said.

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 © 2016, 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 Pharmacotherapy Line
Nov. 23, 2016 * Vol. 23, No. 227
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Nov. 22/29 issue of JAMA (2016; 316).
Adverse Drug Events in the Emergency Department: Anticoagulants, antibiotics, diabetes agents, and opioid analgesics were implicated frequently in emergency department (ED) visits for adverse drug events (ADEs) in 2013–14, researchers report (pp. 2115–25). The National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project data show these insights: “Based on data from 42,585 cases, an estimated 4.0 (95% CI, 3.1–5.0) ED visits for adverse drug events occurred per 1000 individuals annually in 2013 and 2014 and 27.3% (95% CI, 22.2%–32.4%) of ED visits for adverse drug events resulted in hospitalization. An estimated 34.5% (95% CI, 30.3%–38.8%) of ED visits for adverse drug events occurred among adults aged 65 years or older in 2013–2014 compared with an estimated 25.6% (95% CI, 21.1%–30.0%) in 2005–2006; older adults experienced the highest hospitalization rates (43.6%; 95% CI, 36.6%–50.5%). Anticoagulants, antibiotics, and diabetes agents were implicated in an estimated 46.9% (95% CI, 44.2%–49.7%) of ED visits for adverse drug events, which included clinically significant adverse events, such as hemorrhage (anticoagulants), moderate to severe allergic reactions (antibiotics), and hypoglycemia with moderate to severe neurological effects (diabetes agents). Since 2005–2006, the proportions of ED visits for adverse drug events from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased. Among children aged 5 years or younger, antibiotics were the most common drug class implicated (56.4%; 95% CI, 51.8%–61.0%). Among children and adolescents aged 6 to 19 years, antibiotics also were the most common drug class implicated (31.8%; 95% CI, 28.7%–34.9%) in ED visits for adverse drug events, followed by antipsychotics (4.5%; 95% CI, 3.3%–5.6%). Among older adults (aged ≥65 years), 3 drug classes (anticoagulants, diabetes agents, and opioid analgesics) were implicated in an estimated 59.9% (95% CI, 56.8%–62.9%) of ED visits for adverse drug events; 4 anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated. Medications to always avoid in older adults according to Beers criteria were implicated in 1.8% (95% CI, 1.5%–2.1%) of ED visits for adverse drug events.” (N. Shehab, ftn0@cdc.gov)
With medication overdose, opioid use, and liver disease the primary drivers of a decline in life expectancy among middle-aged white women in the U.S., staff members of EDs — including ED-based pharmacists — need to focus on making medication changes when needed for those presenting with ADEs, editorialists write (
pp. 2092–3): “Medication changes in the ED typically occur during brief discussions with anxious and sometimes acutely ill patients and generally without input or records from the patient’s primary care or specialty care clinicians. To accomplish proper and safe medication reconciliation, clinicians need an accurate record of prescribed medications, clear communication with patients about the benefits and risks of prescribed medications, explicitly defined methods for reevaluating their need, and means for communicating with the patient’s primary care or specialty care team, all of which are extremely challenging to complete in a rigorous manner during a brief ED visit. Increased integration and use of ED-based pharmacists is a potential solution that may meet many of these needs and could build on existing team-based, inpatient hospital models.” (C. Kessler, chad.kessler@va.gov)
Training Palliative Care Practitioners: Commenting on mixed results in palliative care trials (pp. 2094–103, A. El-Jawahri, ael-jawahri@partners.org; pp. 2104–14, D. Kavalieratos, diok@pitt.edu), editorialists call for training of “both specialists and nonspecialists to deliver interventions proven to be effective” (pp. 2090–1). “Along with expanding palliative care research and public awareness, [the Palliative Care and Hospice Education and Training Act] is designed to establish a nationwide network of palliative care and hospice education centers that could expand specialist training programs and also train all clinicians in providing high-quality palliative care.” (P. N. Malani, pmalani@umich.edu)

>>>PNN NewsWatch
*
PNN will not be published on Thurs. and Fri., Nov. 24–25, Thanksgiving holidays.

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 © 2016, 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 Pharmacotherapy Line
Nov. 28, 2016 * Vol. 23, No. 228
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source: Early-release article from BMJ (2016; 353).
Prediabetes, Cardiovascular Risk & All-Cause Mortality: Patients with prediabetes are at increased risk of cardiovascular disease but not all-cause mortality, according to a systematic review and meta-analysis of 53 prospective cohort studies of 1.6 million participants (i5953). Prediabetes was defined using criteria of the American Diabetes Association (IFG-ADA; fasting glucose 5.6–6.9 mmol/L), WHO expert group (IFG-WHO; fasting glucose 6.1–6.9 mmol/L), impaired glucose tolerance (2-hour plasma glucose concentration 7.8–11.0 mmol/L during an oral glucose tolerance test), or raised hemoglobin A1c (HbA1c) of 39–47 mmol/mol (5.7–6.4%) according to ADA criteria or 42–47 mmol/mol (6.0–6.4%) according to the National Institute for Health and Care Excellence (NICE) guideline. Concluding that health risk might be elevated at fasting glucose levels of 5.6 mmol/L (101 mg/dL) or mild raised A1c levels of 39 mmol/mol, the authors report: “The median follow-up duration was 9.5 years. Compared with normoglycaemia, prediabetes (impaired glucose tolerance or impaired fasting glucose according to IFG-ADA or IFG-WHO criteria) was associated with an increased risk of composite cardiovascular disease (relative risk 1.13, 1.26, and 1.30 for IFG-ADA, IFG-WHO, and impaired glucose tolerance, respectively), coronary heart disease (1.10, 1.18, and 1.20, respectively), stroke (1.06, 1.17, and 1.20, respectively), and all cause mortality (1.13, 1.13 and 1.32, respectively). Increases in HBA1c to 39–47 mmol/mol or 42–47 mmol/mol were both associated with an increased risk of composite cardiovascular disease (1.21 and 1.25, respectively) and coronary heart disease (1.15 and 1.28, respectively), but not with an increased risk of stroke and all cause mortality.” (Y. Hu, huyunzhao4406@163.com)

>>>Lancet Highlights
Source: Nov. 26 issue of Lancet (2016; 388).
LMWHs & Placenta-Mediated Pregnancy Complications: In 963 women who participated in eight clinical trials, low-molecular-weight heparin did not reduce the risk of recurrent placenta-mediated pregnancy complications, researchers report, adding, “Some decreases in event rates might have been too small for the power of our study to explore” (pp. 2629–41). Individual patient data obtained from investigators who conducted the trials showed these outcomes for receiving or not receiving the drugs: “Participants were mostly white (795/905; 88%) with a mean age of 30.9 years (SD 5.0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference −8%, 95% CI −17.3 to 1.4, p = 0.09; relative risk 0.64, 95% CI 0.36–1.11, p = 0.11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p = 0.006) but not in any of the other subgroups of previous complications.” (M. A. Rodger, mrodger@ohri.ca)

>>>PNN NewsWatch
*
CVS and Kids Relief homeopathic products are being recalled because of variation in belladonna extract content, FDA said on Friday. Distributed nationwide, the products are CVS Homeopathic Infants’ Teething Tablets, Kids Relief Homeopathic Ear Relief Oral Liquid, and CVS Homeopathic Kids’ Ear Relief Liquid.

>>>PNN JournalWatch
* High-Risk Medications in Hospitalized Elderly Adults: Are We Making It Easy to Do the Wrong Thing?, in
Journal of the American Geriatrics Society, 2016; 10.1111/jgs.14703. (J. Poeran, jashvant.poeran@mountsinai.org
* Long Noncoding RNAs in the Regulation of Inflammatory Pathways in Rheumatoid Arthritis and Osteoarthritis, in
Arthritis & Rheumatology, 2016; 68: 2575–83. (S. W. Jones, s.w.jones@bham.ac.uk
* Statins and Risk of Rheumatoid Arthritis: A Nested Case–Control Study, in
Arthritis & Rheumatology, 2016; 68: 2603–11. (S. Suissa, samy.suissa@mcgill.ca
* Predicting Patients at Risk for 3-Day Postdischarge Readmissions, ED Visits, and Deaths, in
Medical Care, 2016; 54: 1017–23. (D. Agrawal) 
* In New Survey Of Eleven Countries, US Adults Still Struggle With Access To And Affordability Of Health Care, in
Health Affairs, 2016; 35: 10.1377/hlthaff.2016.1088. (R. Osborn) 

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 © 2016, 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 Pharmacotherapy Line
Nov. 29, 2016 * Vol. 23, No. 229
Providing news and information about medications and their proper use

>>>Diabetes Report
Source: Dec. issue of Diabetes Care (2016; 39).
Depression & Type 2 Diabetes: Patients with type 2 diabetes (T2D) who have episodes of major depressive disorder (MDD) need ongoing diagnosis and treatment to avoid a “waxing and waning pattern” of MDD throughout the life course, according to a study of 50 participants (pp. 2174–81). MDD is associated with long-term complications, disability, and early mortality in patients with T2D, the authors note, adding these details from interviews and outcomes during a behavioral intervention program: “Average number of MDD episodes was 1.8 with a mean duration of 23.4 months (SD 31.9; range 0.5–231.3). Over the life course, mean exposure to MDD was 43.1 months (SD 46.5; range 0.5–231.3). Kaplan–Meier survival curve analysis indicated median episode duration decreased with subsequent episodes (14 months, first episode; 9 months, second episode; P <0.002). In patients with multiple depressive episodes, recovery time was shorter with each subsequent episode (P = 0.002). No differences in length of episode or remission were observed based on chronology of T2D diagnosis.” (M. de Groot, mdegroot@iu.edu)
Emotional Distress & Adherence in Type 2 Diabetes: Diabetes-related distress and depression symptom severity are risk factors for type 2 diabetes medication nonadherence, researchers report based on findings that somatic but not cognitive–affective symptoms independently predict nonadherence (pp. 2182–9). Electronic monitoring (EM) and self-reported (SR) of medication adherence showed these correlations with distress and depression SRs from 104 patients with type 2 diabetes: “Mean ± SD 3-month medication adherence was 76.1% ± 25.7% for EM and 83.7% ± 21.9% for SR. Higher levels of SR (P < 0.001) and interview-based (P < 0.05) depressive symptom severity (P < 0.05) and diabetes-related distress (P < 0.01) showed a significant bivariate association with EM and SR nonadherence. Regression models showed baseline diabetes distress was a significant independent predictor of EM (beta = −0.29; P = 0.001) and SR adherence (beta = −0.24; P < 0.02) at follow-up. SR depression was an independent predictor of EM and SR adherence and reduced the effects of diabetes distress to nonsignificance. Subsequent models indicated this effect was driven by somatic rather than cognitive-affective symptoms of depression. Results were consistent but weaker for interview-based depressive symptoms.” (J. S. Gonzalez, jeffrey.gonzalez@einstein.yu.edu)
Resveratrol in Well-Controlled Type 2 Diabetes: Added to the antidiabetic regimens of 17 patients with well-controlled type 2 diabetes (T2D), the dietary supplement resveratrol had no significant effect on hepatic or peripheral insulin sensitivity, a study shows, calling into “question the generalized value of resveratrol as an add-on therapy in the treatment of T2D” (pp. 2211–7). Results did show a possible interaction between resveratrol and metformin, one that led might have caused “the lack of a resveratrol-induced insulin-sensitizing effect,” the authors note. (P. Schrauwen, p.schrauwen@maastrichtuniversity.nl)

>>>PNN NewsWatch
* Physician and Member of Congress of
Tom Price of Georgia has been designated Secretary of Health and Human Services by President-elect Donald Trump, the Washington Post reports. The move puts an Obamacare critic at the helm of the agency responsible for dismantling of the Affordable Care Act if so directed by Congress. “Trump also named Seema Verma, a health-care consultant who was the architect of Medicaid changes in Vice president-elect Mike Pence’s home state of Indiana, to run a crucial section of HHS: the Centers for Medicare and Medicaid Services,” the Post reports.
* Sold online and through a sales force, the stimulant, preworkout, and weight-loss product
DMAA is being recalled by NutriVitaShop, also doing business as Naturecom Inc., FDA announced on Saturday. Also known as 1,3-dimethylamylamine, methylhexanamine, or geranium extract, DMAA “is potentially dangerous to health as it can narrow blood vessels and arteries, which can cause a rise in blood pressure or other cardiovascular problems such as shortness of breath, arrhythmias, tightening in the chest, and heart attack,” FDA said.

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 © 2016, 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 Pharmacotherapy Line
Nov. 30, 2016 * Vol. 23, No. 230
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: Nov. issue of Pharmacotherapy (2016; 36).
Anticholinergic Burden & Cognitive Impairment: Using the Anticholinergic Cognitive Burden (ACB) score, investigators find that increased use of anticholinergic drugs in older adults is associated with increased risk for cognitive impairment and more frequent health care utilization (pp. 1123–31). Among 3,344 community-dwelling older adults (217 with baseline cognitive impairment), anticholinergic use during the prior 12 months was used to compute the ACB: “A total daily ACB score was calculated by using pharmacy dispensing data from [the Regenstrief Medical Record System (RMRS)]; each anticholinergic was multiplied by 1, 2, or 3 consistent with anticholinergic burden defined by the ACB scale. The sum of all ACB medications was divided by the number of days with any medication dispensed to achieve the total daily ACB score. Health care utilization included visits to inpatient, outpatient, and the emergency department, and it was determined by using visit data from the RMRS. The overall population had a mean age of 71.5 years, 71% were female, and 58% were African American. Each 1-point increase in mean total daily ACB score was associated with increasing risk of cognitive impairment (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.004–1.27, p = 0.043). Each 1-point increase in mean total daily ACB score increased the likelihood of inpatient admission (OR 1.11, 95% CI 1.02–1.29, p = 0.014) and number of outpatient visits after adjusting for demographic characteristics, number of chronic conditions, and prior visit history (estimate 0.382, standard error [SE] 0.113; p = 0.001). The number of visits to the emergency department was also significantly different after similar adjustments (estimate 0.046, SE 0.023, p = 0.043).” (N. L. Campbell, campbenl@iupui.edu)
Activated Prothrombin Complex Concentrate for Warfarin Bleeding: Compared with plasma, activated four-factor prothrombin complex concentrate (aPCC) reduced posttreatment INR, produced a greater decrease in INR, and more frequently surpassed goal INR in 276 patients with warfarin-associated hemorrhage, researchers report (pp. 1132–7). Retrospective analysis of data from a single medical center showed these patterns: “Those patients who received aPCC achieved a lower posttreatment INR (1.1 [0.1] vs 1.6 [0.5]; p <0.05). In addition, patients who received aPCC had a 4.3 times higher odds of achieving an INR of less than 1.4 (97 [75.8%] vs 65 [43.9%]; p <0.05; odds ratio [OR] = 4.3 [95% confidence interval (CI) 2.6–7.3]). When controlling for vitamin K administration, history of diabetes mellitus, receipt of the recommended reversal agent dose, and pretreatment INR, aPCC administration remained an independent predictor for achieving an … INR of less than 1.4 in the first 24 hours after treatment (OR = 3.75 [95% CI 2.11–6.65]; p <0.001). In addition, there was no statistical difference between the groups with regard to occurrences of infusion reaction, pulmonary embolism, deep vein thrombosis, stroke, or myocardial infarction.” (A. S. Rowe, arowe@uthsc.edu)
Treatment of Complicated Intra-Abdominal Infections: Clinical cures were similar among 417 patients with complicated intra-abdominal infections who received piperacillin/tazobactam (PIP/TAZ) monotherapy or vancomycin plus PIP/TAZ, a retrospective study shows (pp. 1138–44): “There were no statistically significant differences between the monotherapy and combination therapy groups with respect to day 28 clinical cure (33.9% vs 25.5%, p = 0.064), day 7 clinical cure (23.6% vs 17.6%, p = 0.14), or 28-day mortality (7% vs 7.9%, p = 0.72). [length of stay (LOS)] in the ICU was significantly shorter in the monotherapy group (6 days) compared with the combination therapy group (7 days; p = 0.04); however, hospital LOS was not significantly different.” (S. E. Petite, sarah.petite@utoledo.edu)

>>>PNN NewsWatch
* Despite greater availability of
syringe services programs (SSPs), injection drug users share needles and syringes at the same level as a decade ago, CDC said yesterday. One in three (33%) reported in 2015 that they had shared a needle within the past year, similar to the 36% reported in 2005. More than one-half (54%) of people who inject drugs reported in 2015 they used an SSP in the past year, compared with only about one-third (36%) in 2005.

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 © 2016, 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 Pharmacotherapy Line
Dec. 1, 2016 * Vol. 23, No. 231
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Dec. 1 issue of the New England Journal of Medicine (2016; 375).
Genetic Variants & Effects of Statins, PCSK9 Inhibitors: Lowering of LDL cholesterol levels and increases in risk of diabetes are similar with statins and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors regardless of variants in patient genotypes of target enzymes, researchers report (pp. 2144–53). Using genetic scores reflecting variants in the genes for PCSK9 and 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR) for 112,772 participants in 14 studies, the authors found these relationships with 14,120 cardiovascular events and 10, 635 cases of diabetes: “Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes.” (B.A. Ference, bference@med.wayne.edu)
Dapivirine Vaginal Ring for HIV Prevention: Responding to two clinical trials conducted in Africa demonstrating safety and efficacy of a vaginal ring containing dapivirine for the prevention of HIV infection in women (pp. 2121–32, J. M. Baeten, http://jbaeten@uw.edu; pp. 2133–43, N. van Niekerk, nvanniekerk@ipmglobal.org.za), an editorialist notes “substantial progress in strategies for the prevention of HIV infection” over the past few years before concluding, “Nevertheless, considerable work will be required to achieve safe, effective, affordable HIV prevention for all women at risk” (pp. 2195–6). “Although the antiviral agent in a ring should be associated with adequate concentrations in genital-tract tissues, it is unlikely to provide sufficient drug in the rectal tissue to protect women from acquiring HIV by means of anal sex, which is increasingly prevalent. A total of 2% of the participants in one of the vaginal ring studies reported having had anal sex within the previous 3 months.” (A. A. Adimora)
Niraparib Maintenance Therapy in Ovarian Cancer: The oral poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) 1/2 inhibitor niraparib extended the median duration of progression-free survival among 553 patients with platinum-sensitive, recurrent ovarian cancer, a phase 3 trial shows (pp. 2154–64). With participants categorized by presence or absence of a germline BRCA mutation (gBRCA), results showed: “Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P <0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.” (M. R. Mirza, mansoor@rh.regionh.dk)
“It is apparent that this new class of agents has the potential to change the therapy of ovarian cancer in ways that have not been seen since the introduction of paclitaxel in 1993,” editorialists write (
pp. 2197–8). “The curative potential of these drugs has not been established, but treatment with PARP inhibitors will certainly help women with ovarian cancer to live longer and better. It is now up to the oncology community to maximize those benefits in ovarian cancer and extend them to other patients with BRCA-related cancers.” (D. R. Spriggs)

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 © 2016, 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 Pharmacotherapy Line
Dec. 2, 2016 * Vol. 23, No. 232
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source: Dec. issue of Pediatrics (2016; 138).
Treatment of Pediatric Hypertension: Even when cases of pediatric hypertension are identified — testing is infrequent and diagnosis rarer still — they are often not treated, a study shows (10.1542/peds.2016-2195). Among 1.2 million patients in 27 states, retrospective cohort analysis showed the following for 398,079 pediatric patients with three or more blood pressure (BP) measurements: “Of these, 3.3% met criteria for hypertension and 10.1% for prehypertension. Among practices with ≥50 eligible patients, 2,813 of 12,138 patients with hypertension (23.2%; 95% confidence interval, 18.2%–28.2%) and 3,990 of 38,874 prehypertensive patients (10.2%; 95% confidence interval, 8.2%–12.2%) were diagnosed. Age, weight, height, sex, and number and magnitude of abnormal BPs were associated with diagnosis rates. Of 2,813 diagnosed, persistently hypertensive patients, 158 (5.6%) were prescribed antihypertensive medication within 12 months of diagnosis (angiotensin-converting enzyme inhibitors/angiotensin receptive blockers [35%], diuretics [22%], calcium channel blockers [17%], and beta-blockers [10%]).” (D. C. Kaelber)
Single-Dose Influenza Prophylaxis: In children younger than 10 years of age with family exposures to influenza, one dose of inhaled laninamivir octanoate 20 mg was effective and well tolerated, researchers report (10.1542/peds.2016-0109). Using a primary endpoint of proportion of subjects who developed clinical influenza during a 10-day period, investigators found these results in the placebo-controlled trial of 341 participants: “The proportions of subjects who developed clinical influenza were 11% (18/171) in the laninamivir octanoate group and 19% (33/170) in the placebo group (P = .02). The relative risk reduction was 45.8% (95% confidence interval, 7.5% to 68.2%). The incidence of adverse events was similar in both groups.” (T. Nakano)
I.V. v. Oral Antibiotics for Complicated Pneumonia: “Children with complicated pneumonia should preferentially receive oral antibiotics at discharge when effective oral options are available,” conclude authors of a study showing similar clinical results with antibiotics administered orally and by peripherally inserted central venous catheter (PICC) (10.1542/peds.2016-1692). Pediatric patients 2 months through 17 years with complicated pneumonia had these outcomes in 2009–12: “Among 2,123 children, 281 (13.2%) received antibiotics via PICC. Treatment failure rates were 3.2% among PICC and 2.6% among oral antibiotic recipients and were not significantly different between the groups in across-hospital-matched analysis (matched odds ratio [OR], 1.26; 95% confidence interval [CI], 0.54 to 2.94). PICC complications occurred in 7.1%. Adverse drug reactions occurred in 0.6% of children; PICC antibiotic recipients had greater odds of adverse drug reaction in across-hospital-matched analysis (matched OR, 19.1; 95% CI, 4.2 to 87.3). The high rate of PICC complications and differences in adverse drug reactions contributed to higher odds of the composite outcome of all related revisits among PICC antibiotic recipients (matched OR, 4.71; 95% CI, 2.97 to 7.46).” (S. S. Shah)

>>>Psychiatry Highlights
Source: Dec. American Journal of Psychiatry (2016; 173).
Pain as Predictor of OUD: “Careful monitoring and consideration of nonopioid alternative treatments is warranted” to avoid opioid use disorder in adults with moderate to severe pain, according to analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions (pp. 1189–95). For waves 1 (2001–2002) and 2 (2004–2005), a structural equation model showed that “pain and prescription opioid use disorders were significantly associated with one another at baseline and at 3-year follow-up. However, whereas pain at baseline was also significantly associated with prescription opioid use disorder at follow-up, prescription opioid use disorder at baseline was not associated with pain at follow-up.… The path for pain interference was associated with a 41% relative increase in the risk of developing a prescription opioid use disorder.” (C. Blanco)

>>>PNN NewsWatch
* FDA has announced recall of two dietary supplement products, both because of undeclared drug ingredients:
Megajex Natural Male Sex Enhancer capsules (tadalafil and sildenafil) and Ultimate Body Tox PRO capsules (sibutramine).

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 © 2016, 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 Pharmacotherapy Line
Dec. 5, 2016 * Vol. 23, No. 233
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Dec. 3 issue of Lancet (2016; 388).
Certolizumab Pegol in Rheumatoid Arthritis: Added to methotrexate in 915 patients with rheumatoid arthritis, certolizumab pegol was not superior to adalimumab, a 104-week study shows (pp. 2763–74). In the EXXELERATE trial, responders achieved low disease activity (LDA) according to Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) ≤3.2 or DAS28-ESR reduction ≥1.2 from baseline as follows: “No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0.90 [95% CI 0.67–1.20]; p = 0.467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1.09 [0.82–1.45]; p = 0.532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1.2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch.” (J. S. Smolen, josef.smolen@wienkav.at)

>>>BMJ Highlights
Source: Early-release articles from BMJ (2016; 353).
Alpha Blockers for Ureteric Stones: Guidelines recommending use of alpha blockers in treating patients with ureteric stones are supported by results of a systematic review and meta-analysis of 55 trials (i6112). “Alpha blockers seem efficacious in the treatment of patients with ureteric stones who are amenable to conservative management,” the authors write. “The greatest benefit might be among those with larger stones.” (J. M. Hollingsworth, kinks@med.umich.edu)
Testosterone & Risk of Venous Thromboembolism: Men starting testosterone therapy have an increased risk of venous thromboembolism that peaks at 6 months of treatment, researchers report (i5968). Patients at 370 U.K. primary care practices had these outcomes when analyzed in a population-based case–control study: “In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10,000 person years. The rate ratio after more than six months’ treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07).…” (C. Martinez, carlos.martinez@pharmaepi.com)

>>>PNN NewsWatch

*
FDA has approved a new indication for empagliflozin (Jardiance, Boehringer Ingelheim): reducing cardiovascular mortality risk in adults with type 2 diabetes mellitus and cardiovascular disease. A postmarketing study was required by FDA as a condition of its 2014 approval of the product. The trial of more than 7,000 patients with type 2 diabetes and cardiovascular disease showed reduced risk of cardiovascular death among those taking empagliflozin compared with placebo in addition to standard of care therapies for diabetes and atherosclerotic cardiovascular disease.

>>>PNN JournalWatch
* Medical Treatment of Aortic Stenosis, in
Circulation, 2016; 134: 1766–84. (G. Marquis-Gravel) 
* The Risk Continuum of Atherosclerosis and its Implications for Defining CHD by Coronary Angiography, in
Journal of the American College of Cardiology, 2016; 68: 2467–78. (A. Arbab-Zadeh) 
* Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial, in
American Journal of Psychiatry, 2016; 173: 1205–12. (G. Villarreal) 
* Disclosure of Adverse Events in Pediatrics, in
Pediatrics, 2016; 138: 10.1542/peds.2016-3215. (Committee on Medical Liability and Risk Management, Council on Quality Improvement and Patient Safety) 
* Reaffirmation of AAP Clinical Practice Guideline: The Diagnosis and Management of the Initial Urinary Tract Infection in Febrile Infants and Young Children 2–24 Months of Age, in
Pediatrics, 2016; 138: 10.1542/peds.2016-3026. (Subcommittee on Urinary Tract Infection)

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 © 2016, 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 Pharmacotherapy Line
Dec. 6, 2016 * Vol. 23, No. 234
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and the Dec. 6 issue of the Annals of Internal Medicine (2016; 165).
High-Risk Prescribing & Dual Health System Use: U.S. veterans with dementia who have access to both VA and outside services are at high risk of potentially unsafe medication (PUM) prescribing, researchers report (10.7326/M16-0551). A retrospective cohort study of VA and Medicare Part D data shows these patterns of prescribing among 75,829 veterans with dementia based on Healthcare Effectiveness Data and Information Set (HEDIS) high-risk medication in older adults (PUM-HEDIS), any daily exposure to prescriptions with a cumulative Anticholinergic Cognitive Burden (ACB) score of 3 or higher (PUM-ACB), any antipsychotic prescription (PUM-antipsychotic), and any PUM exposure (any-PUM): “Compared with VA-only users, dual users had more than double the odds of exposure to any-PUM (odds ratio [OR], 2.2 [95% CI, 2.2 to 2.3]), PUM-HEDIS (OR, 2.4 [CI, 2.2 to 2.8]), and PUM-ACB (OR, 2.1 [CI, 2.0 to 2.2]). The odds of PUM-antipsychotic exposure were also greater in dual users (OR, 1.5 [CI, 1.4 to 1.6]). Dual users had an adjusted average of 44.1 additional days of any-PUM exposure (CI, 37.2 to 45.0 days).” (J. M. Thorpe, Joshua.Thorpe@va.gov)
Noting that the VA pharmacy system is “perfectly designed to achieve the outcomes it gets,” an editorialist writes (
10.7326/M16-2590): “Thorpe and colleagues note that the VA system has a robust integrated pharmacy and medical record system available in all of the VA health care settings—a system clearly built to achieve better outcomes. Yet when using 3 indicators of unsafe medications among veterans with dementia, the researchers found that approximately 4 of every 10 VA-only users still received potentially harmful medications. Anticholinergic medications were the most commonly prescribed drugs but have long been known to be potentially harmful for elderly persons. The Office of Inspector General of the U.S. Department of Health and Human Services has shown that the leading cause of adverse events in hospitals and skilled nursing facilities is related to medications, many of which induce delirium due to their anticholinergic properties. Yet we as a profession continue to prescribe these medications for our elderly patients. Again, the prioritization of choice holds us back from building a better system.” (D. R. Gifford, dgifford@ahca.org)
Vitamin D Deficiency Screening: In a Grand Rounds article, the debate over routine vitamin D deficiency screening is engaged based on recently issued U.S. Preventive Services Task Force (USPSTF) guidelines (pp. 800–7): “The guidelines were based on randomized trials of vitamin D deficiency screening and treatment, as well as on case–control studies nested within the Women’s Health Initiative. The USPSTF concluded that current evidence is insufficient to assess the benefits and harms of screening for vitamin D deficiency in asymptomatic adults. Compared with placebo or no treatment, vitamin D was associated with decreased mortality; however, benefits were no longer seen after trials of institutionalized persons were excluded. Vitamin D treatment was associated with a possible decreased risk for at least 1 fall and the total number of falls per person but not for fractures. None of the studies examined the effects of vitamin D screening versus not screening on clinical outcomes.” (H. Libman, hlibman@bidmc.harvard.edu)
High Value Care: As part of an initiative on High Value Care, a letter reports on an American College of Physicians survey showing that overuse of antibiotics, aggressive nonpalliative treatment in patients with limited life expectancy, treatment of chronic pain, and dietary supplements may be the most frequently used low value treatment interventions used by physicians (pp. 831–2; ACP).

>>>PNN NewsWatch
* On an 85–13 procedural vote, the U.S. Senate yesterday cleared the way for passage of the
21st Century Cures Act (H.R. 34) later this week, reports the Wall Street Journal. If signed into law by Pres. Obama as expected, the bill would set up $4.8 billion in funding of the “cancer moonshot” initiative of Vice Pres. Joe Biden, provide $1 billion in funding for opioid addiction interventions, and $500 million for FDA projects. The legislation also relaxes FDA criteria for drug approvals to include use of surrogate markers (e.g., LDL cholesterol levels) rather than requiring hard clinical endpoints such as changes in mortality or morbidity.

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 © 2016, 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 Pharmacotherapy Line
Dec. 7, 2016 * Vol. 23, No. 235
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Dec. 6 issue of JAMA, a theme issue on medical education (2016; 316).
Depression Among Medical Students: About one-fourth of medical students have depressive symptoms or depression, and one in 10 has suicidal ideation, a systematic review shows (pp. 2214–36): “Depression or depressive symptom prevalence data were extracted from 167 cross-sectional studies (n = 116,628) and 16 longitudinal studies (n = 5,728) from 43 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of depression or depressive symptoms was 27.2% (37,933/122,356 individuals; 95% CI, 24.7% to 29.9%, I2 = 98.9%). Summary prevalence estimates ranged across assessment modalities from 9.3% to 55.9%. Depressive symptom prevalence remained relatively constant over the period studied (baseline survey year range of 1982–2015; slope, 0.2% increase per year [95% CI, −0.2% to 0.7%]). In the 9 longitudinal studies that assessed depressive symptoms before and during medical school (n = 2,432), the median absolute increase in symptoms was 13.5% (range, 0.6% to 35.3%). Prevalence estimates did not significantly differ between studies of only preclinical students and studies of only clinical students (23.7% [95% CI, 19.5% to 28.5%] vs 22.4% [95% CI, 17.6% to 28.2%]; P = .72). The percentage of medical students screening positive for depression who sought psychiatric treatment was 15.7% (110/954 individuals; 95% CI, 10.2% to 23.4%, I2 = 70.1%). Suicidal ideation prevalence data were extracted from 24 cross-sectional studies (n = 21,002) from 15 countries. All but 1 study used self-report instruments. The overall pooled crude prevalence of suicidal ideation was 11.1% (2,043/21,002 individuals; 95% CI, 9.0% to 13.7%, I2 = 95.8%). Summary prevalence estimates ranged across assessment modalities from 7.4% to 24.2%.” (D. A. Mata, dmata@bwh.harvard.edu)
“Medical schools need to step up to address the mental health crisis among medical students, and solutions cannot just come from the mental health side,” an editorialist writes (
pp. 2195–6). “The problem needs to be viewed as an environmental health issue. Medical school administrators must overcome any lingering indifference and institutional concerns and address this problem by concerted efforts to assess and monitor student well-being and to improve the culture and conditions in the educational environment.” (S. J. Slavin, slavinsj@slu.edu)
End-of-Rotation Transitions & Patient Mortality: Based on outcomes of patients at 10 VA hospitals, mortality is significantly higher when medical residents and interns are changing services, and the association was stronger after the 2011 restriction on medical resident hours became effective (pp. 2204–13). Investigators found adjusted mortality rates of 2.18% in-hospital, 9.45% at 30 days, and 14.43% at 90 days for 230,701 patient discharges in 2008–14. These figures were significantly higher during intern transitions (3.5%) and when both interns and residents changed services (4.0%); an increased rate of 3.3% during resident-only transitions was not significant. Adjusted 30-day (13.8%–15.5%) and 90-day (20.9%–22.8%) mortality rates were greater in all transitions than during control periods. (J. L. Denson, joshua.denson@ucdenver.edu)
This study adds transition periods to the list of times when mortality is higher in teaching hospitals (weekends, early in the academic year), editorialists write (
pp. 2193–4): “It is … curious why service changes were associated with increased 30-day and 90-day mortality, and not increased risk of readmission. Is there something specific to the service change that is vital for longer-term survival that is compromised by service change? Does the new team lack information or context to arrange appropriate follow-up care for patients? Or did the previous team fail to elicit or transmit necessary information? Likewise, the interns both before and after the transition may feel less invested in arranging postacute care for patients. Because these explanations might also be expected to lead to increased risk for readmissions (which was not observed), there is another possibility: an impending service change may result in physicians seeing the ‘forest for the trees’ for a sick patient, for example, leading to the deliberate decision to discharge a patient to hospice.” (V. M. Arora, varora@uchicago.edu)

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 © 2016, 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 Pharmacotherapy Line
Dec. 8, 2016 * Vol. 23, No. 236
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Dec. 8 issue of the New England Journal of Medicine (2016; 375).
Adjuvant Sunitinib in Postnephrectomy Renal-Cell Carcinoma: Disease-free survival and adverse events are increased when sunitinib is used adjunctively in patients who had undergone nephrectomy for high-risk, clear-cell renal cell carcinoma, according to a phase 3 trial (pp. 2246–54). In a group of 615 patients, sunitinib or placebo had these effects on a primary end point of disease-free survival: “The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P = 0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects.” (A. Ravaud, alain.ravaud@chu-bordeaux.fr)
Rising Price of Naloxone: Perspective authors call for governmental action to keep naloxone affordable for those at risk of prescription-opioid and heroin overdoses (pp. 2213–5): “First, naloxone could be purchased in bulk, which would create stable demand that might motivate additional companies to begin manufacturing the medication—a strategy that’s been used for vaccine manufacturing. Second, governments could invoke federal law 28 U.S.C. section 1498 to contract with a manufacturer to act on behalf of the United States and produce less costly versions of Evzio’s patented auto-injector in exchange for reasonable royalties—an approach that was considered for procuring ciprofloxacin during the anthrax threat in 2001. Third, in response to increases in generic drug prices, some observers have proposed allowing importation of generics from international manufacturers that have received approval from regulators with standards comparable to those of the FDA, a strategy that could be pursued for naloxone.” (R. Gupta)
Costs, Quality & Care Coordination: “We should coordinate care not to save money but because coordinated care is better care,” concludes a Perspective author (pp. 2218–20). Maintaining that “to spend less, we need to do less,” the writer notes: “Conflating cost containment and care coordination poses many potential dangers. For starters, it causes care coordination’s merits to be judged on the basis of savings, diminishing the importance of coordinated care itself as a worthy goal—a way of enhancing patients’ experiences and improving outcomes even if it doesn’t reduce utilization or produce savings. Early evaluations of the Medicare [accountable care organization] programs, for example, suggest that their care management and coordination efforts have meaningfully improved patient experiences but not rates of hospitalizations for ambulatory care–sensitive conditions. Achievement of those results should be considered a success.” (J. M. McWilliams)

>>>PNN NewsWatch
* The average
life expectancy among Americans has risen to 78.8 years in 2015 from 51.7 years a century ago, the National Center for Health Statistics reports. But the 2015 figure represents a rare decline, dropping from 78.9 years in 2014 as mortality of 8 of the top 10 causes of death increased. “The rate increased 0.9% for heart disease, 2.7% for chronic lower respiratory diseases, 6.7% for unintentional injuries, 3.0% for stroke, 15.7% for Alzheimer’s disease, 1.9% for diabetes, 1.5% for kidney disease, and 2.3% for suicide,” the agency reports. “The rate decreased by 1.7% for cancer. The rate for influenza and pneumonia did not change significantly.”
* By a 94–5 vote, the Senate sent the
21st Century Cures Act to Pres. Obama’s desk, where signature into law is expected. Using a “patient-focused drug development” term that is new to FDA, the 1,000-page legislation could take years for the agency to translate into final regulatory language, STAT reports. 

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 © 2016, 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 Pharmacotherapy Line
Dec. 9, 2016 * Vol. 23, No. 237
Providing news and information about medications and their proper use

>>>Chest Highlights
Source: Dec. issue of Chest (2016; 150).
Oral Macrolides for Mycobacterium massiliense Lung Disease: Following a 2-week course of combination antibiotics for Mycobacterium massiliense lung disease in patients with cystic fibrosis and non–cystic fibrosis bronchiectasis, oral macrolides were effective for long-term prophylaxis, researchers report (pp. 1211–21). Among 71 patients who had received 2- or 4-week courses of intravenous amikacin and cefoxitin (or imipenem), these results were identified for those on oral macrolides for 12 or 24 months (following the 2- or 4-week courses, respectively) following negative sputum culture conversion: “Total treatment duration was longer in the 4-week IV group (median, 23.9 months) than in the 2-week IV group (15.2 months; P <.001). The response rates after 12 months of treatment were 89% for symptoms, 79% for CT scanning, and 100% for negative sputum culture results in the 4-week IV group. In the 2-week IV group, these values were 100% (P = .057), 91% (P = .177), and 91% (P = .147), respectively. Acquired macrolide resistance developed in two patients in the 2-week IV group. Genotyping analyses of isolates from patients who did not achieve negative sputum culture conversion during treatment and from those with positive culture results after successful treatment completion revealed that most episodes were due to reinfection with different genotypes of M massiliense.” (W-J Koh)
Pneumonia Risks With Antipsychotics in Alzheimer Disease: Using observational data from the Medication and Alzheimer Disease (MEDALZ) cohort, investigators find that use of antipsychotic drugs in patients with Alzheimer disease (AD) was associated with a higher risk of pneumonia (pp. 1233–41). The association held “regardless of applied study design, treatment duration, or the choice of drug,” the authors conclude. The cohort includes all 60,584 individuals in Finland diagnosed with AD in 2005–11. Incident pneumonia occurred in 12,225 patients, yielding these associations in comparison with a matched cohort: “The use of antipsychotic agents was associated with a higher risk of pneumonia (adjusted hazard ratio [HR], 2.01; 95% CI, 1.90–2.13) in the AD cohort and a somewhat higher risk in the non-AD cohort (adjusted HR, 3.43; 95% CI, 2.99–3.93). Similar results were observed with case-crossover analyses (OR, 2.02; 95% CI, 1.75–2.34 in the AD cohort and OR, 2.59; 95% CI, 1.77–3.79 in the non-AD cohort). The three most commonly used antipsychotic agents (quetiapine, risperidone, haloperidol) had similar associations with pneumonia risk.” (A-M Tolppanen)
Macrolides in Clinically Significant Bronchiectasis: Commentary authors review the evidence on long-term macrolides in adults with bronchiectasis (pp. 1187–93): “Long-term macrolide therapy offers an evidence-based treatment to reduce frequent exacerbations in stable adult patients with bronchiectasis. There is limited evidence that these agents also attenuate the decline in lung function and improve health-related quality of life. The benefits and risks of long-term macrolide use need to be clearly explored for individual patients. Further work is needed to understand the optimal drug, dose, and regimen, the mechanisms behind these benefits, appropriate patient selection, sustainability of efficacy, potential long-term risk for the lung microbiome; and their use with or without inhaled antibiotic treatment.” (A. T. Hill)
NOACs in Nonvalvular Atrial Fibrillation: The non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, and apixaban have similar effectiveness in patients with nonvalvular atrial fibrillation, according to analysis of a large U.S. claims database (pp. 1302–12): “We found no differences between the three NOACs in the risk of stroke or systemic embolism (hazard ratio [HR], 1.00; 95% CI, 0.75–1.32 for rivaroxaban vs dabigatran; HR, 0.82; 95% CI, 0.51–1.31 for apixaban vs dabigatran; and HR, 1.05; 95% CI, 0.64–1.72 for apixaban vs rivaroxaban). Apixaban was associated with a lower risk of major bleeding (HR, 0.50; 95% CI, 0.36–0.70; P <.001 vs dabigatran and HR, 0.39; 95% CI, 0.28–0.54; P <.001 vs rivaroxaban). Rivaroxaban was associated with an increased risk of major bleeding (HR, 1.30; 95% CI, 1.10–1.53; P <.01) and intracranial bleeding (HR, 1.79; 95% CI, 1.12–2.86; P <.05) compared with dabigatran.” (P. Noseworthy)

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 © 2016, 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 Pharmacotherapy Line
Dec. 12, 2016 * Vol. 23, No. 238
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Dec. 10 issue of Lancet (2016; 388).
Tau-Aggregation Inhibitor Therapy in Alzheimer Disease: In patients with mild to moderate Alzheimer disease, add-on treatment with the tau-protein aggregation inhibitor leuco-methylthioninium bis(hydromethanesulfonate; LMTM) provided no significant benefit at 15 months, researchers report (pp. 2873–84). Based on coprimary outcomes of progression on two Alzheimer disease scales, 891 participants had these outcomes: “The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes.… Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants.” (C. M. Wischik, cmw@taurx.com)
Myosin Activation to Increase Contractility in Heart Failure: In the phase 2 Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF), pharmacokinetically guided dosing of omecamtiv mecarbil improved cardiac function and decreased ventricular diameter (pp. 2895–903). At 87 sites in 13 countries, 299 patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower had these outcomes on active drug or placebo: “Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18–32, p <0.0001), stroke volume 3.6 mL (0.5–6.7, p = 0.0217), left ventricular end-systolic diameter −1.8 mm (−2.9 to −0.6, p = 0.0027), left ventricular end-diastolic diameter −1.3 mm, (−2.3 to 0.3, p = 0.0128), heart rate −3.0 beats per min (−5.1 to −0.8, p = 0.0070), and N-terminal pro B-type natriuretic peptide concentration in plasma −970 pg/mL (−1672 to −268, p = 0.0069). The frequency of adverse clinical events did not differ between groups.” (J. R. Teerlink, john.teerlink@ucsf.edu)

>>>BMJ Highlights
Source: Early-release article from BMJ (2016; 353).
Chemoprevention of Colorectal Cancer: While nonaspirin NSAIDs are most effective for chemoprevention of colorectal cancer in patients with previous colorectal neoplasia, low-dose aspirin has the most favorable risk–benefit profile, according to a systematic review and network meta-analysis (i6188): “15 randomized controlled trials (12,234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; [surface under the cumulative ranking (SUCRA)] = 0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA = 0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA = 0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA = 0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA = 0.58) but had an inferior safety profile (SUCRA = 0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated.” (S. Singh, sis040@ucsd.edu)

>>>PNN JournalWatch
* Phantom Motor Execution Facilitated by Machine Learning and Augmented Reality as Treatment for Phantom Limb Pain: A Single Group, Clinical Trial in Patients With Chronic Intractable Phantom Limb Pain, in
Lancet, 2016; 388: 2885–94. (M. Ortiz-Catalan, maxo@chalmers.se
* Approach to the Treatment of Diabetic Ketoacidosis, in
American Journal of Kidney Diseases, 2016; 68: 967–72. (K. S. Kamel, kamel.kamel@utoronto.ca
* Measuring Appropriate Antimicrobial Use: Attempts at Opening the Black Box, in
Clinical Infectious Diseases, 2016; 63: 1639–44. (E. S. Spivak, emily.spivak@hsc.utah.edu
* Management of Obesity (
pp. 4295–305; N. Alamuddin, naji.alamuddin@uphs.upenn.edu) and How to Manage the Obese Patient With Cancer (pp. 4284–94; A. G. Renehan, andrew.renehan@ics.manchester.ac.uk), in Journal of Clinical Oncology, 2016; 34.

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 © 2016, 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 Pharmacotherapy Line
Dec. 13, 2016 * Vol. 23, No. 239
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Dec. issue of JAMA Internal Medicine (2016; 176).
Post-MI Beta-Blockers in Nursing Home Residents: While use of beta-blockers is associated with a 26% decline in mortality among nursing home residents with acute myocardial infarction (AMI), those with poorer baseline cognitive or functional impairment appear to have further functional decline with use of the drugs, a study shows (10.1001/jamainternmed.2016.7701). National data for 2007 to 2010 from the Minimum Data Set, version 2.0, and Medicare Parts A and D show these associations: “The initial cohort of 15,720 patients (11,140 women [70.9%] and 4,580 men [29.1%]; mean [SD] age, 83 [8] years) included 8,953 new beta-blocker users and 6,767 nonusers. The propensity-matched cohort included 5,496 new users of beta-blockers and an equal number of nonusers for a total cohort of 10,992 participants (7,788 women [70.9%]; 3,204 men [29.1%]; mean [SD] age, 84 [8] years). Users of beta-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02–1.28), with a number needed to harm of 52 (95% CI, 32–141). Conversely, beta-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67–0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98–1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from beta-blockers (OR, 1.34; 95% CI, 1.11–1.61 and OR, 1.32; 95% CI, 1.10–1.59, respectively). In contrast, little evidence of functional decline due to beta-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89–1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77–1.26) and intermediate (OR, 1.05; 95% CI, 0.86–1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of beta-blockers were similar across all subgroups.” (M. A. Steinman, mike.steinman@ucsf.edu)
After noting potential sources on error based on the methodology of this observational study, editorialists write, “A randomized clinical trial for frail older adults with cognitive and functional impairment to examine guideline-recommended medications for AMI is needed to address biases inherent in observational studies” (
10.1001/jamainternmed.2016.7714). “Furthermore, a trial for discontinuation of beta-blocker therapy in the population of elders with life-limiting illness would be prudent given the changing benefits and risks of treatment across levels of cognitive and functional impairment. The Palliative Care Research Cooperative Group’s discontinuation trial for statin therapy among adults with life-limiting illness provides a useful model for such a study. Regardless of the state of the science, all clinicians should consider improving their approach to communication regarding initiating (and discontinuing) therapy for those in the last quarter of their life.” (J. Tjia, jennifer.tjia@umassmed.edu)
High-Dose Caffeine in Patients With Heart Failure: In patients with systolic heart failure and at high risk for ventricular arrhythmias, oral caffeine 500 mg had no effect on cardiac arrhythmias, researchers report (pp. 1752–9). “We found no statistically significant effect of caffeine ingestion on the frequency of ventricular or supraventricular ectopies, even during the physical stress of a treadmill test,” the authors report. “Exercise test–derived variables, such as ventricular and supraventricular premature beats, duration of exercise, estimated peak oxygen consumption, and heart rate, were not influenced by caffeine ingestion. We observed no increases in ventricular premature beats (91 vs 223 vs 207 beats, respectively) in patients with higher levels of plasma caffeine concentration compared with lower plasma levels (P = .91) or with the placebo group (P = .74).” (L. E. Rohde, rohde.le@gmail.com)

>>>PNN NewsWatch
*
Pioglitazone (Actos, Actoplus Met, Actoplus Met XR, Duetact, Oseni) may be linked to an increased risk of bladder cancer, FDA said yesterday. Product labeling, which already warns of this possibility based on 2010 and 2011 alerts, is being modified to include results of an updated review. The drug should not be used in those with active bladder cancer, and use should be considered carefully in those with a history of this condition.

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 © 2016, 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 Pharmacotherapy Line
Dec. 14, 2016 * Vol. 23, No. 240
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Dec. 13 issue of JAMA (2016; 316).
Evolocumab & Progression of Coronary Disease: Among statin-treated patients, the PCSK9 inhibitor evolocumab further decreased percent atheroma volume (PAV) at week 76 of treatment, indicating a need to elucidate the effects of these drugs on clinical outcomes (pp. 2373–84). In the GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial at 197 hospitals on 6 continents, participants with angiographic coronary disease received monthly evolocumab or placebo subcutaneously for 76 weeks while continuing statin treatment: “Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P <.001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, −1.0% [95% CI, −1.8% to −0.64%]; P < .001). The secondary efficacy parameter, normalized [total atheroma volume (TAV)], decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, −4.9 mm3 [95% CI, −7.3 to −2.5]; P <.001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P <.001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P <.001 for TAV).” (S. J. Nicholls, stephen.nicholls@sahmri.com)
Immunogenicity of 9-Valent HPV Vaccine Regimens: In girls and boys aged 9–14 years, a two-dose regimen of 9-valent human papillomavirus (HPV) vaccine provided noninferior immunogenicity as compared with a three-dose regimen used in adolescent girls and young women aged 16–26 years, researchers report (pp. 2411–21). At 52 ambulatory sites in 15 countries, open-label HPV vaccine administered as two doses 6 or 12 months apart or three doses over 6 months yielded these antibody responses 1 month after the last dose: “Of the 1,518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1,474 completed the study and data from 1,377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P <.001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart.” (O-E Iversen, le-erik.iversen@uib.no">ole-erik.iversen@uib.no)
With data supporting efficacy of the two-dose schedule for HPV vaccine, CDC has shifted away from the three-dose regimen, editorialists write, with an added goal of increasing vaccine acceptability and uptake (
pp. 2370–2): “A 2-dose schedule (at 0 and 6-12 months) will decrease health care appointments needed for HPV vaccination and facilitate clinicians’ ability to deliver vaccine at preventive health visits. Nevertheless, efforts will be needed to increase vaccine initiation and ensure delivery of the second dose.” (L. E. Markowitz, lem2@cdc.gov)
Medical Use of Cannabis: While evidence supports limited use of cannabinoids in some conditions, “no adequate studies of cannabis (botanical marijuana) are available for any of these indications,” concludes a Medical Letter summary (pp. 2424–5): “The cannabinoids dronabinol (Marinol, and generics) and nabilone (Cesamet) are effective for treatment of chemotherapy-induced nausea and vomiting, for which they have been approved in the US. Cannabinoid products may also be effective for second-line treatment of cancer pain and the neuropathic pain and spasticity of multiple sclerosis, but none are currently approved for these indications. Cannabidiol (CBD) alone, which is not psychoactive, may be effective for treatment of epilepsy, but more documentation is required.” (Medical Letter)

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 © 2016, 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 Pharmacotherapy Line
Dec. 15, 2016 * Vol. 23, No. 241
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Early-online article from and Dec. 15 issue of the New England Journal of Medicine (2016; 375).
Dupilumab versus Placebo in Atopic Dermatitis: A human monoclonal antibody against interleukin-4 receptor alpha, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, in the SOLO-1 and -2 trials of 671 and 708 patients (pp. 2335–48): “The primary [efficacy] outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P <0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P <0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P <0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life.…” (E. L. Simpson, simpsone@ohsu.edu)
Human Intestinal Microbiome: The interactions and diverse effects of the complex web of organisms residing in the human gut play an important role in health and disease that is becoming more apparent as the metagenome is identified and catalogued, authors of a review article write (pp. 2369–79): “Several decades ago, environmental microbial ecologists recognized that the diversity of microbes observed by microscopy far exceeded that of organisms recovered with the use of traditional culture-based approaches. A variety of culture-independent molecular assays for detecting and classifying microorganisms (microbiota) and assessing their encoded genes (microbiome) and gene products showed that microbes rarely exist in isolation. Instead, they subsist in complex, interactive, interkingdom, multispecies microbial communities within a habitat. As the field has developed, it has become apparent that virtually every habitat, and every organism, on earth has its own microbiota. This includes the human holobiont, a conglomerate of mammalian and multispecies microbial cells in spatially segregated ecosystems, the genomic content of which is influenced by both topography and biologic individuality.” (S. V. Lynch, susan.lynch@ucsf.edu)
Cannabinoid “Zombie” Outbreak in New York: A mass intoxication of 33 people in a New York neighborhood was caused by a synthetic cannabinoid, methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoate (AMB-FUBINACA, also known as MMB-FUBINACA or FUB-AMB), researchers report (10.1056/NEJMoa1610300). An ingredient in the herbal “incense” product AK-47 24 Karat Gold, “AMB-FUBINACA is an example of the emerging class of ‘ultrapotent’ synthetic cannabinoids and poses a public health concern,” the authors note. “Collaboration among clinical laboratory staff, health professionals, and law enforcement agencies facilitated the timely identification of the compound and allowed health authorities to take appropriate action.” (R. Gerona, roy.gerona@ucsf.edu)

>>>PNN NewsWatch
*
Crisaborole (Eucrisa, Anacor Pharmaceuticals) ointment was approved yesterday to treat mild to moderate atopic dermatitis (eczema) in patients 2 years of age and older. Crisaborole is a topical phosphodiesterase 4 (PDE-4) inhibitor, although its specific mechanism of action in atopic dermatitis is not known. Safety and efficacy were established in two placebo-controlled trials with a total of 1,522 participants ranging in age from 2 to 79 years of age, with mild to moderate atopic dermatitis. Overall, participants receiving crisaborole achieved greater response with clear or almost clear skin after 28 days of treatment.
*
FDA warned yesterday that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

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 © 2016, 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 Pharmacotherapy Line
Dec. 16, 2016 * Vol. 23, No. 242
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Jan. 1 issue of Clinical Infectious Diseases (2017; 64).
Effectiveness of Tdap Vaccine During Pregnancy: Two research studies examine the impact on disease in newborns of the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine administered during or after pregnancy.
Giving the Tdap vaccine as recommended at 27–36 weeks gestation is far preferable to postpartum administration, researchers report (
pp. 3–8). Risk of pertussis was as follows in infants at less than 8 weeks of age when mothers received Tdap vaccine as recommended or within 14 days of delivery: “Tdap vaccination received at 27–36 weeks gestation was found to be 85% (95% confidence interval, 33%–98%) more effective than postpartum Tdap vaccination at preventing pertussis in infants <8 weeks of age. Vaccination at 27–36 weeks gestation was more effective at preventing pertussis in infant than vaccination during the second trimester.” (K. Winter, kathleen.winter@cdph.ca.gov)
When infants developed pertussis, those whose mothers were vaccinated with Tdap had lower risk of hospitalization and intensive care unit admission and shorter hospital stays, a second analysis shows (
pp. 9–14): “Infected infants of vaccinated mothers were significantly less likely to be hospitalized and had significantly shorter hospital stays compared with infants born to unvaccinated mothers, after adjustment for chronological and gestational age and receipt of diphtheria and tetanus toxoids and acellular pertussis vaccine. Unadjusted and adjusted vaccine effectiveness for preventing hospitalization among infants with pertussis was 72% (95% confidence interval [CI], 49%–85%) and 58% (95% CI 15%–80%), respectively. No infants born to vaccinated mothers required intubation or died of pertussis.” (K. Winter, kathleen.winter@cdph.ca.gov)

>>>Oncology Highlights
Source: Dec. issue of the Journal of Clinical Oncology, a theme issue on Obesity and Cancer (2016; 34).
Antidiabetic Medications & Cancer: Authors review preclinical and clinical data regarding the effects of antidiabetic medications on cancer incidence and mortality and the effects of anticancer therapies on glucose homeostasis (pp. 4261–9): “[Type 2 diabetes mellitus (T2DM)] is associated with an increased risk and greater mortality from many cancer types. Metformin use has been associated with a decrease in cancer incidence and mortality, and there are many ongoing randomized trials investigating the effects of metformin on cancer-related outcomes. However, data regarding the association of other antidiabetes medications with cancer incidence and mortality are conflicting. Glucocorticoids, hormone-based therapies, inhibitors that target the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and insulin-like growth factor 1 receptor–targeted therapy have been associated with high rates of hyperglycemia. These agents mediate their deleterious metabolic effects by reducing insulin secretion and increasing insulin resistance in peripheral tissues.” (E. J. Gallagher, emily.gallagher@mssm.edu)
Obesity & Breast Cancer Prognosis: “Obesity is associated with inferior survival in breast cancer,” according to investigators who assessed the literature for relationships among weight, survival, and cancer subtypes and therapies (pp. 4203–16). The authors conclude that “understanding the nature and mechanisms of [the inferior survival] provides an important opportunity for interventions to improve the diagnosis, treatment, and outcomes of obese patients with breast cancer” based on these literature findings: “Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and death and therefore poorer survival outcomes. This is most clearly established for estrogen receptor–positive breast cancer, with the relationship in triple-negative and human epidermal growth factor receptor 2–positive subtypes less well established. A range of biologic mechanisms that may underlie this association has been identified. Weight loss and lifestyle interventions, as well as metformin and other obesity-targeted therapies, are promising avenues that require further study.” (P. J. Goodwin, pgoodwin@mtsinai.on.ca)

>>>PNN NewsWatch
* Updated
CDC recommendations for a two-dose human papillomavirus (HPV) vaccine schedule were published in yesterday’s MMWR.

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 © 2016, 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 Pharmacotherapy Line
Dec. 19, 2016 * Vol. 23, No. 243
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Dec. 17 issue of Lancet (2016; 388).
Fulvestrant in Advanced Breast Cancer: Compared with the current first-line therapy, the selective estrogen receptor degrader fulvestrant “has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy,” investigators conclude (pp. 2997–3005). A phase 3 trial randomized 462 patients to fulvestrant or anastrozole in 2012–14 with these results: “Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0.797, 95% CI 0.637–0.999, p = 0.0486). Median progression-free survival was 16.6 months (95% CI 13.83–20.99) in the fulvestrant group versus 13.8 months (11.99–16.59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events.” (J. F. R. Robertson, john.robertson@nottingham.ac.uk)
Rabbit-ATG After Renal Transplantation: During the first year after renal transplantation, rabbit antithymocyte globulin (rabbit ATG) failed to show superiority over basiliximab induction in 615 patients at 21 German centers (pp. 3006–16). Adults received either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C), with these results: “[Biopsy-proven acute rejection (BPAR)] rates were not reduced by rabbit ATG (9.9%) compared with either treatment arm A (11.2%) or B (10.6%; A versus C: p = 0.75, B versus C p = 0.87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p = 0.0004). Patient survival (94.7% in arm A, 97.4% in arm B, and 96.9% in arm C) and censored graft survival (96.1% in arm A, 96.8% in arm B, and 95.8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms.” (C. Hugo, christian.hugo@uniklinikum-dresden.de)
Nusinersen in Infantile-Onset Spinal Muscular Atrophy: Nusinersen, an antisense agent, had acceptable safety and tolerability in an open-label, phase 2 trial of 20 participants with infantile-onset spinal muscular atrophy (pp. 3017–26): “All participants experienced adverse events, with 77 serious adverse events reported in 16 participants, all considered by study investigators not related or unlikely related to the study drug. In the 12 mg dose group, incremental achievements of motor milestones (p <0.0001), improvements in CHOP-INTEND motor function scores (p = 0.0013), and increased compound muscle action potential amplitude of the ulnar nerve (p = 0.0103) and peroneal nerve (p <0.0001), compared with baseline, were observed. Median age at death or permanent ventilation was not reached and the Kaplan–Meier survival curve diverged from a published natural history case series (p = 0.0014). Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord.” (R. S. Finkel, rfinkel@nemours.org)

>>>PNN NewsWatch
* Risks of serious adverse mood, behavior, or cognitive effects with smoking-cessation medicines
varenicline and bupropion is lower than previously suspected, FDA says.

>>>PNN JournalWatch
* Patient-Centered Outcomes Research To Improve Asthma Outcomes, in
Journal of Allergy and Clinical Immunology, 2016; 138: 1503–10. (A. Anise, aanise@pcori.org)
* Novel Insights Into Tumor Necrosis Factor Receptor, Death Receptor 3, and Progranulin Pathways in Arthritis and Bone Remodeling, in
Arthritis & Rheumatology, 2016; 68: 2845–56. (A. Williams, williamsas@cf.ac.uk)

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 © 2016, 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 Pharmacotherapy Line
Dec. 20, 2016 * Vol. 23, No. 244
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Online-first articles from JAMA (2016; 316).
Marijuana Trends During Pregnancy: Use of past-month marijuana use by pregnant women increased 62% over the decade ending in 2012, researchers report (10.1001/jama.2016.17383). Based on data on women 18–44 years of age from the annual National Survey on Drug Use and Health for 2002 through 2014, the authors found: “Among all pregnant women, the adjusted prevalence of past-month marijuana use increased from 2.37% (95% CI, 1.85%–3.04%) in 2002 to 3.85% (95% CI, 2.87%–5.18%) in 2014 (prevalence ratio [PR], 1.62 [95% CI, 1.09–2.43]). The adjusted prevalence of past-month marijuana use was highest among those aged 18 to 25 years, reaching 7.47% (95% CI, 4.67%–11.93%) in 2014, significantly higher (P = .02) than among those aged 26 to 44 years (2.12% [95% CI, 0.74%–6.09%]). However, increases over time did not differ by age (P = .76). Past-year use was higher overall, reaching 11.63% (95% CI, 9.78%–13.82%) in 2014, with similar trends over time.” (D. S. Hasin, deborah.hasin@gmail.com)
“Pregnant women and those considering becoming pregnant should be advised to avoid using marijuana or other cannabinoids either recreationally or to treat their nausea,” editorialists advise (
10.1001/jama.2016.18612). “Even with the current level of uncertainty about the influence of marijuana on human neurodevelopment, physicians and other health care providers in a position to recommend medical marijuana must be mindful of the possible risks and err on the side of caution by not recommending this drug for patients who are pregnant. Although no states specifically list pregnancy-related conditions among the allowed recommendations for medical marijuana, neither do any states currently prohibit or include warnings about the possible harms of marijuana to the fetus when the drug is used during pregnancy. (Only 1 state, Connecticut, currently includes an exception to the medical marijuana exemption in cases in which medical marijuana use could harm another individual, although potential harm to a fetus is not specifically listed.)” (E. M. Wargo, wargoem@nida.nih.gov)
U.S. Medical Marijuana Use: One in 10 U.S. adult marijuana users cited medical reasons in the National Survey on Drug Use and Health for 2012–14, a study shows (10.1001/jama.2016.18900). Overall, 12.9% of U.S. adults reported using marijuana; 0.8% claimed medical use only and another 0.5% claimed medical and nonmedical use. “Similarities in correlates of medical and nonmedical users, especially co-occurrence with psychiatric conditions and other substance use, suggest that some marijuana users may access medical marijuana without medical need,” the authors write. “However, medical-only marijuana users differed from nonmedical-only users in ways that are consistent with use to address medical problems.” (W. M. Compton, wcompton@nida.nih.gov)

>>>Geriatrics Report

Source: Dec. Journal of the American Geriatrics Society (2016; 64).
Knowledge Transfer & Inappropriate Medication Use: In a Canadian hospital in 2013–14, a knowledge transfer (KT) strategy resulted in a decreased potentially inappropriate medication (PIM) use among adults 75 years or older (pp. 2487–94). Geriatrician presentations, pharmacist interventions with prescribing physicians, and comprehensive geriatric assessments produced these results among 8,622 patients with 14,071 admissions: “One or more PIMs were prescribed on 28,776 (19.8%) patient–days; a higher rate was found for individuals aged 75 to 84 (24.0%) than for those aged 85 and older (14.4%) (P < .001), and in women (20.8%) than in men (18.6%) (P < .001). The drug classes most frequently accounting for the PIM were gastrointestinal agents (21%), antihistamines (18%), and antidepressants (17%). An absolute decrease of 3.5% (P < .001) of patient–days with at least one PIM was observed immediately after the intervention.” (B. Cossette, bcossette.chus@ssss.gouv.qc.ca)

>>>PNN NewsWatch
*
FDA yesterday granted accelerated approval to rucaparib (Rubraca, Clovis Oncology) as monotherapy in patients with assay-confirmed deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies.

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 © 2016, 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 Pharmacotherapy Line
Dec. 21, 2016 * Vol. 23, No. 245
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Dec. 20 issue of JAMA (2016; 316).
Pritelivir in Frequent Genital HSV-2 Shedding: In a phase 2 trial, a novel herpes simplex virus (HSV) helicase-primase inhibitor was more effective than valacyclovir for reducing viral shedding among 91 participants with frequently recurring genital HSV-2, researchers report (pp. 2495–503). Conducted at clinical research centers in four U.S. cities, the trial randomized participants to pritelivir 100 mg or valacyclovir 500 mg. A planned sample size of 98 participants was not reached because FDA placed the trial on hold while it looked at findings from a separate nonclinical toxicity study and the sponsor terminated the trial.
At the point of study termination, these results had been identified: “In intent-to-treat analyses, HSV shedding was detected in 2.4% (173 of 7,276 ) of swabs during pritelivir treatment compared with 5.3% (392 of 7,453) during valacyclovir treatment (relative risk [RR], 42; 95% CI, 0.21 to 0.82; P = .01). In swabs with HSV, the mean quantity of HSV was 3.2 log
10 copies/mL during pritelivir treatment vs 3.7 log10 copies/mL during valacyclovir treatment (difference, −0.1; 95% CI, −0.6 to 0.5; P = .83). Genital lesions were present on 1.9% of days in the pritelivir group vs 3.9% in the valacyclovir group (RR, 0.40; 95% CI, 0.17–0.96; P = .04). The frequency of shedding episodes did not differ by group, with 1.3 per person–month for pritelivir and 1.6 per person–month for valacyclovir (RR, 0.80; 95% CI, 0.52 to 1.22; P = .29). Treatment-emergent adverse events occurred in 62.3% of participants in the pritelivir group and 69.2% of participants in the valacyclovir group.” (A. Wald, annawald@u.washington.edu)
An editorialist, reacting to other articles in this issue that find insufficient evidence to support routine serologic screening for HSV infection in asymptomatic adolescents and adults (
pp. 2525–30, K. Bibbins–Domingo, http://chair@uspstf.net; pp. 2531–43, C. Feltner, cindy_feltner@med.unc.edu), expresses disappointment in the lack of progress against this common sexually transmitted disease (pp. 2493–4): “The recommendation from the [U.S. Preventive Services Task Force] and the results of the accompanying evidence review should not be misinterpreted to assume that currently available tests, despite their limitations, do not have a role in some elements of current HSV management. Nor should these reports be interpreted to suggest that progress is not being made in expanding management options for treatment of genital herpes. Currently available tests, even with their suboptimal performance characteristics, remain useful for diagnostic testing and for evaluation of persons with histories of recurring anogenital lesions and provide information that may influence treatment decisions based on which virus type (HSV-1 or HSV-2) is present in persons with genital HSV. Current tests also provide important information for sex partners of persons diagnosed with HSV who are uncertain of their own status and for other suggestive but not definitive symptoms or signs.” (E. W. Hook III, ehook@uab.edu)
Duration of Antibiotic Therapy in CAP: “The Infectious Diseases Society of America/American Thoracic Society recommendations for duration of antibiotic treatment based on clinical stability criteria can be safely implemented in hospitalized patients” with community-acquired pneumonia (CAP), conclude authors of a noninferiority clinical trial from Spain (pp. 2544–5). Conducted at four teaching hospitals, the analysis included 312 patients with CAP and looked at outcomes with physician-determined therapy (control group) or a minimum of 5 days of treatment with antibiotics stopped when body temperature was 37.8° C for 48 hours  without more than one sign of CAP-associated clinical instability. Statistically similar results were observed at day 10 and day 30 with the two approaches. (M. J. Fine, michael.fine@va.gov)

>>>PNN NewsWatch
* Previously approved to complement fingerstick testing for diabetes treatment decisions,
Dexcom’s G5 Mobile Continuous Glucose Monitoring System was approved yesterday by FDA for replacing fingerstick blood glucose testing for diabetes treatment decisions in people 2 years of age and older with diabetes. This is the first FDA-approved continuous glucose monitoring system that can be used to make diabetes treatment decisions without confirmation with a traditional fingerstick test.

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 © 2016, 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 Pharmacotherapy Line
Dec. 22, 2016 * Vol. 23, No. 246
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Dec. 22 New England Journal of Medicine (2016; 375).
Shortened Antimicrobial Regimens for Acute Otitis Media: Reduced-duration antimicrobial treatment for acute otitis media in young children results in less favorable efficacy outcomes with no reduction in adverse events, a study shows (pp. 2446–56). Among 520 children aged 6–23 months of age, amoxicillin–clavulanate for a standard duration of 10 days or reduced duration of 5 days produced these clinical responses, including symptom scores from 0 to 14: “Children who were treated with amoxicillin–clavulanate for 5 days were more likely than those who were treated for 10 days to have clinical failure (77 of 229 children [34%] vs. 39 of 238 [16%]; difference, 17 percentage points [based on unrounded data]; 95% confidence interval, 9 to 25). The mean symptom scores over the period from day 6 to day 14 were 1.61 in the 5-day group and 1.34 in the 10-day group (P = 0.07); the mean scores at the day-12-to-14 assessment were 1.89 versus 1.20 (P = 0.001). The percentage of children whose symptom scores decreased more than 50% (indicating less severe symptoms) from baseline to the end of treatment was lower in the 5-day group than in the 10-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P = 0.003). We found no significant between-group differences in rates of recurrence, adverse events, or nasopharyngeal colonization with penicillin-nonsusceptible pathogens. Clinical-failure rates were greater among children who had been exposed to three or more children for 10 or more hours per week than among those with less exposure (P = 0.02) and were also greater among children with infection in both ears than among those with infection in one ear (P <0.001).” (A. Hoberman, hoberman@chp.edu)
“For now, 10 days of amoxicillin–clavulanate for children younger than 2 years of age who have a definite diagnosis of acute otitis media seems to be a reasonable option,” an editorialist writes (
pp. 2492–3). “[This] study was not designed to address outcomes in older children, children with less severe acute otitis media or with acute otitis media in one ear, or children with additional risk factors such as cleft palate or trisomy 21. The study of acute otitis media is challenging owing to antibiotic pharmacokinetics, age of the patients, variation in regional pathogens, polymicrobial infection, viral cofactors, antibiotic resistance, status of patients with regard to receipt of [pneumococcal vaccine 7 or 13 valent], and a high rate of spontaneous resolution. In addition, there is a paucity of studies from resource-poor and low-income countries.” (M. A. Kenna)
Bleeding Prophylaxis in Atrial Fibrillation & PCI: In 2,124 patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, “low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus [dual antiplatelet therapy (DAPT)] for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months,” researchers report (pp. 2423–34). Rates of clinically significant bleeding were lower in those receiving low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (group 1), very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (group 2) than in group 3 (standard therapy; 16.8%, 18.0%, and 26.7%, respectively). “The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan–Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant),” the authors added. (C. M. Gibson, mgibson@bidmc.harvard.edu)
This study “was designed primarily to assess safety and to generate hypotheses about clinical outcomes but not to definitively assess clinical outcomes,” editorialists write (
pp. 2490–2). Three other ongoing trials will provide useful information but are not designed to assess ischemic outcomes, they add, concluding, “More than 100,000 patients with atrial fibrillation undergo PCI in the United States annually, and simple, low-cost, randomized trials would help to determine the best possible regimen for these patients.” (S. S. Jolly)

>>>PNN NewsWatch
*
PNN will not be published on Fri. and Mon., Dec. 23 and 26, Christmas holidays (celebrated).

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 © 2016, 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 Pharmacotherapy Line
Dec. 27, 2016 * Vol. 23, No. 247
Providing news and information about medications and their proper use

>>>AJHP Highlights
Source: Jan. 1 issue of the American Journal of Health-System Pharmacy (2017; 74).
Perioperative Omega-3 Fatty Acids for AF Prevention After Cardiothoracic Surgery: Polyunsaturated omega-3 fatty acid (PUFA) supplementation failed to decrease the risk of atrial fibrillation (AF) and several other outcomes within 1 month of cardiothoracic surgery, researchers report (e17–e23). Among 561 patients without a history of AF, PUFA 1 g or placebo twice daily produced these results based on a primary outcome of AF before hospital discharge and secondary endpoints of AF within 1 week after surgery, AF within 1 month after surgery, length of hospital stay, postoperative bleeding complications, and readmission within 1 month after surgery: “No significant reduction in the risk of AF was observed at hospital discharge (relative risk [RR], 0.98; p = 0.922) or at three weeks after surgery (RR, 0.98; p = 0.844). After restricting the analysis to treatment-adherent patients, the association remained nonsignificant at hospital discharge (RR, 0.90; p = 0.374) and at three weeks after surgery (RR, 0.90; p = 0.330). No significant differences were observed between treatments for rates of readmission, death, and bleeding complications or the length of hospital stay.” (J. D. Joss, jajoss@samhealth.org)
Medication Fall Risk Score: Using administrative claims data from two hospitals, investigators improved specificity of a medication review fall-risk screening tool, the “medication fall risk score” (RxFS),” without compromising sensitivity (e32–9). The RxFS is used with nurse-administered tools such as the Morse Fall Scale (MFS). It was analyzed and adjusted based on 33,058 hospitalizations, with these results: “The area under the [receiver operating characteristic (ROC)] curve for the predictive model for falls compromising both MFS and RxFS scores was computed as 0.8014, which was greater than the area under the ROC curve associated with use of the MFS alone (0.7823, p = 0.0030). Screening based on MFS scores alone had 81.25% sensitivity and 61.37% specificity. Combined use of RxFS and MFS scores resulted in 82.42% sensitivity and 66.65% specificity ([net reclassification improvement] = 0.0587, p = 0.0003).” (C. Yazdani, cyrus.yazdani@honorhealth.com)

>>>Medical Care Report
Source: Jan. issue of Medical Care (2017; 55).
Part D PDPs & Medication Adherence: Medicare Part D prescription drug plans “do appear to have some level of influence over their medication adherence scores based on how effectively they manage prescription drug benefits for enrollees,” a study shows (pp. 37–42). CMS and U.S. Census data were combined and analyzed for service reliability, stability/accuracy of drug prices, accessibility of prescription drugs, and availability of drug information, with these results: “Among [Part D] contractors, enrollee satisfaction scores were positively and significantly associated with medication adherence scores. Two of the 4 plan management variables were observed to have both direct and indirect effects on medication adherence scores: accessibility of prescription drugs and service reliability.” (G. J. Young)
ACA Impact on Patient Spending in Part D Doughnut Hole: Provisions in the Affordable Care Act that began the closing period of noncoverage under Medicare Part D “likely contributed to a reduction in out-of-pocket spending for prescription drugs for part D beneficiaries, especially for people who fell into the doughnut hole,” according to analysis Medical Expenditure Panel Survey data through 2013 (pp. 43–9): “Overall out-of-pocket spending significantly decreased after closing the coverage gap, mainly because of a significant reduction in out-of-pocket spending on brand-name drugs. Conversely, the results show that generic drug utilization increased after closing the coverage gap. As expected, the effects were considerably larger for people who fell into the doughnut hole.” (A. Bonakdar Tehrani)

>>>PNN NewsWatch
* Based on priority review,
FDA last week approved the first-and-only treatment for spinal muscular atrophy in pediatric and adult patients nusinersen (Spinraza, Biogen).

>>>PNN JournalWatch
* Bridging the Divide Between Dental and Medical Care, in
Health Affairs, 2016; 35: 2337–9. (G. Subramanian, subramga@sdm.rutgers.edu

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 © 2016, 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 Pharmacotherapy Line
Dec. 28, 2016 * Vol. 23, No. 248
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Dec. 27 issue of JAMA (2016; 316).
Intra-articular Corticosteroids in Knee Osteoarthritis: Future studies of intra-articular corticosteroid injections should include a sham injection control group and imaging that assures correct needle placement, conclude authors who found low-quality evidence currently supporting this intervention (pp. 2671–2). In a JAMA Clinical Evidence Synopsis article, results of the random-effectss meta-analysis were as follows: “Use of intra-articular corticosteroids was associated with a larger pain reduction than control (standardized mean difference [SMD], −0.40 [95% CI, −0.58 to −0.22]), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analog scale between corticosteroids and control. This effect size corresponds to a number needed to treat of 8 (95% CI, 6 to 13), meaning that for every 8 patients treated with corticosteroids rather than sham injection or no intervention, 1 patient will respond to treatment.” (P. Jüni, peter.juni@utoronto.ca)
These findings “somewhat contradict earlier meta-analyses of this same question,” an editorialist writes (
pp. 2607–8). “Ioannidis recently noted the exponential increase in the number of published meta-analyses, including many that address the same question yet yield different conclusions. These differences are generated by marginally different study designs, the capture and inclusion of different studies, and different analytic approaches. It is challenging for knowledgeable patients and physicians to determine which meta-analysis best approximates a true summary of relevant literature. In the meantime, the number of published trials, which provide the basis for the growing number of meta-analyses, has not increased. Perhaps, as da Costa et al suggest, large-scale randomized trials testing the efficacy of different doses of intra-articular steroids combined or uncombined with other treatments would eliminate remaining uncertainty regarding the effectiveness and duration of benefit of intra-articular steroids for patients with knee osteoarthritis.” (D. T. Felson, dfelson@bu.edu)
New-Onset Seizures: While 8% to 10% of people have seizures during their lifetimes, only 2% to 3% develop epilepsy, authors of a review article write (pp. 2657–68). Because “a diagnosis of epilepsy has significant medical, social, and emotional consequences,” the authors note, “A careful patient history and physical examination, electroencephalography, and brain imaging are necessary to separate patients with acute symptomatic seizures, single unprovoked seizures, and nonepileptic events from those with new-onset epilepsy.” (J. R. Gavvala, jay.gavvala@bcm.edu)
Personal Health Care and Public Health Spending: In the U.S., the costs of personal health care and public health increased substantially from 1996 through 2013, with diabetes, ischemic heart disease, and low back and neck pain producing the largest amounts of spending, researchers report (pp. 2627–46). “Diabetes had the highest health care spending in 2013, with an estimated $101.4 billion (uncertainty interval [UI], $96.7 billion–$106.5 billion) in spending, including 57.6% (UI, 53.8%–62.1%) spent on pharmaceuticals and 23.5% (UI, 21.7%–25.7%) spent on ambulatory care,” according to data found in 183 sources. “Ischemic heart disease accounted for the second-highest amount of health care spending in 2013, with estimated spending of $88.1 billion (UI, $82.7 billion–$92.9 billion), and low back and neck pain accounted for the third-highest amount, with estimated health care spending of $87.6 billion (UI, $67.5 billion–$94.1 billion).” (J. L. Dieleman, dieleman@uw.edu)
These results “suggest that the United States needs better strategies for nursing home care and for control of pharmaceutical costs,” an editorialist writes (
pp. 2604–6). “The disaggregated spending for diabetes is indicative of the enormous amount of money devoted to pharmaceuticals each year (Figure 4 in the article by Dieleman et al). For patients with diabetes, nearly 60% of health care costs are for pharmaceuticals, with that percentage increasing much more quickly than for other categories of care. Similar and equally troubling trends are seen for medications to treat hyperlipidemia. For many diseases with limited inpatient or surgical interventions, pharmaceuticals have become a dominant part of care, ensuring that costs have significantly increased in the last decade.” (E. J. Emanuel, mehpchair@upenn.edu)

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 © 2016, 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 Pharmacotherapy Line
Dec. 29, 2016 * Vol. 23, No. 249
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Dec. 29 issue of the New England Journal of Medicine (2016; 375).
Cardiovascular Safety of NSAIDs in Arthritis: In a safety trial of participants with osteoarthritis or rheumatoid arthritis and increased cardiovascular risk, the selective agent celecoxib proved noninferior to ibuprofen and naproxen, researchers report (pp. 2519–29). PRECISION results also show relative gastrointestinal and renal advantages of celecoxib over one or both nonselective NSAIDs, as shown in addition to these risk figures based on a primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke: “A total of 24,081 patients were randomly assigned to the celecoxib group (mean [± SD] daily dose, 209 ± 37 mg), the naproxen group (852 ± 103 mg), or the ibuprofen group (2045 ± 246 mg) for a mean treatment duration of 20.3 ± 16.0 months and a mean follow-up period of 34.1 ± 13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P <0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P <0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P = 0.01) or ibuprofen (P = 0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P = 0.004) but was not significantly lower with celecoxib than with naproxen (P = 0.19).” (S. E. Nissen, nissens@ccf.org)
“Celecoxib, especially at a dose lower than 400 mg per day, may deserve a more central place in the antiinflammatory armamentarium,” an editorialist writes (
pp. 2595–6), adding this caution: “Although celecoxib may be safer than anticipated, two recent meta-analyses of treatment for knee or hip osteoarthritis have reported that celecoxib is among the weakest of NSAIDs in terms of pain control. Only 40% of patients treated with celecoxib at a dose of 200 mg per day, as compared with 78% of those treated with 1 g of naproxen daily, had at least minimal clinically important improvement. In the PRECISION trial, there were significantly greater improvements in pain scores among patients taking naproxen than among those taking celecoxib, although the differences were small.” (D. T. Felson)
Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas: Phase 1 data in 24 children with neurofibromatosis type 1 and inoperable plexiform neurofibromas indicate efficacy of selumetinib, an oral selective inhibitor of mitogen-activated protein kinase 1 and 2 (pp. 2550–60). The dose-ranging study yielded these results for continuous dosing of the drug in 28-day cycles: “Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.” (B. C. Widemann, widemanb@mail.nih.gov)

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 © 2016, 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 Pharmacotherapy Line
Dec. 30, 2016 * Vol. 23, No. 250
Providing news and information about medications and their proper use

>>>PNN’s Top 10 for 2016
A year of change? Hope? Hopelessness? For pharmacy, progress and problems defined many events in 2016. Here’s an overview from the coverage in PNN.
1 Politics & Pharmacy: A turbulent presidential campaign ended surprisingly and promised more unpredictability (Nov. 9). Drug pricing seems sure to stay under the microscope, as 2015 scrutiny led to concerns about affordability of key medicines worldwide (Jan. 4), price increases for EpiPen (Aug. 24), and value and volume in health care (Sept. 14). As the new administration and Congress begin dismantling the Affordable Care Act, pharmacy may be in a position to seek recognition for federal recognition of pharmacists’ patient care services as defined by the Patient Access to Pharmacists’ Care Coalition or the ACCP Medicare Benefit Initiative (Nov. 9).
2 Tragedies of Opioid Epidemic: Numerous articles covered in PNN detailed the flawed ideas that led to abuse of prescription opioids, heroin, and benzodiazepines (Jan. 4, 14; Apr. 18, 22; May 24, 25; Sept. 27; Dec. 8) and the federal response to the epidemic (Mar. 16, 24, 25; Apr. 14, 20; Aug. 26; Sept. 1).
3 Pathogens in Play: Problems wrought by a virus thought to be relatively innocuous since its identification in the 1950s produced a new focus on ways to contain the Zika virus (Feb. 17, 18; Mar. 2, 10; Aug. 2, 29) and develop vaccines (Nov. 18) to prevent its spread.
4 New Drugs, New Indications: A relatively quiet year at FDA in terms of approvals of new chemical entities could set the stage for a blockbuster 2017. With only 22 new drugs, the number of approvals is the lowest since 2010 (21). Biosimilars continue to emerge (Apr. 6), and vaccines (June 13, Aug. 5) will add to FDA’s total in the final compilation. New uses of older drugs continue to be an important area of research (e.g., metformin in obesity, Feb. 4, and in polycystic ovary syndrome in adolescents, May 2). 
5 New Lens on Aging, Care at the End of Life: With 10,000 baby boomers joining the ranks of the 65-and-older population every day, attention is turning to care of older adults, including those who have reached 75 years and those affected by geriatric syndromes and frailty (Apr. 26). Studies are looking at differences in pharmacotherapy of older patients, including anticholinergic burden (Mar. 22, Nov. 30), polypharmacy (Apr. 12), influenza vaccine (Apr. 15), statins for primary prevention (Nov. 16), falls (Dec. 8, 27), and beta blockers after myocardial infarction (Dec. 13).
6 Vaccine Progress & Resistance: Even as new vaccines offer protection against Ebola virus (Apr. 28), meningococcal B (July 21), and cholera (June 13), pediatricians report an increasing number of parents refusing vaccines for their children (Sept. 2). With President-elect Trump having ties to the antivaxxer movement, vaccine advocates are wondering what 2017 will hold.
7 Anti-infective Agents & Stewardship: Pharmacists continue to lead the way in appropriate use of anti-infective agents (Feb. 10, May 4, Nov. 8) and other stewardship efforts (Apr. 8, May 16, Sept. 21). Resistance is changing management of Helicobacter pylori (Nov. 14), and advances in knowledge about the fecal microbiome are leading to fascinating possibilities for future therapies (Jan. 12, June 10, Dec. 15).
8 Rationalizing Medical Marijuana: As in 2015, medical researchers are examining evidence to support the growing trend toward state legalization of marijuana (July 22, Dec. 14), but studies are also showing troubling effects of chronic cannabis use (Mar. 8, June 1, Aug. 5). 
9 Precision Medicine: Passage of the 21st Century Cures Act brings elements of Pres. Obama’s Precision Medicine Initiative into the “cancer moonshot” dream of outgoing VP Biden (Dec. 6). Earlier in the year, research articles detailed increased use of pharmacogenomics in a variety of settings (Jan. 8, Mar. 25, May 16, June 9, Oct. 19, 21, 28).
10 Comparative Controversies: Authors compared acid with T lymphocytes in etiology of GERD (May 18), rate and rhythm control (May 19) and dabigatran versus warfarin (May 31) in AF management, NSAIDs and acetaminophen in treating osteoarthritis (May 23), drugs with ablation in ventricular tachycardia (July 14), and IV versus oral antibiotics in complicated pneumonia (Dec. 2).

>>>PNN NewsWatch
*
PNN will not be published on Mon., Jan. 2, New Year’s Day (celebrated).

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 © 2016, 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.