PNN January–March 2018

PNN Pharmacotherapy Line
Jan. 2, 2018 * Vol. 25, No. 1
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Jan. 2 issue of and early-release articles from the Annals of Internal Medicine (2018; 168).
Statin Guidelines for Primary Prevention: Guidelines recommending that more persons use statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) should prevent more events than guidelines recommending use by fewer persons, according to findings of a systematic review and meta-analysis (10.7326/M17-0681). Researchers conducted an observational study of actual ASCVD events over 10 years followed by a modeling study to estimate the effectiveness of different guidelines in a contemporary cohort of 45,750 persons aged 40 to 75 years who did not use statins and did not have ASCVD at baseline between 2003 and 2009. The percentage of participants eligible for statins was 44% by the Canadian Cardiovascular Society (CCS) guideline, 42% by the American College of Cardiology/American Heart Association (ACC/AHA), 40% by the National Institute for Health and Care Excellence (NICE), 31% by the U.S. Preventive Services Task Force (USPSTF), and 15% by European Society of Cardiology/European Atherosclerosis Society (ESC/EAS). The estimated percentage of ASCVD events that could have been prevented by using statins for 10 years was 34% for CCS, 34% for ACC/AHA, 32% for NICE, 27% for USPSTF, and 13% for ESC/EAS. Guidelines from the ACC/AHA, CCS, or NICE should be followed rather than those from the USPSTF and ESC/EAS, the researchers concluded. (B. G. Nordestgaard, boerge.nordestgaard@regionh.dk)
Blood Pressure Control in Hypertensive Patients: “Multilevel, multicomponent strategies, followed by patient-level strategies, are most effective for [blood pressure (BP)] control in patients with hypertension and should be used to improve hypertension control,” conclude authors of a systematic review and meta-analysis (10.7326/M17-1805): “A total of 121 comparisons from 100 articles with 55,920 hypertensive patients were included. Multilevel, multicomponent strategies were most effective for systolic BP reduction, including team-based care with medication titration by a nonphysician (−7.1 mm Hg [95% CI, −8.9 to −5.2 mm Hg]), team-based care with medication titration by a physician (−6.2 mm Hg [CI, −8.1 to −4.2 mm Hg]), and multilevel strategies without team-based care (−5.0 mm Hg [CI, −8.0 to −2.0 mm Hg]). Patient-level strategies resulted in systolic BP changes of −3.9 mm Hg (CI, −5.4 to −2.3 mm Hg) for health coaching and −2.7 mm Hg (CI, −3.6 to −1.7 mm Hg) for home BP monitoring. Similar trends were seen for diastolic BP reduction.” (J. He, jhe@tulane.edu)
>>>Diabetes Care Report
Source:
Jan. issue of Diabetes Care (2018; 41).
Diabetes & Heart Failure: “The totality of evidence from randomized trials, which is supported by [three] observational analyses published in this issue of Diabetes Care, demonstrates that in patients with diabetes, heart failure is not only common and clinically important, but it can also be prevented and treated,” concludes a Commentary author (pp. 11–3). “This conclusion is particularly significant because physicians have long ignored heart failure in their focus on glycemic control and their concerns about the ischemic macrovascular complications of diabetes.” The author gives this perspective, “Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure.” (M. Packer, milton.packer@baylorhealth.edu)
>>>PNN JournalWatch
* Standards of Medical Care in Diabetes—2018, in Diabetes Care, 2018; 41 (suppl 1).
*
Disparities in Environmental Exposures to Endocrine-Disrupting Chemicals and Diabetes Risk in Vulnerable Populations, in Diabetes Care, 2018; 41: 193–205. (R. M. Sargis, rsargis@uic.edu)
*
Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-1811. (V. Sung)
*
Attention-Deficit/Hyperactivity Disorder and Very Preterm/Very Low Birth Weight: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-1645. (A. P. Franz)
*
Maternal Smoking and Attention-Deficit/Hyperactivity Disorder in Offspring: A Meta-analysis, in Pediatrics, 2018; 141: 10.1542/peds.2017-2465 (L. Huang)

PNN Pharmacotherapy Line
Jan. 3, 2018 * Vol. 25, No. 2
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 2 issue of JAMA (2018; 319).
Infant Formula & Type 1 Diabetes: During 11.5 years of follow-up, the cumulative incidence of type 1 diabetes was unchanged among infants who had been weaned to hydrolyzed versus conventional formula (pp. 38–48). Participants had human leukocyte antigen–conferred disease susceptibility and a first-degree relative with type 1 diabetes at 78 study centers in 15 countries when they were randomized to extensively hydrolyzed casein formula or conventional formula in 2002–07. Results showed the following when follow-up ended in early 2017: “Among 2,159 newborn infants (1,021 female [47.3%]) who were randomized, 1,744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1–Q3, 10.2–12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, −1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1–Q3, 3.1–8.9] vs 5.8 years [Q1–Q3, 2.6–9.1]; difference, 0.2 years [95% CI, −0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group).” (M. Knip, mikael.knip@helsinki.fi)
Recovering From Sepsis: Higher rates of survival among patients with sepsis has created a growing number of people who need posthospital care or recovery, authors of a review article write (pp. 62–75). Of the 19 million people worldwide who have sepsis in a given year, 14 million survive, but one third of them die during the following year and one sixth of them have severe persistent impairments. To provide the care needed by these patients, clinicians can consider these recommendations made in the conclusion of this article: “In the months after hospital discharge for sepsis, management should focus on (1) identifying new physical, mental, and cognitive problems and referring for appropriate treatment, (2) reviewing and adjusting long-term medications, and (3) evaluating for treatable conditions that commonly result in hospitalization, such as infection, heart failure, renal failure, and aspiration. For patients with poor or declining health prior to sepsis who experience further deterioration after sepsis, it may be appropriate to focus on palliation of symptoms.” (H. C. Prescott, hprescot@med.umich.edu)
Exploring Single Payer for U.S. Health Care: “A single-payer system could easily provide for universal coverage, but so could less-comprehensive reforms, if the public would support subsidies and compulsion,” writes a Viewpoint author in exploring options for addressing flaws in the U.S. health care system (pp. 15–6). “Single payer might improve health outcomes by providing more equal access to medical care, but attention to the social determinants of health might be a more effective way to improve health. The strongest case for single payer is its potential to control the cost of care. The current fragmented system of financing care precludes such control.” (V. R. Fuchs, vfuchs@stanford.edu)
A second Viewpoint explores Canadian single-payer experiences (
pp. 17–8). “Canada does offer important lessons for reform in the United States, not least in its relentless commitment to equitable access for some key services, its administrative efficiency, and its success in cost-containment. However, Canada’s health care arrangements are rooted in different values, facilitated by a different model of democratic governance, and reflect a different era, both in the conditions that fostered their creation and in an outmoded architecture that makes them a dubious exemplar for the United States. There is arguably much more for the United States to learn from the panoply of long-standing national experiments with universal coverage that can be found across the [Organisation for Economic Co-operation and Development]. Reinhardt, for one, suggested that Germany, the Netherlands, and Switzerland merited particularly close examination.” (C. D. Naylor, david.naylor@utoronto.ca)

PNN Pharmacotherapy Line
Jan. 4, 2018 * Vol. 25, No. 3
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 4 New England Journal of Medicine (2018; 378).
Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma: Among 75 participants in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression improved event-free and overall survival, compared with cyclophosphamide (pp. 35–47). At 54 months, patients with diffuse cutaneous systemic sclerosis (scleroderma) had these outcomes based on global rank composite scores: “In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1,404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan–Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.” (K. M. Sullivan, keith.sullivan@duke.edu)
Need for Universal Influenza Vaccine: “Even in years when influenza vaccines are well matched to circulating viruses, estimates of vaccine effectiveness range from 40 to 60%, which is lower than that for most licensed noninfluenza vaccines,” public health officials write in calling for renewed emphasis on development of an effective universal vaccine against this virus (pp. 7–9). Pointing to a 10% vaccine effectiveness figure in the 2016–17 Australian influenza season, the authors — including National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD — wrote the following: “Given that most of the U.S. influenza-vaccine supply is currently produced in eggs and the composition of the 2017–2018 Northern Hemisphere vaccine is identical to that used in Australia, it is possible that we will experience low vaccine effectiveness against influenza A (H3N2) viruses and a relatively severe influenza season if they predominate. This possibility underscores the need to strive toward a ‘universal’ influenza vaccine that will protect against seasonal influenza drift variants as well as potential pandemic strains, with better durability than current annual vaccines. Among other advantages, in all likelihood, such a vaccine would not be subject to the limitations of egg-based vaccine technology.” (C. I. Paules)
>>>PNN NewsWatch
* PharMEDium is voluntarily recalling 55 lots of different drug products involving a total of 25,327 units to the hospital/user level because of a lack of assurance of sterility. The recall results from “a commitment made during a recent inspection of the company’s facility,” PharMEDium said in a news release, adding that it “has not received any reports of complaints related to the products but is issuing this recall out of an abundance of caution.”
*
AuroMedics Pharma is voluntarily recalling lot AFO l 17001-A, expiry date Dec. 2018, of Ampicillin and Sulbactam for Injection, USP, 1.5 g in a single-dose vial, to the hospital level, because of presence of glass particles.
* Announcing “new steps to facilitate efficient
generic drug review to enhance competition, promote access, and lower drug prices,” FDA Commissioner Scott Gottlieb, MD, made these commitments to specific actions and initiatives in a statement released yesterday: “We’ll also continue to take steps aimed at making it harder for brand companies to sometimes adopt tactics that prevent generics from coming to market in the time frame that the law intended. This includes guidance development to address three important areas during the first quarter of 2018: potential abuses of the citizen petition process, companies that restrict access to testing samples of branded drugs, and abuses of the single, shared system REMS negotiation process.”

PNN Pharmacotherapy Line
Jan. 5, 2018 * Vol. 25, No. 4
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
Jan. issue of Pediatrics (2018; 141).
Persistent Opioid Use After Adolescent Surgery: Use of opioids by adolescents and young adults following surgery can persist, creating “an important pathway to prescription opioid misuse,” researchers report (10.1542/peds.2017-2439). Retrospective cohort analysis of the Truven Health Marketscan research databases for 2010–14 showed the following for opioid-naive patients ages 13–21 years who underwent 1 of 13 specified surgeries: “Among eligible patients, 60.5% filled a postoperative opioid prescription (88,637 patients). Persistent opioid use was found in 4.8% of patients (2.7%–15.2% across procedures) compared with 0.1% of those in the nonsurgical group. Cholecystectomy (adjusted odds ratio 1.13; 95% confidence interval, 1.00–1.26) and colectomy (adjusted odds ratio 2.33; 95% confidence interval, 1.01–5.34) were associated with the highest risk of persistent opioid use. Independent risk factors included older age, female sex, previous substance use disorder, chronic pain, and preoperative opioid fill.” (C. M. Harbaugh)
Parental Counseling Before Immunization Exemptions: In Washington State, provision of legally mandated parental counseling by a health care provider of parents requesting exemption from required school immunizations significantly reduced exemption rates, a study shows (10.1542/peds.2017-2364). Comparing exemption rates in 2013–14 with those of 1997–98, investigators found this impact of a 2011 law requiring counseling: “After SB5005 was implemented, there was a significant relative decrease of 40.2% (95% confidence interval: −43.6% to −36.6%) in exemption rates. This translates to a significant absolute reduction of 2.9 percentage points (95% confidence interval: −4.2% to −1.7%) in exemption rates.…” (S. B. Omer)
Timing of Inpatient Pentavalent Rotavirus Vaccination: Recommendations to delay administration of the pentavalent human-bovine reassortant rotavirus vaccine (RV5) until discharge from inpatient neonatal units may be misguided, according to data from an academic medical center (10.1542/peds.2017-1110). The recommendations are based on a theoretical risk of nosocomial transmission of vaccine-type rotavirus, but prospective cohort data show that some infants may be age-ineligible by discharge and that the precaution may be unnecessary: “Of 385 study infants, 127 were age-eligible for routine vaccinations during hospitalization. At discharge, 32.7% were up-to-date for rotavirus vaccination, compared with 82.7% for other vaccinations. Of rotavirus-unvaccinated infants, 42.6% were discharged at age >104 days and thus vaccination-ineligible. Of 1,192 stool specimens collected, rotavirus was detected in 13 (1.1%): 1 wild-type strain from an unvaccinated infant; 12 vaccine-type strains from 9 RV5-vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants (incidence rate: 0.0 [95% confidence interval: 0.0–1.5] cases per 1,000 patient days at risk).” (A. M. Hofstetter)
>>>Chest Highlights
Source:
Jan. issue of Chest (2018; 153).
Pharmaceutical Pricing: The 3 Cs of communication, continuity of care, and concordance of expectations (finding the common ground) should be used to address with patients the problems presented by higher-priced older pharmaceuticals, according to a summary of nine editorials based on an interprofessional session at CHEST 2016 (pp. 23–33). In a section on costs of epinephrine autoinjectors, a CVS Health physician writes that “pharmacists want to be part of the solution.… Because pharmacists interact with millions of people every day at the pharmacy counter and online, they understand the effect rising drug costs have on patients and their families.” (R. S. Irwin, Richard.Irwin@umassmemorial.org)
>>>PNN NewsWatch
* Vice President Mike Pence is among proponents pushing for federal right-to-try legislation in the U.S. Congress, Politco reports. As spelled out in H.R. 878, right-to-try allows terminally ill patients to use investigational drugs that have cleared phase 1 safety tests but not been approved for marketing by FDA. Politico has also posted a podcast in which FDA Commissioner Scott Gottlieb, MD, spells out the agency’s agenda for 2018.

PNN Pharmacotherapy Line
Jan. 8, 2018 * Vol. 25, No. 5
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Neoadjuvant Chemotherapy for Advanced Ovarian Cancer: Areas of the U.S. where cancer programs rapidly adopted neoadjuvant chemotherapy (NACT) in women with advanced epithelial ovarian cancer had significantly better mortality within 3 years, a quasi-experimental study shows (j5463): “In the rapidly adopting regions, patients treated in 2012 compared with 2011 had a mortality hazard ratio of 0.81 (95% confidence interval 0.71 to 0.94) after adjusting for mortality time trends, whereas no difference was observed in control regions (1.02, 0.93 to 1.12). Compared with control regions, larger declines in 90 day surgical mortality (7.0% to 4.0% v 5.0% to 4.3%, P = 0.01) and in the proportion of women not receiving surgery and chemotherapy (20.0% to 17.4% v 19.0 to 19.5%, P = 0.04) were observed in rapidly adopting regions. Cross sectional analysis confirmed that treatment in regions with greater use of NACT was associated was lower mortality (P = 0.001).” (A. Melamed, alexander.melamed@mgh.harvard.edu)
>>>Lancet Highlights
Source:
Jan. 6 issue of Lancet (2018; 391).
PCI in Stable Angina: Among 230 patients in the ORBITA trial who had stable angina and severe coronary stenosis, percutaneous coronary intervention (PCI) was no better than a placebo procedure in improving exercise time, researchers report (pp. 31–40). After 6 weeks of medication optimization, randomization to PCI or placebo procedure produced these outcomes: “Lesions had mean area stenosis of 84.4% (SD 10.2), fractional flow reserve of 0.69 (0.16), and instantaneous wave-free ratio of 0.76 (0.22). There was no significant difference in the primary endpoint of exercise time increment between groups (PCI minus placebo 16.6 s, 95% CI −8.9 to 42.0, p = 0.200). There were no deaths. Serious adverse events included four pressure-wire related complications in the placebo group, which required PCI, and five major bleeding events, including two in the PCI group and three in the placebo group.” The authors conclude, “The efficacy of invasive procedures can be assessed with a placebo control, as is standard for pharmacotherapy.” (J. E. Davies, ORBITA.trial@gmail.com)
Stents & Double Antiplatelet Therapy in Older Adults: In the SENIOR trial, patients aged 75 years or older had better outcomes following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) plus a short period of double antiplatelet therapy (DAPT), compared with bare-metal stents (BMS) plus DAPT (pp. 41–50). Participants in nine countries had stable angina, silent ischemia, or an acute coronary syndrome and at least one coronary artery with 70% stenosis. After 1 or 6 months of DAPT in those with stable or unstable presentation, randomization to DES or BES produced these results: “Between May 21, 2014, and April 16, 2016, we randomly assigned 1,200 patients (596 [50%] to the DES group and 604 [50%] to the BMS group). The primary endpoint occurred in 68 (12%) patients in the DES group and 98 (16%) in the BMS group (relative risk [RR] 0.71 [95% CI 0.52–0.94]; p = 0.02). Bleeding complications (26 [5%] in the DES group vs 29 [5%] in the BMS group; RR 0.90 [0.51–1.54]; p=0.68) and stent thrombosis (three [1%] vs eight [1%]; RR 0.38 [0.00–1.48]; p = 0.13) at 1 year were infrequent in both groups.” (O. Varenne, livier.varenne@aphp.fr">olivier.varenne@aphp.fr)
>>>PNN JournalWatch
* Primary Prevention With Statins in the Elderly, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.10.080. (M. B. Mortensen)
*
Obesity: Pathophysiology and Management, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.11.011. (K. M. Gadde)
*
Cannabis Use and Risk of Prescription Opioid Use Disorder in the United States, in American Journal of Psychiatry, 2018; 175: 47–53. (M. Olfson)
*
Psychiatric Genomics: An Update and an Agenda, in American Journal of Psychiatry, 2018; 175: 15–27. (P. F. Sullivan)
*
Classification of Cough as a Symptom in Adults and Management Algorithms, in Chest, 2018; 153: 196–209. (R. S. Irwin, richard.irwin@umassmemorial.org)
*
Clinical Practice and Infrastructure Review of Fecal Microbiota Transplantation for Clostridium difficile Infection, in Chest, 2018; 153: 266–77. (B. J. Kelly, brendank@mail.med.upenn.edu)
*
Intraabdominal Hypertension, Abdominal Compartment Syndrome, and the Open Abdomen, in Chest, 2018; 153: 238–50. (W. K. Rogers, william-k-rogers@uiowa.edu)

PNN Pharmacotherapy Line
Jan. 9, 2018 * Vol. 25, No. 6
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Early-online articles from and Jan. issue of JAMA Internal Medicine (2018; 178).
Cost-effectiveness of New Shingles Vaccine in Older Adults: The adjuvanted herpes zoster subunit vaccine (HZ/su), already demonstrated to be highly efficacious in older adults, may also be more cost-effectiveness than the live attenuated herpes zoster vaccine (ZVL), if the new product is priced as expected (10.1001/jamainternmed.2017.7431). Total costs and quality-adjusted life-years (QALYs) were as follows in a Markov decision model cost-effectiveness evaluation: “Based on randomized clinical trial data, at a price of $280 per series ($140 per dose), HZ/su was more effective and less expensive than ZVL at all ages. The incremental cost-effectiveness ratios compared with no vaccination ranged from $20,038 to $30,084 per QALY, depending on vaccination age. The finding was insensitive to variations in most model inputs other than the vaccine price and certain combinations of low adherence rate with a second dose and low efficacy of a single dose of HZ/su. At the current ZVL price ($213 per dose), HZ/su had lower overall costs than ZVL up to a price of $350 per 2-dose series. In probabilistic sensitivity analysis, HZ/su had 73% probability of being cost-effective for 60-year-olds at $50,000 per QALY.” (P. Le, lep@ccf.org)
“The HZ/su vaccine offers a substantial advantage over ZVL in terms of preventing HZ, while its efficacy appears to persist over a longer duration and in different age groups,” writes an editorialist (
10.1001/jamainternmed.2017.7442). “These clinical benefits directly translate into achieving high economic value as demonstrated by Le and Rothberg in their study. If priced at $280 per 2 required doses, HZ/su appears to be a cost-saving option compared with ZVL and a cost-effective option compared with no-vaccine strategies. However, the value of HZ/su vaccine would be even higher if it could be marketed at a price comparable to that of ZVL. A lower price would avoid additional budget implications for patients and payers and would allow wider use of this innovative product in the US elderly population.” (M. Najafzadeh, mnajafzadeh@bwh.harvard.edu)
Health Care Databases & Supplemental Indications: Could real-world databases be used to support supplemental indications of approved medications? Authors who analyzed longitudinal insurance claims from a national system think so (pp. 55–63). Using inclusion and exclusion criteria from the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET), results for a primary composite outcome of myocardial infarction, stroke, or hospitalization for congestive heart failure were similar to those from the drug’s pivotal trial: “Of the 640,951 patients included in the study, 48,053 were newly prescribed ramipril (mean [SD] age, 68.29 [9.52] years; 31,940 male [66.5%]) and 4,665 were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2,413 male [51.7%]). After propensity score matching, a total of 4,665 patients were newly prescribed telmisartan (mean [SD] age, 69.43 [9.60] years; 2,413 [51.7%]), and 4,665 patients were newly prescribed ramipril (mean [SD] age, 69.36 [9.67] years; 2343 male [50.2%]). As seen in ONTARGET, the composite risk of stroke, myocardial infarction, and hospitalization for congestive heart failure was similar for the 2 medications (hazard ratio, 1.0; 95% CI, 0.9–1.1). In addition, the study found that telmisartan was associated with a substantially decreased risk of angioedema (hazard ratio, 0.1; 95% CI, 0.03–0.56) compared with ramipril.” (M. Fralick, mif823@mail.harvard.edu)
New, Unpronounceable Pharmaceuticals: “An agreed-on pronunciation for new drugs should help prevent errors in prescribing medications and save clinicians the embarrassment of correcting our colleagues,” an editorialist concludes after discussing lack of guidance in drug compendia (10.1001/jamainternmed.2017.7898). “It should make us more willing to communicate accurately using generic names as opposed to using trade names or pharmacologic classes of drugs. Wider adoption of the USAN pronunciation standards would help us as physicians and be better for patients.” (D. S. Frank, daniel.s.frank@gmail.com)

PNN Pharmacotherapy Line
Jan. 10, 2018 * Vol. 25, No. 7
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 9 issue of JAMA (2018; 319).
Idalopirdine in Alzheimer Disease: Trials of adjunctive idalopirdine in 2,525 patients with mild-to-moderate Alzheimer disease (AD) fail to support efficacy claims based on improved cognition over 24 weeks (pp. 130–42). The selective 5-hydroxytryptamine-6 receptor antagonist was used in three doses along with donepezil and in one trial, donepezil, rivastigmine, or galantamine, with these results: “In study 1, the mean change in [Alzheimer’s Disease Assessment Scale (ADAS-Cog)] total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, −0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, −0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, −0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, −0.55 [95% CI, −1.45 to 0.36]).” (A. Atri, atria@cpmcri.org)
“Given the series of failures in rigorous attempts to develop an effective treatment for Alzheimer disease, it may seem difficult to be optimistic, yet lessons from the past century paint a different picture,” an editorialist writes (
pp. 123–5). “For instance, President Nixon signed the National Cancer Act in January 1971 and asked Congress for an additional $100 million in funding (slightly >$600 million in today’s dollars). Since then, numerous treatments for cancer are now available that were unimaginable 45 years ago. President Obama signed the National Alzheimer Project Act in January 2011, directing an initial investment of $50 million in fiscal year 2012, and then asked Congress for an additional $80 million in fiscal year 2013. Since then, federal funding for Alzheimer disease research has increased to approximately $1.4 billion in fiscal year 2017.” (D. A. Bennett, david_a_bennett@rush.edu)
Real-World Hypertension & the 2017 ACC/AHA Guidelines: Writing about the recently released American College of Cardiology/American Heart Association (ACC/AHA) guidelines, a Viewpoint author brings the advice into the real world: “The greatest benefit of the guideline recommendations may be that they emphasize, most likely for young adults, lifestyle interventions, including weight loss, healthy diet, physical exercise, reduced sodium intake, increased potassium intake, and curtailed alcohol consumption,” (pp. 115–6). “In principle, shifting the health care system more toward prevention with lifestyle measures is a welcome move. In the long-term, this emphasis may add value for the current health care system that undervalues prevention, and primary prevention in particular. However, it is unclear whether patients and clinicians are ready for such a change and whether these tens of millions of individuals will be able to obtain appropriate counseling and endorse effective, sustainable lifestyle modifications. Resources, supporting personnel, and infrastructure are still lacking in most places to achieve this long-due change. If primary prevention efforts fail, the likely option will be to resort to medications even for patients who would have done well with lifestyle modification. Thus, an emphasis on lifestyle-based prevention may paradoxically promote further overmedicalization of US society.” (J. P. A. Ioannidis, jioannid@stanford.edu)
“Is the problem fundamentally with the guidelines or with the US lifestyle?” asks a second Viewpoint author (
pp. 117–8). “The problem is not the result of rigorously developed guidelines, but rather is inherent in the high prevalence of unfavorable cardiovascular risk factors. Patients and clinicians need to focus attention where it belongs: on promotion of healthy lifestyles; prevention of the risk factors in the first place; and only when needed, use drugs to reduce cardiovascular risk, following evidence-based recommendations.” (P. Greenland, p-greenland@northwestern.edu)

PNN Pharmacotherapy Line
Jan. 11, 2018 * Vol. 25, No. 8
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 11 New England Journal of Medicine (2018; 378).
Osimertinib in Non–Small-Cell Lung Cancer: Compared with a standard epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), the irreversible agent osimertinib was superior in efficacy and similar in safety in a phase 3 trial of 556 patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC) (pp. 113–25). Researchers report these results from the FLAURA trial: “The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P <0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P = 0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P = 0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).” (S. S. Ramalingam, ssramal@emory.edu)
While factors yet to be determined could affect osimertinib’s role in therapy, “the near doubling in median progression-free survival with first-line osimertinib is profoundly impressive,” writes an editorialist (
pp. 192–3). “It has activity in CNS disease that is superior to that of the other available TKIs, and it is less toxic. Osimertinib also makes detection of the T790M mutation unimportant. We cannot robustly predict in which patients T790M-mediated acquired resistance to first- or second-generation EGFR-TKIs will develop. Moreover, T790M is irrelevant to the 40% of patients who have disease progression by other mechanisms. These factors and the predictable and durable efficacy of first-line osimertinib make it the ideal first-line choice for EGFR-mutated NSCLC.” (S. Popat)
Long-Term Inhaled Budesonide in BPD: In surviving extremely premature neonates, 2-year survival rates were decreased among those receiving early inhaled budesonide for prevention of bronchopulmonary dysplasia, compared with placebo (pp. 148–57). Neurodevelopmental disabilities were similar, as noted in these results for 629 evaluable infants: “148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P = 0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P = 0.04).” (D. Bassler, dirk.bassler@usz.ch)
Massachusetts Medicaid Reforms: Discussing a shift of near-poor adults into private plans as proposed by the State of Massachusetts, Viewpoint authors discuss the potential impact and a related imposition of a closed drug formulary (pp. 109–11): “State attempts to prioritize coverage of expensive new hepatitis C drugs have been blocked by the courts, and supplemental rebates address only about 5% of total Medicaid drug spending. The Massachusetts waiver would depart from this long-standing approach by creating a closed formulary: the state would select which drugs to cover on the basis of clinical effectiveness, cost, and appropriateness, ensuring that at least one drug per therapeutic class was included. Closed formularies are used by most commercial and public payers; for example, pharmacy benefit managers CVS Health and Express Scripts reportedly exclude more than 170 and 150 drugs, respectively, from their formularies.” (B. D. Sommers)
>>>PNN NewsWatch
* International Laboratories is voluntarily recalling 30-count packages labeled as Clopidogrel Tablets, USP 75 mg, lot 117099A, to the consumer level, because they may contain Clopidogrel 75 mg or Simvastatin Tablets, USP 10 mg.

PNN Pharmacotherapy Line
Jan. 12, 2018 * Vol. 25, No. 9
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
Jan. issue of the American Journal of Psychiatry (2018; 175).
Smoking & ADHD in Female Adolescents: Initiation of smoking during adolescence is affected by specific subtypes of attention-deficit/hyperactivity disorder (ADHD) and gender, according to three population studies of 3,762 same-sex twins (pp. 63–70). “The association of inattention with smoking in female adolescents may be causal, whereas hyperactivity-impulsivity appears to act indirectly, through shared propensities for both ADHD and smoking,” the investigators conclude, adding these study results: “Adolescents who had more severe ADHD symptoms as children were more likely to initiate smoking and to start smoking younger. The association of ADHD symptoms with daily smoking, number of cigarettes per day, and nicotine dependence was greater in females than in males. Monozygotic female twins with greater attentional problems than their co-twins had greater nicotine involvement, consistent with possible causal influence. These effects remained when co-occurring externalizing behaviors and stimulant medication were considered. Hyperactivity-impulsivity, while also more strongly related to smoking for female adolescents, appeared primarily noncausal.” (I. J. Elkins)
Asenapine Maintenance Therapy in Mania & Bipolar I Disorder: Compared with placebo, long-term asenapine treatment prevented recurrence of mood events in adults with bipolar I disorder, researchers report (pp. 71–9). During an initial open-label period of 12 to 16 weeks followed by a 26-week double-blind randomized withdrawal period, 549 patients were treated to a target asenapine dose of 10 mg twice daily in the open-label phase (with some patients titrated down to 5 mg twice daily). Those meeting stabilization/stable-responder criteria (n = 253) were randomized to asenapine or placebo treatment in the double-blind period, with these results: “Time to recurrence of any mood episode was statistically significantly longer for asenapine- than placebo-treated subjects. In post hoc analyses, significant differences in favor of asenapine over placebo were seen in time to recurrence of manic and depressive episodes. The most common treatment-emergent adverse events were somnolence (10.0%), akathisia (7.7%), and sedation (7.7%) in the open-label period and mania (11.9% of the placebo group compared with 4.0% of the asenapine group) and bipolar I disorder (6.3% compared with 1.6%) in the double-blind period.” (A. Szegedi)
Cannabis Use & Risk of Prescription Opioid Use Disorder: Using data from the early 2000s, a study shows that cannabis use is associated with the initiation of nonmedical prescription opioid use and opioid use disorder among American adults (pp. 47–53). Odds ratios were in the 5.78 to 7.76 range for incident nonmedical prescription opioid use and opioid use disorder, respectively, in 2004–05 when cannabis use was documented during 2001–02. (M. Olfson)
>>>PNN NewsWatch
* CDC is encouraging use of antiviral agents for treating high-risk patients with influenza and those with more severe symptoms. The agency is working with manufacturers to resolve spot shortages that have developed in recent weeks as the influenza system has worsened in most states of the U.S.
*
FDA said yesterday it is requiring safety labeling changes for prescription cough and cold medicines containing codeine or hydrocodone to limit the use of these products to adults 18 years and older because the risks of these medicines outweigh their benefits in children younger than 18. FDA is also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the boxed warning of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone. Some codeine cough medicines are available OTC in a few states, and FDA is also considering regulatory action for these products.
*
FDA has issued a warning letter to Becton Dickinson (BD) & Company that cited several violations of federal law, including marketing significantly modified versions of certain BD Vacutainer blood collection tubes without required FDA clearance or approval and failing to submit medical device reports to the FDA within the required timeframe.
*
PNN will not be published on Mon., Jan. 15, M. L. King Day.

PNN Pharmacotherapy Line
Jan. 16, 2018 * Vol. 25, No. 10
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 13 issue of Lancet (2018; 391).
Antifibrinolytic Delay in Acute Severe Hemorrhage: When treating patients with acute severe trauma or postpartum hemorrhage, tranexamic acid must be administered immediately to achieve its full benefit, researchers report, as “death from bleeding occurs soon after onset” (pp. 125–32). Individual patient-level data meta-analysis of randomized trials of more than 1,000 patients produced these findings: “We obtained data for 40,138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3,558 deaths, of which 1,408 (40%) were from bleeding. Most (884 [63%] of 1,408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2–3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1.20, 95% CI 1.08–1.33; p = 0.001), with no heterogeneity by site of bleeding (interaction p = 0.7243). Treatment delay reduced the treatment benefit (p <0.0001). Immediate treatment improved survival by more than 70% (OR 1.72, 95% CI 1.42–2.10; p <0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p = 0.5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events.” (I. Roberts, ian.roberts@lshtm.ac.uk)
Enteral v. Parenteral Early Nutrition in Shock With Ventilation: In the NUTRIREA-2 trial at 44 French intensive-care units, “early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition,” investigators conclude (pp. 133–43). The study, stopped early, produced these findings: “By day 28, 443 (37%) of 1,202 patients in the enteral group and 422 (35%) of 1,208 patients in the parenteral group had died (absolute difference estimate 2.0%; [95% CI −1.9 to 5.8]; p = 0.33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0.89 [95% CI 0.72–1.09]; p = 0.25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1.89 [1.62–2.20]; p <0.0001), diarrhoea (432 [36%] vs 393 [33%]; 1.20 [1.05–1.37]; p = 0.009), bowel ischaemia (19 [2%] vs five [<1%]; 3.84 [1.43–10.3]; p = 0.007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3.7 [1.03–13.2; p = 0.04).” (J. Reignier, jean.reignier@chu-nantes.fr)
>>>PNN NewsWatch
* FDA on Friday expanded the approved use of olaparib tablets (Lynparza, AstraZeneca) to include treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Olaparib becomes the first PARP inhibitor approved to treat metastatic breast cancer, and this is the first time any drug has been approved to treat certain patients with metastatic breast cancer who have a BRCA gene mutation. Patients are selected for treatment with olaparib based on an FDA-approved genetic test, the BRACAnalysis CDx (Myriad Genetic Laboratories).
*
Becton-Dickinson (BD) has informed FDA that it is no longer using the rubber stopper material associated with loss of drug potency in its general use syringes. BD has instead returned to a rubber stopper it used previously in the syringes, resolving a problem that applied to compounded or repackaged drugs first uncovered in 2015.
>>>PNN JournalWatch
* Use of Immune Checkpoint Inhibitors in the Treatment of Patients With Cancer and Preexisting Autoimmune Disease: A Systematic Review, in Annals of Internal Medicine, 2018; 168: 121–30. (M. E. Suarez-Almazor, msalmazor@mdanderson.org)
*
Approach to the Investigation and Management of Patients With Candida auris, an Emerging Multidrug-Resistant Yeast, in Clinical Infectious Diseases, 2018; 66: 306–11. (S. Tsay, stsay@cdc.gov)

PNN Pharmacotherapy Line
Jan. 17, 2018 * Vol. 25, No. 11
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 16 issue of JAMA, a theme issue on obesity (2018; 319).
Bariatric Surgery in Obesity Management: Research studies examine the role of bariatric surgery and more conservative options in patients with obesity.
Compared with lifestyle and medical management, Roux-en-Y gastric bypass produced significantly improved measures of glucose, LDL cholesterol, and systolic blood pressure over a 5-year period, researchers report, but the differences waned over time (
pp. 266–78). At four U.S. and Taiwanese sites, 120 patients with obesity had these outcomes based on a composite measure of triple end point of hemoglobin A1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg at 5 years: “At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (difference, 19%; 95% CI, 4%–34%; P = .01). In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle–medical management group achieved an HbA1c level of less than 7.0% (difference, 41%; 95% CI, 19%–63%; P = .002). Gastric bypass had more serious adverse events than did the lifestyle–medical management intervention, 66 events vs 38 events, most frequently gastrointestinal events and surgical complications such as strictures, small bowel obstructions, and leaks. Gastric bypass had more parathyroid hormone elevation but no difference in B12 deficiency.” (C. Billington, billi005@umn.edu)
In a study from Israel of patients with obesity, investigators found that “bariatric surgery using laparoscopic banding, gastric bypass, or laparoscopic sleeve gastrectomy, compared with usual care nonsurgical obesity management, was associated with lower all-cause mortality over a median follow-up of approximately 4.5 years” (
pp. 279–90). “The evidence of this association adds to the limited literature describing beneficial outcomes of these 3 types of bariatric surgery compared with usual care obesity management alone.” (O. Reges, rnare@clalit.org.il">ornare@clalit.org.il)
A third study, which included 1,888 patients with severe obesity, also found benefits of bariatric surgery over a median of 6.5 years of follow-up (
pp. 291–301). Compared with specialized medical treatment at a tertiary care outpatient center in Norway, surgery showed these advantages: “Surgically treated patients had a greater likelihood of remission and lesser likelihood for new onset of hypertension (remission: absolute risk [AR], 31.9% vs 12.4%); risk difference [RD], 19.5% [95% CI, 15.8%–23.2%], relative risk [RR], 2.1 [95% CI, 2.0–2.2]; new onset: AR, 3.5% vs 12.2%, RD, 8.7% [95% CI, 6.7%–10.7%], RR, 0.4 [95% CI, 0.3–0.5]; greater likelihood of diabetes remission: AR, 57.5% vs 14.8%; RD, 42.7% [95% CI, 35.8%–49.7%], RR, 3.9 [95% CI, 2.8–5.4]; greater risk of new-onset depression: AR, 8.9% vs 6.5%; RD, 2.4% [95% CI, 1.3%–3.5%], RR, 1.5 [95% CI, 1.4–1.7]; and treatment with opioids: AR, 19.4% vs 15.8%, RD, 3.6% [95% CI, 2.3%–4.9%], RR, 1.3 [95% CI, 1.2–1.4]). Surgical patients had a greater risk for undergoing at least 1 additional gastrointestinal surgical procedure (AR, 31.3% vs 15.5%; RD, 15.8% [95% CI, 13.1%–18.5%]; RR, 2.0 [95% CI, 1.7–2.4]). The proportion of patients with low ferritin levels was significantly greater in the surgical group (26% vs 12%, P < .001).” (J. Hjelmesæth, joran.hjelmeseth@siv.no)
“The approach to the prevention and treatment of obesity needs to be reimagined,” a
JAMA editor writes in response to this and other material in this theme issue (pp. 238–40). “The relentless increase in the rate of obesity suggests that the strategies used to date for prevention are simply not working. The physical, emotional, and financial cost to society related to obesity is staggering. New approaches are needed, and these must include a realistic assessment of why the population has become obese and what needs to be done to reverse that trend. Hopefully, the next time JAMA publishes a theme issue on obesity, reports will document interventions that have succeeded in reducing the level of obesity in the population.” (E. H. Livingston, edward.livingston@jamanetwork.org)
>>>PNN NewsWatch
* Resolving the shortage of I.V. saline bags “remains one of my highest priorities,” FDA Commissioner Scott Gottlieb, MD, said in a statement released yesterday.

PNN Pharmacotherapy Line
Jan. 18, 2018 * Vol. 25, No. 12
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 18 issue of the New England Journal of Medicine (2018; 378).
Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: In an open-label, phase 3 trial of patients with stage III epithelial ovarian cancer, addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery extended recurrence-free survival and overall survival, compared with surgery alone, without increasing adverse effects (pp. 230–40). The trial included 245 patients who had at least stable disease after three cycles of carboplatin and paclitaxel. Outcomes were as follows: “In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P = 0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P = 0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P = 0.76).” (W. J. van Driel, w.v.driel@nki.nl)
Editorialists conclude that “this randomized trial is a very important first step but should not drive changes in practice yet” (
pp. 293–4): “Primary cytoreductive surgery for certain patients with ovarian cancer remains the preferred approach over neoadjuvant treatment, and administration of HIPEC at the time of interval cytoreductive surgery does not change that. New confirmatory clinical investigations of HIPEC are needed to clarify some of the unanswered questions before HIPEC can become a common treatment strategy. These considerations will be important for clinical trial investigators as they focus on the positive effect of HIPEC as an intervention as compared with the effects of promising new agent combinations or immunotherapy treatments.” (D. R. Spriggs)
Managing Toxic Alcohol Poisonings: “Despite much progress in our understanding of the pathogenesis of reactions to … toxic alcohols and despite the development of effective treatments, much remains to be done to eliminate the severe clinical disturbances that result from exposure to these substances,” authors of a review article conclude (pp. 270–80). “Methanol, ethylene glycol, and diethylene glycol poisoning can cause severe cellular dysfunction and high mortality if not recognized and treated quickly. Isopropanol frequently causes medical complications but has a lower risk of death. A high anion-gap metabolic acidosis, an increased serum osmolal gap, or both can suggest that one of the toxic alcohols is present in the blood, but these abnormal laboratory results are not always present. One of the poisonings should be strongly suspected in persons with the clinical findings described previously, in all obtunded patients, or in those with an unexplained high osmolal gap, high anion-gap metabolic acidosis, or both. Definitive tests such as high-pressure liquid chromatography are not always available, even in developed countries but especially in undeveloped countries. Therefore, there is an unmet need for tests that are accurate and can be completed rapidly.”(J. A. Kraut, jkraut@ucla.edu)
>>>PNN NewsWatch
* FDA recalls: Levofloxacin in 5% Dextrose Injection 250 mg/50 mL in a single-use flexible container (AuroMedics Pharma LLC), lot CLF160003, exp. May 2018, to the hospital level, because of visible particulate matter tentatively identified as mold; Nexterone (amiodarone HCl) 150 mg/100 mL Premixed Injection (Baxter), lot NC109123, because of potential presence of particulate matter.
* Infusions of
rolapitant (Varubi, Tesaro) injectable emulsion have been associated with anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions, some requiring hospitalization. Reactions have occurred during or soon after infusion, most within the first few minutes of administration.

PNN Pharmacotherapy Line
Jan. 19, 2018 * Vol. 25, No. 13
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Feb. 1 issue of Clinical Infectious Diseases (2018; 66).
Penicillin Allergy & Surgical Site Infection Risk: Use of second-line perioperative antibiotics in patients who report penicillin allergies is linked to a 50% increase in surgical site infections (SSIs) in a study from Mass. Genl. Hosp. (pp. 329–36). Retrospective cohort analysis of those undergoing hip arthroplasty, knee arthroplasty, hysterectomy, colon surgery, or coronary artery bypass grafting in 2010–14 showed the following: “Of 8,385 patients who underwent 9,004 procedures, 922 (11%) reported a penicillin allergy, and 241 (2.7%) had an SSI. In multivariable logistic regression, patients reporting a penicillin allergy had increased odds (adjusted odds ratio, 1.51; 95% confidence interval, 1.02–2.22) of SSI. Penicillin allergy reporters were administered less cefazolin (12% vs 92%; P < .001) and more clindamycin (49% vs 3%; P < .001), vancomycin (35% vs 3%; P < .001), and gentamicin (24% vs 3%; P < .001) compared with those without a reported penicillin allergy. The increased SSI risk was entirely mediated by the patients’ receipt of an alternative perioperative antibiotic; between 112 and 124 patients with reported penicillin allergy would need allergy evaluation to prevent 1 SSI.” (K. G. Blumenthal, kblumenthal1@partners.org)
Long-Term Effectiveness of Quadrivalent HPV Vaccine: Women from Denmark, Iceland, Norway, and Sweden who received a three-dose regimen of quadrivalent human papillomavirus (qHPV) vaccine were protected through at least 10 years, a study shows, “with a trend for continued protection through 12 years of follow-up” (pp. 339–45). The combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18 was as follows in the FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease) study: “In the per-protocol population (2,084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9,437 person–years of follow-up. Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years. The number of person–years during the follow-up interval of 10–12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period.” (A. J. Saah, alfred_saah@merck.com)
>>>Oncology Highlights
Source:
Jan. 20 issue of the Journal of Clinical Oncology (2018; 36).
HPV Vaccination & Oral HPV Infections Among Young Adults: Vaccination against human papillomavirus (HPV) decreases oral infections of vaccine-type viruses among young Americans, a study shows, but low uptake of the vaccine is limiting its population-level effects (pp. 262–7). Using a cross-sectional study of men and women 18 to 33 years of age (N = 2,627) within the nationally representative National Health and Nutrition Examination Survey for 2011 to 2014, the investigators report: “Between 2011 and 2014, 18.3% of the US population 18 to 33 years of age reported receipt of at least one dose of the HPV vaccine before the age of 26 years (29.2% in women and 6.9% in men; P < .001). The prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated individuals (0.11% v 1.61%; Padj = .008), corresponding to an estimated 88.2% (95% CI, 5.7% to 98.5%) reduction in prevalence after model adjustment for age, sex, and race. Notably, the prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated men (0.0% v 2.13%; Padj = .007). Accounting for vaccine uptake, the population-level effect of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women, and 6.9% in men.” (A. K. Chaturvedi)
>>>PNN NewsWatch
* A draft guidance published yesterday by FDA outlines circumstances when a company should issue a public warning about a recall, describes the general timeline for companies to issue such a warning, discusses what information should be included in a public warning, and describes situations where the agency may take action to issue its own public warning should a company’s warning be deemed insufficient. This “is just the first in a series of policy steps we’ll take this year,” Commissioner Scott Gottlieb said in a related statement.

PNN Pharmacotherapy Line
Jan. 22, 2018 * Vol. 25, No. 14
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 20 issue of Lancet (2018; 391).
Rivaroxaban Therapy in Arterial Disorders: Two studies examine use of rivaroxaban with or without aspirin in patients with coronary, peripheral, or carotid artery disease.
In patients with stable coronary artery disease, addition of rivaroxaban to aspirin therapy had overall positive effects, with reduced morbidity and mortality despite an increase in major bleeding (
pp. 205–18). In the COMPASS trial, patients had these results based on a primary outcome of myocardial infarction, stroke, or cardiovascular death: “The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8,313 vs 460 [6%] of 8,261; hazard ratio [HR] 0.74, 95% CI 0.65–0.86, p <0.0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8,250 vs 460 [6%] of 8,261; HR 0.89, 95% CI 0.78–1.02, p = 0.094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8,313 vs 158 [2%] of 8,261; HR 1.66, 95% CI 1.37–2.03, p <0.0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8,250 vs 158 [2%] of 8,261; HR 1.51, 95% CI 1.23–1.84, p <0.0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8,313 vs 339 [4%] of 8,261; HR 0.77, 95% CI 0.65–0.90, p = 0.0012). (S. J Connolly, connostu@phri.ca)
Twice-daily, low-dose rivaroxaban combined with aspirin could be “an important advance in the management of patients with peripheral artery disease,” researchers conclude based on findings in 33 countries on six continents (
pp. 219–29). Results in patients with a history of peripheral artery disease of the lower extremities, of the carotid arteries, or coronary artery disease, showed the following: “The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2,492 vs 174 [7%] of 2,504; hazard ratio [HR] 0.72, 95% CI 0.57–0.90, p = 0.0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0.54 95% CI 0.35–0.82, p = 0.0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2,474 vs 174 [7%] of 2,504; HR 0.86, 95% CI 0.69–1.08, p = 0.19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0.67, 95% CI 0.45–1.00, p = 0.05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2,492 vs 48 [2%] of 2,504; HR 1.61, 95% CI 1.12–2.31, p = 0.0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2,474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2,504 in the aspirin alone group (HR 1.68, 95% CI 1.17–2.40; p = 0.0043).” (S. S Anand, anands@mcmaster.ca)
>>>PNN NewsWatch
* The shutdown of the federal government didn’t prevent FDA from posting these recall notices on Sunday for two products that are possibly contaminated with Salmonella: Arthri-D’s dietary supplement Arthri-D 120 count, lot 1701-092, and Break Ventures/California Basics’ dietary supplement Zero for Him 150 count, lot 1710-638.
>>>PNN JournalWatch
* Postsurgical Prescriptions for Opioid Naive Patients and Association With Overdose and Misuse: Retrospective Cohort Study, in BMJ, 2018; 360: j5790. (G. A. Brat, gbrat@bidmc.harvard.edu)
*
The Antiretroviral Agent Nelfinavir Mesylate: A Potential Therapy for Systemic Sclerosis, in Arthritis & Rheumatology, 2018; 70: 115–26. (J. A. Lasky, jlasky@tulane.edu)
*
Intrinsic and Extrinsic Causes of Malignancies in Patients With Primary Immunodeficiency Disorders, in Journal of Allergy and Clinical Immunology, 2018; 141: 59–68.e4. (M. G. Seidel, markus.seidel@medunigraz.at)
*
Dabigatran Reversal in a Patient With End-Stage Liver Disease and Acute Kidney Injury, in American Journal of Kidney Diseases, 2018; 71: 137–41. (J. E. Novak, jnovak2@hfhs.org)

PNN Pharmacotherapy Line
Jan. 23, 2018 * Vol. 25, No. 15
Providing news and information about medications and their proper use

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>>>Health Affairs Highlights
Source:
Jan. issue of Health Affairs (2018; 37).
Med Sync & Adherence: For patients with cardiovascular disease, pharmacy programs that synchronize medication refills increase adherence, a study shows, especially among those with low initial adherence (pp. 125–33). In 2011–14, Medicare beneficiaries with two or more chronic conditions — one of which was hypertension, hyperlipidemia, or diabetes — had these outcomes when receiving medication synchronization services: “Among nearly 23,000 patients matched by propensity score, the mean proportion of days covered (a measure of medication adherence) for the control group of patients without a synchronization program was 0.84 compared to 0.87 for synchronized patients—a gain of 3 percentage points. Adherence improvement in synchronized versus control patients was three times greater in patients with low baseline adherence, compared to those with higher baseline adherence. Rates of hospitalization and emergency department visits and rates of outpatient visits were 9 percent and 3 percent lower in the synchronized group compared to the control group, respectively, while cardiovascular event rates were similar.” (A. A. Krumme, akrumme@bwh.harvard.edu)
Rx Opioid Use & Parental Neglect: When considering the impact of the opioid epidemic, policymakers should factor “the ability of opioid-dependent parents to care for their children,” according to authors who looked at the association between rates of removal of children from homes and the opioid prescription rate in Florida in 2012–15 (pp. 134–9): “We performed a panel data analysis of opioid prescriptions that also controlled for the prescription rates of benzodiazepines and stimulants and for other risk factors for child removal. We found that a one-standard-deviation increase in the opioid prescription rate was associated with a 32 percent increase in the removal rate for parental neglect. When we obtained subset samples by percentage of white residents, the estimated relationships were approximately twice as large in the counties with the highest concentration of whites than in the counties with the lowest. Policy makers should consider the opioid epidemic’s effects on child welfare when determining the appropriate public health response.” (T. Quast, troyquast@health.usf.edu)
>>>Medical Care Report
Source:
Feb. issue of Medical Care (2018; 56).
Trends in Overactive Bladder Treatments: Over a 15-year period, dispensing patterns for medications for overactive bladder (OAB) changed as $4 generic programs and new medications became available (pp. 162–70). Data from the Truven Health Analytics’ Medicare Supplemental Database for 2000–15 showed the following for 9.5 million Medigap beneficiaries: “From 2000 to 2015, 771,609 individuals filled 13,863,998 OAB-related prescriptions. During 2000–2007, 3 new extended-release medications became available (tolterodine, darifenacin, solifenacin), leading to increases in overall OAB-related dispensing rates by 19.1 (99% confidence interval, 17.0–21.2), a 92% increase since 2000; overall rates remained stable during 2008–2015. By 2015, the most common medications were oxybutynin (38%), solifenacin (20%), tolterodine (19%), and mirabegron (12%). Dispensing rates peaked at age 90 (rate, 53.4; 99% confidence interval, 53.1–53.7). Women had higher rates than men at all ages (average ratewomen− ratemen, 22.0). The gap between upper and lower percentiles of medication payments widened between 2008–2015; by 2015, 25% of reimbursed dispensed prescriptions had total payments exceeding $250.” (A. C. Kinlaw, akinlaw@unc.edu)
Med Alerts for Opioid–Benzodiazepine Coprescribing: Among high-risk veteran patients, electronic medical record alerts “hold promise as a means of reducing opioid and benzodiazepine coprescribing,” researchers report (pp. 171–8). Over 12 months, alerts lowered rates of coprescribing among patients with substance use, sleep apnea, and suicide risk. (C. A. Malte, carol.malte@va.gov)
>>>PNN NewsWatch
* Magno-Humphries Laboratories is voluntarily recalling lot 352300 (exp. 01/19) of Basic Drugs Brand of Senna Laxative tablets, 8.6 mg Sennosides to the consumer level following discovery of one bottle that contained Basic Drugs Brand of naproxen sodium 220 mg.

PNN Pharmacotherapy Line
Jan. 24, 2018 * Vol. 25, No. 16
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Jan. 23/30 issue of JAMA (2018; 319).
Oral Treatment of Toenail Fungal Infection: Terbinafine and azole-based drugs are associated with higher clinical and mycological cure rates compared with placebo, according to authors of a JAMA Clinical Evidence Synopsis (pp. 397–8). “Terbinafine was associated with higher clinical cure rates vs placebo (370 vs 62 per 1,000 patients, respectively) and mycological cure rates (755 vs 167) (both P < .001),” the authors write of the 48 trials included in the analysis. “Similarly, treatment with azoles was associated with higher clinical cure rates vs placebo (309 vs 14 per 1,000 patients) and mycological cure rates (431 vs 74) (both P < .001).
“Azoles were associated with lower clinical cure rates vs terbinafine (471 vs 575 per 1,000 patients; P = .006) and mycological cure rates (525 vs 682; P < .001). Griseofulvin (a nonazole antifungal) was associated with (1) clinical and mycological cure rates that were not different than azoles and (2) lower cure rates compared with terbinafine. Terbinafine was associated with a lower recurrence rate vs placebo (33 vs 667 per 1,000 patients; P = .004) as were azoles (550 vs 1,000; P = .08). Recurrence rates were not different for azoles vs terbinafine.” (M. L. van Driel,
m.vandriel@uq.edu.au)
Applying Lessons From the Opioid Epidemic to Tobacco Control: “Perhaps public concern over the opioid epidemic can provide an opportunity to renew a sense of urgency around tobacco control,” Viewpoint authors conclude (pp. 339–40). “Indeed, the epidemics are not completely distinct. The communities most deeply affected by the opioid crisis also have some of the highest smoking rates, and individuals who use tobacco are also more likely to develop prescription opioid misuse. These overlapping epidemics suggest that common conditions may contribute to both and that common solutions may be useful. This moment, with attention focused intently on the opioid epidemic, may also provide the chance to address addiction to nicotine and thereby substantially reduce the harms caused by these 2 threats to health.” (I. Richman, ilana.richman@yale.edu)
Rise and Fall of Mandatory Cardiac Bundled Payments: Abandonment of a mandatory cardiac bundled payment plan by CMS in late 2017 is “a step in the wrong direction for several reasons,” writes a Viewpoint author (pp. 335–6). “Spending on high-cost health care continues to increase—high and rising health care costs cannot be ignored indefinitely. Absent a mandate, hospitals, clinicians, and postacute care facilities have little motivation to collaborate around innovative care redesign to improve coordination and efficiency. A voluntary program, at least a program in which fewer than 10% of hospitals participate and half of those end participation early, will neither invite meaningful changes in care delivery nor provide usable information about what works and what does not. Without testing a bundled payment model across a diverse, representative group of acute care hospitals, it will never be possible to gain actionable insights to inform iterative improvements in the design and implementation of novel payment models.” (K. E. Joynt Maddox, kjoyntmaddox@wustl.edu)
Three Decades of Peer Review Congresses: Reflecting on eight Peer Review Congresses conducted every 4 years since 1989, organizers recount the progress made over 30 years through research into peer review and the scope and diversity of Congress participants (pp. 350–3): “Despite the continued criticism of peer review, even if it were proved to cause harm, few would vote for its abolition, and most would advocate for its improvement, so more research is needed. That is what the congresses have shown. The eighth congress was once again full of discussion and argument, but, as one observer noted, it was remarkably good-humored. Plans for the Ninth International Congress on Peer Review and Scientific Publication are counting on the continued existence, use, and need for assessment of peer review and publication in all their evolving forms.” (A. Flanagin, annette.flanagin@jamanetwork.org)
>>>PNN NewsWatch
* Baxter International has expanded an earlier recall of Nexterone (amiodarone HCl) 150 mg/100 mL Premixed Injection to include lot NC109925, distributed between Aug. 23 and Oct. 2 of last year, because of potential particulate matter.

PNN Pharmacotherapy Line
Jan. 25, 2018 * Vol. 25, No. 17
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Jan. 25 New England Journal of Medicine (2018; 378).
Solanezumab in Mild Alzheimer Disease: Yet another drug designed to clear amyloid-beta plaques and neurofibrillary tangles in patients with Alzheimer disease has failed in a phasae 3 trial (pp. 321–30). The humanized monoclonal antibody solanezumab 400 mg every 4 weeks produced these results in a placebo-controlled, double-blind study of 2,129 patients: “The mean change from baseline in the [cognitive subscale of the Alzheimer’s Disease Assessment Scale] score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the [Mini–Mental State Examination] score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.” (L. S. Honig, lh456@cumc.columbia.edu)
“Although it may not quite be time to give up on [amyloid-beta] immunotherapy for treating Alzheimer’s disease, it would be foolish to ignore the continued failures of antiamyloid approaches,” an editorialist writes (
pp. 391–2). “In spite of the mountain of evidence supporting the primacy of [amyloid-beta] in Alzheimer’s disease, many researchers are coming to the realization that our preclinical models of the disease may be missing the mark. Even if there is some future success in a primary prevention trial, there is still little headway being made in improving the treatment of Alzheimer’s disease. There is some hope that a combination of therapeutic approaches might help, since there is evidence that the different pathologic aspects of Alzheimer’s disease are interactive. Whether a multifaceted strategy or something entirely unforeseen is the answer, the field is clearly in need of innovative ideas. We may very well be nearing the end of the amyloid-hypothesis rope, at which point one or two more failures will cause us to loosen our grip and let go.” (M. P. Murphy)
Influenza & AMI: Confirming past studies that used nonspecific measures, a self-controlled case-series analysis shows a significant association between respiratory infections — influenza in particular — and acute myocardial infarction (pp. 345–53). With “risk interval” defined as the first 7 days after respiratory specimen collection and the “control interval” as 1 year before and 1 year after the risk interval, investigators found these connections in administrative claims data: “We identified 364 hospitalizations for acute myocardial infarction that occurred within 1 year before and 1 year after a positive test result for influenza. Of these, 20 (20.0 admissions per week) occurred during the risk interval and 344 (3.3 admissions per week) occurred during the control interval. The incidence ratio of an admission for acute myocardial infarction during the risk interval as compared with the control interval was 6.05 (95% confidence interval [CI], 3.86 to 9.50). No increased incidence was observed after day 7. Incidence ratios for acute myocardial infarction within 7 days after detection of influenza B, influenza A, respiratory syncytial virus, and other viruses were 10.11 (95% CI, 4.37 to 23.38), 5.17 (95% CI, 3.02 to 8.84), 3.51 (95% CI, 1.11 to 11.12), and 2.77 (95% CI, 1.23 to 6.24), respectively.” (J. C. Kwong, jeff.kwong@utoronto.ca)
>>>PNN NewsWatch
* FDA and the Federal Trade Commission yesterday posted joint warning letters to the marketers and distributors of 12 opioid cessation products for illegally marketing unapproved products with claims about their ability to help in the treatment of opioid addiction and withdrawal. FDA said that it “is taking new steps to make safe and effective medication-assisted treatments available to those who suffer from opioid use disorder and to reduce the stigma that is sometimes associated with use of these therapies. Using products with unsubstantiated claims may prevent those addicted to opioids from seeking approved treatments that have been demonstrated to be safe and effective, delay their path to recovery, and put them at greater risk of death.”

PNN Pharmacotherapy Line
Jan. 26, 2018 * Vol. 25, No. 18
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
Jan. issue of the Journal of the American Geriatrics Society (2018; 66).
Opiate Prescribing in Older Adults: Long-term opioid prescribing is common for older adults in nursing homes and difficult to reduce, a cross-sectional analysis shows (pp. 48–55). Minimum Data Set 3.0 assessments at 13,522 U.S. nursing homes in the second quarter of 2012 and the following 120 days show these outcomes those receiving opioids and nonpharmacologic interventions that could reduce opioid use: “Of all long-stay residents, 32.4% were prescribed any opioid, and 15.5% were prescribed opioids long-term. Opioid users (versus nonusers) were more commonly prescribed pain adjuvants (32.9% vs 14.9%), other pain medications (25.5% vs 11.0%), and nonpharmacological pain management (24.5% vs 9.3%). Long-term opioid use was higher in women (aPR = 1.21, 95% CI = 1.18–1.23) and lower in racial and ethnic minorities (non-Hispanic blacks vs whites: APR = 0.93, 95% CI = 0.90–0.94) and those with severe cognitive impairment (vs no or mild impairment, aPR = 0.82, 95% CI = 0.79–0.83).” (J. N. Hunnicutt, jacob.hunnicutt@umassmed.edu)
“Opiate use is widespread during hospitalization and is associated with significant negative clinical outcomes and quality metrics,” conclude authors of a second study (
pp. 70–5). The retrospective cohort analysis was conducted at a tertiary acute care facility, where 9,245 older adults were treated as follows: “There was no difference in sex, race, ethnicity, or Charlson Comorbidity Index between opiate exposure groups. Participants who had never received opiates had a significantly shorter mean [length of stay (LOS)] than prior and new opiate users (5.2, 6.8, 7.7 days; P <.001) and were more likely to be discharged home (88.6%, 82.8%, 82.5%; P <.001) and significantly less likely to be readmitted within 30 days (19.6%, 25.0%, 22.3%; P <.001). Participants who had never been exposed to opiates had a significantly shorter mean LOS than those receiving short- and long-acting opiates (5.2, 7.3, 8.6 days; P < .001) and were more likely to be discharged home (88.6%, 82.6%, 82.4%; P < .001) and significantly less likely to be readmitted within 30 days (19.6%, 27.7%, 28.9%; P <.001).” (V. Patel, vpatel18@northwell.edu)
Prescription Shopping in America: “CMS [Medicare] Part D regulations are gaining clinical teeth, with [medication therapy management] requirements for certain beneficiaries with high drug expenditures and by incorporating quality measures for pharmacies geared at improving medication safety, adherence, and appropriateness,” conclude authors who assess “prescription shopping” and medication options among older adults in the U.S. (pp. 33–40). “However, much more can be done to lower medication costs and at the same time promote local relationships that maximize the benefits and reduce the risks of medications.” (G. Upchurch, gina@seniorpharmassist.org)
Commenting on this and a second article by two of the same authors (
pp. 25–32; G. Upchurch, gina@seniorpharmassist.org), an editorialist notes that both reports “draw on knowledge and understanding gained by Senior PharmAssist from decades of counseling older adults who seek assistance with medication management and access” (p. 18). “These primers are an excellent starting point for enriching our understanding of these programs and helping us advocate for the older adults we serve.” (D. Saliba)
>>>PNN NewsWatch
* Recommendations of the CDC Advisory Committee on Immunization Practices on use of the recently approved shingles vaccine are summarized in this week’s MMWR. Recombinant zoster vaccine (RZV), adjuvanted (Shingrix, GlaxoSmithKline) is recommended for use in immunocompetent adults aged 50 years or older, including those who previously received the older product, zoster vaccine live (ZVL). ACIP recommended use of RZV over ZVL. Because of a lack of data, ACIP has made no recommendations for use of RZV in immunocompromised patients. The RZV product, which requires reconstitution before administration, differs from ZVL in two practical ways: It is stored under refrigeration rather than in the freezer, and it is administered intramuscularly rather than subcutaneously. RZV can be given concomitantly (at different sites) with other adult vaccines, including most influenza vaccines, but data are not available for coadministration with the adjuvanted influenza vaccine Fluad.

PNN Pharmacotherapy Line
Jan. 29, 2018 * Vol. 25, No. 19
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Jan. 27 issue of Lancet (2018; 391).
Meds for Opioid Relapse Prevention: A 24-week trial provides insights into clinical use of the extended-release opioid antagonist naltrexone (XR-NTX) and sublingual doses of the partial opioid agonist buprenorphine–naloxone (BUP-NX) (pp. 309–18). At 8 U.S. community-based inpatient units and during outpatient follow-up, investigators found XR-NTX more difficult to use for induction but the two approaches similar once initatied. “Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications,” the group concludes after reporting these open-label results: “Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n = 283) or BUP-NX (n = 287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p <0.0001). Among all participants who were randomly assigned (intention-to-treat population, n = 570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1.36, 95% CI 1.10–1.68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n = 474), 24 week relapse events were similar across study groups (p = 0.44). Opioid-negative urine samples (p <0.0001) and opioid-abstinent days (p <0.0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p = 0.0012), then converged by week 24 (p = 0.20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).” (J. D. Lee, joshua.lee@nyumc.org)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
“No Safe Level of Smoking”: Smoking just one cigarette per day significantly increases a person’s risk of stroke and coronary heart disease [CHD], a study shows, with risks going up to about one-half of those associated with smoking 20 cigarettes per day (j5855). “Men who smoked one cigarette per day had 46% of the excess relative risk [of CHD] for smoking 20 cigarettes per day (53% using relative risks adjusted for multiple factors), and women had 31% of the excess risk (38% using relative risks adjusted for multiple factors),” the authors report. “The excess risk for stroke associated with one cigarette per day (in relation to 20 cigarettes per day) was 41% for men and 34% for women (or 64% and 36% using relative risks adjusted for multiple factors).” (A. Hackshaw, a.hackshaw@ucl.ac.uk)
>>>PNN NewsWatch
* FDA on Friday approved lutetium Lu 177 dotatate (Lutathera, Advanced Accelerator Applications) for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. This is the first time a radiopharmaceutical has been approved for the treatment of GEP-NETs. The product received orphan drug designation from the FDA, is a first-in-class drug, and is the first available FDA-approved peptide receptor radionuclide therapy, a form of targeted treatment comprising a targeting molecule that carries a radioactive component.
>>>PNN JournalWatch
* Medications That Cause Dry Mouth As an Adverse Effect in Older People: A Systematic Review and Metaanalysis, in Journal of the American Geriatrics Society, 2018; 66: 76–84. (E Tan, edwin.tan@monash.edu)
*
The Age-Friendly Health System Imperative, in Journal of the American Geriatrics Society, 2018; 66: 22–4. (T. Fulmer, terry.fulmer@johnahartford.org)
*
Mortality Reduction in EMPA-REG OUTCOME Trial: Beyond the Antidiabetes Effect, in Diabetes Care, 2018; 41: 219–23. (S. Suissa, samy.suissa@mcgill.ca)
*
Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis, in Diabetes Care, 2018; 41: 372–82. (G. Targher, giovanni.targher@univr.it)

PNN Pharmacotherapy Line
Jan. 30, 2018 * Vol. 25, No. 20
Providing news and information about medications and their proper use

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>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (2018; 41).
Incretin-Based Therapies & Pancreatic Cancer: An increased short-term risk of pancreatic cancer associated with the start of incretin-based therapies could be the result of “an occult pancreatic cancer that provokes or aggravates diabetes,” investigators conclude based on data from Belgium and the Lombardy region of Italy (pp. 286–92). During 5- or 6-year time periods, the risk of pancreatic cancer among those started on incretin drugs or another noninsulin antidiabetic drug (NIAD) were as follows: “The cohorts included 525,733 patients with diabetes treated with NIADs and 33,292 with incretin drugs. Results in both cohorts were similar. Eighty-five and 1,589 subjects who developed pancreatic cancer were registered among the incretin and NIAD new users, respectively, which represented an aHR of pancreatic cancer of 2.14 (95% CI 1.71–2.67) among those prescribed an incretin compared with an NIAD. The aHR with a drug use lag exposure of 6 months was 1.69 (1.24–2.32). The aHR decreased from 3.35 (2.32–4.84) in the first 3 months after the first incretin prescription to 2.12 (1.22–3.66) in months 3–5.9, 1.95 (1.20–3.16) in months 6–11.9, and 1.69 (1.12–2.55) after 12 months. Among those prescribed an NIAD, pancreatic cancer occurred mostly within the year after the first prescription. The risk of pancreatic cancer among patients subsequently prescribed insulin was 6.89 (6.05–7.85).” (P. Autier, philippe.autier@i-pri.org)
TCF7L2 Variants & Phenotypic Heterogeneity of Type 1 Diabetes: “While many of the type 2 diabetes loci uncovered to date have a clear and unequivocal primary role in the islet beta-cell, this is less clear for the TCF7L2 locus,” authors write (pp. 224–6) in response to a research study showing “a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis” in carriers of this type 2–linked variant (pp. 311–7; M. J. Redondo, redondo@bcm.edu). “Applying a genetic risk score approach with the remaining established type 2 diabetes loci is warranted to investigate whether the effect Redondo et al. have identified can be extended to other key loci. Such an effect could be important as we seek to define type 1 diabetes, which at one end of a spectrum is associated with a potent immunogenetic mix that leads to severe diabetic ketoacidosis and, at the other end, with modest immunogenetic features and limited metabolic damage not requiring insulin treatment.” (R. D. Leslie, r.d.g.leslie@qmul.ac.uk)
>>>Nephrology Report
Source:
Feb. American Journal of Kidney Diseases (2018; 71).
Phosphate-Binder Use in Dialysis: Considering the rapidly increasing costs of phosphate binders in U.S. patients on dialysis ($1.5 billion in 2015), CMS should consider funding a study of the clinical need for these agents using hard outcomes, authors of a review article conclude (pp. 246–53). If higher phosphate concentrations are associated with improved clinical outcomes, such a study could assess “whether particular phosphate binders are superior to placebo or other binders in improving these outcomes,” the authors add. (W. L. St. Peter, stpet002@umn.edu)
“Hyperphosphatemia is presumed to cause disease by promoting vascular calcification and altering key mineral metabolism hormones that contribute to cardiac hypertrophy and bone disease,” notes an associated article (
pp. 254–6). “One expected clinical benefit of lowering phosphate concentrations is a reduction in heart failure, which is among the most common causes of morbidity and hospitalization in dialysis patients and those with [chronic kidney disease]. Although the clinical entity of ‘heart failure’ for patients with kidney disease encompasses heterogeneous causes, including diastolic and systolic dysfunction, vessel stiffness, and impaired responses to volume overload, many of these pathways are suspected to be influenced by phosphate toxicity. Moreover, even a modest impact of phosphate-binder treatment on heart failure would be clinically relevant, given the burden of this disease in the dialysis population.” (B. Kestenbaum, brk@u.washington.edu)
>>>PNN NewsWatch
* All unexpired lots of the prescription medical food Limbrel are being recalled to the patient level at FDA’s request because of a link with elevated liver-function tests or acute hypersensitivity pneumonitis, Primus Pharmaceuticals announced.

PNN Pharmacotherapy Line
Jan. 31, 2018 * Vol. 25, No. 21
Providing news and information about medications and their proper use

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>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (2018; 38).
Philosophy of Practice for Comprehensive Medication Management: Among 30 lead pharmacists participating in a large comprehensive medication management (CMM) study, philosphies of practice varied significantly, a study shows (pp. 69–79). Responses to an instrument with open- and closed-ended items led investigators to propose five core tenets that should be embraced by pharmacists providing CMM: “Twelve codes emerged that participants used to describe their philosophy of practice. These codes were mapped to five predefined tenets of a philosophy of practice. Only 3 (10%) participants included all five tenets in their philosophy of practice, 8 (26.7%) included four, 8 (26.7%) included three, 6 (20%) included two, and 5 (16.7%) included one tenet. Overall, participants rated their alignment with the five tenets highly. ‘Embracing a patient-centered approach’ received the highest mean score of 9.17/10; ‘Meeting a societal need’ had the lowest mean score of 8.37/10.” The other tenets were assuming responsibility for optimizing medication use, caring through an ongoing patient–pharmacist relationship, and working as a collaborative member of the health care team. (D. L. Pestka, pestk003@umn.edu)
>>>AJHP Highlights
Source:
Feb. 1 issue of the American Journal of Health-System Pharmacy (2018; 75).
Managing G6PD Deficiency: In a review of the most common enzyme deficiency in people, authors conclude that glucose-6-phosphate dehydrogenase (G6PD) deficiency “should be considered in patients who experience acute hemolysis after exposure to known oxidative medications, infection, or ingestion of fava beans” (pp. 97–104): “A diagnosis of G6PD deficiency is most often made through enzymatic activity detection, but molecular analysis may be required in females heterozygous for the disorder. When clinically feasible, rasburicase, primaquine, dapsone, pegloticase, and methylene blue should not be used until a G6PD diagnostic test has been performed.” (K. D. Belfield, kristendbelfield@gmail.com)
Minimizing Opioid Use After Acute Major Trauma: At a tertiary medical center, a pain management strategy successfully lowered milligram morphine equivalents (MMEs) of opioids prescribed on discharge following acute major traumatic injuries, researchers report (pp. 105–10). Retrospective analysis of patients admitted with acute trauma before and after implementation of a targeted provider and patient education strategy showed these results: “Compared with the preintervention cohort, the postintervention cohort had a lower median daily discharge MME overall (45 MME versus 90 MME, p < 0.001); after stratification of MME data by baseline opioid use, this finding held true only for patients with no opioid prescription at admission. Although utilization of gabapentinoids, skeletal muscle relaxants, and clonidine increased during the postintervention period, inpatient opioid use did not differ significantly in the 2 cohorts. Utilization of both nonsteroidal antiinflammatory drugs and acetaminophen was lower in the postintervention cohort versus the preintervention cohort.” (D. Oyler, doug.oyler@uky.edu)
>>>PNN NewsWatch
* FDA is working with manufacturers of OTC loperamide to use blister packs or other single-dose packaging and to limit the number of doses in a package, the agency said yesterday. FDA said it continues to receive reports of serious heart problems and deaths with much higher than the recommended doses of loperamide, primarily among people who are intentionally misusing or abusing the product, despite the addition of a warning to the medicine label and a previous communication. Loperamide is a safe drug when used as directed, FDA added.
* Citing the agency’s action on OTC loperamide,
Commissioner of Food and Drugs Scott Gottlieb, MD, yesterday said, “Appropriate prescribing practices, better packaging, and education are important steps within our statutory authority to help address the human and financial toll of opioid addiction. They can reduce harm while still providing effective pain management protocols. Today’s Part 15 hearing, and [these] new actions … are indicative of the kinds of steps we need to take as we confront this epidemic.”

PNN Pharmacotherapy Line
Feb. 1, 2018 * Vol. 25, No. 22
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 1 issue of the New England Journal of Medicine (2018; 378).
Tisagenlecleucel in B-Cell Lymphoblastic Leukemia: Confirming the results of a single-center phase 1–2a study, investigators show in a global study that a single infusion of the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (pp. 439–48). The phase 2 trial was conducted at 25 centers and used a primary end point of overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.
Results showed: “For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.” (S. L. Maude,
maude@email.chop.edu)
CD19 CAR Therapy in Acute Lymphoblastic Leukemia: Median overall survival was 12.9 months —and 20.1 months among those with low disease burden — among 53 adults (23–74 years of age) with relapsed B-cell acute lymphoblastic leukemia who received infusions of autologous T cells expressing the 19-28z CD19-specific chimeric antigen receptor (CAR), a phase 1 trial shows (pp. 448–59). At the Memorial Sloan Kettering Cancer Center, CAR T cells were manufactured and administered, with these results: “After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.” (M. Sadelain, m-sadelain@ski.mskcc.org)
Paradigm Shift in Managing Atrial Fibrillation in HF: Compared with rate or rhythm control using medical therapy, catheter ablation significantly lowered incidence of a composite end point of death from any cause or hospitalization for worsening heart failure in patients with symptomatic paroxysmal or persistent atrial fibrillation, researchers report (pp. 417–27). The CASTLE-AF trial showed the end point occurred in 28.5% of 51 patients undergoing ablation therapy compared with 44.6% of 82 patients on medical therapy. (N. F. Marrouche, nassir.marrouche@carma.utah.edu)
In response to these findings, an editorialist writes (
pp. 468–9). “Where to now? Can we increase the success of the ablative procedure, and would that increase translate into further improvement in reverse remodeling and further reductions in rates of heart failure and mortality? If a reduction in the density of atrial fibrillation to 25% improves outcomes in this trial, what could be accomplished with reductions to 5% or even with elimination? All that is for the future. For the present, it seems reasonable to be more aggressive in offering ablation for atrial fibrillation in patients who also have congestive heart failure.” (M. S. Link)

PNN Pharmacotherapy Line
Feb. 2, 2018 * Vol. 25, No. 23
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
Feb. issue of Pediatrics (2018; 141).
Rhinovirus & Risk of Bacterial Infection in Febrile Infants: While febrile infants with viral respiratory infections are known to have a reduced risk of bacterial infections, a study uncovers a complicated relationship that limits utility of screening for for human rhinovirus (HRV) with polymerase chain reaction (PCR) to infants in the 29–90-day-old range (10.1542/peds.2017-2384). Screening of infants at 22 hospitals from 2007 to 2016 showed these results: “Of 10,964 febrile infants identified, 4,037 (37%) had RVPCR. Of these, 2,212 (55%) were positive for a respiratory virus; 1,392 (35%) for HRV alone. Bacterial infection was identified in 9.5%. Febrile infants with HRV detected were more likely to have bacterial infection than those with non-HRV viruses (7.8% vs 3.7%; P < .001; RR 2.12 [95% CI 1.43–3.15]). Risk of urinary tract infection was not significantly different for HRV-positive infants at any age, nor was risk of invasive bacterial infection (IBI; bacteremia and/or meningitis) meaningfully different for infants 1–28 day olds. Infants 29–90 days old with HRV had a decreased likelihood of IBI (RR 0.52 [95% CI 0.34–0.80]).” (A. J. Blaschke)
Acid-Suppressive Drug Use During Pregnancy & Childhood Asthma: The odds that a child will develop asthma are increased when the mother takes acid-suppressing drugs during pregnancy, according to a meta-analysis of eight population-based studies (10.1542/peds.2017-0889): “When all the studies were pooled, acid-suppressive drug use in pregnancy was associated with an increased risk of asthma in childhood (relative risk [RR] = 1.45; 95% confidence interval [CI] 1.35–1.56; I2 = 0%; P < .00001). The overall risk of asthma in childhood increased among proton pump inhibitor users (RR = 1.34; 95% CI 1.18–1.52; I2 = 46%; P < .00001) and histamine-2 receptor antagonist users (RR = 1.57; 95% CI 1.46–1.69; I2 = 0%; P < .00001).” (T. Lai)
Prophylactic Hydrocortisone in Extremely Preterm Infants: Early low-dose hydrocortisone treatment for preventing bronchopulmonary dysplasia (BPD) in extremely preterm infants is beneficial overall, with a higher treatment effect in those born after placental vascular disease, researchers report (10.1542/peds.2017-1788). In an exploratory analysis of data from the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, “The strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06).” (A. Héneau)
>>>PNN NewsWatch
* FDA is adding a boxed warning and Medication Guide to labeling for obeticholic acid (Ocaliva, Intercept Pharmaceutical) about incorrect dosing of the hepatic medication on a daily instead of weekly basis in patients with moderate-to-severe primary biliary cholangitis (PBC), increasing the risk of serious liver injury. To ensure correct dosing and reduce the risk of liver problems, FDA is clarifying the current recommendations for screening, dosing, monitoring, and managing PBC patients with moderate-to-severe liver disease taking obeticholic acid.
* Efforts to secure sufficient quantities of saline bags, antiviral agents, and other products needed for the
challenging influenza season are recounted by FDA Commissioner Scott Gottlieb, MD, in a statement released yesterday: “The products include large volume saline bags typically used to hydrate patients; small volume IV saline bags (generally in 50 and 100 ml sizes) that are often used to deliver other medicines; as well as empty IV containers of varying sizes that are being used by many health care providers to compound their own IV saline solutions by filling these empty containers. As such, we’re actively working to improve the large and small IV bag shortage and tracking potential shortages of critical medical products, such as the empty IV containers.
“We are also hearing from some health care providers that there are spot shortages of some antivirals used to treat the flu and flu tests; however, at this time, there is no nationwide shortage of these products. The FDA is carefully monitoring the situation and we will provide updates as needed.”

PNN Pharmacotherapy Line
Feb. 5, 2018 * Vol. 25, No. 24
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 360).
Cancer Risk, Chronic Diseases & Disease Markers: Major lifestyle factors are associated with cancer risks, a prospective cohort study indicates, with physical activity is especially important in cancer prevention (k134). Results of standard medical screenings in Taiwan show these relationships among various disease markers and incident cancers for 405,878 participants: “A statistically significantly increased risk of incident cancer was observed for the eight diseases and markers individually (except blood pressure and pulmonary disease), with adjusted hazard ratios ranging from 1.07 to 1.44. All eight diseases and markers were statistically significantly associated with risk of cancer death, with adjusted hazard ratios ranging from 1.12 to 1.70. Chronic disease risk scores summarizing the eight diseases and markers were positively associated with cancer risk in a dose-response manner, with the highest scores associated with a 2.21-fold (95% confidence interval 1.77-fold to 2.75-fold) and 4.00-fold (2.84-fold to 5.63-fold) higher cancer incidence and cancer mortality, respectively. High chronic disease risk scores were associated with substantial years of life lost, and the highest scores were associated with 13.3 years of life lost in men and 15.9 years of life lost in women. The population attributable fractions of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors combined (cancer incidence: 20.5% v 24.8%; cancer mortality: 38.9% v 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was attenuated by 48% for cancer incidence and 27% for cancer mortality.” (X. Wu, xwu@mdanderson.org)
Migraine & Cardiovascular Risks: In a population-based cohort study from Denmark, patients with migraine were significantly more likely to develop several cardiovascular diseases (k96). Concluding that “migraine may be an important risk factor for most cardiovascular diseases,” investigators show increased risks of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thromboembolism, and atrial fibrillation or atrial flutter in patients with migraine over 19 years of follow-up of 51,032 patients with migraine and 510,320 matched controls. (K. Adelborg, kade@clin.au.dk)
>>>Lancet Highlights
Source:
Feb. 3 issue of Lancet (2018; 391).
Long-Term Glucocorticoids in Duchenne Muscular Dystrophy: Cumulative glucocorticoid therapy of 1 year or more is beneficial in patients with Duchenne muscular dystrophy, researchers report, with “reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death” (pp. 451–61). In 440 boys and men aged 2 to 28 years in nine countries, these outcomes were recorded in a prospective cohort study: “Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2.1–4.4 years and upper limb milestones by 2.8–8.0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2.1–2.7 years in comparison with prednisone or prednisolone (log-rank p <0.012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0.47, 95% CI 0.22–1.00; p = 0.0501).” (C. M. McDonald, cmmcdonald@ucdavis.edu)
>>>PNN NewsWatch
* Kareway Products is voluntarily recalling 60,000 lots of Gericare Eye Wash, Sterile Eye Irrigation Solution, 4 fluid ounces to the hospital, retail, or consumer level because of potential microbial contamination.
>>>PNN JournalWatch
* Late-Onset ADHD Reconsidered With Comprehensive Repeated Assessments Between Ages 10 and 25, in American Journal of Psychiatry, 2018; 175: 140–9. (M. H. Sibley)
*
Advocacy for Improving Nutrition in the First 1000 Days to Support Childhood Development and Adult Health, in Pediatrics, 2018; 141: 10.1542/peds.2017-3716. (S. J. Schwarzenberg)

PNN Pharmacotherapy Line
Feb. 6, 2018 * Vol. 25, No. 25
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Feb. 6 issue of Annals of Internal Medicine (2018; 168).
CEA of Individualized Glycemic Control in Type 2 Diabetes: Lower medication costs are an important factor in making individualized approaches to glycemic control cost-effective for U.S. adults with type 2 diabetes, researchers report (pp. 170–8). Using a lifetime horizon and health care sector perspective, a cost-effectiveness analysis produced these outcomes for individualized versus uniform intensive glycemic control for patients aged 30 years or older: “Individualized control saved $13,547 per patient compared with uniform intensive control ($105,307 vs. $118,854), primarily due to lower medication costs ($34,521 vs. $48,763). Individualized control decreased life expectancy (20.63 vs. 20.73 years) due to an increase in complications but produced more [quality-adjusted life-years (QALYs)] (16.68 vs. 16.58) due to fewer hypoglycemic events and fewer medications.” The sensitivity analysis showed that “individualized control was cost-saving and generated more QALYs compared with uniform intensive control, except in analyses where the disutility associated with receiving diabetes medications was decreased by at least 60%.” (N. Laiteerapong, nlaiteer@medicine.bsd.uchicago.edu)
Marijuana Use & Cardiovascular Risk Factors: Evidence is insufficient to assess the effects of marijuana on cardiovascular risk factors and outcomes, according to authors of a systematic review (pp. 187–94). Vascular risk factors (hyperglycemia, diabetes, dyslipidemia, and obesity) and cardiovascular outcomes (stroke, myocardial infarction, cardiovascular mortality, and all-cause mortality in cardiovascular cohorts) were considered in the analysis of published observational studies: “13 and 11 studies examined associations between marijuana use and cardiovascular risk factors and clinical outcomes, respectively. Although 6 studies suggested a metabolic benefit from marijuana use, they were based on cross-sectional designs and were not supported by prospective studies. Evidence examining the effect of marijuana on diabetes, dyslipidemia, acute myocardial infarction, stroke, or cardiovascular and all-cause mortality was insufficient. Although the current literature includes several long-term prospective studies, they are limited by recall bias, inadequate exposure assessment, minimal marijuana exposure, and a predominance of low-risk cohorts.” (D. Ravi, divyaravi.88@gmail.com)
Genomic Sequencing for Precision Cancer Care: “Recent advances in next-generation sequencing technology, coupled with decreasing costs, present a transformative opportunity to improve patient outcomes through implementation of routine, prospective tumor and germline genomic profiling,” authors write in an Ideas and Opinion article (pp. 221–2). “Cancer is a genomic disease defined by diverse somatic and germline alterations that promote aberrant cell growth. Tumor genomic profiling of single genes or limited gene panels to guide therapy selection is now part of standard management of several solid tumor types, including melanoma, lung cancer, colorectal cancer, and ovarian cancer. However, treatment of many solid tumors is still based on the site of origin rather than being personalized to the molecular alterations specific to an individual patient’s cancer.” (D. B. Solit, solitd@mskcc.org)
Provider Types & Obstructive Sleep Apnea: In patients with known or suspected obstructive sleep apnea (OSA), outcomes were similar when care was provided by sleep specialist physicians (SSPs) and non–sleep specialists (NSSs), according to a systematic review of provider types and outcomes (pp. 195–202). While limited by extensive training or experience in sleep medicine for NSSs, review of study outcomes showed the following: “Four observational studies (n = 580; mean age, 52 years; 77% male) reported good agreement between NSSs and SSPs on appropriate diagnostic testing and classification of OSA severity (low-strength evidence). Five randomized trials and 3 observational studies (n = 1515; mean age, 52 years; 68% male) found that care provided by NSSs and SSPs resulted in similar quality of life, adherence, and symptom scores (low-strength evidence). Evidence was insufficient for access to care and adverse events.” (T. J. Wilt, tim.wilt@va.gov)

PNN Pharmacotherapy Line
Feb. 7, 2018 * Vol. 25, No. 26
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Feb. 6 issue of JAMA (2018; 319).
Oral Anticoagulants, Intracerebral Hemorrhage & Mortality: Among patients with intracerebral hemorrhage (ICH) who had received oral anticoagulants (OACs), risk of in-hospital mortality was lower with use of non-warfarin OACs (NOACs) than with warfarin, a study shows (pp. 463–73). The lowest risk of in-hospital mortality was in patients who had received no prior OACs in the retrospective cohort study of 141,311 patients with ICH admitted to 1,662 Get With The Guidelines–Stroke hospitals, which reports these results: “The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant.” (G. C. Fonarow, gfonarow@mednet.ucla.edu)
Fetal Alcohol Spectrum Prevalence: In four U.S. communities, the prevalence of fetal alcohol spectrum disorders was conservatively estimated at 1.1% to 5.0% in a cross-sectional study of first graders (pp. 474–82). The communities, in four different regions of the country, had these numbers of students with the disorder: “A total of 6,639 children were selected for participation from a population of 13,146 first-graders (boys, 51.9%; mean age, 6.7 years [SD, 0.41] and white maternal race, 79.3%). A total of 222 cases of fetal alcohol spectrum disorders were identified. The conservative prevalence estimates for fetal alcohol spectrum disorders ranged from 11.3 (95% CI, 7.8–15.8) to 50.0 (95% CI, 39.9–61.7) per 1,000 children. The weighted prevalence estimates for fetal alcohol spectrum disorders ranged from 31.1 (95% CI, 16.1–54.0) to 98.5 (95% CI, 57.5–139.5) per 1,000 children.” (C. D. Chambers, chchambers@ucsd.edu)
“The message about alcohol use during pregnancy to the public should be clear and consistent: there is no safe amount, time, or type of alcohol to drink during pregnancy or when trying to get pregnant,” editorialists write in reinforcing advice of the American Academy of Pediatrics (
pp. 448–9). “Special attention should be paid to young women who may engage in binge drinking because it can lead to unprotected sex and unplanned pregnancies. Prepregnancy drinking behavior is known to affect the likelihood of prenatal drinking to a great extent. Primary care clinicians should routinely include appropriate screening for alcohol use among all women of childbearing age, preconceptual health promotion, contraceptive counseling, and referral to substance abuse programs for those identified to have an alcohol use disorder. For women for whom it is not possible to ascertain prepregnancy drinking habits, identification of prenatal alcohol use should be a priority because reducing or eliminating alcohol use during pregnancy can potentially reduce the severity of the effects on the fetus. In addition, fetal alcohol spectrum disorders are an intergenerational issue with a high rate of recurrence within families; as such, families of affected children should be provided with ongoing support to reduce the likelihood of bearing additional children with fetal alcohol spectrum disorders.” (S. Lange, shannon.lange@camh.ca)
>>>PNN NewsWatch
* “Compounds in kratom make it so it isn’t just a plant – it’s an opioid,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “And it’s an opioid that’s associated with novel risks because of the variability in how it’s being formulated, sold, and used recreationally” and for self-medication.

PNN Pharmacotherapy Line
Feb. 8, 2018 * Vol. 25, No. 27
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 8 issue of the New England Journal of Medicine (2018; 378).
340B Drug Pricing Program: Availability of 340B-priced drugs “has been associated with hospital–physician consolidation in hematology–oncology and with more hospital-based administration of parenteral drugs in hematology–oncology and ophthalmology,” a study shows (pp. 539–48). The program has not met some of its original objectives, including expanded care or lower mortality for low-income patients, the authors add, based on these findings from Medicare claims data: “Hospital eligibility for the 340B Program was associated with 2.3 more hematologist–oncologists practicing in facilities owned by the hospital, or 230% more hematologist–oncologists than expected in the absence of the program (P = 0.02), and with 0.9 (or 900%) more ophthalmologists per hospital (P = 0.08) and 0.1 (or 33%) more rheumatologists per hospital (P = 0.84). Program eligibility was associated with significantly higher numbers of parenteral drug claims billed by hospitals for Medicare patients in hematology–oncology (90% higher, P = 0.001) and ophthalmology (177% higher, P=0.03) but not rheumatology (77% higher, P = 0.12). Program eligibility was associated with lower proportions of low-income patients in hematology–oncology and ophthalmology and with no significant differences in hospital provision of safety-net or inpatient care for low-income groups or in mortality among low-income residents of the hospitals’ local service areas.” In discussing their results, these researchers note: “The finding that patients served by eligible hospitals were less likely to have Medicaid, which reimburses hospitals less generously than other forms of supplemental coverage, is consistent with the financial incentives of hospitals and with evidence that 340B-participating hospitals have increasingly affiliated with hematology–oncology practices serving affluent communities.” (S. Desai, sunita.desai@nyu.edu)
“The controversy surrounding 340B is an archetypal problem in modern U.S. health care policy,” authors of a Perspective article write (
pp. 501–3). “The legislation was passed because of private industry’s reaction to a prior law mandating discounts. After its passage, the new policy, though well intentioned, was expanded beyond its planned scope as health care organizations figured out how to use it to maximize their revenue. The program became so large and convoluted that it requires scaling back, inevitably causing pain for hospitals that have spent years relying on the revenue it brought in and building businesses around it. The stakeholder groups each argue that their particular point of view is the one that will help patients the most, but no one can be sure who is right. Predictably, stakeholders complain loudly about the effects of changes and Congress delays or alters the implementation. In this case, the American Hospital Association sued to halt the 340B cuts, and members of Congress have introduced legislation to prevent them from happening. As the current debate about 340B plays out and the policy changes are enacted in 2018, stay tuned for the next act in this long-playing drama.” (W. F. Gellad)
Prazosin for PTSD: Among 304 military veterans with posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin proved similar to placebo for alleviating “distressing dreams” and improving sleep quality, researchers report (pp. 507–17). Participants recruited from 13 VA medical centers randomly received prazosin or placeob for 5 weeks in daily maximum doses of 5 or 20 mg. Based on three primary outcome measures, the investigators found: “At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the [Clinician-Administered PTSD Scale] item B2 score (between-group difference, 0.2; 95% confidence interval [CI], −0.3 to 0.8; P = 0.38), in the mean change in [Pittsburgh Sleep Quality Index] score (between-group difference, 0.1; 95% CI, −0.9 to 1.1; P = 0.80), or in the [Clinical Global Impression of Change] score (between-group difference, 0; 95% CI, −0.3 to 0.3; P = 0.96).… At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.” (M. A. Raskind, murray.raskind@va.gov)

PNN Pharmacotherapy Line
Feb. 9, 2018 * Vol. 25, No. 28
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
Feb. issue of Chest (2018; 153).
Inhaled Corticosteroids & Fracture Risk in COPD: In both men and women, long-term use of inhaled corticosteroids (ICSs) for chronic obstructive pulmonary disorder (COPD) is associated with a modest risk hip and upper extremity fracture, according to Quebec health data (pp. 321–8). Nested case-control analysis showed these patterns when each case of fracture was matched with 20 controls: “In the cohort of 240,110 subjects, 19,396 sustained a fracture during a mean 5.3 years (rate, 15.2 per 1,000 per year). Any use of ICSs was not associated with an increased rate of fracture (RR, 1.00; 95% CI, 0.97–1.03). The fracture rate was increased with >4 years of ICS use at daily doses ≥1,000 μg in fluticasone equivalents (RR, 1.10; 95% CI, 1.02–1.19). This risk increase did not differ between men and women.” (S. Suissa, samy.suissa@mcgill.ca)
“Can we finally put this to bed?” ask editorialists with regard to continued widespread use of long-term ICSs in patients with COPD despite a campaign targeting prescribers (
pp. 293–4). “ICS therapy is useful in patients who experience frequent exacerbations,” the writers conclude. “However, they are fraught with significant side effects, which may be dose-dependent. It is now well established that ICSs have deleterious effects on bone that increase the risk of fractures, a side effect that is largely avoidable and can be mitigated by careful monitoring and most importantly by reducing (and in most cases eliminating) the use of ICSs for patients with COPD in the community.” (D. D. Sin, on.Sin@hli.ubc.ca">Don.Sin@hli.ubc.ca)
>>>Circulation Report
Source:
Feb. 6 issue of Circulation (2018; 137).
Validating DAPT Scores in a Japanese PCI Patients: The dual antiplatelet therapy (DAPT) score was useful for predicting ischemic and bleeding risks in a pooled cohort of participants in three Japanese studies of percutaneous coronary interventions, researchers report (pp. 551–62). At 13 to 36 months after percutaneous coronary interventions in those with DAPT scores of 2 or more (high DS) or less than 1 (low DS), outcomes were as follows: “Among 12,223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3,944 patients had high DS and 8,279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, P = 0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, P = 0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, P = 0.03; 1.5% versus 0.8%, P = 0.002; 0.7% versus 0.3%, P <0.001, respectively), whereas the cumulative incidences of noncardiac death and GUSTO severe bleeding were significantly lower in high DS than in low DS (2.4% versus 3.9%, P <0.001; 1.0% versus 1.6%, P = 0.03, respectively).” (T. Kimura, taketaka@kuhp.kyoto-u.ac.jp)
>>>PNN NewsWatch
* Proper use of inhaled corticosteroids and other control medicines in children with asthma is emphasized in a new Vital Signs report from the CDC. Asthma attacks decreased in number among children of all races and ethnicities between 2001 and 2016, but 50% of children with asthma had exacerbations in 2016. “Asthma can’t be cured – but most of the time, we can control asthma symptoms and prevent asthma attacks,” Acting CDC Director Anne Schuchat, M.D., said during a media briefing.
*
FDA yesterday approved the RadioGenix System (NorthStar Medical Radioisotopes) for producing technetium-99m (Tc-99m), the most widely used radioisotope in medical imaging. The Nuclear Regulatory Commission is issuing guidance and will license the RadioGenix System to enable the Tc-99m it produces to be used for its medical purpose. “The system we’ve approved today will not only help save and improve the lives of patients, but will reduce the risk of drug shortages and strengthen our national security by creating a U.S.-based manufacturing capacity that is less vulnerable to supply disruptions,” said FDA Commissioner Scott Gottlieb, M.D.

PNN Pharmacotherapy Line
Feb. 12, 2018 * Vol. 25, No. 29
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Feb. 10 issue of Lancet (2018; 391).
Weight Management & Remission of Type 2 Diabetes: Over a 12-month period, nearly one-half of 306 individuals with type 2 diabetes achieved remission through primary care–delivered intensive weight management interventions (pp. 541–51). The open-label, cluster-randomized DiRECT trial included 49 primary care practices in Scotland and the Tyneside region of England and patients with a type 2 diagnosis within 6 years who had body mass indices of 27–45 kg/sq m and were not receiving insulin. All antidiabetic and antihypertensive drugs were withdrawn and participant diets were totally replaced by formula for 3 to 5 months. Foods were reintroduced in stepped fashion, and structured support was provided for long-term weight loss management.
Results showed: “At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p <0.0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19.7, 95% CI 7.8–49.8; p <0.0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0–5 kg weight loss, 19 (34%) of 56 participants with 5–10 kg loss, 16 (57%) of 28 participants with 10–15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10.0 kg (SD 8.0) in the intervention group and 1.0 kg (3.7) in the control group (adjusted difference −8.8 kg, 95% CI −10.3 to −7.3; p <0.0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7.2 points (SD 21.3) in the intervention group, and decreased by 2.9 points (15.5) in the control group (adjusted difference 6.4 points, 95% CI 2.5–10.3; p = 0.0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study.” (R. Taylor,
roy.taylor@newcastle.ac.uk)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Adverse Effects of Trimethoprim for UTI in Older Adults: Increased risks of kidney injury and hyperkalemia were evident among older patients treated with trimethoprim for urinary tract infections in an analysis of the U.K. Clinical Practice Research Datalink and Hospital Episode Statistics database (k341). Among more than 1.1 million patients aged 65 or older, these outcomes were noted for 178,238 people treated at least once for UTI with antibiotics: “The odds of acute kidney injury in the 14 days following antibiotic initiation were higher following trimethoprim (adjusted odds ratio 1.72, 95% confidence interval 1.31 to 2.24) and ciprofloxacin (1.48, 1.03 to 2.13) compared with amoxicillin. The odds of hyperkalaemia in the 14 days following antibiotic initiation were only higher following trimethoprim (2.27, 1.49 to 3.45) compared with amoxicillin. However, the odds of death within the 14 days following antibiotic initiation were not higher with trimethoprim than with amoxicillin: in the whole population the adjusted odds ratio was 0.90 (95% confidence interval 0.76 to 1.07) while among users of renin-angiotensin system blockers the odds of death within 14 days of antibiotic initiation was 1.12 (0.80 to 1.57).…” (K. Mansfield, kathryn.mansfield@lshtm.ac.uk)
>>>PNN JournalWatch
* Global Impact of 2017 American Heart Association/American College of Cardiology Hypertension Guidelines: A Perspective From Japan, in Circulation, 2018; 137: 543–5. (K. Kario, kkario@jichi.ac.jp)
*
Cough Due to TB and Other Chronic Infections: CHEST Guideline and Expert Panel Report, in Chest, 2018; 153: 467–97. (S. K. Field, sfield@ucalgary.ca)
*
Extending the Reach of Evidence-Based Medicine: A Proposed Categorization of Lower-Level Evidence, in Chest, 2018; 153: 498–506. (F. C. Detterbeck, frank.detterbeck@yale.edu)
*
Addressing the Unknowns of Antimicrobial Resistance: Quantifying and Mapping the Drivers of Burden, in Clinical Infectious Diseases, 2018; 66: 612–6. (G. M. Knight, gmknight@imperial.ac.uk)

PNN Pharmacotherapy Line
Feb. 13, 2018 * Vol. 25, No. 30
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Feb. issue of JAMA Internal Medicine (2018; 178).
LABAs/LAMAs & Cardiovascular Risk in COPD: Initiation of inhaled long-acting bronchodilators in people with chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular events, a nested case–control study from Taiwan shows, “irrespective of prior [cardiovascular disease (CVD)] status and history of exacerbations” (pp. 229–38). Treatment with inhaled long-acting beta-2 agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in 284,220 patients aged 40 years or older with no use in the prior year (new users) or use within the prior year (prevalent users) produced these outcomes for inpatient or emergency care visits for coronary artery disease, heart failure, ischemic stroke, or arrhythmia, according to the Taiwan National Health Insurance Research Database for 2007–11: “During a mean follow-up of 2.0 years, 37,719 patients with CVD (mean age, 75.6 years; 71.6% men) and 146,139 matched controls (mean age, 75.2 years; 70.1% men) were identified. New LABA and LAMA use in COPD was associated with a 1.50-fold (95% CI, 1.35–1.67; P < .001) and a 1.52-fold (95% CI, 1.28–1.80; P < .001) increased cardiovascular risk within 30 days of initiation, respectively, whereas the risk was absent, or even reduced with prevalent use. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not differ in the CVD risks. The risk persisted in an alternative case–crossover study and remained across subgroups without CVD history or prior exacerbations.” (M-T Wang, wmt@mail.ndmctsgh.edu.tw)
Promotional & Legal Maneuvers to Protect Restasis Sales: Thinking about alternative uses for the billions of dollars spent in the U.S. for Allergan’s Restasis product (cyclosporine ophthalmic emulsion, 0.05%) “should bring tears to your eyes,” Viewpoint authors write (pp. 181–2). “Which is what Restasis is supposed to do—just not like this.” The authors note that annual sales of the product have been about $2 billion in the U.S., with demand driven by $645 million in direct-to-consumer advertising over a 10-year period and payments of $9.1 million to 24,152 physicians in 2013–15. “In the case of Restasis, even evidence-based clinical resources may be misleading,” the authors add. “For example, the ‘Dry Eyes’ chapter in UpToDate, a point-of-care resource, summarized a systematic review as follows: ‘All nine [Restasis] trials that evaluated symptoms ... found improvement.’ But 4 of these 9 trials only demonstrated within-group—not between-group—improvements. The other 5 trials found that only 1 or 2 of the 4 to 8 symptoms tested improved. For the symptom score (a primary outcome in drug approval trials), Restasis was superior to artificial tears or placebo in just 1 of the 9 trials of initial treatment. Although the UpToDate authors note that they ‘have not seen such a degree of beneficial results in their practice,’ the chapter does not mention that, as disclosed in the systematic review, the senior author was an Allergan consultant. Moreover, neither the UpToDate chapter nor the systematic review discusses the tenuous evidence of efficacy found in the treasure trove of regulatory documents.” (S. Woloshin, steven.woloshin@dartmouth.edu)
Congressional, regulatory, or judicial actions may stop a novel legal maneuver Allergan is using to extend patent life of Restasis, a Viewpoint article explains (
pp. 179–80): “In September 2017, Allergan Plc announced that it had transferred the 6 patents for cyclosporine ophthalmic emulsion (Restasis), its blockbuster drug for chronic dry eye, to the Saint Regis Mohawk Tribe, a federally recognized Indian tribe of about 15,000 members in rural upstate New York with a $50 million annual budget,” the author writes. “The Tribe received $13.75 million initially and is eligible for $15 million in annual royalties—a small fraction of the roughly $1.5 billion in annual U.S. revenues for Restasis. The deal allows the Tribe, as the patents’ legal owner, to assert what is known as sovereign immunity in a proceeding at the US Patent and Trademark Office (USPTO) where Mylan Pharmaceuticals … is challenging the patents.…
“Whether selling patents to Indian tribes or other sovereigns to protect them from inter partes review is a viable strategy remains highly unsettled, and the situation could shift markedly depending on what Congress, the USPTO, and the Federal Circuit decide in the months ahead.” (G. Ablavsky,
ablavsky@law.stanford.edu)

PNN Pharmacotherapy Line
Feb. 14, 2018 * Vol. 25, No. 31
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Oncology Highlights
Source:
Feb. 10 issue of the Journal of Clinical Oncology (2018; 36).
Out-of-Pocket Costs & Abandonment of Oral Anticancer Agents: Across cancers of all types, higher out-of-pocket (OOP) costs were associated with higher rates of abandonment of oral anticancer drugs, a study shows (pp. 476–82). Retrospective claims data for adjudicated prescriptions from 2014 and 2015 were used to assess rates of claim reversal (failure to purchase approved prescription), delayed initiation (reversal with subsequent fill of same agent within 90 days after adjudication), and abandonment (reversal with no fill of same agent within 90 days) for an index oral anticancer agent. Results showed the following: “Among the final sample (N = 38,111), risk-adjusted rates of claim reversal ranged from 13% to 67%, increasing with higher OOP costs. Although the abandonment rate was 18% overall, risk-adjusted rates were higher in greater OOP cost categories (10.0% for ≤$10 group v 13.5% for $50.01 to $100 group, 31.7% for $100.01 to $500 group, 41.0% for $500.01 to $2,000 group, and 49.4% for > $2,000 group; P < .001 compared with ≤$10 group). Rates remained similar after accounting for use of alternate oral, injectable, or infusible anticancer agents. Delayed initiation was also more frequent for higher OOP cost categories (3% in ≤ $10 group v 18% in > $2,000 group; P < .001). Sensitivity and subgroup analyses by insurance type, pharmacy type, sex, and indication identified similar associations.” (J. A. Doshi, jdoshi@pennmedicine.upenn.edu)
>>>Infectious Diseases Report
Source:
Feb. 15 issue of Clinical Infectious Diseases (2018; 66).
Low CDI Risk With Tetracyclines: Compared with other antibiotics for treating systemic diseases, tetracyclines may be associated with a decreased risk of Clostridium difficile infection (CDI), according to a systematic review and meta-analysis of four case–control and two cohort studies (pp. 514–22): “Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47–0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40–0.75; P < .001).” (S. Khanna, khanna.sahil@mayo.edu)
Pneumococcal Vaccination & Pneumonia Hospitalizations: Public funding of conjugated pneumococcal vaccine (PCV) for infants reduced disease and associated costs in Ontario, researchers report (pp. 541–7). During five intervals with differing policies and vaccine availability [prevaccine period, availability of 7-valent PCV (PCV7) for private purchase, public funding for PCV7, replacement of PCV7 with 10-valent PCV (PCV10), and replacement of PCV10 with 13-valent PCV (PCV13)], population-based health administrative data for vaccine-eligible groups show a 34% to 45% decline in pneumonia hospitalizations and a 38% to 46% decline in hospitalization-related costs, and less disease and lower costs in PCV-ineligible older children and older adults. (D. L. Luca, dleeluca@mathematica-mpr.com)
>>>PNN NewsWatch
* Apace Packaging is voluntarily recalling one lot of Acyclovir Tablet, USP, 400 mg, 50 ct unit dose, NDC 50268-061-15, lot no. 19900, to the retail level, because a small number of blister cards may also include torsemide 20 mg tablets.
* Initiatives included in the Administration’s proposed
fiscal year 2019 budget for FDA include advancing pharmacy outsourcing as a domestic industry and promoting competition through generic drug development and substitution, writes Commissioner Scott Gottlieb, MD, in a statement released yesterday. “These initiatives are aimed at supporting new and ongoing efforts to foster more investment and innovation in the development of therapeutics and diagnostics that target unmet medical needs; advance drug and device competition; stand up new domestic industries – such as pharmacy outsourcing facilities; and create more modern, domestically based manufacturing, including continuous manufacturing of drugs and biological products, including vaccines. These manufacturing platforms can bring more businesses back to the U.S., help lower drug and device development costs, and reduce the risk of shortages.”

PNN Pharmacotherapy Line
Feb. 15, 2018 * Vol. 25, No. 32
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Feb. 15 issue of the New England Journal of Medicine (2018; 378).
Edoxaban for Cancer-Associated VTE: In an open-label comparison with subcutaneous dalteparin in patients with cancer who had acute symptomatic or incidental venous thromboembolism, oral edoxaban was noninferior with respect to a composite primary outcome of recurrent venous thromboembolism or major bleeding, researchers report (pp. 615–24). Edoxaban, a direct anticoagulant, produced a lower rate of venous thromboembolism but a higher rate of major bleeding, as shown in these results for 6–12 months of prophylaxis: “A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P = 0.006 for noninferiority; P = 0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, −3.4 percentage points; 95% CI, −7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).” (G. E. Raskob, gary-raskob@ouhsc.edu)
“Not all patients with cancer and venous thromboembolism are candidates for edoxaban therapy,” editorialists write (
pp. 673–4). “The use of direct oral anticoagulants should be avoided in patients with a creatinine clearance of less than 30 ml per minute, and their use in patients with gastrointestinal cancer should be based on patient preference. Some patients may choose the convenience of an oral agent despite an increased risk of gastrointestinal bleeding.” (J. Hirsh)
Nusinersen in Later-Onset Spinal Muscular Atrophy: The antisense oligonucleotide agent nusinersen produced “significant and clinically meaningful improvement in motor function” in a phase 3 trial of 126 children with later-onset spinal muscular atrophy (pp. 625–35). Compared with a sham procedure, nusinersen produced these changes based on a primary end point of the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment: “In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P <0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P <0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).” (E. Mercuri, eugeniomaria.mercuri@unicatt.it)
Metastatic Prostate Cancer: The “increasingly complex” management of metastatic prostate cancer is reviewed (pp. 645–57): “Although we celebrate the life-prolonging effects of the new hormonal therapies, the diagnosis of metastatic prostate cancer currently leads to lifelong androgen-deprivation therapy. Despite progress on multiple research fronts, we have imperfect tools to identify patients who need therapy in the first place, and once the disease spreads beyond the control of local therapies, we do not know how best to sequence or combine the expanding number of active therapies.” (O. Sartor, sartor@tulane.edu">osartor@tulane.edu)
>>>PNN NewsWatch
* Following a priority review, FDA yesterday approved apalutamide (Erleada, Janssen) for treatment of patients with nonmetastatic, castration-resistant prostate cancer. The first agent approved for this indication, apalutamide is a next-generation androgen receptor inhibitor that decreased the risk of distant metastasis or death by 72% and improved median metastasis-free survival by more than 2 years in phase 3 trials.
* The
Banyan Brain Trauma Indicator is the first marketed blood test for detecting concussions in adults, FDA reports.

PNN Pharmacotherapy Line
Feb. 16, 2018 * Vol. 25, No. 33
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Highlights
Source:
Feb. Journal of the American Geriatrics Society (2018; 66).
PPIs & Dementia Risk: Concerns that long-term PPI use could be associated with increased dementia risk are not supported by results of a prospective population-based cohort study of 3,484 older adults in Kaiser Permanente Washington (pp. 247–53). Among those 65 or older without baseline dementia, these results were identified in every-2-year dementia screens: “Over a mean follow-up of 7.5 years, 827 participants (23.7%) developed dementia (670 with possible or probable AD). PPI exposure was not associated with risk of dementia (P = .66) or AD (P = .77). For dementia, the risk for specific levels of cumulative exposure compared to no use was: 365 [total standardized daily doses (TSDDs)] (HR 0.87, 95% CI 0.65–1.18), 1,095 TSDDs (HR 0.99, CI 0.75–1.30) and 1,825 TSDDs (HR 1.13, CI 0.82–1.56). These TSDD levels represent approximately 1, 3 and 5 years of daily use respectively. Duration of PPI use was not associated with dementia outcomes either.” (S. Gray, slgray@u.washington.edu)
UTI Antibiotics & Confusion: Antibiotic use for suspected urinary-tract infections (UTIs) raises nursing home residents’ risk of developing confusion by 9-fold, a cross-sectional study shows (pp. 274–81). At five Australian facilities, 450 residents had these nonspecific symptoms documented during antibiotic use: “UTI accounted for 33% of all current infections treated with antibiotics and 40% of all infections treated with antibiotics within the last 30 days. One in 5 NH residents had received antibiotics within the last 30 days, of which 45% were for UTI. The most significant factors independently associated with antibiotics for UTI were urinary catheter (OR = 13, 95% CI = 2.4–67, P = .003), urinary frequency (OR = 10, 95% CI = 2.2–47, P = .003), fever (OR = 10, 95% CI = 1.3–85, P = .028), new-onset hypotension (OR = 10, 95% CI = 1.4–73, P = .024), and confusion (OR = 8.9, 95% CI = 3.1–26, P < .001). Of these, confusion was the most prevalent factor in the population.” (S. Mayne, sean.mayne@my.jcu.edu.au)
>>>Allergy/Immunology Report
Source:
Feb. J. Allergy and Clinical Immunology (2018; 141).
Vaccine-Associated Hypersensitivity: Advances in vaccinology create a need to watch for new or different adverse events emerging, authors of a review article write (pp. 463–72): “Postvaccination acute-onset hypersensitivity reactions include self-limited localized adverse events and, rarely, systemic reactions ranging from urticaria/angioedema to full-blown anaphylaxis with multisystem involvement. Risk of anaphylaxis after all vaccines is estimated to be 1.31 (95% CI, 0.90–1.84) per million vaccine doses, respectively. Serious hypersensitivity reactions after influenza vaccines are particularly important because of the large number of persons vaccinated annually. Influenza vaccines are unique in requiring annual changes in the vaccines’ antigenic composition to match the predicted circulating influenza strains. Recently, novel influenza vaccine types were introduced in the United States (recombinant vaccines, some with higher antigen content, and a new adjuvanted vaccine). Providers should be aware of changing recommendations on the basis of recent published evidence for persons with a history of egg allergy to receive annual influenza vaccination. Further research is needed to elucidate the pathophysiology and risk factors for reported vaccine-associated adverse events. Further research is also needed to determine whether repeated annual inactivated influenza vaccination, the number of vaccine antigens administered at the same time, and the current timing of routine infant vaccinations are optimal for overall population well-being.” (M. M. McNeil, mmm2@cdc.gov)
>>>PNN NewsWatch
* Cases of influenza-like illness continue unabated in most of the U.S., government officials said yesterday. Figures for the 2017–18 influenza season are updated in a report in this week’s MMWR, and hospitalizations and physician visits are already approaching the record levels of recent severe seasons — with several weeks remaining. In addition, the proportion of cases caused by influenza B virus is unusually large, which could portend a severe period ahead, since B strains tend to predominate late in the season. Overall vaccine effectiveness is pegged at 36%, according to a second MMWR article.
*
PNN will not be published on Mon., Feb. 19, Presidents Day.

PNN Pharmacotherapy Line
Feb. 20, 2018 * Vol. 25, No. 34
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Feb. 20 issue of the Annals of Internal Medicine (2018; 168).
Perioperative Aspirin in Patients With Prior PCI: A multicenter trial conducted in 23 countries shows that perioperative aspirin may be more beneficial than harmful when used perioperatively in patients who have had percutaneous coronary intervention (PCI) (pp. 237–44). Among more than 10,000 participants aged 45 years or older undergoing noncardiac surgery, these results were recorded for aspirin or placebo therapy initiated within 4 hours before surgery and continued perioperatively: “In patients with prior PCI, aspirin reduced the risk for the primary outcome [of death or nonfatal myocardial infarction within 30 days] (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR], 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%]; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, −2.6% to 5.2%]). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48]; P for interaction = 0.50).” (P. J. Devereaux, philipj@mcmaster.ca)
Hepatitis B Vaccination in Patients With HIV: Missed opportunities to vaccinate patients with HIV infection against hepatitis B virus are common, a study shows, with more than one-third of those living with HIV in the U.S. sample not starting the series while receiving medical care in 2009–12 (pp. 245–54). Among 18,089 adult participants with HIV in the Medical Monitoring Project, results indicated a need for vaccination in alternative sites: “At the beginning of the surveillance period, 44.2% (95% CI, 42.2% to 46.2%) of U.S. HIV patients were candidates to initiate vaccination. By the end of the surveillance period, 9.6% (CI, 8.4% to 10.8%) of candidates were vaccinated, 7.5% (CI, 6.4% to 8.6%) had no documented vaccination but had documented infection or immunity, and 82.9% (CI, 81.1% to 84.7%) remained candidates. Among patients at facilities funded by the Ryan White HIV/AIDS Program (RWHAP), 12.5% (CI, 11.1% to 13.9%) were vaccinated during the surveillance period versus 3.7% (CI, 2.6% to 4.7%) at facilities not funded by RWHAP. At the end of surveillance, 36.7% (CI, 34.4% to 38.9%) of HIV patients were candidates to initiate vaccination.” (J. Weiser, jweiser@cdc.gov)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Paradoxical Effects of Anticoagulation in CKD: “Giving anticoagulants to older people with concomitant atrial fibrillation and chronic kidney disease was associated with an increased rate of ischaemic stroke and haemorrhage but a paradoxical lowered rate of all cause mortality,” conclude authors of a retrospective cohort analysis of Royal College of General Practitioners Research and Surveillance Centre data from 2006 to 2016 (k342). “Careful consideration should be given before starting anticoagulants in older people with chronic kidney disease who develop atrial fibrillation. There remains an urgent need for adequately powered randomised trials in this population to explore these findings and to provide clarity on correct clinical management.” (J. Camm, jcamm@sgul.ac.uk)
>>>PNN NewsWatch
* FDA on Friday expanded the approved indications of durvalumab (Imfinzi, AstraZeneca) to include treatment of patients with unresectable stage III non-small cell lung cancer whose cancer has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
>>>PNN JournalWatch
* Adjunctive Rifampicin for Staphylococcus aureus Bacteraemia (ARREST): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial, in Lancet, 2018; 391: 668–78. (G. E. Thwaites, gthwaites@oucru.org)
*
Individualizing Prevention for Older Adults, in Journal of the American Geriatrics Society, 2018; 66: 229–34. (S. J. Lee, sei.lee@ucsf.edu)
*
Novel Therapies for Alopecia Areata: The Era of Rational Drug Development, in Journal of Allergy and Clinical Immunology, 2018; 141: 499–504. (A. M. Christiano, amc65@cumc.columbia.edu)
*
Intravenous Thrombolysis and Platelet Count, in Neurology, 2018; 90: e690–7. (H. Gensicke)

PNN Pharmacotherapy Line
Feb. 21, 2018 * Vol. 25, No. 35
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
Feb. 20 issue of JAMA (2018; 319).
Haloperidol, Delirium & Survival in Critically Ill Adults: In the REDUCE trial, use of haloperidol for prevention of delirium in high-risk patients in intensive-care units (ICUs) did not improve 28-day survival rates, researchers report (pp. 680–90). Among 1,789 critically ill adults in 21 ICUs in the Netherlands — where nonpharmacological measures are used routinely for delirium prevention — randomization to intravenous haloperidol 1 mg or 2 mg or to placebo had these effects on a primary outcome of number of days survived over a 28-day period: “The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0–0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78–1.30, P = .82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0–0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0–0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group).” (M. van den Boogaard, mark.vandenBoogaard@radboudumc.nl)
“Delirium is a common accompaniment of critical illness, but it need not be so,” editorialists write (
pp. 659–60). “The REDUCE study has demonstrated that in critically ill patients currently receiving best-practice nonpharmacological interventions to prevent delirium, the addition of haloperidol does not improve survival nor reduce the incidence of delirium or the harms associated with delirium. The REDUCE study has demonstrated that the plausible and simple administration of prophylactic haloperidol is not the solution for the complex problem of delirium in critically ill patients.” (A. Delaney, adelaney@med.usyd.edu.au)
Acute Respiratory Distress Syndrome: Pharmacotherapy is not the answer in management of patients with acute respiratory distress syndrome (ARDS), according to results of a narrative review (pp. 698–710): “The cornerstone of management remains mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Aspirin was not effective in preventing ARDS in patients at high-risk for the syndrome. Adjunctive interventions to further minimize VILI, such as prone positioning in patients with a Pao2/Fio2 ratio less than 150 mm Hg, were associated with a significant mortality benefit whereas others (eg, extracorporeal carbon dioxide removal) remain experimental. Pharmacologic therapies such as beta-2 agonists, statins, and keratinocyte growth factor, which targeted pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm. Recent guidelines on mechanical ventilation in ARDS provide evidence-based recommendations related to 6 interventions, including low tidal volume and inspiratory pressure ventilation, prone positioning, high-frequency oscillatory ventilation, higher vs lower positive end-expiratory pressure, lung recruitment maneuvers, and extracorporeal membrane oxygenation.” (E. Fan, eddy.fan@uhn.ca)
“Matching intervention to pathophysiology is essential,” editorialists add (
pp. 664–6). “Physiological studies that better characterize the factors causing ventilator-induced lung injury are indicated prior to undertaking [a randomized controlled trial] aimed at avoiding it. When a damaging threshold is determined, the indication for the most adequate therapy will immediately follow.” (L. Gattinoni, gattinoniluciano@gmail.com)
>>>PNN NewsWatch
* The Advisory Committee on Immunization Practices convenes at the CDC in Atlanta today for a 2-day meeting. On this morning’s agenda, which is streamed live, are discussions and votes on influenza vaccines, including Fluarix Quadrivalent (GlaxoSmithKline) and a reformulated intranasal vaccine from Medimmune/AstraZeneca (FluMist) that uses a new strain of a live attenuated influenza virus (LAIV). Efficacy of LAIV in children aged 2 to 17 years will also be discussed.

PNN Pharmacotherapy Line
Feb. 22, 2018 * Vol. 25, No. 36
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Feb. 22 New England Journal of Medicine (2018; 378).
Larotrectinib in TRK Fusion–Positive Cancers: In adults and children with tropomyosin receptor kinase (TRK) fusion–positive cancers, the highly selective TRK inhibitor larotrectinib produced marked and durable antitumor activity, researchers report (pp. 731–9). Using three protocols based on patient age, the study showed: “A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.” (D. M. Hyman, hymand@mskcc.org)
Calling this study “an illustration of what is likely to be the future of drug development in rare genomic entities,” an editorialist concludes (
pp. 763–5): “To address the challenge of orphan molecular segments such as NTRK fusions, the oncology community must pursue innovative trial designs, implement new biotechnologies for diagnosis, and radically change the current pathways of care. The major unknown factor in this field is how many other orphan molecular entities will meet the same therapeutic success as the one observed with larotrectinib. Finally, since these alterations are rare, there is a need for a global effort. This implies harmonization among regulatory agencies across the world and an expansion of global trials.” (F. AndréWinking
VTE Prophylaxis After Hip or Knee Arthroplasty: Following rivaroxaban prophylaxis for 5 postoperative days following total hip or total knee arthroplasty, extended prophylaxis with aspirin is not significantly different from rivaroxaban for prevention of symptomatic venous thromboembolism, a study shows (pp. 699–707). Randomization on postoperative day 5 to continuation of the direct oral anticoagulant in a 10-mg dose or to aspirin 81 mg daily for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty, 90-day outcomes were as follows: “A total of 3,424 patients (1,804 undergoing total hip arthroplasty and 1,620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1,707 patients (0.64%) in the aspirin group and in 12 of 1,717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], −0.55 to 0.66; P <0.001 for noninferiority and P = 0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, −0.65 to 0.29; P = 0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, −1.07 to 0.47; P = 0.43).” (D. R. Anderson, david.anderson@dal.ca)
>>>PNN NewsWatch
* Facing a lack of clinical data on a reformulated live attenuated influenza vaccine (LAIV) but no way of generating the data without widespread use of the product, the Advisory Committee on Immunization Practices yesterday voted 12–2 to reinstate FluMist (MedImmune/AstraZeneca) to its immunization schedule for the coming season. The decision “may have come too late for the vaccine to play a major role in next winter’s vaccination program,” StatNews reports, since “many doctor’s offices will have already ordered their flu vaccine stocks for next season and the contracts for the publicly funded Vaccines for Children program have already been let.” The ACIP meeting continues today with discussions of pneumococcal vaccines in older adults, use of vaccines and other biologics in health care–associated infections, meningococcal disease, and Japanese encephalitis vaccine.

PNN Pharmacotherapy Line
Feb. 23, 2018 * Vol. 25, No. 37
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Health Affairs Highlights
Source:
Feb. issue of Health Affairs, a theme issue on diffusion of innovations (2018; 37).
Vaccines & Health Equity in Developing Countries: In 41 low- and middle-income countries, vaccines yielded health and economic benefits by averting both deaths and medical impoverishment, a study shows (pp. 316–24). The impact of 10 antigens and their corresponding vaccines were assessed across income quintiles for differential health impact (number of deaths averted) and household economic impact (cases of medical impoverishment averted): “Our analysis indicated that benefits across these vaccines would accrue predominantly in the lowest income quintiles. Policy makers should be informed about the large health and economic distributional impact that vaccines could have, and they should view vaccination policies as potentially important channels for improving health equity. Our results provide insight into the distribution of vaccine-preventable diseases and the health benefits associated with their prevention.” (A. Y. Chang, angela.chang@mail.harvard.edu)
Medicaid v. Marketplace Economics in Near-Poor Adults: In states that did not expand Medicaid eligibility under the Affordable Care Act, nonelderly adults with incomes in the 100% to 138% federal poverty range have lower coverage rates and increased out-of-pocket expenses for enrollees, researchers report (pp. 299–307). Data from 2010 to 2015 show these patterns in the impact of Medicaid expansion versus Marketplace availability: “For adults with family incomes of 100–138 percent of poverty, living in a Medicaid expansion state was associated with a 4.5-percentage-point reduction in the probability of being uninsured, a $344 decline in average total out-of-pocket spending, a 4.1-percentage-point decline in high out-of-pocket spending burden (that is, spending more than 10 percent of income), and a 7.7-percentage-point decline in the probability of having any out-of-pocket spending relative to living in a nonexpansion state. These findings suggest that policies that substitute Marketplace for Medicaid eligibility could lower coverage rates and increase out-of-pocket expenses for enrollees.” (F. Blavin, fblavin@urban.org)
Medicare’s Annual Wellness Visit: Practices that are providing annual wellness visits to at least one-fourth of their Medicare patients have more stable patient assignment and a slightly healthier patient mix, Medicare data for 2008–15 indicate (pp. 283–91). Practices serving racial minorities, dual eligibles, and other underserved populations had lower visit rates, which could worsen inequities, the group reports. (I. Ganguli, iganguli@bwh.harvard.edu)
>>>Medical Care Report
Source:
Mar. issue of Medical Care (2018; 56).
Medication Adherence & Medicaid Utilization: Among more than 1.3 million Medicaid beneficiaries, improvements in medication adherence were associated with substantial reductions in health services utilization, a study shows (pp. 266–73). Benefits were evident even at adherence rates below the commonly used threshold of 0.8 proportion of days covered, the investigators report, adding these details for 2008–10 in 10 states: “Full adherence was associated with 8%–26% fewer hospitalizations and 3%–12% fewer emergency department visits among those with congestive heart failure, hypertension, diabetes, and schizophrenia/bipolar. In all analyses, full adherence was associated with up to 15% fewer outpatient physician/clinic visits. Moreover, low and moderate levels of adherence were also related to less health care use.” The authors conclude, “Interventions should focus not just on perfecting moderate adherers, but also on encouraging Medicaid patients with chronic conditions to initiate pharmacotherapy.” (M. C. Roebuck, cr@rxeconomics.com)
>>>PNN NewsWatch
* Based on findings from the 10-year CLARICOR trial, FDA advises caution before prescribing clarithromycin to patients with heart disease because of a potential increased risk of heart problems or death that can occur years later. The large clinical trial showed an unexpected increase in deaths among patients with coronary heart disease who received a 2-week course of clarithromycin that became apparent after patients had been followed for 1 year or longer. There is no clear explanation for how clarithromycin would lead to more deaths than placebo in these patients.

PNN Pharmacotherapy Line
Feb. 26, 2018 * Vol. 25, No. 38
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Feb. 24 issue of Lancet (2018; 391).
Atezolizumab in Platinum-Refractory Urothelial Carcinoma: Among patients with metastatic urothelial carcinoma overexpressing programmed death–ligand 1 (PD-L1) that had progressed after platinum-based chemotherapy, the anti-PD-L1 atezolizumab was safer than standard chemotherapy, with similar efficacy outcomes, researchers report (pp. 748–57). In an open-label, phase 3 trial at 217 centers, random assignment of 931 patients to platinum-based chemotherapy or atezolizumab produced these results: “In the [population with more PD-L1 expression in tumor-infiltrating immune cells] (n = 234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11.1 months [95% CI 8.6–15.5; n = 116] vs 10.6 months [8.4–12.2; n = 118]; stratified hazard ratio [HR] 0.87, 95% CI 0.63–1.21; p = 0.41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in [this] population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15.9 months [95% CI 10.4 to not estimable] vs 8.3 months [5.6–13.2]; HR 0.57, 95% CI 0.26–1.26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients).” (T. Powles, thomas.powles@bartshealth.nhs.uk)
Gonadotrophins, Intrauterine Insemination for Anovulation in Clomifene Failure: Among normogonadotropic women who were not pregnant after six cycles of clomifene citrate, a switch of treatment to gonadotrophins increased the chance of livebirth over continued treatment with clomifene citrate, a study shows (pp. 758–65). At 48 Dutch hospitals, 666 participants were assigned to six cycles of gonadotrophins plus intrauterine insemination, gonadotrophins plus intercourse, clomifene citrate plus intrauterine insemination, or clomifene citrate plus intercourse, with these results: “Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1.24 [95% CI 1.05–1.46]; p = 0.0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1.14 [95% CI 0.97–1.35]; p = 0.1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins.” (M. van Wely, m.vanwely@amc.uva.nl)
>>>PNN NewsWatch
* Reviewing the new adjuvanted recombinant hepatitis B vaccine (Heplisav-B, Dynavax), the Medical Letter notes the increased immunogenicity of the product’s two-dose series, compared with three doses of the older Engerix-B product. Long-term data are lacking, though. The CDC’s Advisory Committee on Immunization Practices last week recommended addition of Heplisav-B to its adult immunization schedule.
* Hospira is voluntarily recalling 3 lots of
Labetalol Hydrochloride Injection, USP, 100 mg/20 mL vial (NDC 0409-2267-20), and one lot of Labetalol Hydrochloride Injection, USP, Novaplus (NDC 0409-2267-25) to the hospital/institution level because of cracks on the rim surface of vials underneath the stopper and crimp seal.
>>>PNN JournalWatch
* Gastrointestinal Symptoms in Diabetes: Prevalence, Assessment, Pathogenesis, and Management, in Diabetes Care, 2018; 41: 627–37. (M. Horowitz, michael.horowitz@adelaide.edu.au)
*
Review: Defining a Unified Vascular Phenotype in Systemic Sclerosis, in Arthritis & Rheumatology, 2018; 70: 162–70. (Y. Allanore, yannick.allanore@aphp.fr)
*
Intranasal Ketamine and Its Potential Role in Cancer-Related Pain, in Pharmacotherapy, 2018; 38: 10.1002/phar.2090. (R. D. Harvey, donald.harvey@emory.edu)

PNN Pharmacotherapy Line
Feb. 27, 2018 * Vol. 25, No. 39
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
Mar. issue of Diabetes Care (2018; 41).
Niacin Effects on Gut Microbiome: For patients with prediabetes or type 2 diabetes, a delayed-release niacin intervention that improves the gut microbiome is worth exploring, according to a 500-participant study (pp. 398–405). Metabolic phenotypes were identified based on niacin (nicotinic acid [NA] and nicotinamide [NAM]) status and the gut microbiome. Microcapsules that release NA and NAM in the colon were formulated and tested in two additional human intervention studies, with these results: “We found a reduced alpha-diversity and Bacteroidetes abundance in the microbiome of obese human subjects associated with a low dietary niacin intake. We therefore developed delayed-release microcapsules targeting the ileocolonic region to deliver increasing amounts of NA and NAM to the microbiome while preventing systemic resorption to avoid negative side effects (e.g., facial flushing). In vitro studies on these delayed-release microcapsules revealed stable conditions at pH 1.4, 4.5, and 6.8, followed by release of the compounds at pH 7.4, simulating the ileocolonic region. In humans in vivo, gut-targeted delayed-release NA but not NAM produced a significant increase in the abundance of Bacteroidetes. In the absence of systemic side effects, these favorable microbiome changes induced by microencapsulated delayed-release NA were associated with an improvement of biomarkers for systemic insulin sensitivity and metabolic inflammation.” (M. Laudes, matthias.laudes@uksh.de)
Gut Microbiota–Related Metabolites & Weight Loss: Patients with overweight and obesity and decreases in circulating choline or l-carnitine levels while on a low-calorie weight-loss diet had significantly greater weight loss and improved gut microbiota–related metabolites, researchers report (pp. 413–9). Trimethylamine N-oxide (TMAO), its precursors (choline and l-carnitine), body weight (BW), waist circumference (WC), body fat composition, fat distribution, and resting energy expenditure (REE) showed these changes during dieting in the POUNDS Lost trial: “Individuals with a greater reduction of choline (P <0.0001) and l-carnitine (P <0.01) rather than TMAO showed significant losses of BW and WC at 6 months. The reduction of choline was significantly predictive of decreases in body fat composition, fat distribution, and REE. Results of sensitivity analysis showed that the baseline diabetes risk status, such as the presence of hyperglycemia (31% of the total participants) and fasting glucose levels, did not modify the associations. Early changes in choline and l-carnitine were significantly predictive of weight loss over 2 years (P <0.05 for all). Individuals with increases in choline or l-carnitine were 2.35-times (95% CI 1.38, 4.00) or 1.77-times (1.06, 2.95) more likely to fail to lose weight (–5% or more loss) at 2 years.” (L. Qi, lqi1@tulane.edu)
Smoking Cessation in Diabetes Education: Long-term abstinence among smokers with diabetes or prediabetes was increased significantly through use of the Ottawa Model for Smoking Cessation (OMSC) in the cluster-randomized Tobacco Intervention in Diabetes Education study conducted in Ontario (pp.406–12). Compared with 7 sites using a wait-list control (WLC) condition, 7 sites using the OMSC intervention showed these outcomes: “A total of 313 smokers (OMSC group n = 199, WLC group n = 114) with diabetes or prediabetes were enrolled. The [carbon monoxide]-confirmed abstinence rate at 6 months was 11.1% in the OMSC group versus 2.6% in the WLC group (odds ratio 3.73 [95% CI 1.20, 11.58]; P = 0.02).” (R. D. Reid, breid@ottawaheart.ca)
Online ‘Standards of Care’: Instead of a single annual update, the Standards for Medical Care in Diabetes will now be updated online and revised continuously, the American Diabetes Association (ADA) announced (pp. 387–8). “The living Standards of Care represent a paradigm shift that reflects the ADA’s goal and desire to get the latest information into the hands of providers as soon as possible to meet our mission objective to ‘improve the lives of all people living with diabetes,’” authors wrote. Examples of “update worthy” events might be FDA approval of metformin for prevention in prediabetes, major clinical trial results that affect practice, new drug approvals, and new or updated ADA consensus definitions or positions. (W. T. Cefalu, wcefalu@diabetes.org)

PNN Pharmacotherapy Line
Feb. 28, 2018 * Vol. 25, No. 40
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Feb. 27 issue of JAMA (2018; 319).
Meropenem-Vaborbactam in Complicated UTIs: In the phase 3, multicenter, multinational, randomized TANGO I trial of patients with complicated urinary tract infection (UTI), meropenem-vaborbactam was noninferior to piperacillin-tazobactam with respect to a composite outcome of complete resolution or improvement of symptoms along with microbial eradication (pp. 788–99). The primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population; the European Medicines Agency (EMA) end point was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations.
Results showed: “Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, −0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, −4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam.” (K. S. Kaye,
keithka@med.umich.edu)
Gabapentin for Chronic Neuropathic Pain: With 1 in 14 adults having neuropathic pain and few effective remedies available, gabapentin is an important therapeutic option, according to a JAMA Clinical Evidence Synopsis (pp. 818–9). “In people with moderate or severe neuropathic pain, oral gabapentin (1200-3600 mg/d) was associated with greater achievement of substantial (pain intensity reduction of ≥50% or very much improved on Patient Global Impression of Change [PGIC] scale) or moderate (pain intensity reduction of ≥25% or much or very much improved on PGIC scale) benefit than placebo,” the authors write. “In patients with [postherpetic neuralgia], gabapentin was associated with higher rates of substantial benefit (32% for gabapentin vs 17% for placebo) and moderate benefit (46% for gabapentin vs 25% for placebo).” (A. Moore, andrew.moore@ndcn.ox.ac.uk)
“Twenty-five years after the initial FDA approval of gabapentin, there is still limited evidence to support its widespread use for the majority of indications for which it is prescribed, many of which are off-label,” editorialists write (
pp. 776–8). “With hundreds of clinical trials and dozens of Cochrane reviews evaluating different FDA-approved and off-label indications, the history of gabapentin’s availability illustrates how additional regulatory requirements and postmarketing surveillance initiatives might have led to better coordination of evaluation efforts, and could have provided an evidence base that was more expeditiously and rigorously developed, that was reliably reported to patients and clinicians, and that served to improve clinical care.” (J. S. Ross, joseph.ross@yale.edu)
Varicose Veins & Venous Thromboembolism: Adults with varicose veins have a higher risk of incident deep vein thrombosis (DVT) but perhaps not pulmonary embolism or peripheral arterial disease, a retrospective analysis of national health data from Taiwan indicates (pp. 807–17). “Whether the association between varicose veins and DVT is causal or represents a common set of risk factors requires further research.,” conclude the investigators. (P-C Chen, peichun@mail.cmu.edu.tw)
>>>PNN NewsWatch
* Bella All Natural is voluntarily recalling its Diet Capsules labeled as Bella, lot number MFD:10.15.2017 EXP: 10.14.2019, to the consumer level because of the presence of sibutramine, FDA said.

PNN Pharmacotherapy Line
Mar. 1, 2018 * Vol. 25, No. 41
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Mar. 1 issue of the New England Journal of Medicine (2018; 378).
Hydrocortisone Therapy in Septic Shock: The uncertainty over the role of hydrocortisone support in critically ill patients with septic shock continues with differing results from two large clinical trials.
Continuous hydrocortisone infusion at 200 mg/d for up to 7 days in 3,658 patients with septic shock who were on ventilation produced no significant benefits in a primary end point of all-cause death at 90 days (27.9% versus 28.8% with placebo), the ADRENAL trial shows (
pp. 797–808). Those on hydrocortisone had faster resolution of shock (median of 3 days versus 4 days with placebo) and a shorter duration of ventilation (median of 6 days versus 7 days with placebo). (B. Venkatesh, bvenkatesh@georgeinstitute.org.au)
In the APROCCHSS trial of 1,241 patients with septic shock, the 90-day all-cause mortality rate was significantly lower with hydrocortisone plus fludrocortisone than placebo (43.0% versus 49.1%) (
pp. 809–18). This trial, which began as a three-drug comparison that included drotrecogin alfa (activated) before that agent’s market withdrawal, also showed benefits in a number of secondary outcomes. (D. Annane, djillali.annane@aphp.fr)
“Will these two trials change clinical practice?” asks an editorialist (
pp. 860–1). “Although 90-day survival differed between the studies, both showed the beneficial effects of hydrocortisone on secondary outcomes of shock reversal and the duration of mechanical ventilation. It is unlikely that in the near future sufficiently powered trials will provide us with better data. Thus, clinicians will have to use these data and subsequent meta-analyses to decide how best to treat patients with septic shock. Estimating 90-day mortality at the bedside is not practical. It is likely that some practitioners caring for a patient with a deteriorating condition who is receiving escalating doses of vasopressors, in whom other core interventions have been instituted (i.e., appropriate antibiotics and adequate volume resuscitation and source control), will consider that the short-term benefits of low-dose hydrocortisone may exceed any risks (e.g., antiinflammatory effects) as an added therapy in selected patients.” (A. F. Suffredini)
Balanced Crystalloids versus Saline: In trials at Vanderbilt U. that compared clinical effects of balanced crystalloids with those of saline infusions, benefits are demonstrated in critically ill but not noncritically ill patients.
Comparing lactated Ringer’s solution or Plasma-Lyte A with saline in 13,347 noncritically ill patients in the emergency department, SALT-ED investigators found no difference in the number of days alive after discharge before day 28 (median of 25 days in each group) (
pp. 819–28). Major adverse kidney events within 30 days were lower with balanced crystalloids than with saline. (T. W. Rice, todd.rice@vanderbilt.edu)
SMART investigators showed a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction with balanced crystalloids in 7,942 critically ill patients, compared with saline (
pp. 829–39). Lactated Ringer’s solution or Plasma-Lyte A significantly lowered the rate of major kidney adverse events (14.3% versus 15.45 with saline); differences in in-hospital mortality at 30 days, new renal-replacement therapy, and incidence of persistent renal dysfunction showed statistical trends (0.05 < P < 0.1). (T. W. Rice, todd.rice@vanderbilt.edu)
“What clinicians need to consider is whether the results of an open-label trial conducted in a single, major U.S. medical center can be generalized to the ways in which their own patients survive, feel, and function,” an editorialist writes (
pp. 862–3). “None of the currently used resuscitation fluids are ‘physiological,’ and questions regarding their safety and efficacy will remain, despite the results of these two trials and any randomized, controlled trials that are currently recruiting participants. Considerations remain regarding the effects of different types of resuscitation fluids and the ways they are used in specific, high-risk patient populations. Assessments of longer-term, patient-centered outcomes and health economics are fundamental to informing clinicians about their choice of resuscitation fluids in critically ill patients. The trials presented here inform that thinking but do not provide unequivocal clinical direction.” (J. Myburgh)

PNN Pharmacotherapy Line
Mar. 2, 2018 * Vol. 25, No. 42
Providing news and information about medications and their proper use

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>>>Psychiatry Report
Source:
Mar. issue of the American Journal of Psychiatry (2018; 175).
Adjunctive Cannabidiol in Schizophrenia: In an exploratory study of 88 patients with schizophrenia, cannabidiol (CBD) had beneficial effects mediated through a mechanism other than dopamine antagonism (pp. 225–31). The results could indicate the possibility of a new class of drugs for this disorder, the investigators conclude. Results based on responses on the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S) were as follows: “After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=−1.4, 95% CI=−2.5, −0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=−0.5, 95% CI=−0.8, −0.1) and as not severely unwell (CGI-S: treatment difference=−0.3, 95% CI=−0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=−0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=−0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.” (P. McGuire)
SSRIs in Mild Cognitive Impairment: In the longitudinal Alzheimer’s Disease Neuroimaging Initiative, long-term SSRI treatment was associated with a slower progression from mild cognitive impairment (MCI) to Alzheimer’s dementia (pp. 232–41). Results for 755 currently nondepressed participants showed these results: “In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with a delayed progression to Alzheimer’s dementia by approximately 3 years, compared with short-term SSRI treatment, treatment with other antidepressants, or no treatment and compared with MCI patients without a history of depression. No differences in CSF biomarker levels were observed between treatment groups.” (C. Bartels)
Antidepressant Outcomes Predicted by Genetic Variation: A single-nucleotide polymorphism (SNP) affecting the hypothalamic-pituitary-adrenal (HPA) axis function “may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective,” researchers report (pp. 251–61). Complete genotyping data for 636 patients in the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits showed these associations and outcomes for 16 candidate SNPs during treatment with escitalopram, sertraline, or extended-release venlafaxine: “The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.” (C. P. O’Connell)
>>>PNN NewsWatch
* FDA said yesterday it is alerting health care professionals and patients not to use drug products from Cantrell Drug Company of Little Rock, AR, including opioid products and other drugs intended for sterile injection, that were produced by the company and distributed nationwide. The agency cited concerns “about serious deficiencies in Cantrell’s compounding operations, including its processes to ensure quality and sterility assurance that put patient safety at risk.”

PNN Pharmacotherapy Line
Mar. 5, 2018 * Vol. 25, No. 43
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Mar. 3 issue of Lancet (2018; 391).
Dolutegravir–Rilpivirine for HIV-1 Suppression: In the phase 3 SWORD-1 and SWORD-2 trials, the combination of dolutegravir and rilpivirine was noninferior to patients’ current antiretroviral therapy (ART) regimens (CARs), researchers report (pp. 839–49). Based on a primary endpoint of proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication, investigators found these results in 1,028 participants with HIV-1 in 12 countries: “At week 48 (last patient visit was Nov. 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir–rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0.2% (95% CI −3.0 to 2.5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir–rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir–rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir–rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]).” (L. P. Kahl, lesley.p.kahl@viivhealthcare.com)
Triple Antiplatelet Therapy in Acute Cerebral Ischemia: In an international, prospective, randomized, open-label, blinded-endpoint trial in 3,096 adult participants with ischemic stroke or transient ischemic attack (TIA) within 48 hours of onset, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA but did significantly increase the risk of major bleeding (pp. 850–9). Intensive antiplatelet therapy consisted of aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily; this regimen was compared with guideline-based therapy with clopidogrel alone or combined aspirin and dipyridamole. Results showed: “The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0.90, 95% CI 0.67–1.20, p = 0.47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2.54, 95% CI 2.05–3.16, p <0.0001).” (P. M. Bath, philip.bath@nottingham.ac.uk)
>>>PNN NewsWatch
* Biogen and AbbVie on Friday announced a voluntary worldwide withdrawal of their daclizumab product (Zinbryta) for relapsing multiple sclerosis. The companies said they believe that characterizing the complex and evolving benefit/risk profile of the drug will not be possible going forward given the limited number of patients being treated. The action followed announcement of an urgent review after eight patients in Germany and Spain who have multiple sclerosis developed encephalitis and other serious inflammatory brain disorders after taking the injectable agent, the Wall Street Journal reported.
*
FDA is warning consumers to be wary of promotions of products claiming to prevent, treat, or cure influenza. “Consumers should be aware that there are no legally marketed over-the-counter (OTC) drugs to prevent or cure the flu,” the agency said. “However, there are legal OTC products to reduce fever and to relieve muscle aches, congestion and other symptoms typically associated with the flu. Products sold online are fraudulent if they claim to prevent, treat or cure the flu, and have not been evaluated by the FDA for that intended use.”
>>>PNN JournalWatch
* 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, in Journal of the American College of Cardiology, 2018; 71: 10.1016/j.jacc.2017.12.048. (K. A. Hicks)
*
Pediatric Medication Safety in the Emergency Department, in Pediatrics, 2018; 141: 10.1542/peds.2017-4066. (L. Benjamin)
* Guidelines for Adolescent Depression in Primary Care (GLAD-PC):
Part I. Practice Preparation, Identification, Assessment, and Initial Management, and Part II. Treatment and Ongoing Management, in Pediatrics, 2018; 141: 10.1542/peds.2017-4081 and 10.1542/peds.2017-4082. (GLAD-PC Steering Group)

PNN Pharmacotherapy Line
Mar. 6, 2018 * Vol. 25, No. 44
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-release articles from and the Mar. 6 issue of Annals of Internal Medicine (2018; 168).
Glycemic Control in Type 2 Diabetes Mellitus: In an updated guidance statement, the American College of Physicians recommends relaxed glycemic targets for pharmacologic treatment of nonpregnant adults with type 2 diabetes (10.7326/M17-0939). Based on review of conflicting guidelines, the College formulated these guidance statements (A. Qaseem, aqaseem@acponline.org):
* Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients’ preferences, patients’ general health and life expectancy, treatment burden, and costs of care.
* Clinicians should aim to achieve an HbA
1c level between 7% and 8% in most patients with type 2 diabetes.
* Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA
1c levels less than 6.5%.
* Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA
1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.
Direct-Acting Antivirals in Kidney Transplantation: Used as prophylaxis before and after kidney transplantation from donors infected with hepatitis C virus (HCV) to noninfected recipients, direct-acting antivirals (DAAs) were safe and effective in a small study (10.7326/M17-2871). The transplant kidneys came from deceased donors aged 13 to 50 years with confirmed HCV infection. All recipients received grazoprevir 100 mg and elbasvir 50 mg immediately before transplant and continued receiving this combination for 12 weeks after transplant. Recipients who received organs from donors with HCV genotype 2 or 3 infection had sofosbuvir 400 mg added to their regimen. Among the 10 organ recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. “If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection,” the authors conclude. (C. M. Durand, christinedurand@jhmi.edu)
Vaccination in Infants Born to Mothers Taking Adalimumab: Because of persistence of adalimumab in some infants born to mothers being treated for active inflammatory bowel disease during gestation, administration of live vaccinations should be delayed until the agent is not detectable, authors of a letter recommend (10.7326/L17-0629). Researchers report the case of a 34-year-old woman who took adalimumab for Crohn disease during her pregnancy. Once her Crohn disease was under control, the mother continued to take a maintenance dose until her baby was born at 39 weeks. While the birth was uneventful, the infant has had persistent serum presence of adalimumab up to its last test at 19 months. The persistence of this agent remains unexplained, but the researchers caution that clinicians should be aware of this possibility and delay vaccines in children born to mothers treated for inflammatory bowel disease with infliximab or adalimumab. (R. Labetoulle)
Physical Activity & Frailty: In a study of 1,635 community-dwelling adults aged 70–89 years, a structured, moderate-intensity physical activity program failed to reduce risks for frailty during a 2-year period (pp. 309–16). Compared with a health education program consisting of workshops and stretching exercises, the physical activity intervention was associated only with significant improvement in inability to rise from a chair, one of three criteria in the Study of Osteoporotic Fractures. (A. Trombetti, Andrea.Trombetti@hcuge.ch)
>>>PNN NewsWatch
* Hospira is voluntarily recalling three lots of Hydromorphone HCl Injection, USP CII 10 mg/mL, 1 mL in 2 mL single dose vials, lot numbers 71330DD (NDC 0409-2634-01), and 691853F and 700753F (NDC 0703-0110-01 – Teva lots) to the hospital/institution level because some units may be empty or cracked at the bottom of the glass vial.

PNN Pharmacotherapy Line
Mar. 7, 2018 * Vol. 25, No. 45
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 6 issue of JAMA (2018; 319).
Meds for Chronic Back Pain or Osteoarthritis Pain: Opioids were not superior nonopioids in a 12-month study of pain-related function in 240 patients with moderate-to-severe chronic back pain or hip or knee osteoarthritis pain (pp. 872–82). At VA primary care clinics, these results were generated for immediate-release morphine, oxycodone, or hydrocodone/acetaminophen or acetaminophen/NSAIDs: “Groups did not significantly differ on pain-related function over 12 months (overall P = .58); mean 12-month {Brief Pain Inventory (BPI)] interference was 3.4 for the opioid group and 3.3 for the nonopioid group (difference, 0.1 [95% CI, −0.5 to 0.7]). Pain intensity was significantly better in the nonopioid group over 12 months (overall P = .03); mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group (difference, 0.5 [95% CI, 0.0 to 1.0]). Adverse medication-related symptoms were significantly more common in the opioid group over 12 months (overall P = .03); mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group (difference, 0.9 [95% CI, 0.3 to 1.5]).” (E. E. Krebs, erin.krebs@va.gov)
Vaccine Antigen Exposure in Young Children: Concerns that multiple vaccines in young children can weaken the immune system are unfounded, according to an case–control study of patients seen at institutions participating in the Vaccine Safety Datalink (VSD) (pp. 906–13). Emergency department and inpatient visits for nonvaccine-targeted infections showed these patterns based on cumulative vaccine antigen exposure: in 193 cases and 751 controls: “Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was −2.3 (95% CI, −10.1 to 5.4; P = .55). Among children with vs without non–vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07).” (J. M. Glanz, jason.m.glanz@kp.org)
“The present study provides further reassurance to parents that the U.S. childhood vaccination schedule is safe in terms of not being associated with an increased risk of non–vaccine-targeted infections, yet the small but vocal minority of antivaccine groups may not be satisfied by the evidence provided through VSD and other vaccine safety surveillance,” editorialists write (
pp. 870–1). “For example, insistence by such groups that vaccines cause autism persists, despite overwhelming science to the contrary. Although the VSD and other mechanisms, such as the Post-Licensure Immunization Safety Monitoring system, must continue to study the scientific questions, closer attention must also be paid to fulfilling the VSD’s second purpose of strengthening the public’s confidence in vaccines.” (S. T. O’Leary, sean.oleary@ucdenver.edu)
Vitamin & Mineral Supplements: “When reviewing medications with patients, clinicians should ask about use of micronutrient (and botanical or other dietary) supplements in counseling about potential interactions,” write authors of a Viewpoint article (pp. 859–60). “For example, supplemental vitamin K can decrease the effectiveness of warfarin, and biotin (vitamin B7) can interfere with the accuracy of cardiac troponin and other laboratory tests. Patient-friendly interaction checkers are available free of charge online (search for interaction checkers on drugs.com, WebMD, or pharmacy websites).” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
>>>PNN NewsWatch
* FDA yesterday granted fast-track approval to ibalizumab-uiyk (Trogarzo, TaiMed Biologics USA Corp.) for treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen. The first agent in a new class of HIV drugs in a decade, ibalizumab-uiyk is a CD4-directed post-attachment HIV-1 inhibitor that blocks HIV by binding to CD4+ receptors on host cells.
*
Sagent Pharmaceuticals has recalled 10 lots of Methylprednisolone Sodium Succinate for Injection, USP, 40 mg, 125 mg, and 1 g to the user level because of unknown impurities.

PNN Pharmacotherapy Line
Mar. 8, 2018 * Vol. 25, No. 46
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Mar. 8 issue of the New England Journal of Medicine (2018; 378).
Increasing Glucocorticoid Doses in Asthma Exacerbations: Two studies yield conflicting results concerning management of asthma exacerbations with sharply increased doses of inhaled glucocorticoids.
In 254 children ages 5–11 years with mild-to-moderate persistent asthma, quintupling maintenance fluticasone propionate doses at early signs of loss of asthma control failed to reduce the rate of severe asthma exacerbations or improve other asthma outcomes, and may have been associated with diminished linear growth, researchers report (
pp. 891–901). Participants treated for 48 weeks had these outcomes during the double-blind study: “The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P = 0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was −0.23 cm per year (P = 0.06).” (D. J. Jackson, djj@medicine.wisc.edu)
A similar study of adults and adolescents showed fewer severe asthma exacerbations when inhaled glucocorticoid doses were increased 4-fold as part of a personalized self-management plan (
pp. 902–10): “A total of 1,922 participants underwent randomization, of whom 1,871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P = 0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group.” (T. Harrison, tim.harrison@nottingham.ac.uk)
“Currently, clinicians are challenged to prevent and treat asthma exacerbations and to implement self-management plans,” concludes an editorialist (
pp. 950–2). “Evidence indicates that substantial escalation of regularly used inhaled glucocorticoids, even by a factor of 4 or 5, fails to prevent most asthma exacerbations. A small subgroup of adults and adolescents with asthma may have a response to an escalation strategy; however, their baseline and exacerbation characteristics remain to be defined.” (P. G. Bardin)
Tenofovir for Preventing Perinatal Hepatitis B Transmission: Reacting to a negative study of tenofovir disoproxil fumarate (TDF) for preventing perinatal hepatitis B virus (HBV) transmission from hepatitis B e antigen (HBeAg)–positive mothers to children (pp. 911–23, G. Jourdain, gonzague.jourdain@ird.fr), an editorialist reaches this conclusion (pp. 952–3): “Vaccination, particularly if delayed, may fail to protect infants born to mothers with high serum levels of HBV DNA or HBeAg; the current levels of evidence supporting antiviral therapy with TDF (or possibly lamivudine or telbivudine) to reduce levels of maternal HBV DNA during pregnancy have been accepted by the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver. Preventing the residuum of chronic neonatal infections requires testing for [hepatitis B surface antigen] and HBV DNA and antiviral treatment or, alternatively, simple measures that bypass additional testing and treatment.… HBV vaccination at birth, despite the challenges for poverty-affected countries to deliver vaccination in rural and isolated locales, is feasible. A conjoint mobilization of HIV services to serve persons with chronic HBV infection is required. [This statistically “negative”] trial … puts down an intriguing marker attesting to the possibility that rapidly phasing in the timely administration of a safe monovalent HBV vaccine within a few hours after birth could contribute to the interruption of mother-to-child transmission and avert preventable HBV infections in childhood.” (G. Dusheiko)

PNN Pharmacotherapy Line
Mar. 9, 2018 * Vol. 25, No. 47
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Cardiology Report
Source:
Mar. issue of the Journal of the American College of Cardiology (2018; 71).
Digoxin & Mortality in AF: Use of digoxin is an independent risk factor for mortality in patients with atrial fibrillation (AF), a study shows, regardless of whether they have heart failure (10.1016/j.jacc.2017.12.060). Showing that those with the highest serum digoxin levels are at greatest risk, the authors report these findings from 17,897 patients with AF using a propensity score–adjusted analysis: “At baseline, 5,824 (32.5%) patients were receiving digoxin. Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 0.96 to 1.23; p = 0.19). However, patients with a serum digoxin concentration ≥1.2 ng/ml had a 56% increased hazard of mortality (adjusted HR: 1.56; 95% CI: 1.20 to 2.04) compared with those not on digoxin. When analyzed as a continuous variable, serum digoxin concentration was associated with a 19% higher adjusted hazard of death for each 0.5-ng/ml increase (p = 0.0010); these results were similar for patients with and without heart failure. Compared with propensity score–matched control participants, the risk of death (adjusted HR: 1.78; 95% CI: 1.37 to 2.31) and sudden death (adjusted HR: 2.14; 95% CI: 1.11 to 4.12) was significantly higher in new digoxin users.” (R. D. Lopes)
Resource Use & Costs of Cardiovascular Care: The immense resource and financial cost of cardiovascular disease (CVD) is quantified based on 10-year health care costs for 6,814 asymptomatic participants enrolled in MESA (Multi-Ethnic Study of Atherosclerosis) (10.1016/j.jacc.2017.12.064). Concluding that “maintenance of a healthy population has the potential to markedly reduce the economic burden of CVD among asymptomatic individuals,” the investigators report these findings: “Risk factor prevalence increased dramatically and, by 10 years, diabetes, hypertension, and dyslipidemia was reported in 19%, 57%, and 53%, respectively. Self-reported symptoms (i.e., chest pain or shortness of breath) were common (approximately 40% of enrollees). At 10 years, approximately one-third of enrollees reported having an echocardiogram or exercise test, whereas 7% underwent invasive coronary angiography. These utilization patterns resulted in 10-year health care costs of $23,142. The largest proportion of costs was associated with CVD medication use (78%). Approximately $2 of every $10 were spent for outpatient visits and diagnostic testing among the elderly, obese, those with a high-sensitivity C-reactive protein level >3 mg/l, or coronary artery calcium score (CACS) ≥400. Costs varied widely from <$7,700 for low-risk (Framingham risk score <6%, 0 CACS, and normal glucose measurements at baseline) to >$35,800 for high-risk (persons with diabetes, Framingham risk score ≥20%, or CACS ≥400) subgroups. Among high-risk enrollees, CVD costs accounted for $74 million of the $155 million consumed by MESA participants.” (L. J. Shaw)
NOACs & Risk of Serious Liver Injury: Non–vitamin K antagonist oral anticoagulants (NOACs) are not associated with increased risk of hepatic injury, compared with vitamin K antagonists (VKAs), according to data from Quebec health insurance administrative databases (10.1016/j.jacc.2018.01.009). In a cohort analysis of patients with or without prior liver disease who were newly diagnosed with nonvalvular atrial fibrillation, these associations of medication use and hepatic risks were made: “The cohort comprised 51,887 patients, including 3,778 with prior liver disease. During 68,739 person–years of follow-up, 585 patients experienced a serious liver injury. Compared with current use of VKAs, current use of NOACs was not associated with an increased risk of serious liver injury in patients without or with prior liver disease (adjusted HR: 0.99; 95% CI: 0.68 to 1.45; and adjusted HR: 0.68; 95% CI: 0.33 to 1.37, respectively).” (A. Douros)
>>>PNN NewsWatch
* Testifying yesterday before a House Committee on Energy and Committee subcommittee, FDA Commissioner Scott Gottlieb, MD, said the agency is using CMS data to study the difference in efficacy between cell- and egg-based influenza vaccines. FDA is also “looking at how we develop a more robust recombinant vaccine manufacturing process to increase yield, while reducing cost,” Gottlieb said.

PNN Pharmacotherapy Line
Mar. 12, 2018 * Vol. 25, No. 48
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Mar. 10 issue of Lancet (2018; 391).
Need for Self-monitored Blood Pressure: Patient self-monitoring of blood pressure “could become the cornerstone of hypertension management in primary care,” TASMINH4 investigators conclude based on findings of significantly lower blood pressures among those titrated based on patient readings than on clinic determinations (pp. 949–59). The study compared self-monitoring blood pressure (self-monitoring group), self-monitoring blood pressure with telemonitoring (telemonitoring group), and usual care (clinic blood pressure; usual care group) at 152 U.K. general practices, with these results: “1,182 participants were randomly assigned to the self-monitoring group (n = 395), the telemonitoring group (n = 393), or the usual care group (n = 394), of whom 1,003 (85%) were included in the primary analysis. After 12 months, systolic blood pressure was lower in both intervention groups compared with usual care (self-monitoring, 137.0 [SD 16.7] mm Hg and telemonitoring, 136.0 [16.1] mm Hg vs usual care, 140.4 [16.5]; adjusted mean differences vs usual care: self-monitoring alone, −3.5 mm Hg [95% CI −5.8 to −1.2]; telemonitoring, −4.7 mm Hg [–7.0 to −2.4]). No difference between the self-monitoring and telemonitoring groups was recorded (adjusted mean difference −1.2 mm Hg [95% CI −3.5 to 1.2]). Results were similar in sensitivity analyses including multiple imputation. Adverse events were similar between all three groups.” (R. J McManus, richard.mcmanus@phc.ox.ac.uk)
>>>BMJ Highlights
Source:
Early-release articles from BMJ (2018; 360).
Fluoroquinolones & Aortic Integrity: In a nationwide study conducted in Sweden in 2006–18, patients taking oral fluoroquinolones had significantly higher risk of aortic aneurysm or dissection, researchers report (k678). Based on 360,088 treatment episodes, 78% of them with ciprofloxacin, these 60-day risk levels were identified in comparison with people taking amoxicillin: “Within the 60 day risk period, the rate of aortic aneurysm or dissection was 1.2 cases per 1,000 person years among fluoroquinolone users and 0.7 cases per 1,000 person years among amoxicillin users. Fluoroquinolone use was associated with an increased risk of aortic aneurysm or dissection (hazard ratio 1.66 (95% confidence interval 1.12 to 2.46)), with an estimated absolute difference of 82 (95% confidence interval 15 to 181) cases of aortic aneurysm or dissection by 60 days per 1 million treatment episodes. In a secondary analysis, the hazard ratio for the association with fluoroquinolone use was 1.90 (1.22 to 2.96) for aortic aneurysm and 0.93 (0.38 to 2.29) for aortic dissection.” (B. Pasternak, bjorn.pasternak@ki.se)
Vitamin D & Cancer Risk: In Japan, a prospective case–cohort study indicates lower overall cancer risks among people with higher plasma levels of 25-hydroxyvitamin D (k671). The study, conducted at nine public health centers across the country, compared 3,301 people with incident cancers with 4,044 randomly selected cohorts. Vitamin D quartile results showed: “Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend = 0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend = 0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios.” (T. Yamaji, tyamaji@ncc.go.jp)
>>>PNN JournalWatch
* Designing Surveillance of Healthcare-Associated Infections in the Era of Automation and Reporting Mandates, Clinical Infectious Diseases, 2018: 66: 970–6. (M. S. M. van Mourik, M.S.M.vanMourik-2@umcutrecht.nl)
*
Efficacy of Acupuncture Is Noninferior to Nicotine Replacement Therapy for Tobacco Cessation, Chest, 2018: 153: 680–8. (J-s Yang, zml@ibucm.com)
*
Targeting HER2 by Combination Therapies, Journal of Clinical Oncology, 2018: 36: 808–11. (M. M. Moasser, mark.moasser@ucsf.edu)

PNN Pharmacotherapy Line
Mar. 13, 2018 * Vol. 25, No. 49
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
Early-online articles from and Mar. issue of JAMA Internal Medicine (2018; 178).
In-Hospital Multifaceted Clinical Pharmacist Intervention: In Denmark, a multifaceted pharmacist intervention based on medication review, patient interview, and follow-up may have reduced the number of readmissions and emergency department (ED) visits (pp. 375–82). In the Odense Pharmacist Trial Investigating Medication Interventions at Sector Transfer (OPTIMIST), participants were randomized into 3 groups: usual care (no intervention), a basic intervention (medication review), and an extended intervention (medication review, 3 motivational interviews, and follow-up with the primary care physician, pharmacy, and nursing home). Results showed: “A total of 1,467 patients (679 men [46.3%] and 788 women [53.7%]; median age, 72 years; interquartile range, 63–80 years) were part of the primary analysis, including 498 randomized to usual care, 493 randomized to the basic intervention, and 476 randomized to the extended intervention. The extended intervention had a significant effect on the numbers of patients who were readmitted within 30 days (hazard ratio [HR], 0.62; 95% CI, 0.46–0.84) or within 180 days (HR, 0.75; 95% CI, 0.62–0.90) after inclusion and on the number of patients who experienced the primary composite end point (HR, 0.77; 95% CI, 0.64–0.93). The study showed a nonsignificant reduction in drug-related readmissions within 30 days (HR, 0.65; 95% CI, 0.39–1.09) and within 180 days (HR, 0.80; 95% CI, 0.59–1.08) after inclusion and in deaths (HR, 0.83; 95% CI, 0.22–3.11). The number needed to treat to achieve the primary composite outcome for the extended intervention (vs usual care) was 12.” (L. Vestergaard Ravn-Nielsen, leneravn.nielsen@gmail.com)
Atorvastatin Usage After Patent Expiration: In the 2 years following marketing of generic atorvastatin in 2012, costs fell by 28% while usage rose by 20%, according to a study of the nationally representative, longitudinal Medical Expenditure Panel Survey (MEPS) database (doi: 10.1001/jamainternmed.2018.0990). The authors report: “From 2012 to 2014, of 110,789 MEPS participants, 75,174 were eligible for the study (age, mean [standard error], 47.0 [0.2] years; 52% were female). From 2012 to 2014, overall atorvastatin users increased 20%, from 12.5 million adults (5.3% of U.S. adults) to 15.0 million adults (6.2% of U.S. adults), and prescriptions increased from 50.3 million to 74.0 million. Lipitor use decreased from 3.9 million adults in 2012 to 0.7 million adults in 2014, with a concomitant increase in uptake of generic statin from 8.6 million in 2012 to 14.3 million in 2014.
“In this time period, total atorvastatin-associated expenditures decreased from $7.0 billion to $5.4 billion. Total national expenditures associated with Lipitor were $3.5 billion (50% of total atorvastatin cost) in 2012 vs $357 million (7% of total cost) in 2014. Excess expenditure associated with continued Lipitor use totaled $2.1 billion from 2012 to 2014. More than half (57%) of excessive spending ($1.2 billion) was noted among patients with Medicare or Medicaid, who accounted for 58% of Lipitor users. We found that per-user total expenditure for Lipitor were higher compared with generic throughout 2012 to 2014. However, in 2014, Lipitor per-user [out-of-pocket] cost was lower than generic atorvastatin ($27 vs $49).” (K. Nasir,
khurram.nasir@yale.edu)
Menthol Cigarette Ban & Smoking Behavior: Planned behaviors of smokers did not match what they actually did following a total ban of menthol cigarettes in Ontario at the start of 2017 (doi: 10.1001/jamainternmed.2017.8650). Most participants (59.7% of 325 smokers) recruited by telephone indicated they planned to switch to nonmenthol cigarettes, but only 28.2% did so the first month of the ban. Instead, the authors report that “a larger proportion (60 [29.1%) attempted to quit compared with only 30 (14.5%) who said they would do so.” Another third of smokers switched to other flavored tobacco or e-cigarette products. more than the 5.8% of respondents who had planned to do so. (M. Chaiton, michael.chaiton@utoronto.ca)
>>>PNN NewsWatch
* PDX Aromatics, doing business as Kraken Kratom, Phytoextractum, and Soul Speciosa, has initiated a recall of certain kratom-containing powder products because it has the potential to be contaminated with Salmonella.

PNN Pharmacotherapy Line
Mar. 14, 2018 * Vol. 25, No. 50
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 13 issue of JAMA (2018; 319).
Copayments Exceeding Prescription Drug Costs: Prescription copayments exceed the drug costs in more than one-third of claims, according to data from the first half of 2013, with an average overpayment of $6.94 and 12 of the 20 most commonly prescribed drugs having overpayments of more than 33% (pp. 1045–7): “Among 9.5 million claims, 2.2 million (22.94% [95% CI, 22.91%–22.97%]) involved overpayments. The 28.17% rate (95% CI, 28.14%–28.20%) for generic drugs was significantly greater than for brand drugs (5.95% [95% CI, 5.92%–5.98%]); difference, 22.22% (95% CI, 22.17%–22.26%), P < .001. The mean overpayment was $7.69 (SD, $8.59); 17.15% (95% CI, 17.10%–17.20%) exceeded $10. Although less common, overpayments were significantly larger on brand drugs (mean, $13.46 [SD, $18.01]) than on generic drugs (mean, $7.32 [SD, $7.43]); difference, $6.14 (95% CI, $6.09–$6.19), P < .001. Aggregate overpayments totaled $135 million for 2013 or $10.51 per covered member.” (K. Van Nuys, vannuys@usc.edu)
Acetylcysteine/Salbutamol During Invasive Ventilation: For patients on invasive ventilation in intensive-care units (ICUs), on-demand nebulized acetylcysteine with salbutamol may be “a reasonable alternative” to routine nebulization, researchers report (pp. 933–1001). Adult patients who needed invasive ventilation for more 24 hours in seven Dutch ICUs had these outcomes: “Nine hundred twenty-two patients (34% women; median age, 66 (interquartile range [IQR], 54–75 years) were enrolled and completed follow-up. At 28 days, patients in the on-demand group had a median 21 (IQR, 0–26) ventilator-free days, and patients in the routine group had a median 20 (IQR, 0–26) ventilator-free days (1-sided 95% CI, −0.00003 to &infinWinking. There was no significant difference in length of stay or mortality, or in the proportion of patients developing pulmonary complications, between the 2 groups. Adverse events (13.8% vs 29.3%; difference, −15.5% [95% CI, −20.7% to −10.3%]; P < .001) were more frequent with routine nebulization and mainly related to tachyarrhythmia (12.5% vs 25.9%; difference, −13.4% [95% CI, −18.4% to −8.4%]; P < .001) and agitation (0.2% vs 4.3%; difference, −4.1% [95% CI, −5.9% to −2.2%]; P < .001).” (M. J. Schultz, marcus.j.schultz@gmail.com)
U.S. Health Care Spending: Expenditures for health care in the U.S. is nearly twice that of 10 high-income countries, despite similar utilization levels, a study shows (pp. 1024–39). “In 2016, the U.S. spent 17.8% of its gross domestic product on health care, and spending in the other countries ranged from 9.6% (Australia) to 12.4% (Switzerland),” investigators write. “The proportion of the population with health insurance was 90% in the U.S., lower than the other countries (range, 99%–100%), and the U.S. had the highest proportion of private health insurance (55.3%). For some determinants of health such as smoking, the U.S. ranked second lowest of the countries (11.4% of the U.S. population ≥15 years smokes daily; mean of all 11 countries, 16.6%), but the U.S. had the highest percentage of adults who were overweight or obese at 70.1% (range for other countries, 23.8%–63.4%; mean of all 11 countries, 55.6%). Life expectancy in the U.S. was the lowest of the 11 countries at 78.8 years (range for other countries, 80.7–83.9 years; mean of all 11 countries, 81.7 years), and infant mortality was the highest (5.8 deaths per 1,000 live births in the U.S.; 3.6 per 1,000 for all 11 countries). The U.S. did not differ substantially from the other countries in physician workforce (2.6 physicians per 1,000; 43% primary care physicians), or nursing workforce (11.1 nurses per 1,000).… For pharmaceutical costs, spending per capita was $1,443 in the U.S. vs a range of $466 to $939 in other countries. Salaries of physicians and nurses were higher in the U.S.; for example, generalist physicians salaries were $218,173 in the U.S. compared with a range of $86,607 to $154,126 in the other countries.” (I. Papanicolas, i.n.papanicolas@lse.ac.uk)
Even limited reductions in health care costs could save billions, an author writes in one of four editorials (
pp. 983–5): “Can the United States reduce the cost of health care? Yes. But will the country do it? Answering that question is up to the medical profession, health systems, payers, and policy makers. The future of the U.S. health care system is in their hands.” (E. J. Emanuel, MEHPchair@upenn.edu)

PNN Pharmacotherapy Line
Mar. 15, 2018 * Vol. 25, No. 51
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
Mar. 15 New England Journal of Medicine (2018; 378).
Cultured Cells/ROCK Inhibitor for Bullous Keratopathy: Administered with a rho-associated protein kinase (ROCK) inhibitor into the anterior chamber of the eye, human corneal endothelial cells (CECs) increased CEC density after 24 weeks in 11 persons with bullous keratopathy, researchers report (pp. 995–1003). The uncontrolled, single-group study included patients with no detectable CECs. Results showed the following: “At 24 weeks after cell injection, we recorded a CEC density of more than 500 cells per square millimeter (range, 947 to 2833) in 11 of the 11 treated eyes (100%; 95% confidence interval [CI], 72 to 100), of which 10 had a CEC density exceeding 1,000 cells per square millimeter. A corneal thickness of less than 630 μm (range, 489 to 640) was attained in 10 of the 11 treated eyes (91%; 95% CI, 59 to 100), and an improvement in best corrected visual acuity of two lines or more was recorded in 9 of the 11 treated eyes (82%; 95% CI, 48 to 98).” (S. Kinoshita, shigeruk@koto.kpu-m.ac.jp)
“These outcomes are encouraging; however, as the authors acknowledge, there are questions that must be addressed before introduction of this approach into wider clinical practice can be considered,” an editorialist writes (
pp. 1057–8). “What is the acceptable age range of the donor (a factor that can influence cell number, viability, and proliferation potential)? What is the acceptable density of the cells used for seeding? What is the maximum number of culture passages that would permit the production of high-quality homogeneous endothelial cell populations for transplantation purposes?” (R. Dana)
Treating Cryptococcal Meningitis in Africa: As induction therapy for cryptococcal meningitis in resource-limited settings, amphotericin B plus flucytosine for 1 week and fluconazole plus flucytosine for 2 weeks proved effective and safe in 721 patients living with HIV (pp. 1004–17). This or other induction regimens followed by fluconazole consolidation therapy for 10 weeks yielded these results: “Mortality in [an] oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.” (T. S. Harrison, tharriso@sgul.ac.uk)
HIV-Associated Cancers: Reviewing cancers and other conditions that occur in patients with HIV, authors provide these insights (pp. 1029–41): “Although the development of [antiretroviral therapy (ART)] has done much to improve overall survival and reduce the incidence of AIDS-defining cancers, other cancers have come to the forefront and have become common causes of complications and death among persons with HIV infection. As the HIV-infected population ages, a wide variety of HIV-associated cancers have become increasingly important. These cancers pose both challenges and opportunities. The National Cancer Institute sponsors a range of clinical studies in the United States and globally to prevent and treat HIV-associated cancers through the AIDS Malignancy Consortium, the Intramural Program, the Cancer Immunotherapy Trials Network, and the Bone and Marrow Transplant Clinical Trials Network. Results from previous studies support evidence-based guidelines for the treatment of several HIV-associated cancers. However, many questions remain. Addressing these questions will open new approaches for the prevention, diagnosis, and treatment of cancer among the more than 35 million people globally who are infected with HIV.” (R. Yarchoan, robert.yarchoan@nih.gov)

PNN Pharmacotherapy Line
Mar. 16, 2018 * Vol. 25, No. 52
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
Mar. 15 issue of Clinical Infectious Diseases (2018; 66).
Twice-Annual Influenza Vaccination in Older Adults: In Hong Kong, twice-annual administration of influenza vaccine to older adults may have improved protection against continued circulation of an A/H3N2 strain in the summer and autumn, researchers report (pp. 904–12). However, later immune responses to the vaccine were lower among twice-annual recipients, which could complicate efforts to extend protection in tropical and subtropical areas with more prolonged influenza seasons. Among older adults aged 75 years or older, receipt of the mismatched 2014–15 vaccine with or without a follow-up vaccination with the 2015 southern hemisphere influenza vaccine produced these results: “We enrolled 978 older adults with 470 vaccinations for summer 2015 and 827 vaccinations for winter 2015–2016. Recipients of southern hemisphere vaccination had higher geometric mean titers (GMTs) by the hemagglutination inhibition assay against all 3 vaccine strains. When receiving influenza vaccination for the subsequent winter, the southern hemisphere vaccine recipients had higher prevaccination GMTs but lower postvaccination GMTs, compared to those who had not received the southern hemisphere vaccine. Furthermore, cellular immunity was impacted by biannual vaccination, with reduced influenza-specific CD4 T-cell responses in the second season of vaccination.” (B. J. Cowling, bcowling@hku.hk)
TB & AMI: Latent tuberculosis infection (LTBI) is independently associated with acute myocardial infarction (AMI), according to a case–control study from Peru (pp. 886–92). In 2015–17, 105 case patients with first-time diagnosis of type 1 (spontaneous) AMI had these outcomes compared with 110 controls without a history of AMI: “Overall, the median age was 62 years (interquartile range, 56–70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08–3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05–3.45).” (M. A. Huaman, moises.huaman@uc.edu)
>>>Oncology Highlights
Source:
Mar. 20 issue of the Journal of Clinical Oncology (2018; 36).
Osimertinib As First-Line Treatment of NSCLC: Osimertinib proved useful as first-line treatment of EGFR-mutated advanced non–small-cell lung cancer (NSCLC), according to these results from the AURA study (pp. 841–9): “Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median [progression-free survival] time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected.” (S. S. Ramalingam, suresh.ramalingam@emory.edu)
>>>PNN NewsWatch
* FDA yesterday issued an advance notice of proposed rulemaking to explore a product standard to lower nicotine in cigarettes to minimally or nonaddictive levels, FDA Commissioner Scott Gottlieb, MD, said in a statement posted to the agency website. “This new regulatory step advances a comprehensive policy framework that we believe could help avoid millions of tobacco-related deaths across the country,” Gottlieb wrote. “We believe this unprecedented approach to nicotine and tobacco regulation not only makes sense, but also offers us the best opportunity for achieving significant, meaningful public health gain.”

PNN Pharmacotherapy Line
Mar. 19, 2018 * Vol. 25, No. 53
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
Mar. 17 issue of Lancet (2018; 391).
Cannabidiol in Lennox–Gastaut Seizures: In the GWPCARE4 trial, addition of cannabidiol to anticonvulsant therapy reduced the frequency of drop seizures in 171 children and adults with Lennox–Gastaut syndrome while producing tolerable adverse events, researchers report (pp. 1085–96). At 24 clinical sites in the U.S. and Europe, oral cannabidiol or matched placebo for 14 weeks produced these results: “14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43.9% (IQR −69.6 to −1.9) in the cannabidiol group and 21.8% (IQR −45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was −17.21 (95% CI −30.32 to −4.09; p=0.0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.” (E. A. Thiele, ethiele@mgh.harvard.edu)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
Immunologic Adverse Events & Anti-PD-1 Drugs: A small but increased risk of organ-specific immune-related adverse events is associated with use of anti-programmed cell death 1 (PD-1) drugs, according to authors who conducted a systematic review and meta-analysis of 13 studies (k793): “Studies compared nivolumab (n = 6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.” (D. Korenstein, korenstd@mskcc.org)
>>>PNN NewsWatch
* Bayer is voluntarily recalling Alka-Seltzer Plus packages that were sold only in the U.S. at Walmart, CVS, Walgreens, and Kroger (including subsidiary units) after Feb. 9, 2018, because the ingredients on the front sticker may not match the actual product in the carton. The affected packages can be identified by checking the Bayer logo located on the lower left corner of the front of the carton. If the logo has an orange or green background, the product is included in the recall.
* Based on tests conducted of United Pharmacy products that were recalled in November 2017,
FDA is advising compounders to perform stability studies for solutions containing glutamine to confirm that the glutamine is not degrading before the product’s specified beyond-use date.
>>>PNN JournalWatch
* Extrafine Inhaled Triple Therapy Versus Dual Bronchodilator Therapy in Chronic Obstructive Pulmonary Disease (TRIBUTE): A Double-Blind, Parallel Group, Randomised Controlled Trial, Lancet, 2018: 391: 1076–84. (A. Papi, ppa@unife.it)
*
Delirium—A Framework to Improve Acute Care for Older Persons, Journal of the American Geriatrics Society, 2018: 66: 446–51. (S. K. Inouye, AgingBrainCenter@hsl.harvard.edu)
*
IL-31: A New Key Player in Dermatology and Beyond, Journal of Allergy and Clinical Immunology, 2018: 141: 858–66. (I. S. Bağci, Bagci.Isin_Sinem@med.uni-muenchen.de)
*
Cancer in Primary Immunodeficiency Diseases: Cancer Incidence in the United States Immune Deficiency Network Registry, Journal of Allergy and Clinical Immunology, 2018: 141: 1028–35. (B. H. Segal, Brahm.Segal@RoswellPark.org)

PNN Pharmacotherapy Line
Mar. 20, 2018 * Vol. 25, No. 54
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
Mar. 20 issue of Annals of Internal Medicine (2018; 168).
Hydroxychloroquine in Hand Osteoarthritis: Hydroxychloroquine is no more effective than placebo for relieving moderate to severe hand pain and radiographic osteoarthritis, according to a 248-participant study (pp. 385–95). Conducted at 13 English centers, the study produced these results based on a primary end point of average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]): “At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of −0.16 point (95% CI, −0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group).” (S. Kingsbury, s.r.kingsbury@leeds.ac.uk)
Opioid Analgesic Use & Invasive Pneumococcal Diseases: Records from the Tennessee Medicaid database link opioid use with increased risk of invasive pneumococcal disease (IPD), researchers report (pp. 396–404). Nested case–control analysis of 1,233 children aged 5 years or older and adults with IPD and 24,399 matched controls yielded these findings: “Persons in the case group had greater odds than control participants of being current opioid users (adjusted odds ratio [aOR], 1.62 [95% CI, 1.36 to 1.92]). Associations were strongest for opioids that were long acting (aOR, 1.87 [CI, 1.24 to 2.82]), of high potency (aOR, 1.72 [CI, 1.32 to 2.25]), or were used at high dosages (50 to 90 morphine milligram equivalents [MME]/d: aOR, 1.71 [CI, 1.22 to 2.39]; ≥90 MME/d: aOR, 1.75 [CI, 1.33 to 2.29]). Results were consistent when the IPD risk score was taken into account and pneumonia and nonpneumonia IPD were analyzed separately.” (A. D. Wiese, andrew.d.wiese.1@vanderbilt.edu)
Antithyroid Drugs & Congenital Malformations: A nationwide cohort study conducted using the Korean National Health Insurance database shows an increased risk of congenital malformations following exposure to antithyroid drugs (ATDs) during the first trimester of pregnancy (pp. 405–13). The risk was particularly high when methimazole (MMI) was used alone or in combination with propylthiouracil, the investigators found. Results for 2.9 million completed pregnancies with live-born infants born to 2.2 million women in 2008–14: “12,891 pregnancies (0.45%) were exposed to ATDs during the first trimester. The prevalence of malformations in exposed offspring was 7.27%, compared with 5.94% in offspring of women who were not prescribed ATDs during pregnancy (P < 0.001) (adjusted odds ratio, 1.19 [95% CI, 1.12 to 1.28]). Absolute increases in the prevalence of congenital malformations per 1,000 live births were 8.81 cases (CI, 3.92 to 13.70 cases) for propylthiouracil alone, 17.05 cases (CI, 1.94 to 32.15 cases) for [MMI] alone, and 16.53 cases (CI, 4.73 to 28.32 cases) for propylthiouracil and MMI, compared with pregnancies without ATD prescriptions. In the MMI group, a high cumulative dose (>495 mg) during the first trimester was associated with an increased risk for malformations compared with a low dose (1 to 126 mg) (adjusted odds ratio, 1.87 [CI, 1.06 to 3.30]).” (J. H. Chung, thyroid@skku.edu)
>>>PNN NewsWatch
* The case count for Salmonella-contaminated kratom products is up to 87, CDC said in an update last week. People in 35 states have developed illnesses, including 27 who were hospitalized. Symptoms of diarrhea, fever, and abdominal cramps last for 4 to 7 days. Kratom — also known as Thang, Kakuam, Thom, Ketom, and Biak — is a plant consumed for its stimulant effects and as an opioid substitute.
*
“Global Introduction of New Vaccines: Delivering More to More” is a live continuing education webinar being broadcast from the CDC today at 1 pm Eastern time. Speakers will address regional and global outbreaks of new and emerging vaccine-preventable diseases.

PNN Pharmacotherapy Line
Mar. 21, 2018 * Vol. 25, No. 55
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>>>JAMA Report
Source:
Mar. 20 issue of JAMA (2018; 319).
Home-Based HIV Testing & Same-Day ART: In sub-Saharan Africa, offering home-based HIV testing and immediate initiation of antiretroviral therapy (ART) enhanced patient linkage to services at 3 months and produced higher viral suppression rates at 12 months, researchers report (pp. 1103–12). Conducted in northern Lesotho in 2016–17, the study compared usual care with clinic referral with same-day, home-based ART following home-based HIV testing, with these results: “Among 278 randomized individuals (median age, 39 years [interquartile range, 28.0–52.0]; 180 women [65.7%]), 274 (98.6%) were included in the analysis (137 in the same-day group and 137 in the usual care group). In the same-day group, 134 (97.8%) indicated readiness to start ART that day and 2 (1.5%) within the next few days and were given a 1-month supply of ART. At 3 months, 68.6% (94) in same-day group vs 43.1% (59) in usual care group had linked to care (absolute difference, 25.6%; 95% CI, 13.8% to 36.3%; P < .001). At 12 months, 50.4% (69) in the same-day group vs 34.3% (47) in usual care group achieved viral suppression (absolute difference, 16.0%; 4.4%-27.2%; P = .007). Two deaths (1.5%) were reported in the same-day group, none in usual care group.” (N. D. Labhardt, n.labhardt@unibas.ch)
Editorialists write that this approach offers advantages in areas with continued high rates of HIV infections (
pp. 1094–5): “Household-based HIV testing [is] a pathway to identifying HIV-negative individuals at risk of HIV acquisition, and linking them to HIV prevention services such as voluntary medical male circumcision and pre-exposure prophylaxis while providing access to condoms and reproductive health services. Home-based testing should be part of a package of testing and outreach services to be determined based on the testing needs, preferences, and constraints of a given population. Large-scale studies are ongoing that aim to utilize such diverse strategies to enhance HIV prevention and treatment outcomes in communities. Although much has been achieved in confronting the HIV epidemic, more remains to be done to achieve global targets for treatment and prevention. Innovative, patient-centered, effective, and scalable innovations are needed to get to the finish line.” (I. T. Katz, ikatz2@bwh.harvard.edu)
USPSTF Statement on Skin Cancer Prevention: In an update to previous recommendations on behavioral counseling for the primary prevention of skin cancer and skin self-examination for prevention of skin cancer, the U.S. Preventive Services Task Force (USPSTF) emphasizes sun-protection behaviors in infants, children, and young adults through age 24 with fair skin types (pp. 1134–42). For older people, behavioral counseling interventions yielded “a small increase in sun protection behaviors,” and the task force said evidence was inadequate to recommend counseling all adults about prevention or about skin self-examination as a means of preventing skin cancer. (D. C. Grossman, chair@uspstf.net)
“Promoting skin cancer knowledge and awareness more broadly may have a greater effect,” writes a
JAMA Oncology editorialist (doi: 10.1001/jamaoncol.2018.0469). “Using a photograph of melanoma during skin examination was shown to be associated with thinner melanomas, and having an atypical-appearing melanoma, such as one that is predominately pink in color, is associated with having a thicker melanoma. Thus, better educating patients on what is concerning is likely an important component to improving early self-detection. Such educational initiatives are difficult to validate, but using newer technologies such as web and text-based interventions that have proven effective in promoting sun-protective behaviors could potentially be used to improve self-detection as well. An [insufficient evidence] statement is not a recommendation against, but rather a call for more research to better determine how to improve patient self-detection of early melanoma and its effect on outcomes.” (L. K. Ferris, ferrislk@upmc.edu)
>>>PNN NewsWatch
* FDA yesterday approved brentuximab vedotin (Adcetris, Seattle Genetics) to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. This is the fifth FDA-approved indication for this product.

PNN Pharmacotherapy Line
Mar. 22, 2018 * Vol. 25, No. 56
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>>>NEJM Report
Source:
Mar. 22 issue of the New England Journal of Medicine (2018; 378).
H. pylori Therapy for Prevention of Metachronous Gastric Cancer: Positive outcomes followed use of Helicobacter pylori eradication therapy in patients with early gastric cancer or high-grade adenoma, researchers report (pp. 1085–95). In 396 patients included in a modified intention-to-treat analysis, antibiotics or placebo produced these outcomes with respect to subsequent (metachronous) development of new gastric cancer at 1-year follow-up: “During a median follow-up of 5.9 years, metachronous gastric cancer developed in 14 patients (7.2%) in the treatment group and in 27 patients (13.4%) in the placebo group (hazard ratio in the treatment group, 0.50; 95% confidence interval, 0.26 to 0.94; P = 0.03). Among the 327 patients in the subgroup that underwent histologic analysis, improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% of the patients in the treatment group and in 15.0% of those in the placebo group (P <0.001). There were no serious adverse events; mild adverse events were more common in the treatment group (42.0% vs. 10.2%, P <0.001).” (I. J. Choi, cij1224@ncc.re.kr)
H. pylori eradication is still effective in patients with advanced preneoplastic lesions,” writes an editorialist (pp. 1154–6). “The intervention prevents later gastric cancer in only a subgroup of patients, so endoscopic or histologic surveillance remains mandatory. This requirement extends to all patients with severe atrophic gastritis with or without intestinal metaplasia even after successful eradication. Since the selection of eradication therapy is aimed at minimizing the development of antimicrobial resistance, bismuth-based regimens should be given preference.” (P. Malfertheiner)
Venetoclax–Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: In a phase III trial of patients with relapsed or refractory chronic lymphocytic leukemia, progression-free survival was significantly higher with venetoclax plus rituximab than with bendamustine plus rituximab (pp. 1107–20). The open-label study included 389 participants and reports these results: “After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax–rituximab group (32 events of progression or death in 194 patients) than in the bendamustine–rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P <0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax–rituximab group versus 27.8% in the bendamustine–rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax–rituximab group than in the bendamustine–rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax–rituximab group was 3.1% (6 of 194 patients).” (J. F. Seymour, john.seymour@petermac.org)
Genetic Variant and Protection from Chronic Liver Disease: A protein-truncating variant of an allele associated with serum hepatic enzymes appears to be protective against nonalcoholic steatohepatitis and fibrosis as well as progression to advanced liver disease, according to the DiscovEHR cohort study (pp. 1096–106). Identification of the loss-of-function variant in HSD17B13 could lead to identification of subpopulations who could benefit from agents that inhibit the production or action of the gene product coded by this allele. (F. E. Dewey, frederick.dewey@regeneron.com)

PNN Pharmacotherapy Line
Mar. 23, 2018 * Vol. 25, No. 57
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Highlights
Source:
Mar. Journal of the American Geriatrics Society (2018; 66).
Drug-Related Hospital Readmissions: Hospital readmissions caused by medications are common, especially in older adults, according to a systematic review of 19 published studies, researchers report (pp. 602–8). Concluding that further research into specific causes and possible interventions are needed, the authors report these findings: “Nine [studies] measured readmissions due to drug-related problems, seven due to adverse drug reactions, two due to adverse drug events, and one due to drug–drug interactions. Rates of readmissions due to drugs varied from 3% to 64% (median 21%, interquartile range (IQR) 14–23%). Readmissions were deemed preventable in 5% to 87% of cases (median 69%, IQR 19–84%). Evidence regarding the risk factors for drug-related readmissions and drugs causing these readmissions was inconsistent.” (F. Karapinar-Çarkıt, f.karapinar@olvg.nl)
Influenza Underdiagnosis in Hospitalized Older Adults: Among hospitalized patients with fever or respiratory symptoms, older individuals are less likely to have provider-ordered influenza tests, a study shows (pp. 467–72). A total of 1,422 participants at four Tennessee hospitals were examined, with these results for laboratory surveillance using reverse-transcriptase polymerase chain reaction (RT-PCR): “Twenty-eight percent (399/1,422) of participants had provider-ordered influenza testing. Participants who were tested were younger than those not tested (58 ± 18 vs 66 ± 15, p <.001) and more likely to have influenza-like illness (ILI) (71% vs 49%, p <.001). ILI decreased with increasing age (aged 18–49, 63%; aged 50–64, 60%; aged ≥65, 48%). ILI and younger age were independent predictors of provider-ordered testing. Of the 136 participants with influenza confirmed using RT-PCR, ILI was the only significant predictor of provider-ordered testing (adjusted odds ratio = 3.43, 95% confidence interval = 1.22–9.70).” (L. M. Hartman, lauren.hartman@vanderbilt.edu)
Academic Detailing & Prescribing Quality for Older Veterans: Prescribing of potentially inappropriate medications (PIMs) was reduced through academic detailing and tools provided to primary care providers (PCPs) and pharmacists at four rural outpatient clinics in Georgia (pp. 621–7). Audits and prescribing feedback were also a part of the intervention, which was based on the Integrated Management and Polypharmacy Review of Vulnerable Elders (IMPROVE) model and yielded these findings: “More than 7,000 older veterans were seen in more than 20,000 PCP encounters during the 14-month intervention period. Implementation of the IMPROVE intervention reduced PIM prescribing incidence from 9.6 new medications per 100 encounters during baseline to 8.7 after the intervention (P = .009). IMPROVE reduced PIM prevalence (proportion of encounters involving veterans who were taking at least 1 PIM) from 22.6% to 16.7% (P < .001). These approaches were effective in reducing PIMs prescribed to older veterans in a rural setting and constitute a feasible model for disseminating geriatric best practices to the primary care setting.” (A. Mirk, anna.mirk@va.gov)
Oral Health & Physical Frailty: Oral health problems increase older men’s risks of being frail and developing frailty, according to a cross-sectional and longitudinal study of 1,622 community-dwelling men (pp. 473–9). Data from the British Regional Health Study show these results based on objective assessments of tooth count and periodontal disease: “Three hundred three (19%) men were frail at baseline (aged 71–92). Having fewer than 21 teeth, complete tooth loss, fair to poor self-rated oral health, difficulty eating, dry mouth, and more oral health problems were associated with greater likelihood of being frail. Of 1,284 men followed for 3 years, 107 (10%) became frail. The risk of incident frailty was higher in participants who were edentulous (odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.03–3.52); had 3 or more dry mouth symptoms (OR = 2.03, 95% CI = 1.18–3.48); and had 1 (OR = 2.34, 95% CI = 1.18–4.64), 2 (OR = 2.30, 95% CI = 1.09–4.84), or 3 or more (OR = 2.72, 95% CI = 1.11–6.64) oral health problems after adjustment for age, smoking, social class, history of cardiovascular disease or diabetes mellitus, and medications related to dry mouth.” (S. E. Ramsay, sheena.ramsay@newcastle.ac.uk)

PNN Pharmacotherapy Line
Mar. 26, 2018 * Vol. 25, No. 58
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
Mar. 24 issue of Lancet (2018; 391).
Sirolimus for SLE: In an open-label, phase 1/2 trial, sirolimus therapy is linked to “progressive improvement in disease activity … associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus,” researchers report (pp. 1186–96). The 12-month, single-arm trial started oral sirolimus at doses of 2 mg/d and titrated to serum sirolimus levels of 6–15 ng/mL, with these effects on the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI): “Mean SLEDAI score decreased from 10.2 (SD 5.6) at enrolment to 4.8 (4.5) after 12 months of treatment (p <0.001) and the mean total BILAG index score decreased from 28.4 (12.4) at enrolment to 17.4 (10.7) after 12 months of treatment (p <0.001). The mean daily dose of prednisone required to control disease activity decreased from 23.7 mg (SD 9.6) to 7.2 mg (2.3; p <0.001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4−CD8− double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z = –2.50, p = 0.012), neutrophil counts (Z = –1.92, p = 0.054), and haemoglobin (Z = –2.83, p = 0.005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z = 2.06, p = 0.0400).” (A. Perl, perla@upstate.edu)
>>>BMJ Highlights
Source:
Early-release article from BMJ (2018; 360).
DPP-4 Inhibitors & IBD: “The use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease” in a population-based study, investigators after following experiences of 141,170 patients at 700 general practices in the U.K. Clinical Practice Research Datalink (k872). In 2007–16, adjusted hazard ratios for incident inflammatory bowel disease associated with new use of the agents showed these patterns: “During 552,413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100,000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 v 34.5 per 100,000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses.” (L. Azoulay, laurent.azoulay@mcgill.ca)
>>>PNN NewsWatch
* FDA on Friday issued a draft guidance limiting the bulk drug substances that can be used in compounding by outsourcing facilities. The guidance interprets the “clinical need” provision of the Drug Quality and Security Act and outlines factors the agency proposes to evaluate bulk drug substances.
>>>PNN JournalWatch
* Lenvatinib Versus Sorafenib in First-Line Treatment of Patients With Unresectable Hepatocellular Carcinoma: A Randomised Phase 3 Non-inferiority Trial, Lancet, 2018; 391: 1163–73. (M. Kudo, m-kudo@med.kindai.ac.jp)
*
NGM282 for Treatment of Non-Alcoholic Steatohepatitis: A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial, Lancet, 2018; 391: 1174–85. (S. A Harrison, sharrison@pinnacleresearch.com)
*
Cardiovascular Complications in Pregnancy: It Is Time for Action, Circulation, 2018; 137: 1213–5. (C. R. Graves, cgraves@tnmfm.com)
*
Antibiotic-Resistant Infection Treatment Costs Have Doubled Since 2002, Now Exceeding $2 Billion Annually, Health Affairs, 2018: doi.org/10.1377/hlthaff.2017.1153. (K. E. Thorpe, kthorpe@emory.edu)
*
Explicit Disability Bias in Peer Review, Medical Care, 2018; 56: 277–8. (L. I. Iezzoni, liezzoni@mgh.harvard.edu)
*
Personal Bias in Scientific Review: We Can Do Better, Medical Care, 2018; 56: 279–80. (J. J. Allison, jeroan.allison@umassmed.edu)

PNN Pharmacotherapy Line
Mar. 27, 2018 * Vol. 25, No. 59
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
Apr. issue of Diabetes Care (2018; 41).
Insulin Resistance Markers & DPP-4 Inhibitor Responses: As a starting point to charting a path to “a precision diabetes approach to DPP-4 inhibitor therapy,” researchers report that “markers of higher insulin resistance are consistently associated with reduced glycemic response” to these drugs (pp. 705–12). The Predicting Response to Incretin Based Agents (PRIBA) study included 254 noninsulin-treated participants who were starting DPP-4 inhibitor therapy and looked at 6-month responses. Laboratory results on markers available in the Clinical Practice Research Datalink (CPRD) were used as comparators that considered baseline markers and 3-year durability of response: “In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [P = 0.03], HOMA2 insulin resistance [P = 0.01], and triglycerides [P < 0.01]) were associated with reduced 6-month HbA1c response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA1c response (both P < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m2) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA1c reduction 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and normal triglycerides]; P = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; P < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists.” (A. G. Jones, angus.jones@exeter.ac.uk)
Sulfonylureas & Risk of Serious Cardiovascular Events: Based on retrospective cohort analysis of 1999–2010 U.S. Medicaid claims from five large states, use of glyburide is associated with lower risks of sudden cardiac arrest and ventricular arrhythmia (SCA/VA) than treatment with glipizide (pp. 713–22). These findings are consistent with those of “a very small clinical trial suggesting that glyburide may reduce ventricular tachycardia and isolated ventricular premature complexes,” the authors write. “This potential benefit must be contextualized by considering putative effects of different sulfonylureas on other cardiovascular end points, cerebrovascular end points, all-cause death, and hypoglycemia.” The analysis used a validated ICD-9–based algorithm with a positive predictive value of ~85% to show the following: “Of sulfonylurea users under study (N = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person–years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude incidence rate of 3.6 per 1,000 person–years. Compared with glipizide, propensity score–adjusted hazard ratios for SCA/VA were 0.82 (95% CI 0.69–0.98) for glyburide and 1.10 (0.89–1.36) for glimepiride. Numerous secondary analyses showed a very similar effect estimate for glyburide; yet, not all CIs excluded the null.” (C. E. Leonard, celeonar@pennmedicine.upenn.edu)
Disease-Modifying Therapy in Type 1 Diabetes: “What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes?” ask authors of a Perspectives in Care article (pp. 653–61). “Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health–funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial–Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium’s plans for the future.” (C. J. Greenbaum, cjgreen@benaroyaresearch.org)

PNN Pharmacotherapy Line
Mar. 28, 2018 * Vol. 25, No. 60
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
Mar. 27 issue of JAMA (2018; 319).
High-Dose Oral Ibuprofen for Preterm PDA: In a systematic review and network meta-analysis of 68 randomized trials with 4,802 infants, high doses of oral ibuprofen were associated with higher likelihood of hemodynamically significant patent ductus arteriosus (PDA) closure, a study shows, compared with placebo or intravenous ibuprofen or indomethacin (pp. 1221–38). Trials included preterm infants with a gestational age younger than 37 weeks. Results of the meta-analysis showed the following: “The overall PDA closure rate was 67.4% (2,867 of 4,256 infants). A high dose of oral ibuprofen was associated with significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64–8.17; absolute risk difference, 199 [95% CrI, 95–258] more per 1,000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08–5.31]; absolute risk difference, 124 [95% CrI, 14–188] more per 1,000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities.” (S. Mitra, souvik.mitra@iwk.nshealth.ca)
County-Level Trends in Infectious Disease Mortality: Lower respiratory infections were the most common cause of death from infectious diseases in a county-level analysis of mortality rates from 1980 to 2014 (pp. 1248–60). Notable in the death records were large differences among counties, especially for lower respiratory infections and HIV/AIDS, and an increase in deaths from diarrheal infections in 2000–14: “Between 1980 and 2014, there were 4,081,546 deaths due to infectious diseases recorded in the United States. In 2014, a total of 113,650 (95% uncertainty interval [UI], 108,764–117,942) deaths or a rate of 34.10 (95% UI, 32.63–35.38) deaths per 100,000 persons were due to infectious diseases in the United States compared to a total of 72,220 (95% UI, 69,887–74,712) deaths or a rate of 41.95 (95% UI, 40.52–43.42) deaths per 100,000 persons in 1980, an overall decrease of 18.73% (95% UI, 14.95%–23.33%). Lower respiratory infections were the leading cause of infectious diseases mortality in 2014 accounting for 26.87 (95% UI, 25.79–28.05) deaths per 100,000 persons (78.80% of total infectious diseases deaths). There were substantial differences among counties in death rates from all infectious diseases. Lower respiratory infection had the largest absolute mortality inequality among counties (difference between the 10th and 90th percentile of the distribution, 24.5 deaths per 100,000 persons). However, HIV/AIDS had the highest relative mortality inequality between counties (10.0 as the ratio of mortality rate in the 90th and 10th percentile of the distribution). Mortality from meningitis and tuberculosis decreased over the study period in all U.S. counties. However, diarrheal diseases were the only cause of infectious diseases mortality to increase from 2000 to 2014, reaching a rate of 2.41 (95% UI, 0.86–2.67) deaths per 100,000 persons, with many counties of high mortality extending from Missouri to the northeastern region of the United States.” (C. J. L. Murray, cjlm@uw.edu)
“Despite the substantial progress in reducing infectious disease–related mortality, important challenges remain, including the increasing threat of antimicrobial resistance and the ongoing risk of new and emerging pathogens,” editorialists write (
pp. 1205–6; P. N. Malani, pmalani@umich.edu).
>>>PNN NewsWatch
* FDA yesterday permitted marketing of the Dexcom G6 integrated continuous glucose monitoring system for determining blood glucose levels in children aged 2 and older and adults with diabetes. The agency said this is the first type of continuous glucose monitoring system it has permitted to be used as part of an integrated system with other compatible medical devices and electronic interfaces, including automated insulin dosing systems, insulin pumps, blood glucose meters, or other electronic devices used for diabetes management.

PNN Pharmacotherapy Line
Mar. 29, 2018 * Vol. 25, No. 61
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
Mar. 29 issue of the New England Journal of Medicine (2018; 378).
Adjuvant Chemotherapy for Stage III Colon Cancer: In six phase 3 trials of adjuvant therapy in patients with stage III colon cancer, overall results did not show noninferiority for shorter regimens of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin), the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration reports (pp. 1177–88). In lower-risk patients, CAPOX for 3 months was as effective as 6 months, the investigators conclude. Based on a primary end point of disease-free survival at 3 years, the 3- and 6-month regimens produced these results: “After 3,263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P = 0.01 for superiority).” (A. Grothey, grothey.axel@mayo.edu)
“To truly optimize the application of adjuvant chemotherapy, we need two things: better markers to assess the risk of recurrence and the likelihood of benefit and more effective, less toxic treatments,” editorialists conclude (
pp. 1242–4). “Until we see improvements in these two important areas, the findings of the IDEA collaboration provide useful information in helping oncologists discuss the duration of adjuvant therapy that best suits the goals, preferences, and tolerances of their patients.” (R. L. Schilsky)
Cardiovascular Safety of Gout Medications: While febuxostat and allopurinol had similar rates of adverse cardiovascular events in patients with concomitant gout and cardiovascular disease, the risks of all-cause mortality and cardiovascular mortality were slightly but significantly higher with febuxostat, researchers report (pp. 1200–10). A double-blind noninferiority trial produced these findings based on a primary composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization: “In total, 6,190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P = 0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis.” (W. B. White, wwhite@uchc.edu)
>>>PNN NewsWatch
* FDA said yesterday that a federal court has ordered Florida-based MyNicNaxs, LLC, and two company officers to stop selling drugs and dietary supplements until the company complies with the Federal Food, Drug, and Cosmetic Act and other requirements in a consent decree. MyNicNaxs distributed weight loss and sexual enhancement products, which the company marketed as dietary supplements, directly to consumers online. Some products tested positive for undeclared active pharmaceutical ingredients, FDA said.

PNN Pharmacotherapy Line
Mar. 30, 2018 * Vol. 25, No. 62
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Nephrology Report
Source:
Apr. issue of the American Journal of Kidney Diseases (2018; 71).
Health Insurance & Peritoneal Dialysis: Americans continue to encounter insurance-coverage problems during the initiation of peritoneal dialysis (PD), despite a Medicare policy of coverage of the intervention as patients develop end-stage renal disease (ESRD), researchers report (pp. 479–87). Retrospective analysis of patients in the U.S. Renal Data System for 2006–12 showed these results for those aged 60–64 years with “limited insurance” (Medicaid or no insurance) at ESRD onset and patients 66–70 years who were dually eligible for Medicare and Medicaid at ESRD onset: “After adjusting for observable patient and geographic differences, patients with limited insurance had an absolute 2.4% (95% CI, 1.1%–3.7%) lower probability of PD use by dialysis month 4 compared with patients with Medicare at ESRD onset. The association between insurance and PD use reversed when patients became Medicare eligible; patients with limited insurance had a 3-fold higher rate of switching to PD therapy between months 4 and 12 of dialysis (HR, 2.9; 95% CI, 1.8–4.6) compared with patients with Medicare at ESRD onset.” (K. F. Erickson, kevin.erickson@bcm.edu)
The above authors conclude that “educating providers about Medicare reimbursement policy and expanding access to pre-ESRD education and training may help overcome these barriers,” and an editorialist points to these additional options for improving provision of PD (
pp. 455–7): “As Perez et al acknowledge, they are unable to rule out the possibility of factors other than insurance delaying the start of PD therapy despite an analytic approach that attempts to compare like populations (eg, Medicaid or uninsured ages 60–64 vs dual-eligible ages 66–70 years). This is because, as Perez et al note, there may be unmeasured patient factors correlated with health insurance that predispose patients to a later PD therapy initiation. Such factors include lack of education, social support, patient activation, and knowledge about treatment options. In some cases, there may be a lack of nephrologist training or experience with PD that may make it difficult to share information about treatment options with patients in a timely manner.” (M. Turenne, marc.turenne@arborresearch.org)
>>>PNN NewsWatch
* FDA yesterday granted accelerated approval to blinatumomab (Blincyto, Amgen) to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse. This product is the first-and-only approved bispecific CD19-directed CD3 T cell engager immunotherapy, Amgen noted in a news release, and it is now also the first-and-only therapy to be FDA-approved for MRD.
* Deaths of Americans from
overdoses of opioids, cocaine, and psychostimulants continued to climb in 2016, the CDC reported in an MMWR article released yesterday (pp. 349–58). Drug overdoses killed 63,632 Americans. Nearly two-thirds of these deaths (66%) involved a prescription or illicit opioid. Overdose deaths increased in all categories of drugs examined for men and women, people ages 15 and older, all races and ethnicities, and across all levels of urbanization. CDC said that its new analysis confirms that recent increases in drug overdose deaths are driven by continued sharp increases in deaths involving synthetic opioids other than methadone, such as illicitly manufactured fentanyl (IMF). IMF is mixed into counterfeit opioid and benzodiazepine pills, heroin, and cocaine, likely contributing to increases in overdoses involving these other substances. Data from 31 states and the District of Columbia showed that across demographic categories, the largest increase in opioid overdose death rates was in men aged 25–44. Death rates from overdoses involving synthetic opioids increased in 21 states, with 10 states doubling their rates from 2015 to 2016. New Hampshire, West Virginia, and Massachusetts had the highest death rates from synthetic opioids. Eight states had significant increases in death rates involving prescription opioids. West Virginia, Maryland, Maine, and Utah had the highest rates.


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. Copyright © 2018, 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 October–December 2017

PNN Pharmacotherapy Line
Oct. 2, 2017 * Vol. 24, No. 189
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Sept. 30 issue of Lancet (2017; 390).
Vaccine-Induced Immunity Against Gonorrhea? A retrospective analysis indicates that adolescents and young adults may have received some protection against gonorrhea after vaccination with outer membrane vesicle meningococcal B vaccine (MeNZB) (pp. 1603–10). In New Zealand, a case–control study of patients at sexual health clinics showed these odds ratios for laboratory-confirmed cases of gonorrhea (cases) or chlamydia (controls) among those aged 15– 30 years: “Vaccinated individuals were significantly less likely to be cases than controls (511 [41%] vs 6,424 [51%]; adjusted OR 0.69 [95% CI 0.61–0.79]; p <0.0001). Estimate vaccine effectiveness of MeNZB against gonorrhoea after adjustment for ethnicity, deprivation, geographical area, and sex was 31% (95% CI 21–39).” (H. Petousis-Harris, h.petousis-harris@auckland.ac.nz)
C1 Esterase Inhibitor for Hereditary Angioedema: In a phase 2 trial of 26 participants, recombinant human C1 esterase inhibitor reduced the frequency of hereditary angioedema attacks, but assessment of the pharmacokinetics of the agent led the authors to conclude that “efficacy of C1-inhibitor replacement therapy might not be a direct function of plasma trough concentrations of C1 inhibitor” (pp. 1595–602): “The mean number of attacks of hereditary angio-oedema over 4 weeks was significantly reduced with recombinant human C1 esterase inhibitor twice weekly (2.7 attacks [SD 2.4]) and once weekly (4.4 attacks [3.2]) versus placebo (7.2 attacks [3.6]), with mean differences of −4.4 attacks (p <0.0001) and −2.8 attacks (p = 0.0004), respectively. We recorded adverse events in ten (34%) of 29 patients given twice-weekly recombinant human C1 esterase inhibitor, 13 (45%) of 29 patients given the once-weekly regimen, and eight (29%) of 28 patients given placebo. Headache (twice-weekly treatment) and nasopharyngitis (once-weekly treatment) were the most common adverse events. Two (7%) adverse events (fatigue and headache) were deemed possibly related to treatment with recombinant human C1 esterase inhibitor, but both resolved without additional treatment.” (M. A. Riedl, mriedl@ucsd.edu)
Romosozumab in Bisphosphonate Transitioning: Postmenopausal women transitioning from bisphosphonate therapy for osteoporosis had better outcomes with the sclerostin monoclonal antibody romosozumab than with teriparatide, researchers report (pp. 1585–94). Based on a primary end point of percentage change from baseline in areal bone mineral density (BMD) by dual-energy x-ray absorptiometry at the total hip through month 12 after transition (mean of months 6 and 12), the investigators found these results among 415 patients: in a phase 3, open-label trial: “Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2.6% (95% CI 2.2 to 3.0) in the romosozumab group and −0.6% (−1.0 to −0.2) in the teriparatide group; difference 3.2% (95% CI 2.7 to 3.8; p <0.0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal.” (B. L. Langdahl, bente.langdahl@aarhus.rm.dk)
>>>PNN JournalWatch
* Misleading Guidance From Pharmacogenomic Testing, in American Journal of Psychiatry, 2017; 174: 922–4. (T. Rahman) 
* Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors, in 
American Journal of Psychiatry, 2017; 174: 927–42. (S. Leucht)
* 2017 National Standards for Diabetes Self-Management Education and Support, in 
Diabetes Care, 2017; 40: 1409–19. (L. E. Kolb, lkolb@aadenet.org
* Efficacy of Recommended Drugs Against Soil Transmitted Helminths: Systematic Review and Network Meta-Analysis, in 
BMJ, 2017; 358: j4307. (J Keiser, jennifer.keiser@unibas.ch)

PNN Pharmacotherapy Line
Oct. 3, 2017 * Vol. 24, No. 190
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Oct. 3 issue of the Annals of Internal Medicine (2017; 167).
Low-Dose IVIg for Long-Standing Complex Regional Pain Syndrome: In 103 patients with moderate or severe symptoms of complex regional pain syndrome (CRPS), low-dose intravenous immunoglobulin (IVIg) was not effective for relieving pain during 6 weeks of treatment, researchers report (pp. 476–83). At seven U.S. pain management centers, IVIg 0.5 g/kg or placebo of 0.1% albumin in saline produced these results based a primary outcome of 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale: “Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, −0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of −1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events.” (A. Goebel, andreasgoebel@rocketmail.com)
While critical of the drug dose and other aspects of this study, editorialists conclude that further research into immunomodulatory therapy for patients with CRPS should go forth, but with other agents (
pp. 515–6): “We congratulate Goebel and colleagues for the tremendous effort they devoted to the current trial, but the possible pitfalls we discuss here should prevent us from prematurely closing the book on immunomodulatory treatment of CRPS. Nevertheless, we need better hypotheses, leading to more elaborate protocols; biomarkers for better patient selection, particularly if approaches with more potential for harm are studied; and active drugs. On the basis of the results presented by Goebel and colleagues, however, IVIg is not our first choice of an agent to investigate in future trials.” (F. Birklein, frank.birklein@unimedizin-mainz.de)
Sedentary Behavior & Mortality: Middle-aged and older adults have higher all-cause mortality rates when their lifestyles include greater total amounts of sedentary time and when inactivity occurs in “prolonged, uninterrupted bouts,” a study shows (pp. 465–75). A prospective cohort study conducted in the contiguous U.S. shows these associations in 7,985 white and black adults aged 45 years or older: “Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22 [95% CI, 0.74 to 2.02]; HR, 1.61 [CI, 0.99 to 2.63]; and HR, 2.63 [CI, 1.60 to 4.30]; P for trend <0.001) and longer sedentary bout duration (HR, 1.03 [CI, 0.67 to 1.60]; HR, 1.22 [CI, 0.80 to 1.85]; and HR, 1.96 [CI, 1.31 to 2.93]; P for trend <0.001) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death.” (K. Diaz, kd2442@columbia.edu)
“Daily sedentary time, uninterrupted sedentary bout length, and moderate to vigorous physical activity may each play an important and distinct role in long-term health behaviors and survival,” an editorialist writes (
pp. 513–4). “Interventions with the greatest effect on population outcomes may be those that take each into account. Such interventions may require us to count the total number of hours we are sedentary per day, the total number of minutes we sit at a time, the total number of standing breaks we take per hour, the total number of steps we take per day, and the total metabolic equivalent of task–minute volume of exercise we achieve per week. Yikes! That sure is a lot of counting over the course of a lifetime—all to reverse the evolutionary patterns of a society gone lazy. Might it not just be easier to return to our origins as hunters and gatherers?” (D. Alter, dalter@ices.on.ca)
>>>PNN NewsWatch
Adults with asthma are at increased risk for pneumococcal disease, yet according to a new CDC study published last week in the American Journal of Preventive Medicine, just 54% of adults with work-related asthma have received the recommended pneumococcal polysaccharide vaccination.

PNN Pharmacotherapy Line
Oct. 4, 2017 * Vol. 24, No. 191
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source: Oct. 3 issue of JAMA (2017; 318).
Risk of Bleeding With NOAC Interactions: Bleeding risks were elevated among patients in Taiwan when non–vitamin K oral anticoagulants (NOACs) were taken with amiodarone, fluconazole, rifampin, or phenytoin, according to a retrospective cohort study of the national health insurance database (pp. 1250–9). All patients using a NOAC in 2012–16 were included in the analysis, which showed the following: “Among 91,330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45,347 patients; rivaroxaban, 54,006 patients; and apixaban, 12,886 patients), 4,770 major bleeding events occurred during 447,037 person–quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person–quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1,000 person–years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 [99% CI, 9.76–18.13]); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 [99% CI, 80.96–195.97]); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 [99% CI, 1.59–72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 [99% CI, 32.18–72.44]; P < .01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone.” (C-F Kuo, zandis@gmail.com)
Antithrombotic Medication & Hematuria: Use of oral anticoagulants or antiplatelet agents in older people in Ontario was associated with higher rates of hematuria-related complications, researchers report (pp. 1260–71). In a population-based, retrospective cohort study, those age 66 years or older between 2002 and 2014 had these outcomes: “Among 2,518,064 patients, 808,897 (mean [SD] age, 72.1 [6.8] years; 428,531 [53%] women) received at least 1 prescription for an antithrombotic agent over the study period. Over a median follow-up of 7.3 years, the rates of hematuria-related complications were 123.95 events per 1000 person–years among patients actively exposed to antithrombotic agents vs 80.17 events per 1000 person–years among patients not exposed to these drugs (difference, 43.8; 95% CI, 43.0-44.6; P < .001, and incidence rate ratio [IRR], 1.44; 95% CI, 1.42–1.46). The rates of complications among exposed vs unexposed patients (80.17 events/1000 person–years) were 105.78 for urologic procedures (difference, 33.5; 95% CI, 32.8–34.3; P < .001, and IRR, 1.37; 95% CI, 1.36–1.39), 11.12 for hospitalizations (difference, 5.7; 95% CI, 5.5–5.9; P < .001, and IRR, 2.03; 95% CI, 2.00–2.06), and 7.05 for emergency department visits (difference, 4.5; 95% CI, 4.3–4.7; P < .001, and IRR, 2.80; 95% CI, 2.74–2.86). Compared with patients who were unexposed to thrombotic agents, the rates of hematuria-related complications were 191.61 events per 1000 person–years (difference, 117.3; 95% CI, 112.8–121.8) for those exposed to both an anticoagulant and antiplatelet agent (IRR, 10.48; 95% CI, 8.16–13.45), 140.92 (difference, 57.7; 95% CI, 56.9–58.4) for those exposed to anticoagulants (IRR, 1.55; 95% CI, 1.52–1.59), and 110.72 (difference, 26.5; 95% CI, 25.9–27.0) for those exposed to antiplatelet agents (IRR, 1.31; 95% CI, 1.29–1.33). Patients exposed to antithrombotic agents, compared with patients not exposed to these drugs, were more likely to be diagnosed as having bladder cancer within 6 months (0.70% vs 0.38%; odds ratio, 1.85; 95% CI, 1.79–1.92).” (R. K. Nam, robert.nam@utoronto.ca)
>>>PNN NewsWatch
* Bilateral hemorrhagic occlusive retinal vasculitis has been reported following cataract surgery in those receiving injections of a triamcinolone, moxifloxacin, and vancomycin formulation compounded by New Jersey’s Imprimis Pharmaceuticals, FDA said yesterday.


PNN Pharmacotherapy Line
Oct. 5, 2017 * Vol. 24, No. 192
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Oct. 5 New England Journal of Medicine (2017; 377).
Rivaroxaban ± ASA in Stable Cardiovascular Disease: A low dose of rivaroxaban plus low-dose aspirin provided protection from cardiovascular events but with increased major bleeding events, according to the COMPASS investigators (pp. 1319–30). Among 27,395 patients with stable atherosclerotic vascular disease, these outcomes were identified based on a primary outcome of a composite of cardiovascular death, stroke, or myocardial infarction: “The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P <0.001; z = −4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P <0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P = 0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.” (J. W. Eikelboom, eikelbj@mcmaster.ca)
“This trial represents an important step forward in thrombocardiology, and it is likely to change practice guidelines,” writes an editorialist (
pp. 1387–8). “But is it the end of clinical investigation in this area? Probably not.… First, a meta-analysis of dual antiplatelet therapy as compared with aspirin monotherapy for secondary prevention of cardiovascular events in patients with previous myocardial infarction also showed a significant between-group difference (in favor of dual therapy) in the same primary end point used in the COMPASS trial as well as in cardiovascular death, myocardial infarction, and stroke individually.…
“Second, perhaps substituting a P2Y
12 inhibitor or thrombin-receptor antagonist for aspirin, together with a very low dose of a factor Xa inhibitor, might lead to even greater efficacy by reducing myocardial infarction. Third, it is possible that different subgroups of patients with stable ischemic heart disease, such as those with a history of an acute coronary syndrome or those with heart failure, will have different responses to these various drug combinations, and this could lead to a more personalized approach to patients with stable ischemic heart disease.” (E. Braunwald)
First-Line Obinutuzumab for Follicular Lymphoma: In a study of induction therapy in 1,202 patients with follicular lymphoma, longer progression-free survival resulted from obinutuzumab-based immunochemotherapy and maintenance therapy than rituximab-based therapy but with more high-grade adverse events (pp. 1331–44): “After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P = 0.001).… Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%).” (R. Marcus, marcus.re@googlemail.com)
“Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma?” editorialists ask (
pp. 1389–90). “Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzumab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1000 mg might reduce or eliminate any difference in progression-free survival — that is, if the difference is primarily a dose effect.” (J. O. Armitage)

PNN Pharmacotherapy Line
Oct. 6, 2017 * Vol. 24, No. 193
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Cardiology Report
Source:
 Oct. 10 issue of the Journal of the American College of Cardiology (2017; 70).
Palliative Care in Heart Failure: Evidence supporting the use of palliative care in patients with heart failure (HF) is reviewed (pp. 1919–30): “Patients with HF and their families experience stress and suffering from a variety of sources over the course of the HF experience. Palliative care is an interdisciplinary service and an overall approach to care that improves quality of life and alleviates suffering for those living with serious illness, regardless of prognosis. In this review, we synthesize the evidence from randomized clinical trials of palliative care interventions in HF. While the evidence base for palliative care in HF is promising, it is still in its infancy and requires additional high-quality, methodologically sound studies to clearly elucidate the role of palliative care for patients and families living with the burdens of HF. Yet, an increase in attention to primary palliative care (e.g., basic physical and emotional symptom management, advance care planning), provided by primary care and cardiology clinicians, may be a vehicle to address unmet palliative needs earlier and throughout the illness course.” (D. Kavalieratos, diok@pitt.edu)
>>>Circulation Highlights
Source:
 Oct. 3 issue of Circulation (2017; 136).
Subclinical Atrial Fibrillation in Older Patients: In older patients who undergo continuous ECG monitoring, subclinical atrial fibrillation (SCAF) is often detected, but the condition has uncertain clinical significance, researchers report (pp. 1276–83). Among patients 65 or older who met stroke risk, apnea, and obesity criteria, monitoring for SCAF lasting 5 minutes or more showed the following: “Two hundred fifty-six patients were followed up for 16.3 ± 3.8 months. Baseline age was 74 ± 6 years; mean CHA2DS2-VASc score was 4.1 ± 1.4; left atrial diameter averaged 4.7 ± 0.8 cm; and 48% had a prior stroke, transient ischemic attack, or systemic embolism. SCAF ≥5 minutes was detected in 90 patients (detection rate, 34.4%/y; 95% confidence interval [CI], 27.7–42.3). Baseline predictors of SCAF were increased age (hazard ratio [HR] per decade, 1.55; 95% CI, 1.11–2.15), left atrial dimension (HR per centimeter diameter, 1.43; 95% CI, 1.09–1.86), and blood pressure (HR per 10 mm Hg, 0.87; 95% CI, 0.78–0.98), but not prior stroke. The rate of occurrence of SCAF in those with a history of stroke, systemic embolism, or transient ischemic attack was 39.4%/y versus 30.3%/y without (P = 0.32). The cumulative SCAF detection rate was higher (51.9%/y) in those with left atrial volume above the median value of 73.5 mL.” (J. S. Healey, Jeff.Healey@phri.ca)
“Study of individuals with SCAF has also yielded intriguing observations suggesting that the current paradigm of stroke pathophysiology in patients with AF may be overly simplistic,” editorialists write (
pp. 1284–7). “Despite the clear link between SCAF and ischemic stroke, the temporal relationship between the conditions is not straightforward.… This raises the possibility that systemic or local factors increase the embolic risk independently of (or in addition to) atrial arrhythmia in some individuals, with SCAF representing an accessible biomarker of this process rather than the vital precipitant to cardiac thrombus formation. This may also have wider relevance to patients with clinical AF because CHA2DS2-VASc scoring does not identify pathophysiological factors specific to thrombus development.…” (B. Casadei, barbara.casadei@cardiov.ox.ac.uk)
>>>PNN NewsWatch
* Baxter has announced a voluntary recall of one shipment from a single lot of Intralipid 20% IV Fat Emulsion, 100 mL, distributed between Aug. 11 and 31 to hospitals and health care providers in the U.S., to the user level, because of exposure to subfreezing temperatures during transit, FDA said.
* In an expansion of previously announced recall (see PNN, Sept. 22), 
Gadget Island is voluntarily recalling Rhino 7 Platinum 5000 capsules, all lots; Papa Zen 3300 capsules, lot NSS050888; Fifty Shades 6000 capsules, all lots; Grande X 5800 capsules, all lots, to the consumer level. FDA analysis has found the products to be tainted with sildenafil and tadalafil, as well as desmethyl carbodenafil, which is structurally similar to sildenafil, the agency said.
PNN will not be published on Mon., Oct. 9, Columbus Day.

PNN Pharmacotherapy Line
Oct. 10, 2017 * Vol. 24, No. 194
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Outcomes With Recently Approved Oncology Drugs: Despite high costs, medications approved in 2009–13 by the European Medicines Agency (EMA) with oncology indications usually lacked clear evidence of improvements in “clinically meaningful outcomes like survival or quality of life” and only rarely showed such benefits in postmarketing randomized trials, a systematic review shows (j4530). After considering pivotal and postmarketing trials of 48 oncology medications with 68 indications, the authors conclude: “This systematic evaluation of oncology approvals by the EMA in 2009–13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.” (C. Davis, courtney.davis@kcl.ac.uk)
>>>Internal Medicine Report
Source:
 Online content from JAMA Internal Medicine (2017; 177).
Compounded Bioidentical Hormone Therapy: “Clinicians should be cautious about prescribing [compounded bioidentical hormone therapy (cBHT)], and women should be cautious about filling prescriptions,” conclude authors of a Viewpoint article (doi: 10.1001/jamainternmed.2017.5141). Because all FDA-approved menopausal hormone therapy products have classwide warnings pertaining to a variety of risks, the authors write, “State pharmacy boards could take the initiative to request that compounding pharmacists provide a patient package insert when these medications are dispensed, or state legislatures could pass laws mandating that this information is provided to patients. Congress could also provide the FDA with full legal authority over cBHT. In the absence of such measures, clinicians should fully inform their patients. One way or another, let’s tell patients the truth.” (C. A. Stuenkel, castuenkel@ucsd.edu)
>>>PNN NewsWatch
FDA on Friday approved a new implantable treatment option, The Remede System (Respicardia), for patients with moderate to severe central sleep apnea. It stimulates neurons responsible for initiating diaphragmatic breathing.
* Securing the 
pharmaceutical manufacturing base in Puerto Rico in the aftermath of Hurricanes Irma and Maria is an important current mission of FDA, the Commissioner said in a statement on Friday. “Puerto Rico is vital to the health and well-being of all Americans,” Scott Gottlieb, MD, said. “We’re keeping a close watch on the most critical medical products. These are the products for which a shortage could have substantial impact on the public health. This list currently comprises about 40 pharmaceutical and biological drug products. In some cases, we’re in daily communication with the companies to stay on top of the evolving challenges and to act quickly when we can to prevent drug and device shortages.”
>>>PNN JournalWatch
* Infectious Diseases Team for the Early Management of Severe Sepsis and Septic Shock in the Emergency Department, in Clinical Infectious Diseases, 2017; 65: 1253–9. (P. Viale) 
* Pull Incentives for Antibacterial Drug Development: An Analysis by the Transatlantic Task Force on Antimicrobial Resistance, in 
Clinical Infectious Diseases, 2017: 65: 1378–82. (C. Årdal) 
* Discontinuing Inappropriate Medication Use in Nursing Home Residents: A Cluster Randomized Controlled Trial, in 
Annals of Internal Medicine, 2017; doi: 10.7326/M16-2729. (H. Wouters, j.wouters@umcg.nl
* Exenatide Once Weekly Versus Placebo in Parkinson’s Disease: A Randomised, Double-Blind, Placebo-Controlled Trial, in 
Lancet, 2017; 390: 1664–75. (T. Foltynie, t.foltynie@ucl.ac.uk)
* Interim Results From the CATNON Trial (EORTC Study 26053-22054) of Treatment With Concurrent and Adjuvant Temozolomide for 1p/19q Non-Co-Deleted Anaplastic Glioma: A Phase 3, Randomised, Open-Label Intergroup Study, in 
Lancet, 2017; 390: 1645–53. (M. J. van den Bent, m.vandenbent@erasmusmc.nl
* Bevacizumab for Advanced Cervical Cancer: Final Overall Survival and Adverse Event Analysis of a Randomised, Controlled, Open-Label, Phase 3 Trial (Gynecologic Oncology Group 240), in 
Lancet, 2017; 390: 1654–63. (K. S. Tewari, ktewari@uci.edu)
* Translating Cough Mechanisms Into Better Cough Suppressants, in 
Chest, 2017; 152: 833–41. (S. B. Massone, stuart.mazzone@unimelb.edu.au)

PNN Pharmacotherapy Line
Oct. 11, 2017 * Vol. 24, No. 195
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Oct. 10 issue of JAMA (2017; 318).
Insulin Pump v. Injection Therapy in Type 1 Diabetes: Significantly improved outcomes — fewer episodes of severe hypoglycemia or diabetic ketoacidosis and lower A1C levels — were associated with insulin pump therapy in young people with type 1 diabetes, compared with insulin injection therapy, researchers report (pp. 1358–66). In a population-based cohort study conducted in 2011–15 at 446 European diabetes centers, these changes in primary and secondary outcomes were observed: “Of 30,579 patients (mean age, 14.1 years [SD, 4.0]; 53% male), 14,119 used pump therapy (median duration, 3.7 years) and 16,460 used insulin injections (median duration, 3.6 years). Patients using pump therapy (n = 9,814) were matched with 9,814 patients using injection therapy. Pump therapy, compared with injection therapy, was associated with lower rates of severe hypoglycemia (9.55 vs 13.97 per 100 patient–years; difference, −4.42 [95% CI, −6.15 to −2.69]; P < .001) and diabetic ketoacidosis (3.64 vs 4.26 per 100 patient–years; difference, −0.63 [95% CI, −1.24 to −0.02]; P = .04). Glycated hemoglobin levels were lower with pump therapy than with injection therapy (8.04% vs 8.22%; difference, −0.18 [95% CI, −0.22 to −0.13], P < .001). Total daily insulin doses were lower for pump therapy compared with injection therapy (0.84 U/kg vs 0.98 U/kg; difference, −0.14 [−0.15 to −0.13], P < .001). There was no significant difference in body mass index between both treatment regimens. Similar results were obtained after propensity score inverse probability of treatment weighting analyses in the entire cohort.” (B. Karges)
Behavioral Interventions on Inappropriate Antibiotic Prescribing: Interventions designed to influence prescribing behaviors regarding antibiotics must be sustained, investigators conclude based on a study of 47 primary care practices in Boston and Los Angeles (pp. 1391–2). Using cluster randomization, 248 clinicians were assigned to receive 0, 1, 2, or 3 interventions over an 18-month period. The interventions used electronic health records (EHRs) to suggest nonantibiotic alternatives to antibiotics for acute respiratory infections (ARIs) or prompt clinicians to enter free-text written justifications for prescribing antibiotics for ARIs. Results in 2011–12 showed the following: “There were 14,753 visits for antibiotic-inappropriate ARIs during the baseline period, 16,959 during the intervention period, and 7,489 during the postintervention period. During the postintervention period, the rate of inappropriate antibiotic prescribing decreased in control clinics from 14.2% to 11.8% (absolute difference, −2.4%); increased from 7.4% to 8.8% (absolute difference, 1.4%) for suggested alternatives (difference-in-differences, 3.8% [95% CI, −10.3% to 17.9%]; P = .55); increased from 6.1% to 10.2% (absolute difference, 4.1%) for accountable justification (difference-in-differences, 6.5 [95% CI, 4.2% to 8.8%]; P < .001); and increased from 4.8% to 6.3% (absolute difference, 1.5%) for peer comparison (difference-in-differences, 3.9% [95% CI, 1.1% to 6.7%]; P < .005). During the postintervention period, peer comparison remained lower than control (P < .001; 1-tailed test), whereas accountable justification was not different from control (P = .99; 1-tailed test).” (J. N. Doctor, jdoctor@usc.edu)
Perioperative Management of High-Risk Patients: The Intraoperative Norepinephrine to Control Arterial Pressure (INPRESS) study (pp. 1346–57; E. Futier, efutier@chu-clermontferrand.fr) “gives new meaning to the advice to ‘avoid hypoxia and hypotension,’” editorialists write (pp. 1330–2). “The pathway to improved outcomes will no doubt be long and confounded by many circumstances, but it will be well worth the effort. The INPRESS trial not only provides a view of the important domain of perioperative randomized clinical trial design for conventional treatment of common conditions but also offers a glimpse of what may lie beyond when attention is focused on the clinical science of perioperative medicine.” (S. Aronson, solomon.aronson@duke.edu)
>>>PNN NewsWatch
* Kiriko, LLC, is voluntarily recalling all lots of A1 Slim 30 capsules to the consumer level. FDA laboratory analysis has found the product to be tainted with sibutramine, phenolphthalein, and N-desmethylsibutramine, the agency said.

PNN Pharmacotherapy Line
Oct. 12, 2017 * Vol. 24, No. 196
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Oct. 12 New England Journal of Medicine (2017; 377).
Fracture Prevention in Women with Osteoporosis: Monthly subcutaneous romosozumab 210 mg for 12 months produced significantly better protection against fracture among 4,093 postmenopausal women with osteoporosis than did weekly oral alendronate 70 mg, researchers report (pp. 1417–27). Results based on primary end points of cumulative incidence of new vertebral fracture at 24 months (12 months of randomized therapy followed by 12 months of alendronate) and cumulative incidence of nonvertebral and symptomatic vertebral fracture were as follows: “Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2,046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2,047 patients]) (P <0.001). Clinical fractures occurred in 198 of 2,046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2,047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P <0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2,046 patients [8.7%] vs. 217 of 2,047 patients [10.6%]; P = 0.04), and the risk of hip fracture was lower by 38% (41 of 2,046 patients [2.0%] vs. 66 of 2,047 patients [3.2%]; P = 0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2,040 patients [2.5%] vs. 38 of 2,014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.” (K. G. Saag)
An editorialist asks: “What can we learn from this trial, which is unique as a fracture efficacy trial comparing a new bone-active drug with a long-established therapy — a true comparative-effectiveness trial?” (
pp. 1479–80). “Romosozumab is very effective in preventing fractures among high-risk postmenopausal women, particularly when taken for 1 year followed by alendronate. Romosozumab has strong antiresorptive properties, although it is unclear whether the sequence of romosozumab followed by alendronate increases the risk of atypical femoral fractures. Finally, the cardiovascular signal for romosozumab is particularly troubling. Although it may be surprising that a bone-specific drug has off-target cardiovascular effects, this finding is very consistent with our recent understanding of the skeleton as an endocrine tissue that modulates whole-body homeostasis by secreting peptides such as sclerostin, fibroblast growth factor 23 (FGF-23), and osteocalcin. Moreover, other bone-targeted therapies, including estrogen and odanacatib, have adverse cardiovascular effects.” (C. J. Rosen)
Ebola Outcomes & Vaccines: Reacting to a study of two Ebola vaccines (pp. 1438–77; H. C. Lane, clane@niaid.nih.gov) and a report of Ebola RNA persistence in semen of men surviving the disease (pp. 1428–37; G. F. Deen, gibrilladeen1960@yahoo.com), editorialists write (pp. 1480–2): “Vaccines against [Ebola virus disease (EVD)] have been traditionally thought of as countermeasures that might be used in the context of a bioterrorism event, as protection for front-line workers during EVD outbreaks, and as a means to control outbreaks by stopping transmission. To this list we might add the protection of the contacts of survivors of EVD. If such protection allows communities and public health agencies some measure of certainty that the end of an outbreak is truly the end, perhaps the survivors of EVD can be granted some peace and the opportunity to resume their lives beyond Ebola.” (A. Sprecher)
>>>PNN NewsWatch
* Noting the first meeting of FDA’s Patient Engagement Advisory Committee, Commissioner Scott Gottlieb, MD, said in a statement that this is not a “new door for patient groups” but that the “preference is for patient groups to interface directly with the review programs. For groups that don’t know how to access the FDA, this new function can serve as an initial entry point.”

PNN Pharmacotherapy Line
Oct. 13, 2017 * Vol. 24, No. 197
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>>>Infectious Diseases Report
Source:
 Oct. 15 issue of Clinical Infectious Diseases (2017; 65).
Influenza Vaccination & Disease Severity: Adults of all ages hospitalized for laboratory-confirmed influenza had less severe disease if they had received the 2013–14 vaccine, researchers report (pp. 1289–97). During that season, circulating viruses were antigenically similar to the vaccine viruses. Severity outcomes of death, intensive care unit (ICU) admission, and hospital and ICU lengths of stay (LOS) showed these results: “Influenza vaccination was associated with a reduction in the odds of in-hospital death among patients aged 18−49 years (adjusted odds ratios [aOR] = 0.21; 95% confidence interval [CI], 0.05 to 0.97), 50–64 years (aOR = 0.48; 95% CI, 0.24 to 0.97), and ≥65 years (aOR = 0.39; 95% CI, 0.17 to 0.66). Vaccination also reduced ICU admission among patients aged 18−49 years (aOR = 0.63; 95% CI, 0.42 to 0.93) and ≥65 years (aOR = 0.63; 95% CI, 0.48 to 0.81), and shortened ICU LOS among those 50−64 years (adjusted relative hazards [aRH] = 1.36; 95% CI, 1.06 to 1.74) and ≥65 years (aRH = 1.34; 95% CI, 1.06 to 1.73), and hospital LOS among 50−64 years (aRH = 1.13; 95% CI, 1.02 to 1.26) and ≥65 years (aRH = 1.24; 95% CI, 1.13 to 1.37).” (C. S. Arriola, wus3@cdc.gov)
C. difficile Infection Rates & Antibiotic Use: In a case-cohort study of Clostridium difficile infection (CDI) incidence across 131 acute and 120 long-term care facilities, antibiotic use in acute care was the main factor driving differences between the two settings (pp. 1282–8). This VA study included 8 patient and 5 facility factors and reported these results: “CDI incidence in acute care was 5 times that observed in long-term care (median, 15.6 vs 3.2 per 10,000 person-–days). History of antibiotic use was greater in acute care compared to long-term care (median, 739 vs 513 per 1,000 person–days) and explained 72% of the variation in C. difficile rates. Importation of C. difficile cases (acute care: patients with recent long-term care attributable infection; long-term care: residents with recent acute care attributable infection) was 3 times higher in long-term care as compared to acute care (median, 52.3 vs 16.2 per 10,000 person–days).” (K. A. Brown, kevin.brown@utoronto.ca)
Sepsis Management by ID Teams in the ED: Early management of severe sepsis/septic shock (SS/SS) in the emergency department (ED) by an infectious disease (ID) team improved adherence to the Surviving Sepsis Campaign (SSC) bundle and appropriateness of initial antibiotic therapy, according to authors of a quasiexperimental pre–post study (pp. 1253–9). Compared with data prospectively collected during a pre-phase (June 2013–July 2014), results from the post-phase (Aug. 2014–Oct. 2015) showed that “overall compliance with the SSC bundle and appropriateness of initial antibiotic therapy improved from 4.6% to 32% (P < .001) and from 30% to 79% (P < .001), respectively.” (M. Giannella, maddalena.giannella@unibo.it)
>>>Oncology Highlights
Source:
 Oct. 10 issue of the Journal of Clinical Oncology (2017; 35).
Part D Subsidies for Patients With Myeloma: Financial barriers are substantial among Medicare Part D beneficiaries who need novel oral immunomodulatory drugs (IMiDs; lenalidomide and thalidomide) for myeloma, a study shows (pp. 3306–14). In 2007–11, these expenses were identified for those receiving a low-income subsidy (LIS) or paying out-of-pocket: “Among 3,038 beneficiaries, 41% received first-line IMiDs. Median out-of-pocket cost for the first IMiD prescription was $3,178 for LIS nonrecipients and $3 for LIS recipients, whereas the respective median costs for the first year of therapy were $5,623 and $6, respectively. Receipt of the LIS was associated with a 32% higher (95% CI, 16% to 47%) probability of receiving IMiDs among beneficiaries age 75 to 84 years and a significantly lower risk of delays between refills in all age groups (adjusted relative risk, 0.54; 95% CI, 0.32 to 0.92). Duration of therapy did not significantly differ between LIS recipients and nonrecipients (median, 7.6 months). Patients treated with IMiDs had significantly fewer emergency department visits and hospitalizations compared with patients receiving bortezomib (without IMiDs), but 1-year overall survival and cumulative Medicare costs were similar.” (A. J. Olszewski, adam_olszewski@brown.edu)

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Oct. 16, 2017 * Vol. 24, No. 198
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>>>Lancet Highlights
Source:
 Oct. 14 issue of Lancet (2017; 390).
Oral Anticoagulants in Atrial Fibrillation: In the IMPACT-AF trial, educational interventions aimed at improving oral anticoagulation led to greater use of the medications among patients with atrial fibrillation and at risk for stroke, researchers report (pp. 1737–46). Concluding that the “multifaceted and multilevel educational intervention” could “improve stroke prevention around the world for patients with atrial fibrillation,” the authors report these results for the two-arm, cluster-randomized study: “2,281 patients from five countries (Argentina, n = 343; Brazil, n = 360; China, n = 586; India, n = 493; and Romania, n = 499) were enrolled from 48 clusters between June 11, 2014, and Nov 13, 2016. Follow-up was at a median of 12.0 months (IQR 11.8–12.2). Oral anticoagulant use increased in the intervention group from 68% (804 of 1,184 patients) at baseline to 80% (943 of 1,184 patients) at 1 year (difference 12%), whereas in the control group it increased from 64% (703 of 1,092 patients) at baseline to 67% (732 of 1,092 patients) at 1 year (difference 3%). Absolute difference in the change between groups was 9.1% (95% CI 3.8–14.4); odds ratio of change in the use of oral anticoagulation between groups was 3.28 (95% CI 1.67–6.44; adjusted p value = 0.0002). Kaplan–Meier estimates showed a reduction in the secondary outcome of stroke in the intervention versus control groups (HR 0.48, 95% CI 0.23–0.99; log-rank p value = 0.0434).” (C. B. Granger, christopher.granger@duke.edu)
Guided De-escalation of Antiplatelet Treatment in ACS: “Early de-escalation of antiplatelet treatment can be considered as an alternative approach [to standard therapy with prasugrel] in patients with acute coronary syndrome managed with [percutaneous coronary intervention (PCI)],” conclude TROPICAL-ACS investigators based on 1-year results at 33 European study sites (pp. 1747–57). Net clinical benefits with the approaches were similar with standard versus step-down therapy in 1,304 patients in the guided de-escalation group and in 1,306 patients in the control group: “The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority = 0.0004; hazard ratio [HR] 0.81 [95% CI 0.62–1.06], psuperiority = 0.12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority = 0.0115). There were 64 [Bleeding Academic Research Consortium] 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0.82 [95% CI 0.59–1.13]; p = 0.23).” (D. Sibbing, dirk.sibbing@med.uni-muenchen.de)
>>>PNN NewsWatch
FDA and Baxter are working to avoid a shortage of 0.9% sodium chloride injection minibags that could result from hurricane damage to plants in Puerto Rico, Commissioner Scott Gottlieb, MD, said on Friday. The agency is trying to restore production of the minibags, Gottlieb said, adding, “The FDA is also expediting reviews and approvals of other dosage forms and generic versions of products as alternate sources of critical products.”
* A California dietary supplement manufacturer, 
Custompax, recently was ordered by a federal court to stop selling its products until the company comes into compliance with federal regulations, FDA said on Friday.
>>>PNN JournalWatch
* Review: Enhancers in Autoimmune Arthritis: Implications and Therapeutic Potential, in Arthritis & Rheumatology, 2017; 69: 1925–36. (J. van Loosdregt, J.vanloosdregt@umcutrecht.nl
* Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines—2016 revision, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 950–8. (J. L. Brozek, jan.l.brozek@gmail.com
* Promising Approaches for the Treatment and Prevention of Viral Respiratory Illnesses, in 
Journal of Allergy and Clinical Immunology, 2017; 140: 921–32. (N. G. Papadopoulos, ngp@allergy.gr
* Nephrotic Syndrome With Cancer Immunotherapies: A Report of 2 Cases, in 
American Journal of Kidney Diseases, 2017; 70: 581–5. (A. Kitchlu, abhijat.kitchlu@uhn.ca
* Atazanavir-Associated Crystalline Nephropathy, in 
American Journal of Kidney Diseases, 2017; 70: 576–80. (D. Santoriello, ds3356@cumc.columbia.edu)

PNN Pharmacotherapy Line
Oct. 17, 2017 * Vol. 24, No. 199
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>>>Internal Medicine Report
Source:
 Online articles from Annals of Internal Medicine (2017; 167).
Preventable Spending in High-Cost Medicare Patients: Potentially preventable spending for high-cost Medicare beneficiaries is concentrated among the frail elderly subpopulation, an observational study shows, followed by nonelderly disabled persons and those with complex chronic disorders (10.7326/M17-0767). Analysis of fee-for-service claims for 6 million beneficiaries showed the following patterns of potentially preventable spending: “In 2012, 4.8% of Medicare spending was potentially preventable, of which 73.8% was incurred by high-cost patients. Despite making up only 4% of the Medicare population, high-cost frail elderly persons accounted for 43.9% of total potentially preventable spending ($6,593 per person). High-cost nonelderly disabled persons accounted for 14.8% of potentially preventable spending ($3,421 per person) and the major complex chronic group for 11.2% ($3,327 per person). Frail elderly persons accounted for most spending related to admissions for urinary tract infections, dehydration, heart failure, and bacterial pneumonia.” (A. K. Jha, ajha@hsph.harvard.edu)
While “success will not be easy and is in no way assured” with the move to value-based care under the Affordable Care Act, editorialists write that “new payment and patient assignment models are also needed, and their creation will not be easy” (
10.7326/M17-2627). “To make a pathway for the development of innovative payment models in [fee-for-service (FFS)] Medicare, [the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA)] created the Physician-Focused Payment Model Technical Advisory Committee. Although the process is still early in its development and implementation, most proposals that have come to the Committee have been incremental and built on the culture and chassis of the FFS model.
“This all needs to happen as our health system addresses the critical challenges of lack of universal access to health care, underinvestment in primary care, administrative inefficiency, and disparities in delivery of care. Studies … can help point the way to ‘coolable’ hot spots. The onus is now on organizations and systems to shift culture and learn to implement the care and contracting methods used by their ‘coolest’ peers.” (B. Leff, 
bleff@jhmi.edu)
Gender Differences in HPV Infection: The high prevalence of human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma (OPSCC) among U.S. men is evident in 2011–14 National Health and Nutritional Examination Survey data (10.7326/M17-1363). The “findings provide several policy implications to guide future OPSCC prevention efforts to combat this disease,” the authors conclude, reporting: “The overall prevalence of oral HPV infection was 11.5% (95% CI, 9.8% to 13.1%) in men and 3.2% (CI, 2.7% to 3.8%) in women (equating to 11 million men and 3.2 million women nationwide). High-risk oral HPV infection was more prevalent among men (7.3% [CI, 6.0% to 8.6%]) than women (1.4% [CI, 1.0% to 1.8%]). Oral HPV 16 was 6 times more common in men (1.8% [CI, 1.3% to 2.2%]) than women (0.3% [CI, 0.1% to 0.5%]) (1.7 million men vs. 0.27 million women). Among men and women who reported having same-sex partners, the prevalence of high-risk HPV infection was 12.7% (CI, 7.0% to 18.4%) and 3.6% (CI, 1.4% to 5.9%), respectively. Among men who reported having 2 or more same-sex oral sex partners, the prevalence of high-risk HPV infection was 22.2% (CI, 9.6% to 34.8%). Oral HPV prevalence among men with concurrent genital HPV infection was fourfold greater (19.3%) than among those without it (4.4%). Men had 5.4% (CI, 5.1% to 5.8%) greater predicted probability of high-risk oral HPV infection than women. The predicted probability of high-risk oral HPV infection was greatest among black participants, those who smoked more than 20 cigarettes daily, current marijuana users, and those who reported 16 or more lifetime vaginal or oral sex partners.” (A. A. Deshmukh, aadeshmukh@phhp.ufl.edu)
“Future observational studies should be designed explicitly to estimate the transitional probabilities not only for acquisition of oral HPV infection from a recent sexual partner, but also autoinoculation from other anogenital sites and recurrent detection of an immunologically controlled (that is, latent) infection,” editorialists write (
10.7326/M17-2628; P. E. Gravitt, pgravitt@gwu.edu).

PNN Pharmacotherapy Line
Oct. 18, 2017 * Vol. 24, No. 200
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>>>JAMA Report
Source:
 Oct. 17 issue of JAMA (2017; 318).
Systematic Triage of Critically Ill Older Patients: Pointing to the need for further research into decisions regarding admission of critically ill older patients to intensive care units (ICUs), a French study showed that systematic triage increased use of intensive care services but may have worsened 6-month mortality rates (pp. 1450–9). The cluster-randomized trial of 3,037 critically ill patients aged 75 years or older was conducted at 24 hospitals in 2012–15 showed the following for individuals who on admission were free of cancer, had preserved functional status, and good nutritional status: “One patient withdrew consent, leaving 3,036 patients included in the trial (median age, 85 [interquartile range, 81–89] years; 1,361 [45%] men). Patients in the systematic strategy group had an increased risk of death at 6 months (45% vs 39%; relative risk [RR], 1.16; 95% CI, 1.07–1.26) despite an increased ICU admission rate (61% vs 34%; RR, 1.80; 95% CI, 1.66–1.95). After adjustments for baseline characteristics, patients in the systematic strategy group were more likely to be admitted to an ICU (RR, 1.68; 95% CI, 1.54–1.82) and had a higher risk of in-hospital death (RR, 1.18; 95% CI, 1.03–1.33) but had no significant increase in risk of death at 6 months (RR, 1.05; 95% CI, 0.96–1.14). Functional status and physical quality of life at 6 months were not significantly different between groups.” (B. Guidet, bertrand.guidet@aphp.fr)
“This well-conducted study by Guidet et al provides the first randomized data on the effects of ICU care for a broad range of critically ill elderly patients, an important question for resource-intensive health care systems worldwide,” editorialists write (
pp. 1443–4). “However, a number of persistent questions arise. First, were there patients within the trial who were harmed by ICU care in ways that could be better predicted in the future? For example, did the intervention unintentionally suppress the better judgment of physicians regarding when to avoid ICU care by failing to capture key patient variables? Second, if ICU admission rates that are poorly adherent with consensus criteria yield equally good or better outcomes, then what criteria should be used to audit ICU use going forward? Third, are there beneficial practices on the general hospital ward that can be promoted and harmful practices in the ICU that can be eradicated? Moreover, for countries like Germany or the United States, with 3 to 4 times higher ICU bed supply, the findings from the trial by Guidet et al certainly support an argument for close examination of ICU admission decisions, with the potential to safely reduce ICU beds, care, and costs.” (D. C. Angus, angusdc@upmc.edu)
Oral Semaglutide in Type 2 Diabetes: In a phase 2 dose-ranging trial, patients with type 2 diabetes had better glycemic control over a 26-week period when treated with the oral glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, compared with placebo, researchers report (pp. 1460–70). At 100 sites in 14 countries in 2013–14, these results were recorded for 632 patients with type 2 diabetes randomized after having insufficient glycemic control using diet and exercise alone or a stable dose of metformin: “Baseline characteristics were comparable across treatment groups. Of the 632 randomized patients (mean age, 57.1 years [SD, 10.6]; men, 395 (62.7%); diabetes duration, 6.3 years [SD, 5.2]; body weight, 92.3 kg [SD, 16.8]; BMI, 31.7 [SD, 4.3]), 583 (92%) completed the trial. Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%); oral semaglutide reductions were significant vs placebo (dosage-dependent estimated treatment difference [ETD] range for oral semaglutide vs placebo, –0.4% to –1.6%; P = .01 for 2.5 mg, <.001 for all other dosages). Reductions in body weight were greater with oral semaglutide (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg), and significant for oral semaglutide dosages of 10 mg or more vs placebo (dosage-dependent ETD range, –0.9 to –5.7 kg; P < .001). Adverse events were reported by 63% to 86% (371 of 490 patients) in the oral semaglutide groups, 81% (56 of 69 patients) in the subcutaneous semaglutide group, and 68% (48 of 71 patients) in the placebo group; mild to moderate gastrointestinal events were most common.” (M. Davies, melanie.davies@uhl-tr.nhs.uk)

PNN Pharmacotherapy Line
Oct. 19, 2017 * Vol. 24, No. 201
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>>>NEJM Report
Source:
 Oct. 19 issue of the New England Journal of Medicine (2017; 377).
Dual Antithrombotics After PCI in AF: Results of the RE-DUAL PCI trial demonstrate a safety advantage of dual antithrombotic therapy following percutaneous coronary intervention (PCI) for patients with atrial fibrillation, compared with standard-of-care triple therapy, and similar efficacy for the two approaches (pp. 1513–24). Triple therapy included warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin for 1 to 3 months, while dual therapy was dabigatran 110 mg or 150 mg twice daily plus a P2Y12 inhibitor. Results showed: “The incidence of the primary [safety—bleeding] end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P <0.001 for noninferiority; P <0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P <0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P = 0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.” (C. P. Cannon, christopher.cannon@baiminstitute.org)
“No single trial has been adequately powered to completely rule out an increase in ischemic events with dual therapy versus triple therapy,” editorialists write (
pp. 1580–2). “However, the consistency across … three major trials and the significantly lower risk of bleeding with dual therapy make it hard to argue that triple therapy should be used routinely. The aggregate evidence suggests that the net clinical benefit of dual therapy should give cardiologists confidence to drop aspirin when they are using a contemporary PCI strategy with drug-eluting stents. Moving forward, the key questions will be: What combination of drugs should be included in dual therapy, and how will we test this strategy?” (W. S. Jones)
Tofacitinib for Psoriatic Arthritis: Phase 3 trials (pp. 1525–36, D. Gladman, dafna.gladman@utoronto.capp. 1537–50, P. Mease, pmease@philipmease.com) and an editorial examine use of tofacitinib in patients with psoriatic arthritis.
“The Arthritis Advisory Committee of the FDA recently recommended the approval of tofacitinib for the treatment of psoriatic arthritis, with the caution that a lower rate of progression (as assessed radiographically) has not been shown,” editorialists write in response to the trials (
pp. 1582–4). “Comparisons of tofacitinib with other biologic DMARDs will inform its place in the treatment algorithm of psoriatic arthritis. The numbers needed to treat in order to observe an ACR20 response with tofacitinib at a dose of 5 mg twice daily were 5.8 in the trial by Mease et al. and 3.9 in the trial by Gladman et al., whereas the numbers needed to treat in pivotal trials of ustekinumab were 3.8 and 4.4 and in pivotal trials of secukinumab were 3.0 and 2.6. Further experience and direct comparisons will help to determine whether these relative efficacies are genuine. Differences in safety will also inform the choice of treatments. Although all biologic DMARDs and tofacitinib are broadly immunosuppressive, tofacitinib appears to carry an additional risk of herpes zoster infection. Alterations in serum lipid levels also occur with tofacitinib, the long-term clinical consequences of which are still unclear.” (R. A. Colbert)
>>>PNN NewsWatch
FDA yesterday approved the second gene therapy product, axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma). The product — a chimeric antigen receptor T cell (CAR T) — is not indicated for the treatment of patients with primary central nervous system lymphoma. Product labeling for axicabtagene ciloleucel warns of risks of cytokine release syndrome and neurologic toxicities. FDA has mandated a REMS for Yescarta.

PNN Pharmacotherapy Line
Oct. 20, 2017 * Vol. 24, No. 202
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>>>Medical Care Report
Source:
 Nov. issue of Medical Care (2017; 55).
Opioid-Related Inpatient Stays & ICD-10-CM Codes: The International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), may be capturing more opioid-related inpatient stays compared with ICD-9-CM, contributing recent increases, researchers report (pp. 918–23). Data from the Healthcare Cost and Utilization Project State Inpatient Databases for 14 states in 2015−16 show these patterns in the U.S.: “Overall, stays involving any opioid-related diagnosis increased by 14.1% during the ICD transition—which was preceded by a much lower 5.0% average quarterly increase before the transition and followed by a 3.5% average increase after the transition. In stratified analysis, stays involving adverse effects of opioids in therapeutic use showed the largest increase (63.2%) during the transition, whereas stays involving abuse and poisoning diagnoses decreased by 21.1% and 12.4%, respectively.” (K. C. Heslin)
Hospital Finances & Value-Based Care: Resource-poor hospitals in the Mississippi Delta fared poorly during implementation of value-based programs, further threatening their financial viability, a study shows (pp. 924–30). Compared with other U.S. hospitals, Delta hospitals had these operating and total margins during preperiod (2008–10); postperiod 1 (2011–12); and postperiod 2 (2013–14) implementation of the Hospital Readmissions Reduction Program (HRRP) and Hospital Value-Based Purchasing Program (HVBP): “The Delta hospitals had a 0.89% and 4.24% reduction in operating margin in postperiods 1 and 2, respectively, whereas the non-Delta hospitals had 1.13% and 1% increases in operating margin in postperiods 1 and 2, respectively. The disparity in total margins also widened as Delta hospitals had a 1.98% increase in postperiod 1, but a 0.30% reduction in postperiod 2, whereas non-Delta hospitals had 1.27% and 2.28% increases in postperiods 1 and 2, respectively.” (H-F Chen)
>>>Health Affairs Highlights
Source:
 Oct. issue of Health Affairs (2017; 36).
Opioid Abuse & Poisoning: While inpatient and emergency department (ED) discharges for opioid abuse, dependence, and poisoning declined for prescription agents starting in 2010, heroin-related discharges have climbed, a study shows (pp. 1748–53). Healthcare Cost and Utilization Project data show these patterns when combined with census data from 1997 through 2014: “Discharge rates for prescription opioid poisoning increased significantly by 8.0 percent annually from 1997 to 2010 in the inpatient setting and 5.0 percent annually from 2006 to 2010 in the ED. In both settings, rates decreased significantly from 2010 to 2014—declining annually by 5.1 percent and 5.0 percent, respectively.
“ED discharge rates for heroin poisoning significantly increased after 2008, at an annual rate of 31.4 percent. Overall, opioid-related discharge rates increased significantly by 10.5 percent annually in 2006–14 in the ED and 4.9 percent annually in 1997–2014 in the inpatient setting.… In both settings, opioid dependence and nondependent abuse had similar trends: Discharge rates from EDs increased significantly by 11.7 percent per year in 2006–12 for dependence and 16.6 percent per year in 2008–14 for abuse. And discharge rates from the inpatient setting increased significantly by 4.1 percent per year in 1997–2014 for dependence and 6.6 percent per year in the same period for abuse.” (T. Hernandez-Boussard, 
boussard@stanford.edu)
>>>PNN NewsWatch
* Rates of drug overdose deaths are rising in rural areas, surpassing rates in urban areas, according to a new report in Morbidity and Mortality Weekly Report (MMWR). Most overdose deaths occurred in homes, where rescue efforts may fall to relatives who have limited knowledge of or access to life-saving treatment and overdose follow-up care, the MMWR authors note, adding these details: “In 2015, approximately six times as many drug overdose deaths occurred in metropolitan areas than occurred in nonmetropolitan areas (metropolitan: 45,059; nonmetropolitan: 7,345). Drug overdose death rates (per 100,000 population) for metropolitan areas were higher than in nonmetropolitan areas in 1999 (6.4 versus 4.0), however, the rates converged in 2004, and by 2015, the nonmetropolitan rate (17.0) was slightly higher than the metropolitan rate (16.2).”

PNN Pharmacotherapy Line
Oct. 23, 2017 * Vol. 24, No. 203
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>>>Lancet Highlights
Source:
 Oct. 21 issue of Lancet (2017; 390).
Canakinumab in Lung Cancer in Patients With Atherosclerosis: In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of interleukin-1-beta–mediated inflammation showed promise for reducing incident lung cancer and lung cancer mortality (pp. 1833–42). The hypothesis-generating trial compared three doses of canakinumab and placebo in 10,061 patients atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. Results showed: “Baseline concentrations of hsCRP (median 6.0 mg/L vs 4.2 mg/L; p <0.0001) and interleukin 6 (3.2 vs 2.6 ng/L; p <0.0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3.7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p <0.0001 for all comparisons). Total cancer mortality (n = 196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0.0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0.49 [95% CI 0.31–0.75]; p = 0.0009). Incident lung cancer (n = 129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39–0.97]; p = 0.034) and 300 mg groups (HR 0.33 [95% CI 0.18–0.59]; p <0.0001; p <0.0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0.23 [95% CI 0.10–0.54]; p = 0.0002) and in the pooled canakinumab population than in the placebo group (p = 0.0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0.94 [95% CI 0.83–1.06]; p = 0.31).” (P. M. Ridker, pridker@partners.org)
Pembrolizumab for Advanced Melanoma: Supporting evidence for “use of pembrolizumab as a standard of care for advanced melanoma,” researchers report these phase 3 KEYNOTE-006 results for 811 patients in 16 countries (pp. 1853–62): “Median follow-up was 22.9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16.0 months with ipilimumab (hazard ratio [HR] 0.68, 95% CI 0.53–0.87 for pembrolizumab every 2 weeks vs ipilimumab; p = 0.0009 and 0.68, 0.53–0.86 for pembrolizumab every 3 weeks vs ipilimumab; p = 0.0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.” (J. Schachter, jacob.schachter@sheba.health.gov.il)
>>>PNN NewsWatch
GlaxoSmithKline has received FDA approval for a two-dose zoster vaccine (Shingrix [Zoster Vaccine Recombinant, Adjuvanted]) for use in adults aged 50 years or older. Given the vaccine’s far superior effectiveness over the product currently on the U.S. market, the approval sets the stage for interesting discussions about a preferential recommendation in the adult vaccine schedule at the CDC’s Advisory Committee on Immunization Practices on Wednesday morning in Atlanta.
SCA Pharmaceuticals is voluntarily recalling various lots of injectable products to the hospital level because of the potential for microbial contamination.
>>>PNN JournalWatch
* Comparative Safety of Direct Oral Anticoagulants and Warfarin in Venous Thromboembolism: Multicentre, Population Based, Observational Study, in BMJ, 2017; 359: j4323. (B. Hemmelgarn, Brenda.Hemmelgarn@ahs.ca
* Reducing Branded Prescription Drug Prices: A Review of Policy Options, in 
Pharmacotherapy, 2017; 10.1002/phar.2013. (G. C. Alexander, galexan9@jhmi.edu
* Stem Cell Transplantation for Frailty, in 
Journals of Gerontology Series A, 2017; 72: 1503–4. (D. G. Le Couteur, david.lecouteur@sydney.edu.au
* The Clinical Potential of Senolytic Drugs, in 
Journal of the American Geriatrics Society, 2017; 65: 2297–301. (J. Kirkland, kirkland.james@mayo.edu
* Trends in Aging-Related Services During Nephrectomy: Implications for Surgery in an Aging Population, in 
Journal of the American Geriatrics Society, 2017; 65: 2290–6. (H-J Tan, hjtan@med.unc.edu)

PNN Pharmacotherapy Line
Oct. 24, 2017 * Vol. 24, No. 204
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>>>Allergy/Immunology Report
Source:
 Oct. issue of the Journal of Allergy and Clinical Immunology (2017; 140).
Treatment/Prevention of Viral Respiratory Illnesses: Numerous promising strategies for managing or preventing viral respiratory tract infections are under development, according to authors of a review article (pp. 921–32): “Hundreds of viral species and subtypes have been associated with these conditions, with influenza viruses, respiratory syncytial virus, and rhinoviruses being the most frequent and with the highest burden. When considering prevention or treatment of viral respiratory tract infections, potential targets include the causative pathogens themselves but also the immune response, disease transmission, or even just the symptoms. Strategies targeting all these aspects are developing concurrently, and several novel and promising approaches are emerging. In this perspective we overview the entire range of options and highlight some of the most promising approaches, including new antiviral agents, symptomatic or immunomodulatory drugs, the re-emergence of natural remedies, and vaccines and public health policies toward prevention. Wide-scale prevention through immunization appears to be within reach for respiratory syncytial virus and promising for influenza virus, whereas additional effort is needed in regard to rhinovirus, as well as other respiratory tract viruses.” (N. G. Papadopoulos, ngp@allergy.gr)
Viral Infections in Childhood Asthma: “Developing a greater understanding of personal and environmental factors that promote more severe viral illnesses might lead to new strategies for the prevention of viral wheezing illnesses and perhaps reduce the subsequent risk for asthma,” conclude authors who reviewed respiratory syncytial virus (RSV) and rhinovirus (RV) as causes of bronchiolitis and wheezing, respectively (pp. 895–906). “There is definitive evidence that RSV-induced bronchiolitis can damage the airways to promote airway obstruction and recurrent wheezing,” the authors write. “RV likely causes less structural damage and yet is a significant contributor to wheezing illnesses in young children and in the context of asthma.… Treatments that inhibit inflammation have efficacy for RV-induced wheezing, whereas the anti-RSV mAb palivizumab decreases the risk of severe RSV-induced illness and subsequent recurrent wheeze.” (T. Jartti, tuomas.jartti@utu.fi)
Allergic Inflammation & Viral Infections: Research into mechanisms by which viral infections lead to asthma in younger people and exacerbations in older individuals is reviewed, producing these findings (pp. 909–20): “Although how viruses influence asthma inception is poorly understood, much research has focused on the host response to respiratory viruses and how viruses can promote; or how the host response is affected by subsequent allergen sensitization and exposure. This review focuses on the innate interferon-mediated host response to respiratory viruses and discusses and summarizes the available evidence that this response is impaired or suboptimal. In addition, the ability of respiratory viruses to act in a synergistic or additive manner with TH2 pathways will be discussed. In this review we argue that these 2 outcomes are likely linked and discuss the available evidence that shows reciprocal negative regulation between innate interferons and TH2 mediators. With the renewed interest in anti-TH2 biologics, we propose a rationale for why they are particularly successful in controlling asthma exacerbations and suggest ways in which future clinical studies could be used to find direct evidence for this hypothesis.” (M. R. Edwards, michael.edwards@imperial.ac.uk)
>>>PNN NewsWatch
FDA said yesterday that Octapharma USA Inc. is initiating a voluntary market withdrawal of octagam 10% [Immune Globulin Intravenous (human)] 10% Liquid Preparation], lot numbers K724B8541 and K725A8541. “Although there have been no reports of serious injury at this time, Octapharma has determined, through consultation with the public health authorities at FDA, the most prudent course of action is to suspend further administration of octagam 10% from these particular production lots,” the agency said in an unusually worded statement. Distributors are asked to immediately quarantine these lots and contact Octapharma for return instructions.

PNN Pharmacotherapy Line
Oct. 25, 2017 * Vol. 24, No. 205
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Oct. 24/31 issue of JAMA (2017; 318).
Addressing the Opioid Epidemic: In two Viewpoint articles, authors outline ideas for action to address the opioid epidemic.
“The opioid epidemic is largely iatrogenic, and the health care system has a responsibility to support actions … that could prevent addiction and save lives,” former CDC director Tom Frieden writes with a colleague (
pp. 1537–8). “Rapid implementation of [these 10 steps] could enable tracking and reduction of both new opioid addiction and fatal overdoses” (T. R. Frieden, tfrieden@resolvetosavelives.org):
* Improve surveillance of possible opioid addiction.
* Improve reporting of and response to opioid-related overdoses and fatalities.
* Promote more cautious prescribing for acute pain.
* Change labeling for chronic pain and greatly restrict or eliminate marketing of opioids for this indication. 
* Increase insurance coverage of and access to nonopioid and nonpharmacologic management of pain. 
* Interrupt the supply of heroin and illicitly produced synthetic opioids and improve coordination between legal and public health authorities.
* Identify possible opioid addiction early and link individuals to treatment.
* Expand low-threshold access to opioid agonist treatment, particularly with methadone and buprenorphine.
* Implement harm reduction measures for current users, including access to clean syringes and naloxone. 
* Consider removing ultra-high-dosage-unit opioid analgesics from the market.
Despite concerns that declaration of a national opioid emergency will lead to “more punitive responses focused on incarceration,” authors write that the 600,000 opioid-related deaths to date make such an action necessary (
pp. 1539–40): “A federal emergency declaration is warranted by the addictive quality of opioids, substantial increases in opioid abuse and related deaths, potential for continued catastrophic losses of life, and epidemic-like spread of needle-borne infections through social networks. It may have taken years for this epidemic to reach crisis levels, but it could take only months for coordinated, bipartisan interventions across public and private sectors to take hold. Preventable deaths and injuries attributable to opioid misuse will never be acceptable, but the emergency should come to an end when opioid addiction and death rates return to historic lower levels.” (L. O. Gostin, gostin@law.georgetown.edu)
Need for HIV Vaccine: “Development of a moderately effective vaccine together with optimal implementation of existing treatment and prevention modalities could end the current HIV pandemic,” concludes NIAID director Tony Fauci (pp. 1535–6). “Recent advances in HIV vaccine research provide hope that at least a moderately effective vaccine can be developed. It is critical to continue to accelerate a robust research effort in that direction while aggressively scaling-up the implementation of current treatment and prevention tools. To do anything less would lead to failure, which for HIV is not an option.” (A. S. Fauci, afauci@niaid.nih.gov)
Continuous Glucose Monitors for Insulin Dosing: Describing FDA approval of new labeling for the Dexcom G5 Mobile continuous glucose monitor (CGM) as “a potentially risky decision,” an author reviews capabilities of the device and the approval history on which the decision was made (pp. 1541–2). This “device measures interstitial fluid glucose concentrations to estimate blood glucose concentrations,” the author writes, and by Oct. 2016, “more than 25,000 medical device reports indicating large inaccuracies with blood glucose levels measured with the CGM device had been filed with the FDA since the start of 2015.” FDA nevertheless approved new labeling in Dec. 2016, and CMS followed the action with a reclassification making it eligible for reimbursement. “To make a useful class III device such as the Dexcom G5 CGM more accessible to the public, the FDA determined that necessary safety procedures (in particular, the confirmation of device readings before treatment interventions) were no longer indicated,” the article concludes. “This decision lacked adequate nuance and evidentiary support and may have created a potentially hazardous situation for some patients who use these devices.” (A. R. Shapiro, alan.shapiro@med.nyu.edu)

PNN Pharmacotherapy Line
Oct. 26, 2017 * Vol. 24, No. 206
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>>>NEJM Report
Source:
 Oct. 26 issue of the New England Journal of Medicine (2017; 377).
Mepolizumab for Eosinophilic COPD: In phase 3 trials of patients with chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype, mepolizumab 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo, researchers report (pp. 1613–29). The anti-interleukin-5 monoclonal antibody mepolizumab (subcutaneous 100 mg in METREX, 100 or 300 mg in METREO, every 4 weeks for 52 weeks) was compared with placebo, with these results: “In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P = 0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P >0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P = 0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P = 0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo.” (F. C. Sciurba, sciurbafc@upmc.edu)
“In the past, ‘lumping together’ patients with different clinical COPD phenotypes may have prevented the detection of clinical responses in subgroups,” writes an editorialist (
pp. 1680–2). “The results of the current trials indicate that a subgroup of patients with COPD may benefit from biologic therapies, but I think that blood eosinophil count is an imperfect biomarker and that other disease factors confound the eosinophil signal, even in carefully selected subgroups.” (C. F. McDonald)
Surgery for Drug-Resistant Pediatric Epilepsy: Epilepsy surgery produced significantly better outcomes among 116 children and adolescents with drug-resistant conditions, compared with medical therapy, a study shows (pp. 1639–47). Based on a primary outcome of freedom from seizures at 12 months, randomization to brain surgery or medical therapy (with placement on a waiting list for surgery) showed the following: “At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P <0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P <0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P <0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P <0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P = 0.03), but not on the Binet–Kamat intelligence quotient (difference, 2.5; 95% CI, −0.1 to 5.1; P = 0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%).” (M. Tripathi, mtripathiaiims@gmail.com)
>>>PNN NewsWatch
* In an 8–7 vote, the Advisory Committee on Immunization Practices (ACIP) recommended preferential use of GlaxoSmithKline’s herpes zoster subunit vaccine (HZ/su, Shingrix) over Merck’s zoster vaccine live (Zostavax). Members voting against the recommendation were concerned about ending up with only one zoster vaccine on the U.S. market and the presence of a new adjuvant in HZ/su, but the superior efficacy across older age ranges convinced just enough members. ACIP also recommended HZ/su for vaccination of immunocompetent adults aged 50 years or older and for revaccination of those who previously received the Merck product.
* ACIP also recommended a third dose of 
mumps vaccine in people at high risk during outbreaks of the virus, often among teenagers and young adults in close contact.

PNN Pharmacotherapy Line
Oct. 27, 2017 * Vol. 24, No. 207
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
 Oct. issue of the Journal of the American Geriatrics Society (2017; 65).
Vitamin D & Cognition: Low serum levels of vitamin D are associated with poorer cognition, according to a systematic review and meta-analysis, but supplementation has not been clearly linked to benefits (pp. 2161–8). In 26 observational and 3 intervention studies, researchers found, “Low vitamin D was associated with worse cognitive performance (OR = 1.24, CI = 1.14–1.35) and cognitive decline (OR = 1.26, CI = 1.09–1.23); with cross-sectional yielding a stronger effect compared to longitudinal studies. Vitamin D supplementation showed no significant benefit on cognition compared with control (SMD = 0.21, CI = −0.05 to 0.46).” The group concluded: “Observational evidence demonstrates low vitamin D is related to poorer cognition; however, interventional studies are yet to show a clear benefit from vitamin D supplementation. From the evidence to date, there is likely a therapeutic age window relevant to the development of disease and therefore vitamin D therapy. Longitudinal lifespan studies are necessary to depict the optimal timing and duration in which repletion of vitamin D may protect against cognitive decline and dementia in aging, to better inform trials and practice towards a successful therapy.” (C. Szoeke, cszoeke@unimelb.edu.au)
Preventing Alzheimer Disease, One Patient at a Time: A special article author argues for a precision medicine approach to research into prevention of Alzheimer’s disease (AD) (pp. 2128–33): “AD affects more than 5 million Americans, with substantial consequences for individuals with AD, families, and society in terms of morbidity, mortality, and healthcare costs. With disease-modifying treatment trials unsuccessful at the present time and only medications to treat symptoms available, an emerging approach is prevention. Advances in diagnostic criteria, biomarker development, and greater understanding of the biophysiological basis of AD make these initiatives feasible. Ongoing pharmacological trials using anti-amyloid therapies are underway in sporadic and genetic forms of AD, although a large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects through amyloid or tau. This suggests that prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. Rather than relying solely on large-sample, long-duration, randomized clinical trial designs, a precision medicine approach using N-of-1 trials may provide more-rapid information on whether personalized prevention plans can improve person-centered outcomes. Because there appear to be multiple pathways to developing AD, there may also be multiple ways to prevent or delay the onset of AD. Even if these precision approaches alone are not successful in preventing AD, they may greatly improve the likelihood of amyloid- or tau-specific therapies to reach their endpoints by reducing comorbidities. Keeping this in mind, dementia may be a disorder that develops over a lifetime, with individualized ways to build a better brain as we age.” (J. E. Galvin, galvinj@health.fau.edu)
“In the end, much of the argument may come down to a matter of semantics,” an editorialist writes (
pp. 2153–4). “Is it really possible to absolutely prevent a heart attack or a stroke? No. But decades of evidence favors the potential for significant risk reduction. Although the totality of the evidence in AD prevention is not as robust, the opportunities to apply emerging evidence in the clinic today are burgeoning. Preliminary results from the [Alzheimer’s Prevention Clinic at New York-Presbyterian Weill Cornell Medical Center] cohort have shown that the clinical practice of AD prevention is feasible, and significant improvements in cognition and laboratory markers of AD risk have been demonstrated over time. Based on the totality of evidence and early experiences in the clinical management of AD prevention, we anticipate the continued growth of this medical specialty. Further research is warranted, and Galvin provides a roadmap for like-minded individuals to follow.” (R. Isaacson)
PNN NewsWatch
FDA is ready to use “all facets” of its regulatory authority to change the trajectory of the opioid epidemic, FDA Commissioner Scott Gottlieb said yesterday in response to the declaration that the epidemic constitutes a public health emergency.

PNN Pharmacotherapy Line
Oct. 30, 2017 * Vol. 24, No. 208
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Oct. 28 issue of Lancet (2017; 390).
Very Low LDL-Cholesterol Levels with PCSK9 Inhibitors: Use of PCSK9 inhibitors to lower LDL-cholesterol levels “well below current recommendations” is supported by efficacy and safety outcomes of a prespecified secondary analysis of the FOURIER trial (pp. 1962–71). Among 25,982 participants receiving evolocumab or placebo, LDL-cholesterol levels at 4 weeks were as low as 20 mg/dL, with outcomes over a median follow-up of 2.2. years as follows: “2,669 (10%) of 25,982 patients achieved LDL-cholesterol concentrations of less than 0.5 mmol/L, 8,003 (31%) patients achieved concentrations between 0.5 and less than 1.3 mmol/L, 3,444 (13%) patients achieved concentrations between 1.3 and less than 1.8 mmol/L, 7,471 (29%) patients achieved concentrations between 1.8 to less than 2.6 mmol/L, and 4,395 (17%) patients achieved concentrations of 2.6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0.2 mmol/L; p = 0.0012 for the primary endpoint, p = 0.0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events.” (R. P. Giugliano, rgiugliano@bwh.harvard.edu)
Rucaparib for Recurrent Ovarian Carcinoma: Maintenance dosing of the poly(ADP-ribose) polymerase inhibitor “rucaparib significantly improved progression-free survival in [753] patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy,” according to results of the ARIEL3 trial (pp. 1949–61): “Median progression-free survival in patients with a BRCA-mutant carcinoma was 16.6 months (95% CI 13.4–22.9; 130 [35%] patients) in the rucaparib group versus 5.4 months (3.4–6.7; 66 [35%] patients) in the placebo group (hazard ratio 0.23 [95% CI 0.16–0.34]; p <0.0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13.6 months (10.9–16.2) versus 5.4 months (5.1–5.6; 0.32 [0.24–0.42]; p <0.0001). In the intention-to-treat population, it was 10.8 months (8.3–11.4) versus 5.4 months (5.3–5.5; 0.36 [0.30–0.45]; p <0.0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none).” (R. L. Coleman, rcoleman@mdanderson.org)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
VTE Risk in Pregnancy: Antepartum or postpartum prophylaxis for venous thromboembolism (VTE) should be considered in women with antithrombin, protein C, or protein S deficiency or with homozygous factor V Leiden, according to findings of a systematic review and Bayesian analysis of 36 studies (j4452):“All thrombophilias increased the risk for pregnancy associated VTE (probabilities ≥91%). Regarding absolute risks of pregnancy associated VTE, high risk thrombophilias were antithrombin deficiency (antepartum: 7.3%, 95% credible interval 1.8% to 15.6%; post partum: 11.1%, 3.7% to 21.0%), protein C deficiency (antepartum: 3.2%, 0.6% to 8.2%; post partum: 5.4%, 0.9% to 13.8%), protein S deficiency (antepartum: 0.9%, 0.0% to 3.7%; post partum: 4.2%; 0.7% to 9.4%), and homozygous factor V Leiden (antepartum: 2.8%, 0.0% to 8.6%; post partum: 2.8%, 0.0% to 8.8%). Absolute combined antepartum and postpartum risks for women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutations, or compound heterozygous factor V Leiden and prothrombin G20210A mutations were all below 3%.” (F. N. Croles, f.croles@erasmusmc.nl)
>>>PNN JournalWatch
* Association Between Adherence to Pharmacotherapy and Outcomes in Type 2 Diabetes: A Meta-analysis, in Diabetes Care, 2017; 40: 1588–96. (K. Khunti, kk22@leicester.ac.uk)

PNN Pharmacotherapy Line
Oct. 31, 2017 * Vol. 24, No. 209
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>>>Diabetes Report
Source:
 Nov. issue of Diabetes Care (2017; 40).
Diabetes With Hepatocyte Nuclear Factor 1B Molecular Defects: Genotypic and phenotypic patterns among patients with molecular defects of hepatocyte nuclear factor 1B (HNF1B) are described based on findings in 159 patients with diabetes caused by the condition (pp. 1436–43). “In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, [chronic kidney disease stages 3–4], and [end-stage renal disease] are highly prevalent,” the authors conclude. “At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.” (D. Dubois-Laforgue, daniele.dubois@aphp.fr)
“While the retrospective cohort design [of this study] has some limitations (such as a survival bias that could reduce the effect of the 
HNF1B deletion), the study benefits from the large number of participants and careful clinical evaluation,” an editorialist writes (pp. 1433–5). “Because of its retrospective design, some data were missing, but the study is the largest of HNF1B-related outcomes. Although the study cannot provide accurate frequency of diabetes in those with HNF1B alterations or the clinical outcomes, the impact of the genetic heterogeneity, even within a ‘homogeneous [maturity-onset diabetes of the young (MODY)] subtype,’ should provide insights as to the difficulty in applying this information in a public health setting. The MODY5–HNF1B relationship is difficult to diagnose, has variable clinical presentation, and has only characteristic renal outcomes to aid in diagnosis. Perhaps members of a family with a history of MODY also consciously (or subconsciously) alter their lifestyle to one that is ‘diabetes-protective’ (diet, exercise, weight loss).” (S. S. Rich, ssr4n@virginia.edu)
Adherence a Problem With Newer Antidiabetic Agents: The gap between clinical efficacy as shown in randomized controlled trials (RCTs) and real-world (RW) effectiveness of type 2 diabetes medications is the result of poor RW adherence, a study shows, and this suggests “an urgent need to effectively address adherence among patients with type 2 diabetes” (pp. 1469–78). Using mixed-methods quasi-experimental methods to link retrospective claims and glycosylated hemoglobin levels in patients with type 2 diabetes who began treatment with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase 4 (DPP-4) inhibitors, the investigators found: “RW patients initiating a GLP-1 RA (n = 221) or a DPP-4 (n = 652) experienced smaller reductions in HbA1c (GLP-1 RA: −0.52% [−6 mmol/mol], DPP-4: −0.51% [−6 mmol/mol]) than reported in RCTs (−1.30% [−14 mmol/mol] from seven GLP-1 RA RCTs, n = 2,600; −0.68% [−8 mmol/mol] from four DPP-4 RCTs, n = 1,889). Baseline HbA1c, additional medications, and adherence were significant explanatory factors in the RW HbA1c change. Modeled estimates of RCT efficacy (−1.04% GLP-1 RA [−12 mmol/mol], −0.69% DPP-4 [−8 mmol/mol]) were within the RCTs’ reported range (GLP-1 RA: −0.84% to −1.60% [−9 to −18 mmol/mol], DPP-4: −0.47% to −0.90% [−5 to −10 mmol/mol]). Poor medication adherence accounted for approximately three-fourths of the gap between RW and expected RCT results (gap = 0.51% [6 mmol/mol] GLP-1 RA; 0.18% [3 mmol/mol] DPP-4).” (R-D Tan,  ruo-ding.tan@analysisgroup.com)
>>>PNN NewsWatch
FDA will hold a 2-day public workshop on the opioid epidemic on Dec. 11–12, with a focus on packaging (such as unit of use), storage, and disposal of products containing the drugs. In a statement, FDA Commissioner Scott Gottlieb, MD, wrote, “We believe that innovation in packaging, storage, and disposal could have a meaningful impact on preventing or deterring misuse, abuse, or inappropriate access to prescription opioids – especially when coupled with additional efforts that the FDA and others are undertaking to reduce the scope of the opioid epidemic. We look forward to the two-day meeting and the opportunity to discuss the potential for new, innovative tools and strategies the FDA can take to address the public health crisis of opioid addiction.”

PNN Pharmacotherapy Line
Nov. 1, 2017 * Vol. 24, No. 210
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>>>Kidney Diseases Report
Source:
 Nov. American Journal of Kidney Diseases (2017; 70).
Targeted Deprescribing in Outpatient Hemodialysis: In a quality-improvement study of 240 patients in a tertiary-care outpatient hemodialysis unit, deprescribing tools were successfully used to reduce polypharmacy while maintaining patient safety and satisfaction, researchers report (pp. 611–8). With primary and secondary outcomes of proportion of target medications deprescribed at 4 weeks and 6 months, respectively, the study showed these results: “A deprescribing tool for specific medications was developed and implemented in the hemodialysis unit. 5 medication classes were selected: quinine, diuretics, alpha-1-blockers, proton pump inhibitors, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins). All 240 patients in the unit were screened using the deprescribing tool. There were 171 of 240 (71%) patients prescribed at least 1 of the 5 target medications, and after applying the tool, 35 of 40 (88%) eligible patients had the medications deprescribed. There were 31 of 40 (78%) target medications completely deprescribed. 6 months after the study, only 5 of 31 (16%) medications discontinued were represcribed. At the end of the study, 57% of patients were taking fewer medications than at baseline. No adverse events were observed.” (M. Battistella, marisa.battistella@uhn.ca)
“Battistella et al make an important contribution to deprescribing efforts in kidney disease and demonstrate that a relatively intensive protocol can be used safely and successfully in an end-stage renal disease population,” editorialists write (
pp. 596–8). “However, just as the automobile never caught on until Henry Ford introduced the mass-produced Model T, it remains a challenge for the renal care community to develop deprescibing regimens that can be usable by a range of providers, whether they work in solo or multidisciplinary settings or in environments that are collaborative or disjointed. Nevertheless, it is a challenge worth taking because the potential harm of the polypharmacy which many patients with kidney disease experience likely exceeds the assumed benefit.” (J. C. Fink, jfink@som.umaryland.edu)
Treatment of Uremic Pruritus: Evidence for treatment of uremic pruritus is weak for most drugs and needs to be improved through “large, simple, rigorous, multiarm [randomized controlled trials (RCTs)] of promising therapies,” authors of a systematic review conclude (pp. 638–55). The exception is gabapentin, the authors explain, providing these details about managing this common symptom of advanced chronic kidney disease: “44 RCTs examining 39 different treatments were included in the review. These treatments included gabapentin, pregabalin, mast cell stabilizers, phototherapy, hemodialysis modifications, and multiple other systemic and topical treatments. The largest body of evidence was found for the effectiveness of gabapentin. Due to the limited number of trials for the other treatments included, we are unable to comment on their efficacy. Risk of bias in most studies was high.” (C. Rigatto, crigatto@sbgh.mb.ca)
Quinine-Induced Thrombotic Microangiopathy: Quinine-induced thrombotic microangiopathy (TMA) “causes severe acute kidney injury that commonly results in chronic kidney disease,” conclude investigators who assessed 19 patients treated with plasma exchange (pp. 686–95). “All patients had microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury,” the authors report. “All were initially misdiagnosed as having [thrombotic thrombocytopenic purpura] or hemolytic uremic syndrome, and adverse reactions to quinine were not initially suspected.” (james-george@ouhsc.edu)
>>>PNN NewsWatch
FDA yesterday granted accelerated approval to the kinase inhibitor acalabrutinib (Calquence, AstraZeneca) for treatment of adults with mantle cell lymphoma who have received at least one prior therapy. The decision was based on complete or partial tumor shrinkage in a single-arm trial of 124 previously treated patients with mantle cell lymphoma; 81% of patients had a complete or partial response (40% complete response, 41% partial response).
* In a move toward a more efficient global system, FDA said yesterday it will recognize
 inspections of manufacturing facilities that meet FDA requirements conducted by eight European drug regulatory authorities.

PNN Pharmacotherapy Line
Nov. 2, 2017 * Vol. 24, No. 211
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 2 New England Journal of Medicine (2017; 377).
Nusinersen in Infantile-Onset Spinal Muscular Atrophy: Compared with sham therapy, the antisense nucleotide nusinersen improved survival and motor function among infants with spinal muscular atrophy (SMA), researchers report (pp. 1723–32). The drug “modifies pre–messenger RNA splicing of the SMN2gene and thus promotes increased production of full-length SMN protein”; phase 3 results showed: “In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P <0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.” (R. S. Finkel, richard.finkel@nemours.org)
For treating SMA, “an important advantage of scAAV9 gene therapy is that it may require only a single intravenous infusion, whereas nusinersen probably requires lifelong repetitive intrathecal treatment,” editorialists write (
pp. 1786–7). “Follow-up has been short in both studies, and the durability of the effects is uncertain for both treatments. If the expression of the scAAV9 gene therapy declines over time, the same treatment may not be able to be repeated, because antibodies against AAV capsid proteins are anticipated to form. As the children grow, the phenotype may expand to affect other organs and tissues, which would then require confirmation that therapies such as scAAV9 and antisense oligonucleotides target other cell types.” (A. T. van der Ploeg)
ACEIs & Statins in Adolescents with Type 1 Diabetes: Albumin-to-creatinine ratios were unaffected over time in a study of ACE inhibitors and statins used in 443 adolescents with type 1 diabetes (pp. 1733–45): “The primary outcome [of change in albumin excretion] was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non–high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima–media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups.” (D. B. Dunger, dbd25@cam.ac.uk)
>>>PNN NewsWatch
* The President’s Commission on Combating Drug Addiction and the Opioid Crisis issued its final report yesterday. Among the 56 recommendations made by the group are two that pertain directly to pharmacists. One recommends that federal agencies and pharmacy associations “train pharmacists on best practices to evaluate legitimacy of opioid prescriptions, and not penalize pharmacists for denying inappropriate prescriptions.” Another calls for community-based stakeholders to use “Take Back Day to inform the public about drug screening and treatment services” and “encourages more hospitals/clinics and retail pharmacies to become year-round authorized collectors and explore the use of drug deactivation bags.” Naloxone for treating overdoses and availability of the drug in community pharmacies is highlighted; HIV-prevention efforts such as syringe-exchange programs are not.
FDA said yesterday it has issued warning letters to four companies for claiming that marijuana-derived products can treat or cure cancer.

PNN Pharmacotherapy Line
Nov. 3, 2017 * Vol. 24, No. 212
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Pediatrics Report
Source:
 Nov. issue of Pediatrics (2017; 140).
Postvaccination Presyncope in Adolescents: While “drinking water before vaccination did not prevent postvaccination presyncope” in a group of adolescents receiving vaccines, investigators find that “predictors of postvaccination presyncope suggest opportunities for presyncope and syncope prevention interventions” (e20170508). A randomized trial of 1,807 participants tested the effects of water 500 mL consumed 10–60 minutes before one or more intramuscular injection, with these results: “None had syncope. Presyncope occurred in 36.2% of subjects by using the primary definition, and in 8.0% of subjects by using the restrictive definition. There were no significant differences in presyncope by intervention group for the primary (1-sided test, P = .24) or restrictive outcome (1-sided test, P = .17). Among intervention subjects vaccinated within 10 to 60 minutes after drinking all 500 mL of water (n = 519), no reduction in presyncope was observed for the primary or restrictive outcome (1-sided tests, P = .13, P = .17). In multivariable regression analysis, presyncope was associated with younger age, history of passing out or nearly passing out after a shot or blood draw, prevaccination anxiety, receiving >1 injected vaccine, and greater postvaccination pain.” (A. R. Kemper)
Prenatal Acetaminophen & ADHD Risk: Long-term maternal use of acetaminophen during pregnancy increased the risk of attention-deficit/hyperactivity disorder (ADHD) among 112,973 offspring. the Norwegian Mother and Child Cohort Study shows (e20163840). “The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50–3.24),” the investigators write. “Use for <8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81–1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71–22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD.” (E. Ystrom)
>>>Psychiatry Report
Source:
 Nov. issue of the American Journal of Psychiatry (2017; 174).
Treating Mania in Older Patients With Bipolar Disorder: In the GERI-BD study, lithium produced a greater reduction in mania scores over a 9-week period, compared with divalproex, researchers report (pp. 1086–93). Both agents were efficacious and “adequately tolerated,” the authors write, noting these results in 224 inpatients and outpatients aged 60 years or older: “Attrition rates were similar for lithium and divalproex (14% and 18% at week 3 and 51% and 44% at week 9, respectively). The groups did not differ significantly in sedation. Participants in the lithium group tended to experience more tremor. Similar proportions of participants in the lithium and divalproex groups achieved target concentrations (57% and 56%, respectively). A longitudinal mixed model of improvement (change from baseline in [Young Mania Rating Scale] score) favored lithium (change in score, 3.90; 97.5% CI = 1.71, 6.09). Nine-week response rates did not differ significantly between the lithium and divalproex groups (79% and 73%, respectively). The need for adjunctive risperidone was low and similar between groups (17% and 14%, respectively).” (R. C. Young, ryoung@med.cornell.edu)
“Bipolar disorder is a recurrent condition for which there are four target areas related to treatment: acute mania, acute depressive episodes, prevention of recurrent manic or hypomanic episodes, and prevention of depressive episodes,” writes an editorialist (
pp. 1032–3). “The choice of medication for treatment of an acute manic episode should be tempered by considerations for maintenance therapy. In this regard, lithium may be useful as a maintenance therapy in the elderly, but its usefulness may be limited by an increased frequency of side effects that may occur in this population when treated long-term.… The relevant clinical question underlying the Young et al. study is not whether lithium worked well for acute mania in elderly bipolar patients but whether lithium is the preferred drug for maintenance treatment in elderly bipolar patients compared with other options that do not pose the risk of renal and cardiac effects associated with long-term lithium use.” (D. L. Dunner, dldunner@comcast.net)

PNN Pharmacotherapy Line
Nov. 6, 2017 * Vol. 24, No. 213
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Nov. 4 issue of Lancet (2017; 390).
Fixed-Dose, Bictegravir-Based Antiretroviral Therapy: The integrase strand transfer inhibitor bictegravir coformulated with emtricitabine and tenofovir alafenamide provides a useful, guideline-recommended option in antiretroviral therapy for rapid or same-day initiation of therapy, a phase 3 study shows, by avoiding the need for HLA B*5701 testing to rule out drug interactions (pp. 2063–72). Based on a prespecified noninferiority margin based on the proportion of patients with low plasma HIV-1 RNA levels, the 122-center comparison with a dolutegravir regimen shows: “At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92.4% of patients (n = 290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93.0% of patients (n = 293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference −0.6%, 95.002% CI −4.8 to 3.6; p = 0.78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n = 32] vs 23% [n = 72]; p <0.0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n = 82] vs 40% [n = 127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n = 17] vs 17% [n = 55]; p <0.0001).” (H. Martin, hal.martin@gilead.com)
In a sister study, fixed-dose bictegravir-based antiretroviral therapy was noninferior to the dolutegravir regimen, safe, and well tolerated, researchers report (
pp. 2073–82). “At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference −3.5%, 95.002% CI −7.9 to 1.0, p = 0.12),” the authors write. “Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p = 0.022).” (D. SenGupta, devi.sengupta@gilead.com)
>>>PNN NewsWatch
FDA said on Friday that Fresenius Kabi USA is voluntarily recalling lot 6400048 of Midazolam Injection, USP, 2 mg/2 mL packaged in a 2 mL prefilled single-use glass syringe to the hospital/user level. The product mislabeled as Midazolam Injection, USP, 2 mg/2 mL contains syringes containing and labeled as Ondansetron Injection, USP, 4 mg/2 mL.
* Ridge Properties DBA 
Pain Relief Naturally is voluntarily recalling all lots within expiry of Naturally HL Bedsore Relief Cream, Extra Strength PreTAT by TAT Balm Carbomer Free Gel, and Extra Strength Naturally HL Hemorrhoid Numbing with Lidocaine to the consumer level, FDA said. These products are being recalled after an FDA inspection found significant violations of current good manufacturing practice regulations.
>>>PNN JournalWatch
* Circulating Vitamin D Concentration and Risk of Seven Cancers: Mendelian Randomisation Study, in BMJ, 2017; 359: j4761. (K. K. Tsilidis, ktsilidi@cc.uoi.gr
* The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics, in 
Journal of the American College of Cardiology, 2017; 70: 2393–410. (S. Divakaran) 
* Infection Prevention and Control in Pediatric Ambulatory Settings, in 
Pediatrics, 2017; 140: 10.1542/peds.2017-2857. (M. H. Rathore) 
* Clinical Practice Guidelines for the Care of Girls and Women With Turner Syndrome, in 
Pediatrics, 2017; 140: 10.1542/peds.2017-2626. (American Academy of Pediatrics) 
* Copy Number Variation in Syndromic Forms of Psychiatric Illness: The Emerging Value of Clinical Genetic Testing in Psychiatry, in 
American Journal of Psychiatry, 2017; 174: 1036–50. (C. G. Bouwkamp)
* Mechanisms, Consequences, and Prevention of Coronary Graft Failure, in 
Circulation, 2017; 136: 1749–64. (M. Gaudino, mfg9004@med.cornell.edu)

PNN Pharmacotherapy Line
Nov. 7, 2017 * Vol. 24, No. 214
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Nov. 7 issue of the Annals of Internal Medicine (2017; 167).
Inappropriate Medication Use in Nursing Homes: In 59 Dutch nursing home wards for long-term care, a medication review tool proved “effective in discontinuing inappropriate medication use in frail nursing home residents without a decline in their well-being,” researchers report (pp. 609–17). The Multidisciplinary Multistep Medication Review (3MR) was used to evaluate the patient perspective, medical history, critical appraisal of medications, a meeting between the treating elder care physician and the pharmacist, and implementation of medication changes among residents with a life expectancy of more than 4 weeks. Using a pragmatic cluster-randomized controlled trial design, the investigators found: “Nineteen elder care physicians (33 wards) performed the 3MR, and 16 elder care physicians (26 wards) followed standard procedures. A total of 426 nursing home residents (233 in the intervention group and 193 in the control group) were followed for an average of 144 days (SD, 21). In an analysis of all participants, use of at least 1 inappropriate medication was successfully discontinued for 91 (39.1%) residents in the intervention group versus 57 (29.5%) in the control group (adjusted relative risk, 1.37 [95% CI, 1.02 to 1.75]). Clinical outcomes did not deteriorate between baseline and follow-up.”. (H. Wouters, j.wouters@umcg.nl)
“Clinicians practicing in the nursing home setting should take important messages from this study,” editorialists write (
pp. 671–2). “Medication reconciliation can be a complex process requiring substantial expertise, but improvements in medication use can be facilitated by working closely with the multidisciplinary team, particularly the consultant pharmacist. Focusing on a specific set of criteria, such as the nursing home–adapted STOPP [Screening Tool of Older Persons’ potentially inappropriate Prescriptions] criteria, or a specific class of drugs, such as antipsychotics or benzodiazepines, might be the best first approach. Finally, a deprescribing process that incorporates the STOPPFrail [Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy] criteria may be more appropriate for this population that is characterized by frailty, advanced dementia, and reduced life expectancy.” (H. M. Holmes, Holly.m.holmes@uth.tmc.edu)
Outcomes With Stents/Scaffolds: Bioresorbable vascular scaffolds (BVSs) produced worse outcomes than everolimus-eluting metallic stents (EESs) in patients undergoing percutaneous coronary interventions, according to a systematic review and meta-analysis of 7 randomized trials and 37 observational studies (pp. 642–54). Based on a main outcome of reported scaffold or stent thrombosis or a secondary outcomes such as death, myocardial infarction, or revascularization, the analysis showed the following: “The pooled incidence of definite or probable scaffold thrombosis after BVS implantation was 1.8% (95% CI, 1.5% to 2.2%) at a median follow-up of 1 year (41 studies, 21,884 patients) and 0.8% (CI, 0.5% to 1.3%) beyond 1 year (14 studies, 4,688 patients). Seven trials involving 5,578 patients that directly compared BVSs with EESs showed an increased risk for definite or probable scaffold thrombosis (odds ratio [OR], 3.40 [CI, 2.01 to 5.76]) with BVSs at a median follow-up of 25 months. Increased risks were present at early (prominently subacute), late, and very late stages, and odds beyond 1 year were almost double those seen within 1 year. Bioresorbably vascular scaffolds increased risks for myocardial infarction (OR, 1.63 [CI, 1.26 to 2.10]), target lesion revascularization (OR, 1.31 [CI, 1.03 to 1.67]), and target lesion failure (OR, 1.37 [CI, 1.12 to 1.66]); the odds for these 3 end points also increased over time. The incidences of all-cause, cardiac, and noncardiac death and of target vessel and any revascularization did not differ.” (B. Xu, xubiao@medmail.com.cn)
>>>PNN NewsWatch
FDA yesterday cleared for marketing a CLIA-waved complete blood count analyzer, the XW-100 Automated Hematology Analyzer (Sysmex America). The analyzer is intended for use in patients 2 years of age and older who require a whole blood cell count and white blood cell differential; the CLIA waiver for this device allows it to be used by a variety of nontraditional laboratory sites.

PNN Pharmacotherapy Line
Nov. 8, 2017 * Vol. 24, No. 215
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 7 issue of JAMA (2017; 318).
Analgesics for Acute Extremity Pain in the ED: Comparison of opioid analgesics and the combination of ibuprofen 400 mg plus acetaminophen 1000 mg for patients presenting to the emergency department (ED) with moderate to severe acute extremity pain showed no significant or clinically important differences in pain reduction at 2 hours, researchers report (pp. 1661–7). An 11-point numerical rating scale (NRS) was used to rate patient pain, with these results for opioids with acetaminophen and the nonopioid option: “Of 416 patients randomized, 411 were analyzed (mean [SD] age, 37 [12] years; 199 [48%] women; 247 [60%] Latino). The baseline mean NRS pain score was 8.7 (SD, 1.3). At 2 hours, the mean NRS pain score decreased by 4.3 (95% CI, 3.6 to 4.9) in the ibuprofen and acetaminophen group; by 4.4 (95% CI, 3.7 to 5.0) in the oxycodone and acetaminophen group; by 3.5 (95% CI, 2.9 to 4.2) in the hydrocodone and acetaminophen group; and by 3.9 (95% CI, 3.2 to 4.5) in the codeine and acetaminophen group (P = .053). The largest difference in decline in the NRS pain score from baseline to 2 hours was between the oxycodone and acetaminophen group and the hydrocodone and acetaminophen group (0.9; 99.2% CI, −0.1 to 1.8), which was less than the minimum clinically important difference in NRS pain score of 1.3. Adverse events were not assessed.” (A. K. Chang, achang3@yahoo.com)
“Stemming the opioid addiction crisis will also require reexamination of the long-standing assumptions that opioids are superior to nonopioids in most clinical situations requiring management of moderate to severe pain,” writes an editorialist (
pp. 1655–6). “Genuine efforts should be made to reduce overall opioid prescribing in the ED setting while still providing adequate pain relief. The trial by Chang et al provides important evidence that nonopioid analgesia can provide similar pain reduction as opioid analgesia for selected patients in the ED setting. The demonstrated effectiveness of the ibuprofen and acetaminophen combination for moderate to severe pain may also translate to outpatient management and other clinical settings of patients with acute pain. However, this will require future investigations.” (D. N. Kyriacou, demetrios.kyriacou@jamanetwork.org)
Pharmaceuticals & U.S. Health Care Spending: Responding to an analysis of changes in U.S. health care spending based on factors such as population size and demographic make-up, disease occurrence, and service use, price, and intensity (pp. 1668–78; J. L. Dieleman, dieleman@uw.edu), an editorialist makes these comments about medications (pp. 1657–8): “Pharmaceutical spending is one of the major areas that must be addressed in the United States. Some potential approaches to address these cost increases include value-based purchasing in which payment for the drug is linked to health outcomes, reference-based pricing in which the price is set based on the reference product in a drug class (eg, the drug with the lowest or second-lowest cost in the class), indications-based pricing in which payment may be adjusted when the drug is used for indications with strongest evidence base on improved outcomes, and increased competition and negotiation (eg, between health plans and pharmaceutical companies or the government and pharmaceutical companies). Presumably, the US health care system needs a tighter linkage between the health outcomes produced by a new drug and its price.” (P. H. Conway, patrickconway0@gmail.com)
Lymphoma in Inflammatory Bowel Disease: Use of thiopurines or anti–tumor necrosis factor agents for inflammatory bowel disease (IBD) is associated with development of lymphoma, a study shows (pp. 1679–86). Analyzing French data for adults with IBD, the investigators found a small but statistically significant increased risk of lymphoma with either agent, compared with no medication, and a higher risk with combination therapy. (R. Dray-Spira, rosemary.dray-spira@ansm.sante.fr)
>>>PNN NewsWatch
FDA on Monday expanded the approval of vemurafenib (Zelboraf, Roche) to include the treatment of adult patients with the rare hematologic malignancy Erdheim–Chester disease with BRAF V600 mutation. The approval is based on an overall response rate of 54.5% in the phase 2 VE-BASKET study of 22 people.

PNN Pharmacotherapy Line
Nov. 9, 2017 * Vol. 24, No. 216
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 9 New England Journal of Medicine (2017; 377).
Adjuvant Therapy of Advanced Melanoma: Clinical trials and an editorial examine use of new agents for adjuvant management of patients with advanced melanoma.
Compared with placebo in a phase 3 trial of 870 patients with stage III melanoma with 
BRAF V600E or V600K mutations, combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib produced lower risks of recurrence without new toxic effects, researchers report (pp. 1813–23): “At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P <0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P = 0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P = 0.000019. Rates of distant metastasis–free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.” (G. V. Long, georgina.long@sydney.edu.au)
In a comparison of approved checkpoint inhibitors in 906 patients with resected stage IIIB, IIIC, or IV melanoma, “adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab,” investigators conclude (
pp. 1824–35): “At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P <0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.” (J. Weber, jeffrey.weber2@nyumc.org)
“These trial results will change practice and, of course, raise questions,” an editorialist writes (
pp. 1888–90). “When choosing adjuvant therapy, the clinician will need to consider the risk of recurrence, the presence of BRAF mutations, the unique side-effect profile of each treatment, and the patient’s coexisting illnesses and preferences. Longer follow-up of the current trials is needed to assess the effects of these drugs on overall survival. Also needed are the results of other ongoing trials of adjuvant treatments for melanoma. As we care for our patients with melanoma, we joyfully accept these new challenges and questions, even as our heads are spinning.” (L. M. Schuchter)
Breast-Cancer Recurrence After Endocrine Therapy: Recurrence of breast cancer “continued to occur steadily” up to year 20 after 5 years of endocrine therapy ended, an EBCTCG study shows (pp. 1836–46). “The risk of distant recurrence was strongly correlated with the original [tumor diameter and nodal status (TN)] status, with risks ranging from 10 to 41%, depending on TN status and tumor grade,” the investigators conclude. (EBCTCG Secretariat, bc.overview@ndph.ox.ac.uk)
>>>PNN NewsWatch
FDA yesterday announced a new shared-system submission and review process for a risk evaluation and mitigation strategy (REMS) that would cover multisource (generic) drugs. “My hope is that the use of a standardized process for collecting information in the new REMS document template will help streamline the drafting and review of shared system REMS, making it easier for companies to engage in a shared REMS,” FDA Commissioner Scott Gottlieb, MD, said.
* In a safety alert, 
FDA said it has received an adverse event report stating that two patients developed tissue erosion at the injection site following the administration of an injectable glutamine, arginine, and carnitine product compounded by Florida-based United Pharmacy, LLC.

PNN Pharmacotherapy Line
Nov. 10, 2017 * Vol. 24, No. 217
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Chest Highlights
Source:
 Nov. issue of Chest (2017; 152).
Treatment for Acute Cough During Common Colds: OTC cough and cold medicines are not proven effective for acute cough associated with the common cold (CACC), according to a CHEST Expert Panel Report that suggests honey over medications other than dextromethorphan in pediatric patients 1 year or older (pp. 1021–37). Based on six systematic reviews and four primary studies, the panel provides these recommendations and suggestions, all of which are “ungraded consensus-based statements” (M. A. Malesker, markmalesker@creighton.edu):
* For adult and pediatric patients with cough due to the common cold, we suggest against the use of over the counter cough and cold medicines until they have been shown to make cough less severe or resolve sooner.
* In adult patients with cough due to the common cold, we suggest against the use of nonsteroidal anti-inflammatory agents until they have been shown to make cough less severe or resolve sooner.
* In pediatric patients (aged 1–18 years) with cough due to the common cold, we suggest honey may offer more relief for cough symptoms than no treatment, diphenhydramine, or placebo, but it is not better than dextromethorphan.
* In pediatric patients (aged < 18 years) with cough due to the common cold, we suggest avoiding use of codeine-containing medications because of the potential for serious side effects including respiratory distress.
Cough Etiology in Ambulatory Immunocompromised Adults: “No high-quality evidence [is available] to guide the clinician in determining the likely causes of cough specifically in immunocompromised ambulatory patients with normal chest radiographs,” according to a CHEST Expert Panel Report (pp. 1038–42): “We found no evidence to assess whether or not the proper initial evaluation of cough in immunocompromised patients is different from that in immunocompetent persons. A consensus of the panel suggested that the initial diagnostic algorithm should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social determinants be considered. The major modifications to the 2006 CHEST Cough Guidelines are the suggestions that [tuberculosis (TB)] should be part of the initial evaluation of patients with cough and HIV infection who reside in regions with a high prevalence of TB, regardless of the radiographic findings, and that specific causes and immune defects be considered in all patients in whom the initial evaluation is unrevealing.” (M. J. Rosen, markjrosenmd@gmail.com)
Obstructive Sleep Apnea & Diabetes: The potentially bidirectional link between obstructive sleep apnea (OSA) and both types of diabetes is examined in a review article (pp. 1070–86): “The relationship between OSA and type 2 diabetes may be bidirectional in nature given that diabetic neuropathy can affect central control of respiration and upper airway neural reflexes, promoting sleep-disordered breathing. Despite the strong association between OSA and type 2 diabetes, the effect of treatment with CPAP on markers of glucose metabolism has been conflicting. Variability with CPAP adherence may be one of the key factors behind these conflicting results. Finally, accumulating data suggest an association between OSA and type 1 diabetes as well as gestational diabetes. This review explores the role of OSA in the pathogenesis of type 2 diabetes, glucose metabolism dysregulation, and the impact of OSA treatment on glucose metabolism. The association between OSA and diabetic complications as well as gestational diabetes is also reviewed.” (B. Mokhlesi, bmokhles@medicine.bsd.uchicago.edu)
>>>Cardiology Report
Source:
 Nov. 7 issue of the Journal of the American College of Cardiology (2017; 70).
Sleep Apnea & Cardiovascular Disease: “Emerging research highlights the complex interrelationships between sleep-disordered breathing and cardiovascular disease,” review article authors write (pp. 1840–50). “Central sleep apnea associated with Cheyne–Stokes respiration predicts incident heart failure and atrial fibrillation; among patients with heart failure, it strongly predicts mortality.” (L. F. Drager, luciano.drager@incor.usp.br)

PNN Pharmacotherapy Line
Nov. 13, 2017 * Vol. 24, No. 218
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Symptomatic Treatment of Uncomplicated UTIs: While the need for antibiotics was reduced by use of diclofenac in ambulatory women with uncomplicated lower urinary tract infection (UTI), the risk of pyelonephritis was increased in a comparative trial with the antibiotic norfloxacin (j4784). Among 253 women at 17 Swiss general practices, results based on a primary outcome of symptom resolution at day 3 and a secondary outcome of use of any antibiotic up to 30 days were as follows: “72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P = 0.98 for non-inferiority, P <0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P <0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P = 0.03).” (A. Kronenberg, andreas.kronenberg@ifik.unibe.ch)
“Clearly, more evidence to inform best practice is necessary,” writes an editorialist (
j5037). “but in the meantime a pragmatic strategy of using paracetamol [acetaminophen] regularly, ibuprofen when necessary, and backed up with a delayed antibiotic prescription using a drug with a low resistance profile (eg, nitrofurantoin) could potentially balance competing needs to reduce antibiotic consumption, provide reasonable symptom control, and minimise the risk of complications.” (P. Little, p.little@soton.ac.uk)
>>>Lancet Highlights
Source:
 Nov. 11 issue of Lancet (2017; 390).
HPV-9 Vaccine Trial Results: Final results of an efficacy/safety trial of nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine show broad protection against the covered viral strains for up to 6 years, researchers report (pp. 2143–59). At 105 sites in 18 countries, women aged 16–26 years received 9vHPV or quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine, with these effects on infection, cytological abnormalities, high-grade lesions, and cervical procedures: “Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14,215 participants to receive 9vHPV (n = 7,106) or qHPV (n = 7,109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0.5 cases per 10,000 person–years in the 9vHPV and 19.0 cases per 10,000 person–years in the qHPV groups, representing 97.4% efficacy (95% CI 85.0–99.9). HPV 6, 11, 16, and 18 [geometric mean titers] were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.” (W. K Huh, whuh@uabmc.edu)
>>>PNN JournalWatch
* 2017 HIV Medicine Association of Infectious Diseases Society of America Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With Human Immunodeficiency Virus, in Clinical Infectious Diseases, 2017; 65: 1601–6. (R. D. Bruce, robert.bruce@yale.edu
* Evolving Understanding of the Causes of Pneumonia in Adults, With Special Attention to the Role of Pneumococcus, in 
Clinical Infectious Diseases, 2017; 65: 1736–44. (D. M. Musher, aniel.musher@va.gov">Daniel.musher@va.gov
* Short-Term Peripheral Venous Catheter–Related Bloodstream Infections: A Systematic Review, in 
Clinical Infectious Diseases, 2017; 65: 1757–62. (L. Mermel, lmermel@lifespan.org
* Associations Between Sexual Orientation and Overall and Site-Specific Diagnosis of Cancer: Evidence From Two National Patient Surveys in England, in 
Journal of Clinical Oncology, 2017; 35: 3654–61. (C. L. Saunders, ks659@medschl.cam.ac.uk
* Evolution of a Geriatric Syndrome: Pathophysiology and Treatment of Heart Failure With Preserved Ejection Fraction, in 
Journal of the American Geriatrics Society, 2017; 65: 2431–40. (D. W. Kitzman, dkitzman@wakehealth.edu
* Surviving With Smog and Smoke, in 
Chest, 2017; 152: 925–9. (H. Cai, hcai@mednet.ucla.edu)

PNN Pharmacotherapy Line
Nov. 14, 2017 * Vol. 24, No. 219
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Nov. issue of JAMA Internal Medicine (2017; 177).
Medication Prices: Several articles examine drug and biological pricing policies in the U.S.
Using federally mandated filings of 10 drug companies with no agents on the U.S. market that have received approval of a product for cancer since 2006, researchers determine that the average price for developing a new agent is $648 million before FDA approval and that the median income for the agents from approval to the present is $1.658 billion (
pp. 1569–75). Cumulative research and development (R&D) costs and company income were as follows from 2006 to the present: “The 10 companies had a median time to develop a drug of 7.3 years (range, 5.8–15.2 years). Five drugs (50%) received accelerated approval from the US Food and Drug Administration, and 5 (50%) received regular approval. The median cost of drug development was $648.0 million (range, $157.3 million to $1950.8 million). The median cost was $757.4 million (range, $203.6 million to $2601.7 million) for a 7% per annum cost of capital (or opportunity costs) and $793.6 million (range, $219.1 million to $2827.1 million) for a 9% opportunity cost. With a median of 4.0 years (range, 0.8–8.8 years) since approval, the total revenue from sales of these 10 drugs since approval was $67.0 billion compared with total R&D spending of $7.2 billion ($9.1 billion, including 7% opportunity costs).” (S. Mailankody, mailanks@mskcc.org)
The relationship between market exclusivity and high prices of prescription drugs in the U.S. is reviewed in a policy and law special communication article (
pp. 1658–64): “Manufacturers of brand-name drugs can command high prices because they are protected from generic competition by two types of government-granted monopoly rights. The first are patents on the drugs that generally define the basic period of brand-name-only sales. The second is awarded at the time of US Food and Drug Administration (FDA) approval and usually defines the minimum time until a generic can be sold. The initial patents last for 20 years and may be extended to account for time spent in clinical trials and regulatory review; other laws prevent approval of other manufacturers’ versions of new drugs for about 6 to 7 years, and for new biologics for 12 years. Overall, most new drugs receive about 12 to 16 years of market exclusivity from both kinds of monopoly protection combined. We reviewed the peer-reviewed medical and health policy literature to identify studies that described the different types of patent protection and regulatory exclusivities that shield brand-name prescription drugs from competition and thus help to sustain high drug prices. We also identified potential policy reforms intended to modify exclusivity periods to address public health needs by balancing drug affordability and industry revenue. The goal of policy in this area should be to ensure that drug market exclusivity periods provide for fair return on investment but do not indefinitely block availability of lower-cost generic drugs.” (A. S. Kesselheim, akesselheim@partners.org)
The legal tactics used to delay market entry of generic alternatives could be addressed through changes in patent law interpretation, Congressional action, or timely FDA decisions, authors conclude (
pp. 1665–9): “Strategies to forestall generic competition include patenting peripheral aspects of a drug or modified formulations that do not add clinical value, paying generic manufacturers to settle lawsuits challenging the validity of patents on brand-name drugs (‘reverse payment’ settlements), denying generic manufacturers access to drug samples necessary for bioequivalence testing, misusing risk evaluation and mitigation strategies, and filing citizen petitions with [FDA].” (A. Sarpatwari, asarpatwari@bwh.harvard.edu)
>>>PNN NewsWatch
* FDA yesterday approved the first drug product in the U.S. with a digital ingestion tracking system. Aripiprazole tablets with sensor (Abilify MyCite, Otsuka) has an ingestible sensor from Proteus Digital Health embedded in the pill that records that the medication was taken. The product is approved for the treatment of schizophrenia, acute treatment of manic and mixed episodes associated with bipolar I disorder, and for use as an add-on treatment for depression in adults.

PNN Pharmacotherapy Line
Nov. 15, 2017 * Vol. 24, No. 220
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 14 issue of JAMA (2017; 318).
The “Firearm Epidemic”: The need to address the needs of physically injured survivors and those with psychological injuries after mass shootings is often overlooked but badly needed, write authors reflecting on the Las Vegas and other shootings (pp. 1753–4): “Mass shootings are inescapably horrific and provoke needed attention to the challenge of firearm mortality and injury in the United States and other countries. Yet these rampage shootings remain a very small fraction of all firearm deaths and injuries. The important public and scientific discussions that emerge after each of these shootings should be encouraged as a way toward finding solutions. However, the discussion will be better served if complemented by a focus on the issues highlighted herein that are as important, if not more so, than many aspects of the firearm epidemic that currently dominate public discussion and debate.” (J. M. Shultz, jshultz1@med.miami.edu)
“We, as editors of the journals in the JAMA Network, are committed to providing policy makers, as well as the medical community and the US public, with accurate, timely information to guide interventions that will reduce injuries and deaths from guns,” editorialists write (
pp. 1763–4). “Guns kill people. More background checks; more hotel, school, and venue security; more restrictions on the number and types of guns that individuals can own; and development of ‘smart guns’ may help decrease firearm violence. But the key to reducing firearm deaths in the United States is to understand and reduce exposure to the cause, just like in any epidemic, and in this case that is guns.” (H. Bauchner, howard.bauchner@jamanetwork.org)
Biomedical Research in Pandemic Preparedness: Writing in a Viewpoint article on the “critical role of biomedical research in pandemic preparedness,” NIH officials conclude that “while priority-pathogen lists might not reflect the next emerging threat, platform and prototype-pathogen approaches run the risk of taking too long” (pp. 1757–8): “The most prudent path is to invest in research on all 3, bolstering the current ability to predict emerging infections, developing platforms that can be more rapidly adapted to new threats, and pursuing prototype-pathogen efforts to accelerate candidate development. However, broad availability of vaccines requires partnerships with industry, affected countries, and local communities. Moreover, even though considerable attention has been given to improved vaccine preparedness, solutions for treatments and diagnostics require further consideration, as both may play critical roles in any effective response.” (A. S. Fauci, afauci@niaid.nih.gov)
Global Budgets for Safety-Net Hospitals: “There are alternatives to all-payer hospital global budgeting for aligning hospital incentives with outpatient and community-based prevention efforts,” according to Viewpoint authors (pp. 1759–60). “One is for hospitals to assume financial risk for all health care expenditures for a population of patients. Many hospitals are developing their own insurance products, joining or leading advanced accountable care organizations, and establishing the management infrastructure to take a percentage of premium from managed care organizations in the Medicaid program or private insurers. A key question, however, is whether these innovations cover enough patients to realign the hospital’s overall incentives. If not, a majority of the patients admitted to a hospital might not be covered by the new incentives, and there is little likelihood of true transformation and long-term cost savings without the addition of a global hospital budgeting approach.” (J. M. Sharfstein, joshua.sharfstein@jhu.edu)
>>>PNN NewsWatch
* “It’s very troubling to the FDA that patients believe they can use kratom to treat opioid withdrawal symptoms,” FDA Commissioner Scott Gottlieb, MD, said in a statement about the southeast Asian botanical that has gained popularity in the U.S. “The FDA is devoted to expanding the development and use of medical therapy to assist in the treatment of opioid use disorder. However, an important part of our commitment to this effort means making sure patients have access to treatments that are proven to be safe and effective. There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder.”

PNN Pharmacotherapy Line
Nov. 16, 2017 * Vol. 24, No. 221
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>>>NEJM Report
Source:
 Nov. 16 New England Journal of Medicine (2017; 377).
Durvalumab After Chemoradiotherapy in NSCLC: In 709 patients with locally advanced, unresectable, non–small-cell lung cancer (NSCLC) with disease progression during chemotherapy plus radiation therapy, primary and secondary outcomes were better during consolidation therapy with the anti–programmed death ligand 1 antibody durvalumab than with placebo, PACIFIC results show (pp. 1919–29): “The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P <0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P <0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P <0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events.” (S. J. Antonia, scott.antonia@moffitt.org)
“Immune checkpoint blockade is currently being evaluated in multiple ongoing clinical trials of neoadjuvant immune checkpoint-blockade approaches in patients with early-stage NSCLC,” editorialists write (
pp. 1986–8). “Blood-based next-generation sequencing of tumor DNA may allow investigators to prospectively identify patients with resectable stage I to III NSCLC who are at the greatest risk for relapse. In a recent study, after resection of NSCLC, at least two detectable single-nucleotide variants were identified preoperatively in 13 of 14 patients with relapse. The data from the PACIFIC study provide support for the integration of immune checkpoint blockade for unresectable stage III NSCLC and will undoubtedly shape the design of future trials in stage I to III NSCLC.” (N. A. Rizvi)
Tolvaptan in Polycystic Kidney Disease: Commenting on the positive results of the REPRISE trial in 1,370 patients with early autosomal dominant polycystic kidney disease (ADPKD) (pp. 1930–42V. E. Torres, torres.vicente@mayo.edu), an editorialist concludes (pp. 1988–9): “These results are, like the trial acronym, a reprise, but with the important difference that many participants in the present trial already had a markedly decreased [glomerular filtration rate], and those taking tolvaptan enjoyed a small but clinically important slowing of their decline in kidney function. Further studies will be needed to show whether these results can translate into meaningful delays in the need for renal-replacement therapy and whether the adverse events observed presage more substantial issues over time.” (J. R. Ingelfinger)
>>>PNN NewsWatch
FDA yesterday approved vestronidase alfa-vjbk (Mepsevii, Ultragenyx Pharmaceutical) to treat pediatric and adult patients with the extremely rare inherited metabolic condition mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is a progressive condition that affects about 150 patients worldwide; the features of MPS VII vary widely, but most patients have various skeletal abnormalities that become more pronounced with age, including short stature.
FDA has granted a new indication to the percutaneous nerve field stimulator device system NSS-2 Bridge (Innovative Health Solutions) for use in helping to reduce the symptoms of opioid withdrawal.
* Baxter is voluntarily recalling one lot of 
Nexterone (amiodarone HCl) 150 mg/100 mL Premixed Injection because of potential presence of particulate matter, FDA said.
FDA is alerting the public that preliminary results from a safety clinical trial show an increased risk of heart-related death with febuxostat (Uloric) compared with allopurinol. FDA required Takeda to conduct this safety study when the medicine was approved in 2009; final results are not yet available.

PNN Pharmacotherapy Line
Nov. 17, 2017 * Vol. 24, No. 222
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>>>Geriatrics Report
Source:
 Nov. Journal of the American Geriatrics Society (2017; 65).
Anticoagulant Selection for Atrial Fibrillation: While fewer than one half of older adults with atrial fibrillation (AF) are receiving clot prophylaxis, the availability of new oral anticoagulants (NOACs) has increased use of the drugs, according to a retrospective observational cohort study (pp. 2405–12). At an academic medical center, patients older than 75 years or older who were admitted in 2010–15 had these anticoagulants ordered at discharge: “NOAC use increased over time (correlation coefficient (r) = 0.87, P < .001), warfarin use did not change (r = −0.16, P = .50), and overall anticoagulant use (NOACs and warfarin) increased (r = 0.68, P = .001). NOAC use increased over time in all age groups (75–79, 80–84, 85–89) except aged 90 and older, but increasing age attenuated the rate of NOAC uptake. There was no consistent relationship between age and warfarin or overall anticoagulant use, except that individuals aged 90 and older had consistently lower use. Overall, fewer than 45% of participants were prescribed an anticoagulant. In multivariable analysis, younger age, white race, female sex, higher hemoglobin, higher creatinine clearance, being on a medical service, hypertension, stroke or transient ischemic attack, no history of intracranial hemorrhage, and a modified HAS-BLED score of less than 3 increased the likelihood of receiving NOACs.” (M. W. Rich, mrich@wustl.edu)
Secondary CVD Meds After MI in Nursing Home Residents: Retrospective analysis of minimum data sets show that more than one third of U.S. nursing home residents do not receive secondary prevention medicines after acute myocardial infarction (AMI), as shown in these results (pp. 2397–404): “Thirty-seven percent of residents had no secondary prevention medications initiated after AMI, 41% had 1 initiated, and 22% had 2 initiated. After covariate adjustment, fewer secondary prevention medications were used in older residents (proportional odds ratio (POR) = 0.48, 95% confidence interval (CI) = 0.40–0.57 for ≥95 vs 65–74); women (POR = 0.88, 95% CI = 0.80–0.96);and those with a do-not-resuscitate order (POR = 0.90, 95% CI = 0.83–0.98), functional impairment (dependent or totally dependent vs independent to limited assistance, POR = 0.77, 95% CI = 0.69–0.86), and cognitive impairment (moderate to severe vs no impairment, POR = 0.79, 95% CI = 0.70–0.89).” (A. R. Zullo, andrew_zullo@brown.edu)
Primary CVD Prevention in Older Men: In the Physicians’ Health Study, 7,213 older men without a history of cardiovascular disease (CVD) had lower risks of mortality when treated with statins at age 70 and 76 years (pp. 2362–8): “Median baseline age was 77 (70–102), median follow-up was 7 years. Non-users were matched to 1,130 statin users. Statin use was associated with an 18% lower risk of all-cause mortality, HR 0.82 (95% CI 0.69–0.98) and non-significant lower risk of CVD events, HR 0.86 (95% CI 0.70–1.06) and stroke, HR 0.70 (95% CI 0.45–1.09). In subgroup analyses, results did not change according to age group at baseline (70–76 or >76 years) or functional status. There was a suggestion that those >76 at baseline did not benefit from statins for mortality, HR 1.14 (95% CI 0.89–1.47), compared to those 70–76 at baseline, HR 0.83 (95% CI 0.61–1.11); however the CIs overlap between the two groups, suggesting no difference. Statin users with elevated total cholesterol had fewer major CVD events than non-users, HR 0.68 (95% CI 0.50–0.94) and HR 1.43 (95% CI 0.99–2.07)), respectively.” (A. Orkaby, aorkaby@partners.org)
>>>PNN NewsWatch
Emicizumab-kxwh (Hemlibra, Genentech), a first-in-class agent, was approved yesterday by FDA for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors. Nearly one in three people with severe hemophilia A can develop inhibitors to factor VIII replacement therapies.
FDA yesterday expanded the approved indications for sunitinib malate (Sutent, Pfizer) to include adjuvant treatment of adults at high risk of renal cell carcinoma returning after nephrectomy. 
* Greenstone LLC, a Pfizer subsidiary, is voluntarily recalling multiple lots of 
diphenoxylate hydrochloride and atropine sulfate tablets, USP, to the consumer level because of possible superpotency or subpotency, FDA said.

PNN Pharmacotherapy Line
Nov. 20, 2017 * Vol. 24, No. 223
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Nov. 18 issue of Lancet (2017; 390).
Fluticasone Furoate/Vilanterol in Asthma: Once-daily fluticasone furoate and vilanterol improved asthma control without increasing serious adverse events, researchers report in a comparison with usual care in 4,233 patients diagnosed by U.K general practitioners (pp. 2247–55). The open-label trial assessed the percentage of patients who achieved an asthma control test (ACT) score of 20 or greater or an increase in ACT score from baseline of 3 or greater at 24 weeks, with these results: “At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1,373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1,399 in the usual care group; odds ratio [OR] 2.00 [95% CI 1.70–2.34], p <0.0001). At week 24, the adjusted mean ACT score increased by 4.4 points from baseline in patients initiated with fluticasone furoate and vilanterol, compared with 2.8 points in the usual care group (difference 1.6 [95% CI 1.3–2.0], p <0.0001). This result was consistent for the duration of the study. Pneumonia was uncommon, with no differences between groups; there was no difference in other serious adverse events between the groups.” (A. Woodcock, ashley.woodcock@manchester.ac.uk)
VEGFR-2 Inhibition in Refractory Urothelial Cancer: In a phase 3 trial of 530 patients with platinum-refractory advanced urothelial carcinoma, the IgG1 VEGFR-2 antagonist ramucirumab plus docetaxel improved progression-free survival compared with chemotherapy (pp. 2266–77): “Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4.07 months [95% CI 2.96–4.47] vs 2.76 months [2.60–2.96]; hazard ratio [HR] 0.757, 95% CI 0.607–0.943; p = 0.0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24.5%, 95% CI 18.8–30.3) of 216 patients allocated ramucirumab and 31 (14.0%, 9.4–18.6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects.…” (D. P. Petrylak, daniel.petrylak@yale.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Weight Loss Interventions & Mortality: Results of a systematic review and meta-analysis show reduced all-cause mortality in adults who receive weight-loss interventions with or without exercise advice (j4849). Diets were usually low in fat and saturated fat, the authors write, and produce these all-cause, cardiovascular, and cancer outcomes: “For the primary outcome, high quality evidence showed that weight loss interventions decrease all cause mortality (34 trials, 685 events; risk ratio 0.82, 95% confidence interval 0.71 to 0.95), with six fewer deaths per 1,000 participants (95% confidence interval two to 10). For other primary outcomes moderate quality evidence showed an effect on cardiovascular mortality (eight trials, 134 events; risk ratio 0.93, 95% confidence interval 0.67 to 1.31), and very low quality evidence showed an effect on cancer mortality (eight trials, 34 events; risk ratio 0.58, 95% confidence interval 0.30 to 1.11). Twenty four trials (15,176 participants) reported high quality evidence on participants developing new cardiovascular events (1,043 events; risk ratio 0.93, 95% confidence interval 0.83 to 1.04). Nineteen trials (6,330 participants) provided very low quality evidence on participants developing new cancers (103 events; risk ratio 0.92, 95% confidence interval 0.63 to 1.36).” (A. Avenell, a.avenell@abdn.ac.uk)
>>>PNN JournalWatch
* Global Issues in Allergy and Immunology: Parasitic Infections and Allergy, in Journal of Allergy and Clinical Immunology, 2017; 140: 1217–28. (A. A. Cruz, cruz.proar@gmail.com)
* Review: The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases, in 
Arthritis & Rheumatology, 2017; 69: 2102–13. (V. M. Holers, michael.holers@UCDenver.edu)

PNN Pharmacotherapy Line
Nov. 21, 2017 * Vol. 24, No. 224
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>>>Internal Medicine Report
Source:
 Nov. 21 issue of the Annals of Internal Medicine (2017; 167).
Administration Options for Once-Weekly Isoniazid/Rifapentine: In U.S. patients with latent tuberculosis, self-administration of once-weekly isoniazid and rifapentine is a reasonable alternative to directly observed therapy, a study shows, and it also should be considered in other places where directly observed therapy is not feasible (pp. 689–97). The phase 4 study included 1,002 adults who were randomized to open-label treatment with self-administered or directly observed therapy. The noninferiority trial used a primary outcome of treatment completion (11 or more doses within 16 weeks measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event–monitoring devices for self-administration). 
Results showed: “Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration–with–reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.” (R. Belknap, 
robert.belknap@dhha.org)
“Belknap and colleagues’ findings provide evidence that, in some settings, we should promote self-administered treatment of [latent TB infection (LTBI)],” editorialists write (
pp. 742–3). “A platform of shared decision making between patients and providers will be essential in identifying circumstances in which self-administration is likely to be successful. Evidence-based incentives and approaches tailored to the specific needs of patients and their families need to be promoted as part of programmatic management of LTBI.” (H. Getahun, getahunh@who.int)
Potentially Preventable Spending in Medicare: Among high-cost Medicare beneficiaries, potentially preventable spending is highest in the frail elderly population, researchers report (pp. 706–13). Investigators analyzed a 20% sample of fee-for-service (FFS) claims for 2012, with attention on these six groups: nonelderly disabled, frail elderly, major complex chronic, minor complex chronic, simple chronic, and relatively healthy: “In 2012, 4.8% of Medicare spending was potentially preventable, of which 73.8% was incurred by high-cost patients. Despite making up only 4% of the Medicare population, high-cost frail elderly persons accounted for 43.9% of total potentially preventable spending ($6593 per person). High-cost nonelderly disabled persons accounted for 14.8% of potentially preventable spending ($3421 per person) and the major complex chronic group for 11.2% ($3327 per person). Frail elderly persons accounted for most spending related to admissions for urinary tract infections, dehydration, heart failure, and bacterial pneumonia.” (A. K. Jha, ajha@hsph.harvard.edu)
Editorialists ask, “What will it take to provide high-value care for all high-need, high-cost older adults?” (
pp. 746–7): “The shift in health care culture toward value-based care under the Patient Protection and Affordable Care Act requires rapid acceleration. The culture of leadership and management of the U.S. health care system still predominantly lives in the FFS construct that focuses its energy and resources on managing high-tech, specialty-focused, facility-based care. This is the system that managers know how to manage—many leaders are incapable of thinking outside the FFS box, even as incentives for value-based care come into play. The inability of organizations to adjust to new paradigms is well-established in other service industries. This is perhaps best illustrated by the existence of (but widespread failure to reliably offer) palliative care programs to seniors with limited life expectancies.” (B. Leff, bleff@jhmi.edu)
Gender Differences in Oral HPV Infection: Oral human papillomavirus infection is much more prevalent among U.S. men than women, a study shows, and higher numbers of men have high-risk strains (pp. 714–24; A. A. Deshmukh, aadeshmukh@phhp.ufl.edu).

PNN Pharmacotherapy Line
Nov. 22, 2017 * Vol. 24, No. 225
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Nov. 21 issue of JAMA (2017; 318).
Sertraline, Depression & Renal Function: In the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST), sertraline was not effective for reducing depressive symptoms in 201 patients with stage 3, 4, or 5 non–dialysis-dependent chronic kidney disease (CKD) (pp. 1876–90). Based on a primary outcome of improvement in depressive symptom severity from baseline to 12 weeks as measured in the 16-item Quick Inventory of Depression Symptomatology–Clinician Rated (QIDS-C16) (score range, 0–27; minimal clinically important difference, 2 points), the study showed these effects of sertraline and placebo: “The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by −4.1 in the sertraline group and by −4.2 in the placebo group (between-group difference, 0.1 [95% CI, −1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, −10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02).” (S. S. Hedayati, susan.hedayati@utsouthwestern.edu)
“The illustrative experience of statin therapy, repeatedly shown ineffective at improving cardiovascular outcomes in patients with chronic kidney failure requiring dialysis, is an object lesson that even the most important and effective therapies in more general populations must be tested in CKD before clinicians can be confident of benefit,” editorialists write (
pp. 1873–4). “Thus, Hedayati et al have made an important contribution to the care of patients with CKD. The nephrology and psychiatry communities now have the responsibility to conduct further trials that use rigorous criteria for identifying depression, include more severely depressed patients, and evaluate other SSRIs to further probe for effective and safe treatments for depression in patients with CKD.” (W. C. Winkelmayer, winkelma@bcm.edu)
Oral Insulin & Diabetes Prevention in Patients’ Relatives: Among 560 autoantibody-positive, first- or second-degree relatives of patients with type 1 diabetes, oral insulin 7.5 mg/d did not prevent or delay onset of the disease, researchers report (pp. 1891–902). Over 2.7 years of the Type 1 Diabetes TrialNet Oral Insulin Study, these outcomes were observed: “Diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0–1.2; P = .21). In secondary stratum 1 [of those with identical antibody profiles] (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006).” (J. P. Krischer, jpkrischer@epi.usf.edu)
>>>PNN NewsWatch
FDA yesterday approved dolutegravir 50 mg and rilpivirine 25 mg (Juluca, ViiV Healthcare), a two-drug, once-daily, fixed-dose product, as a complete regimen for the maintenance treatment of HIV-1 infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components. This is the first dual-drug, complete regimen for HIV.
* Serious adverse events (liver injury and hypersensitivity pneumonitis) involving 
Limbrel, an oral capsule being marketed as a medical food to manage the metabolic processes associated with osteoarthritis, are being investigated by FDA.
FDA yesterday issued a final guidance for development of generic versions of abuse-deterrent formulations of opioids.
PNN will not be published on Thurs. and Fri., Nov. 23–24, Thanksgiving Day.

PNN Pharmacotherapy Line
Nov. 27, 2017 * Vol. 24, No. 226
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 23 issue of the New England Journal of Medicine (2017; 377).
CFTR Modulation in Cystic Fibrosis: In two research articles, “preliminary results of … combination therapy in patients with the Phe508del mutation look very promising,” an editorialist writes, but “other approaches need to be explored as well” (pp. 2085–8; H. Grasemann).
The first study, a phase 3 trial of the investigational cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor demonstrates safety and efficacy for improving clinical outcomes in adolescents and adults with cystic fibrosis who were homozygous for the 
CFTR Phe508del mutation (pp. 2013–23). Based on primary and secondary end points for improved pulmonary function, the study found these results for tezacaftor and the already-approved agent ivacaftor: “Of the 510 patients who underwent randomization, 509 received tezacaftor–ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV1 at baseline was 60.0% of the predicted value. The effects on the absolute and relative changes in the percentage of the predicted FEV1 in favor of tezacaftor–ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (P <0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor–ivacaftor group than in the placebo group (P = 0.005). The incidence of adverse events was similar in the two groups. Most adverse events were of mild severity (in 41.8% of patients overall) or moderate severity (in 40.9% overall), and serious adverse events were less frequent with tezacaftor–ivacaftor (12.4%) than with placebo (18.2%). A total of 2.9% of patients discontinued the assigned regimen owing to adverse events. Fewer patients in the tezacaftor–ivacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation.” (J. S. Elborn, j.elborn@imperial.ac.uk)
In 248 patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a 
CFTR residual-function mutation, tezacaftor–ivacaftor or ivacaftor alone improved pulmonary outcomes (pp. 2024–35): “The number of analyzed intervention periods was 162 for tezacaftor–ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor–ivacaftor and 4.7 percentage points for ivacaftor alone (P <0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire–Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor–ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%).” (J. C. Davies, j.c.davies@imperial.ac.uk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Adjuvant Low-Dose Aspirin in Leg Ulceration: Based on a pragmatic randomized trial conducted at five nursing centers in New Zealand, adjuvant low-dose aspirin should not be used in patients with venous leg ulcers, investigators conclude (j5157). “The median number of days to healing of the reference ulcer was 77 in the aspirin group and 69 in the placebo group (hazard ratio 0.85, 95% confidence interval 0.64 to 1.13, P = 0.25),” the group reports. “The number of participants healed at the endpoint was 88 (70%) in the aspirin group and 101 (80%) in the placebo group (risk difference −9.8%, 95% confidence interval −20.4% to 0.9%, P = 0.07).” (A. Jull, a.jull@auckland.ac.nz)
>>>PNN NewsWatch
* Sun Pharmaceutical is recalling two lots of Riomet (Metformin Hydrochloride Oral Solution), 500 mg/5 mL, to the retail level because of contamination with Scopulariopsis brevicaulisFDA said.
>>>PNN JournalWatch
* Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis, in New England Journal of Medicine, 2017; 377: 2063–72. (A. M. Diehl, annamae.diehl@duke.edu
* Continuous Glucose Monitoring In Pregnant Women With Type 1 Diabetes (CONCEPTT): A Multicentre International Randomised Controlled Trial, in 
Lancet, 2017; 390: 2347–59. (D. S. Feig, d.feig@utoronto.ca)

PNN Pharmacotherapy Line
Nov. 28, 2017 * Vol. 24, No. 227
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from the Annals of Internal Medicine (2017; 167).
Seasonal Allergic Rhinitis Guidance: An expert panel provides recommendations for clinician management of patients with seasonal allergic rhinitis (10.7326/M17-2203). The Joint Task Force on Practice Parameters (American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology) suggests the following (N. Aumann, naumann@aaaai.org):
Recommendation 1: For initial treatment of seasonal allergic rhinitis in persons aged 12 years or older, routinely prescribe monotherapy with an intranasal corticosteroid rather than an intranasal corticosteroid in combination with an oral antihistamine. (Strong recommendation)
Recommendation 2: For initial treatment of seasonal allergic rhinitis in persons aged 15 years or older, recommend an intranasal corticosteroid over a leukotriene receptor antagonist. (Strong recommendation)
Recommendation 3: For treatment of moderate-to-severe seasonal allergic rhinitis in persons aged 12 years or older, the clinician may recommend the combination of an intranasal corticosteroid and an intranasal antihistamine for initial treatment. (Weak recommendation)
Out-of-Hospital Naloxone for Suspected Opioid Overdose: Intranasal naloxone products with higher concentrations have opioid-reversal rates similar to those with intramuscular administration, a systematic review concludes, and people treated with naloxone but not transported to a health facility have low rates of death and serious adverse events (10.7326/M17-2224): “Of 13 eligible studies, 3 randomized controlled trials and 4 cohort studies compared different administration routes. At the same dose (2 mg), 1 trial found similar efficacy between higher-concentration intranasal naloxone (2 mg/mL) and intramuscular naloxone, and 1 trial found that lower-concentration intranasal naloxone (2 mg/5 mL) was less effective than intramuscular naloxone but was associated with decreased risk for agitation (low [strength of evidence]). Evidence was insufficient to evaluate other comparisons of route of administration. Six uncontrolled studies reported low rates of death and serious adverse events (0% to 1.25%) in nontransported patients after successful naloxone treatment.” (R. Chou, chour@ohsu.edu)
>>>Medical Care Report
Source:
 Dec. issue of Medical Care (2017; 55).
Medicaid Expansion & Cigarette Smoking Cessation: Smoking cessation rates improved among low-income adults without dependent children in states that expanded Medicaid coverage after passage of the Affordable Care Act, a study shows (pp. 1023–9). This outcome may have occurred through “greater access to preventive health care services, including evidence-based smoking cessation services,” the investigators conclude based on the following patterns in pooled cross-sectional data from the Behavioral Risk Factor Surveillance Survey for 2011–15: “Residence in a state with Medicaid coverage among low-income adult smokers ages 18–64 years was associated with an increase in recent smoking cessation of 2.1 percentage points (95% confidence interval, 0.25–3.9). In the comparison group of individuals ages 65 years and above, residence in a state with Medicaid coverage expansion was not associated with a change in recent smoking cessation (−0.1 percentage point, 95% confidence interval, −2.1 to 1.8). Similar increases in smoking cessation among those ages 18–64 years were estimated for females and males (1.9 and 2.2 percentage point, respectively).” (J. W. Koma, jwk41@pitt.edu)
Prescription Fill Rates & Risk Stratification Model Performance: Used in claims-based risk prediction models, prescription fill rates produced modest improvements in a retrospective cohort study of 43,097 primary care patients (pp. 1052–60): “The overall, primary 0–7, and 0–30 days fill rates were 72.30%, 59.82%, and 67.33%.… Adding fill rates modestly improved the performance of all models in explaining medical costs (improving concurrent R2 by 1.15% to 2.07%), followed by total costs (0.58% to 1.43%), and pharmacy costs (0.07% to 0.65%). The impact was greater for concurrent costs compared with prospective costs. Base models without diagnosis information showed the highest improvement using prescription fill rates.” (H. Kharrazi, kharrazi@jhu.edu)

PNN Pharmacotherapy Line
Nov. 29, 2017 * Vol. 24, No. 228
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 28 issue of JAMA (2017; 318).
Fecal Microbiota Transplantation Delivered Via Oral Capsules: Treatment of patients for recurrent Clostridium difficile infection (RCDI) using oral capsules to deliver fecal microbiota transplantation (FMT) appears to be effective, according to a comparison with colonoscopy-delivered transplantation (pp. 1985–93). Among 116 patients in Alberta, these results were recorded in a noninferiority trial using a margin of 15%: “In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, −6.1% to infinity; P < .001), meeting the criterion for noninferiority. One patient in each group died of underlying cardiopulmonary illness unrelated to FMT. Rates of minor adverse events were 5.4% for the capsule group vs 12.5% for the colonoscopy group. There was no significant between-group difference in improvement in quality of life. A significantly greater proportion of participants receiving capsules rated their experience as ‘not at all unpleasant’ (66% vs 44%; difference, 22% [95% CI, 3%-40%]; P = .01).” (D. Kao, dkao@ualberta.ca)
“While it is encouraging that capsules appear to be a viable delivery route for FMT, a number of additional approaches still deserve consideration in future research,” editorialists write (
pp. 1979–80). “These include vancomycin tapers with and without ‘chasers’ of fidaxomicin/rifaximin, defined microbial communities, and sterile fecal-derived products. If these latter approaches prove to be effective, they may supplant standard FMT and other undefined microbial consortia, making even convenient, capsule-based FMT a tough pill to swallow.” (P. N. Malani, pmalani@umich.edu)
Selective Androgen Receptor Modulators Sold Online: Analysis of 44 products marketed as selective androgen receptor modulators and sold online contained unapproved drugs and substances, researchers report (pp. 2004–10). In 2016, products claiming performance enhancement through selective androgen receptor modulation were purchased and analyzed, with these results: “Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-delta agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%).” (S. Bhasin, sbhasin@bwh.harvard.edu)
FDA has responsibility for policing adulterated and misbranded dietary supplements, editorialists write, but “flagrant violations of these statutes abound, and the FDA does not have the resources to address all of these cases in enough detail to take corrective legal action” (
pp. 1983–4). “The US Drug Enforcement Administration (DEA) shares responsibility because androgens are schedule III drugs. However, the DEA is overwhelmed with the opioid epidemic, and industry-sponsored legislation last year seriously impaired efforts of the DEA to thwart complicit narcotic distributors.” (R. J. Auchus, rauchus@med.umich.edu)
>>>PNN NewsWatch
* Dietary supplements — including vitamins — containing biotin can interfere with cardiovascular diagnostic and hormone tests, FDA warned yesterday. The agency said it has received a report that one patient taking high levels of biotin died following falsely low troponin test results when a troponin test known to have biotin interference was used.
William Schimmel is the new Executive Director and CEO of the Pharmacy Technician Certification Board, succeeding Everett B. McAllister, MPA, RPh, Colonel, USAF (Ret.). Schimmel, previously PTCB’s Associate Executive Director, takes the reins in December, the same month that PTCB launches a Certified Compounded Sterile Preparation Technician Program

PNN Pharmacotherapy Line
Nov. 30, 2017 * Vol. 24, No. 229
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>>>NEJM Report
Source:
 Nov. 30 New England Journal of Medicine (2017; 377).
CGRP Antagonists for Migraine: Antagonists of the neuropeptide calcitonin gene–related peptide (CGRP) are showing promise in the treatment of migraine, according to two research articles and an editorial.
Tested in a phase 3, 12-week trial for prevention of chronic migraine, fremanezumab significantly reduced the frequency of headache compared with placebo, researchers report (
pp. 2113–22). Outcomes were as follows for 1,130 patients based on a primary end point of mean change in number of headache days (days with 4 or more consecutive hours of symptoms of moderate severity or days with use of rescue medications) per month: “The mean number of baseline headache days (as defined above) per month was 13.2, 12.8, and 13.3, respectively. The least-squares mean (± SE) reduction in the average number of headache days per month was 4.3 ± 0.3 with fremanezumab quarterly, 4.6 ± 0.3 with fremanezumab monthly, and 2.5 ± 0.3 with placebo (P <0.001 for both comparisons with placebo). The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P <0.001 for both comparisons with placebo). Abnormalities of hepatic function occurred in 5 patients in each fremanezumab group (1%) and 3 patients in the placebo group (<1%).” (S. D. Silberstein, stephen.silberstein@jefferson.edu)
A second humanized monoclonal antibody, erenumab, reduced migraine frequency, effects of migraines on daily activities, and use of acute migraine medications over a period of 6 months in a placebo-controlled, phase 3 comparison (
pp. 2123–32): “A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group. The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P <0.001 for each dose vs. placebo). A 50% or greater reduction in the mean number of migraine days per month was achieved for 43.3% of patients in the 70-mg erenumab group and 50.0% of patients in the 140-mg erenumab group, as compared with 26.6% in the placebo group (P <0.001 for each dose vs. placebo), and the number of days of use of acute migraine–specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (P <0.001 for each dose vs. placebo). Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (P <0.001 for each dose vs. placebo), and everyday-activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (P <0.001 for each dose vs. placebo). The rates of adverse events were similar between erenumab and placebo.” (P. J. Goadsby, peter.goadsby@kcl.ac.uk)
“With the ongoing development of four different antibodies targeting the CGRP pathway, it will be difficult to determine whether unique patient populations will have a response to a specific drug or whether one agent is superior to others,” writes an editorialist (
pp. 2190–1). “Furthermore, many patients will probably still have a response to standard multidisciplinary treatment that is less costly in patient and provider time and dollars. It is of interest that these agents worked rapidly and that a number of patients became completely headache-free. Thus, these drugs may find a specific role in the treatment of patients who have migraines that are refractory to treatment or who are severely disabled by headaches. For the long term, it will be important to determine whether the beneficial effect can be sustained after discontinuation or whether continued treatment will be necessary.” (A. D. Hershey)
Trajectories of Childhood Obesity into Adulthood: Simulation of childhood obesity and overweight predicts continuation of the current epidemic into adulthood, particularly in children who were severely obese (pp. 2145–53; Z. J. Ward, zward@hsph.harvard.edu).

PNN Pharmacotherapy Line
Dec. 1, 2017 * Vol. 24, No. 230
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>>>Diabetes Report
Source:
 Dec. issue of Diabetes Care (2017; 40).
Metformin, DPP-4 Inhibitors & Cardiovascular Outcomes: In a hypothesis-generating analysis, investigators show that metformin use may be a moderator of the cardiovascular effects of dipeptidyl peptidase 4 inhibitors (DPP-4i) (pp. 1787–9). Meta-analysis of three major cardiovascular outcomes trials of DPP-4i using meta-regression found these outcomes in prevalent metformin users and baseline nonusers: “While prevalent metformin users experienced a trend toward improved cardiovascular outcomes with DPP-4i (summary hazard ratio [HR] 0.92 [95% CI 0.84, 1.01]), baseline metformin nonusers showed a trend toward harm (HR 1.10 [95% CI 0.97, 1.26]). The difference in overall DPP-4i effect between metformin user and nonuser subgroups was statistically significant (P = 0.036).” (M. J. Crowley, matthew.crowley@dm.duke.edu)
Improving Continuous Glucose Monitoring: The European Association for the Study of Diabetes and the American Diabetes Association Diabetes Technology Working Group provide these ideas on ways of improving the clinical value and utility of continuous glucose monitoring (CGM) (pp. 1614–21): “The first systems for CGM became available over 15 years ago. Many then believed CGM would revolutionize the use of intensive insulin therapy in diabetes; however, progress toward that vision has been gradual. Although increasing, the proportion of individuals using CGM rather than conventional systems for self-monitoring of blood glucose on a daily basis is still low in most parts of the world. Barriers to uptake include cost, measurement reliability (particularly with earlier-generation systems), human factors issues, lack of a standardized format for displaying results, and uncertainty on how best to use CGM data to make therapeutic decisions. This Scientific Statement makes recommendations for systemic improvements in clinical use and regulatory (pre- and postmarketing) handling of CGM devices. The aim is to improve safety and efficacy in order to support the advancement of the technology in achieving its potential to improve quality of life and health outcomes for more people with diabetes.” (J. R. Petrie, john.petrie@glasgow.ac.uk)
International View on Continuous Glucose Monitoring: Summarizing the consensus of a Feb. 2017 Advanced Technologies & Treatments for Diabetes (ATTD) Congress, an international panel of physicians, researchers, and patients make these points (pp. 1631–40): “Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use or intermittently viewed, addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1cmeasurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established.” (T. Danne, danne@hka.de)
>>>PNN NewsWatch
FDA yesterday approved the first once-monthly injectable buprenorphine product, Sublocade (Indivior), for treatment of moderate-to-severe opioid use disorder in adults who have initiated treatment with a transmucosal buprenorphine product. It is indicated for patients on a stable buprenorphine dose for at least 7 days.
* Approved yesterday under the FDA/CMS Parallel Review Program, the 
FoundationOne CDx (Foundation Medicine) is the first breakthrough-designated, next generation sequencing–based in vitro diagnostic test that can detect genetic mutations in 324 genes and two genomic signatures in any solid tumor type, FDA said. 
* Following 
FDA identification of sildenafil in the products, Bull 1800 mg capsules with the production date of 05/08/2016 and Chao Jimengnan 150 mg tablets with lot number 20151018 are being recalled to the consumer level by Nutra Labs Inc.

PNN Pharmacotherapy Line
Dec. 4, 2017 * Vol. 24, No. 231
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 358).
Vitamin D Supplements During Pregnancy: There is not enough definitive evidence to support or refute claims of benefits from vitamin D supplementation during pregnancy, authors of a systematic review conclude (j5237). In 43 randomized trials testing placebo, no vitamin D, or vitamin D ≤600 IU/day with 8,406 participants, these results were generated: “Vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12,530 additional participants to future reviews.” (D. E. Roth, daniel.roth@sickkids.ca)
Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: Direct-acting oral anticoagulants (DOACs) have advantages over warfarin in the prevention of stroke in patients with atrial fibrillation, researchers report based on findings from a network meta-analysis (j5058). A trial directly comparing DOACs with warfarin is needed, the group concludes, adding these findings from 23 trials of 94,656 patients: “Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.” (J. A. C. Sterne, jonathan.sterne@bristol.ac.uk)
>>>PNN NewsWatch
* FDA on Friday approved trastuzumab-dkst (Ogivri, Mylan GmbH) as a biosimilar to trastuzumab (Herceptin, Genentech) for treatment of patients with HER2+ breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
* Fading print affecting readability of expiration dates is the subject of a warning concerning AlbuRx 25, 
Albumin (Human) 25% solution. CSL Behring is taking no action for products on the market; customers are asked to contact CSL Customer Support if the lot number and expiration dating cannot be verified.
>>>PNN JournalWatch
* Diet Behavior Change Techniques in Type 2 Diabetes: A Systematic Review and Meta-analysis, in Diabetes Care, 2017; 40: 1800–10. (L. R. Quinlan, leo.quinlan@nuigalway.ie
* Urinary Tract Infection Antibiotic Trial Study Design: A Systematic Review, in 
Pediatrics, 2017; 140: 10.1542/peds.2017-2209. (R. Basmaci) 
* Refusal of Treatment of Childhood Cancer: A Systematic Review, in 
Pediatrics, 2017; 140: 10.1542/peds.2017-1951. (A. E. Caruso Brown) 
* Transgender Research in the 21st Century: A Selective Critical Review From a Neurocognitive Perspective, in 
American Journal of Psychiatry, 2017; 174: 1155–62. (S. C. Mueller) 
* The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder, in 
American Journal of Psychiatry, 2017; 174: 1214–22. (G. E. Doucet)

PNN Pharmacotherapy Line
Dec. 5, 2017 * Vol. 24, No. 232
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Dec. 5 issue of the Annals of Internal Medicine (2017; 167).
Aspirin for Primary Prevention: Grand rounds discussion considers whether aspirin should be used in a 57-year-old man for primary disease prevention (pp. 786–93): “Aspirin exerts antiplatelet effects through irreversible inhibition of cyclooxygenase-1, whereas its anticancer effects may be due to inhibition of cyclooxygenase-2 and other pathways. In 2009, the U.S. Preventive Services Task Force endorsed aspirin for primary prevention of cardiovascular disease. However, aspirin’s role in cancer prevention is still emerging, and no groups currently recommend its use for this purpose. To help physicians balance the benefits and harms of aspirin in primary disease prevention, the Task Force issued a guideline titled, ‘Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer’ in 2016. In the evidence review conducted for the guideline, cardiovascular disease mortality and colorectal cancer mortality were significantly reduced among persons taking aspirin. However, there was no difference in nonfatal stroke, cardiovascular disease mortality, or all-cause mortality, nor in total cancer mortality, among those taking aspirin. Aspirin users were found to be at increased risk for major gastrointestinal bleeding.” (R. B. Burns, rburns@bidmc.harvard.edu)
Hepatitis B Virus Vaccination & Screening: The American College of Physicians’ High Value Care Task Force and the Centers for Disease Control and Prevention present best practice statements for hepatitis B vaccination, screening, and linkage to care (pp. 794–804). Based on a literature review of evidence and clinical guidelines, the groups advise the following (A. Qaseem, aqaseem@acponline.org):
* Clinicians should vaccinate against hepatitis B virus (HBV) in all unvaccinated adults (including pregnant women) at risk for infection due to sexual, percutaneous, or mucosal exposure; health care and public safety workers at risk for blood exposure; adults with chronic liver disease, end-stage renal disease (including hemodialysis patients), or HIV infection; travelers to HBV-endemic regions; and adults seeking protection from HBV infection.
* Clinicians should screen (hepatitis B surface antigen, antibody to hepatitis B core antigen, and antibody to hepatitis B surface antigen) for HBV in high-risk persons, including persons born in countries with 2% or higher HBV prevalence, men who have sex with men, persons who inject drugs, HIV-positive persons, household and sexual contacts of HBV-infected persons, persons requiring immunosuppressive therapy, persons with end-stage renal disease (including hemodialysis patients), blood and tissue donors, persons infected with hepatitis C virus, persons with elevated alanine aminotransferase levels (≥19 IU/L for women and ≥30 IU/L for men), incarcerated persons, pregnant women, and infants born to HBV-infected mothers.
* Clinicians should provide or refer all patients identified with HBV (HBsAg-positive) for posttest counseling and hepatitis B–directed care.
>>>PNN NewsWatch
* “Men try — women do,” former First Lady Michelle Obama told an enthusiastic crowd of several thousand yesterday at the ASHP Midyear Clinical Meeting in Orlando. Describing women’s efforts to achieving work–life balance in their busy professional lives, Obama played off techniques she used in the White House, including putting events for yourself and your kids on your calendar first as a way of keeping professional demands from interfering with personal obligations.
Opioid overdoses are just the tip of the iceberg in misuse of these drugs, CDC emphasized during a news conference yesterday. A pyramid depicting the problem helps to illustrate the scope of the opioid-use disorder in the U.S. is available on the CDC website.
* “Patients have already benefitted from 
3D-printed medical products through access to personalized devices and innovative drugs that have led to significant health improvements,” FDA Commissioner Scott Gottlieb, MD, says in a statement. “FDA is now preparing for a significant wave of new technologies that are nearly certain to transform medical practice. We’re working to provide a more comprehensive regulatory pathway that keeps pace with those advances, and helps facilitate efficient access to safe and effective innovations that are based on these technologies.”

PNN Pharmacotherapy Line
Dec. 6, 2017 * Vol. 24, No. 233
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Dec. 5 issue of JAMA (2017; 318).
2017 ACC/AHA Clinical Practice Guideline for High Blood Pressure: Four categories of blood pressure (BP) — normal (<120/80 mm Hg); elevated (120–129/<80 mm Hg); stage 1 hypertension (130–139/80–89 mm Hg); and stage 2 hypertension (≥140/≥90 mm Hg) — are suggested in a new clinical practice guideline from the American College of Cardiology (ACC) and American Heart Association (AHA) (pp. 2132–4). Treatment decisions are preferably based on out-of-office BP measurements. In those with elevated BP or hypertension, therapy should be initiated using nonpharmacologic interventions. Patients with no history of cardiovascular disease (CVD) and an estimated 10-year atherosclerotic CVD (ASCVD) risk of less than 10%, BP-lowering medications are recommended when BPs reach 140/90 mm Hg. Those with CVD orhigher ASCVD risks should be treated when BPs reach 130/80 mm Hg, with a BP goal of less than 130/80 mm Hg. Recommended first-line medications are thiazide diuretics, calcium channel blockers, and ACE inhibitors or angiotensin II receptor blockers, and therapy should begin with two agents in those with stage 2 hypertension and an average BP more than 20/10 mm Hg over their BP target. (A. S. Cifu, adamcifu@uchicago.edu)
“The new 2017 ACC/AHA consensus BP guideline recommends many substantial changes for the field of hypertension and hypertension management,” editorialists write (
pp. 2083–4). “The majority of the recommendations support a more aggressive diagnostic and treatment approach and are consistent with growing evidence from clinical trials and epidemiological studies. A huge challenge for clinicians will be to translate these guidelines into clinical practice. Only approximately half of patients classified as having hypertension under the previous guidelines had their BP controlled, and the proportion at the new goals will be even lower. Thus, the ‘pressure’ is on to more effectively treat BP at individual and population levels.” (P. Greenland, p-greenland@northwestern.edu)
“Similar to JNC 7, the 2017 guideline recommends antihypertensive drug therapy for all adults, irrespective of ASCVD risk, with an average SBP of 140 mm Hg or greater or DBP of 90 mm Hg or greater,” add Viewpoint authors (
pp. 2073–4). “It also recommends use of BP-lowering drugs for older adults (≥65 years) with an average SBP of 130 mm Hg or greater. An analysis based on the 2011–2014 National Health and Nutrition Examination Survey, estimates that application of the new guideline recommendations would result in antihypertensive drug therapy for an additional 1.9% of US adults (4.2 million) compared with JNC 7.” (P. K. Whelton, pkwhelton@gmail.com)
GM-CSF & Exercise in PAD: In the PROPEL trial, the benefits of supervised treadmill exercise are confirmed for patients with lower-extremity peripheral artery disease (PAD), while treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to improve outcomes when used alone or with such exercise (pp. 2089–98). Based on a clinically important difference of at least a 20-m change in the 6-minute walking distance at 12-week follow-up, investigators found: “At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, −6.3 m [95% CI, −30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, −1.4 m [95% CI, −25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02).” (M. M. McDermott, mdm608@northwestern.edu)
Recent Trends in Drug Approvals: In 2012–16, FDA used one or more expedited programs for 60% of the drugs it approved, a study shows (pp. 2137–8). The median time to approval was 0.9 years shorter for expedited compounds. (A. S. Kesselheim, akesselheim@partners.org)
>>>PNN NewsWatch
* FDA has approved the once-weekly GLP-1 receptor agonist semaglutide (Ozempic), Novo-Nordisk announced yesterday.

PNN Pharmacotherapy Line
Dec. 7, 2017 * Vol. 24, No. 234
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Dec. 7 New England Journal of Medicine (2017; 377).
Hormonal Contraception & Breast Cancer: Significant but small increases in risk of breast cancer were associated with current or recent use of hormonal contraceptives, compared to never users, researchers report (pp. 2228–39). A nationwide prospective cohort study of all women in Denmark between ages 15 and 49 without histories of cancer, venous thromboembolism, or infertility showed these patterns: “Among 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P = 0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen–progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7,690 women using hormonal contraception for 1 year.” (L. S. Mørch, linamorch@yahoo.dk)
“Investigators in countries that have universal access to health care and those who have community agreement for the linkage of various databases are better able to conduct research that clarifies both the risks and benefits of common exposures, including prescription medicines,” writes an editorialist (
pp. 2276–7). The following implications of the study are examined (D. J. Hunter):
* “The approximately 20% higher risk of breast cancer among women who currently use hormonal contraceptives and those who do not must be placed in the context of the low incidence rates of breast cancer among younger women.”
* “The risk of breast cancer needs to be balanced against the benefits of the use of oral contraceptives.”
* “These data suggest that the search for an oral contraceptive that does not elevate the risk of breast cancer needs to continue.”
Pharmacomechanical Catheter-Directed Thrombolysis for DVT: Compared with anticoagulation alone, addition of a pharmacomechanical catheter-directed thrombolysis both increased risk of major bleeds and failed to lower the risk of postthrombotic syndrome, according to a study of 692 patients with acure proximal deep-vein thrombosis (pp. 2240–52). Based on a primary outcome of development of postthrombotic syndrome between 6 and 24 months, the study showed the following: “Between 6 and 24 months, there was no significant between-group difference in the percentage of patients with the post-thrombotic syndrome (47% in the pharmacomechanical-thrombolysis group and 48% in the control group; risk ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.11; P = 0.56). Pharmacomechanical thrombolysis led to more major bleeding events within 10 days (1.7% vs. 0.3% of patients, P = 0.049), but no significant difference in recurrent venous thromboembolism was seen over the 24-month follow-up period (12% in the pharmacomechanical-thrombolysis group and 8% in the control group, P = 0.09). Moderate-to-severe post-thrombotic syndrome occurred in 18% of patients in the pharmacomechanical-thrombolysis group versus 24% of those in the control group (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P = 0.04). Severity scores for the post-thrombotic syndrome were lower in the pharmacomechanical-thrombolysis group than in the control group at 6, 12, 18, and 24 months of follow-up (P <0.01 for the comparison of the Villalta scores at each time point), but the improvement in quality of life from baseline to 24 months did not differ significantly between the treatment groups.” (S. Vedantham, vedanthams@wustl.edu)

PNN Pharmacotherapy Line
Dec. 8, 2017 * Vol. 24, No. 235
Providing news and information about medications and their proper use

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>>>Pediatrics Highlights
Source:
 Dec. issue of Pediatrics (2017; 140).
Increasing Vaccine Acceptance Through Social Media: In Colorado in 2013–16, Web-based vaccine information provided to pregnant women using social media apps positively influenced parents to get their infants immunized, a study shows (10.1542/peds.2017-1117). Pregnant women were assigned to a website with vaccine information and interactive social media components (VSM), a website with vaccine information (VI), or usual care (UC). Vaccination of infants during their first 200 days of life followed these patterns: “Infants of 888 participants were managed for 200 days. By using a nonparametric rank-based analysis, mean ranks for days undervaccinated were significantly lower in the VSM arm versus UC (P = .02) but not statistically different between the VI and UC (P = .08) or between VSM and VI arms (P = .63). The proportions of infants up-to-date at age 200 days were 92.5, 91.3, and 86.6 in the VSM, VI, and UC arms, respectively. Infants in the VSM arm were more likely to be up-to-date than infants in the UC arm (odds ratio [OR] = 1.92; 95% confidence interval [CI], 1.07–3.47). Up-to-date status was not statistically different between VI and UC arms (OR = 1.62; 95% CI, 0.87–3.00) or between the VSM and VI arms (OR = 1.19, 95% CI, 0.70–2.03).” (J. M. Glanz)
ADHD Medications During Pregnancy: Seizures, other CNS adverse events, and neonatal morbidity occurred more frequently in infants born to women who used medications for attention-deficit/hyperactive disorder (ADHD) during pregnancy, researchers report (10.1542/peds.2017-0747). Based on data from Swedish registries in 2006–14, the authors found the following in the observational data: “Among 964,734 infants, 1,591 (0.2%) were exposed to ADHD medication during pregnancy and 9475 (1.0%) had mothers treated before or after pregnancy. Exposure during pregnancy increased the risk for admission to a NICU compared with both no use and use before or after pregnancy (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.3–1.7; and aOR, 1.2; 95% CI, 1.1–1.4, respectively). Infants exposed during pregnancy had more often central nervous system–related disorders (aOR, 1.9; 95% CI, 1.1–3.1) and were more often moderately preterm (aOR, 1.3; 95% CI, 1.1–1.6) than nonexposed infants. There was no increased risk for congenital malformations or perinatal death.” (U. Nörby)
IV Antibiotics for UTIs in Neonates: “The proportion of infants ≤60 days old receiving long IV treatment [for urinary tract infections] decreased substantially from 2005 to 2015 without an increase in hospital readmissions,” conclude authors who retrospectively analyzed experiences at a children’s hospital for those receiving IV antibiotics (10.1542/peds.2017-1021). “These findings support the safety of short-course IV antibiotic therapy for appropriately selected neonates.” (W. W. Lewis-de los Angeles)
>>>PNN NewsWatch
Influenza A(H3N2) viruses are predominating in the early part of the current season, CDC officials write in this week’s MMWR. Increased activity thus far has been in southern states, especially Louisiana and Mississippi. Antigenic drift has not occurred, with 63 of 64 A/H3N2 viruses tested inhibited by antiserum against egg-propagated virus. Some data indicate that the cell-based vaccine may be more effective than vaccines produced with egg-propagated virus. Seasons in which A/H3N2 predominate tend to be more severe, as exemplified by the 2016–17 season during which influenza was linked to 31 million illnesses, 14.5 million medical visits, and 602,000 hospitalizations. Vaccine effectiveness is frequently lower in H3N2-predominant seasons.
CDC has also released early influenza vaccination coverage figures. The percentage of vaccinated adults is 2.1% lower than in mid-November of the prior season (38.5% this season, compared with 40.6% last season). Older adults are covered very similarly (both years at 56.6%), while coverage rates are significantly lower in adults aged 18–49 years (30.6% versus 34.3%). and in adults aged 18–64 years overall (33.9% versus 36.7%). Children are better vaccinated, 38.8% this season, compared with 37.3% last season (not a significant difference). Among health professionals, pharmacists led the coverage rates at 86.4%, followed by physicians (82.7%), nurses (80.9%), and nurse practitioners/physician assistants (79.7%).

PNN Pharmacotherapy Line
Dec. 11, 2017 * Vol. 24, No. 236
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Dec. 9 issue of Lancet (2017; 390).
Managing Hypertension in China: Nearly one half of adults aged 35–75 years in China have hypertension, a study shows, and only one third of these patients are being treated, with just 1 in 12 cases under control (pp. 2549–58). In the China Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project, the results from 2014–17 led investigators to this conclusion, “The low number of people in control is ubiquitous in all subgroups of the Chinese population and warrants broad-based, global strategy, such as greater efforts in prevention, as well as better screening and more effective and affordable treatment.” (L. Jiang, jiangl@fwoxford.org)
Lack of availability and use of high-value antihypertensive medications is a likely contributor to this situation, according to a 2016–17 nationwide, cross-sectional survey (
pp. 2559–68). The PEACE Million Persons Project primary health care survey assessed antihypertensive care in 31 provinces, with these results: “Our study sample included 3,362 primary health-care sites and around 1 million people (613,638 people at 2,758 rural sites and 478,393 people at 604 urban sites). Of the 3,362 sites, 8.1% (95% CI 7.2–9.1) stocked no antihypertensive medications and 33.8% (32.2–35.4) stocked all four classes that were routinely used. Village clinics and sites in the western region of China had the lowest availability. Only 32.7% (32.2–33.3) of all sites stocked high-value medications, and few high-value medications were prescribed (11.2% [10.9–11.6] of all prescription records). High-cost medications were more likely to be prescribed than low-cost alternatives.” (L. Jiang, jiangl@fwoxford.org)
>>>Infectious Diseases Report
Source:
 Dec. 15 issue of Clinical Infectious Diseases (2017; 65).
Tdap During Pregnancy & Neonatal Pertussis: Administration of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy is effective for preventing pertussis in newborn infants, according to results of a case–control study conducted in 6 U.S. Emerging Infection Program Network states (pp. 1977–83). In 2011–14, pertussis cases among infants younger than 2 months of age were matched with controls born at the same hospitals. Based on demographic, household, and health professional information provided by mothers and immunization histories from providers, the researchers report: “A total of 240 cases and 535 controls were included; 17 (7.1%) case mothers and 90 (16.8%) control mothers received Tdap during the third trimester of pregnancy. The multivariable [vaccine effectiveness (VE)] estimate for Tdap administered during the third trimester of pregnancy was 77.7% (95% confidence interval [CI], 48.3%–90.4%); VE increased to 90.5% (95% CI, 65.2%–97.4%) against hospitalized cases.” (T. H. Skoff, tlh9@cdc.gov)
Statins, ACEs, ARBs & HIV: In 3,949 people living with HIV, statins, angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARB) produced “modest declines in neurocognitive performance” but did not have a consistent effect on global neurocognitive function (pp. 2042–9). AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort participants who were taking ACEI/ARB had a significant negative effect during the first year of therapy but minimal effects thereafter; statins showed mixed effects. (K. M. Erlandson, Kristine.Erlandson@ucdenver.edu)
>>>PNN JournalWatch
* Modifiable Pathways in Alzheimer’s Disease: Mendelian Randomisation Analysis, in BMJ, 2017; 359: j5375. (S. C, Larsson, susanna.larsson@ki.se
* Stool Microbiota at Neutrophil Recovery Is Predictive for Severe Acute Graft vs Host Disease After Hematopoietic Cell Transplantation, in 
Clinical Infectious Diseases, 2017; 65: 1984–91. (D. N. Fredricks, dfredric@fredhutch.org
* 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea, in 
Clinical Infectious Diseases, 2017; 65: 1963–73. (A. L. Shane, ashane@emory.edu
* Alcohol and Cancer: A Statement of the American Society of Clinical Oncology, in 
Journal of Clinical Oncology, 2017; 35: 10.1200/JCO.2017.76.1155. (N. K. LoConte, ns3@medicine.wisc.edu
* Changes in Insurance Coverage and Stage at Diagnosis Among Nonelderly Patients With Cancer After the Affordable Care Act, in 
Journal of Clinical Oncology, 2017; 35: 3906–15. (A. Jemal, ahmedin.jemal@cancer.org)

PNN Pharmacotherapy Line
Dec. 12, 2017 * Vol. 24, No. 237
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Dec. issue of JAMA Internal Medicine (2017; 177).
Warfarin Use & Cancer in Older Adults: A new population-based cohort study from Norway provides an unique reason for preferring warfarin in adults older than 50: cancer prevention (pp. 1774–80). Looking for evidence that warfarin’s inhibition of AXL receptor tyrosine kinase–dependent tumorigenesis and enhancement of antitumor immune responses might be clinically relevant, investigators analyzed the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. Among 1.3 million people born in 1924–54 and residing in Norway in 2006–12, age- and sex-adjusted incidence rate ratio of cancer among warfarin users was significantly lower than in nonusers, the study shows. (J. B. Lorens, jim.lorens@uib.no)
Sustainability of Diabetes Prevention Approaches: Lifestyle modification (LSM) and use of medications for weight loss or insulin sensitization both reduce the incidence of diabetes in at-risk adults, researchers report, but drug effects are short-lived while LSMs are more sustainable (pp. 1808–17). Based on a systematic review and meta-analysis of 43 studies of 49,029 participants, the authors found: “At the end of the active intervention (range, 0.5–6.3 years), LSM was associated with an RR reduction of 39% (RR, 0.61; 95% CI, 0.54–0.68), and medications were associated with an RR reduction of 36% (RR, 0.64; 95% CI, 0.54–0.76). The observed RD for LSM and medication studies was 4.0 (95% CI, 1.8–6.3) cases per 100 person–years or a number-needed-to-treat of 25. At the end of the washout or follow-up periods, LSM studies (mean follow-up, 7.2 years; range, 5.7–9.4 years) achieved an RR reduction of 28% (RR, 0.72; 95% CI, 0.60–0.86); medication studies (mean follow-up, 17 weeks; range, 2–52 weeks) showed no sustained RR reduction (RR, 0.95; 95% CI, 0.79–1.14).” (J. S. Haw, jhaw@emory.edu)
Gestational Diabetes & Long-term CVD: The Nurses Health Study II shows an association between gestational diabetes (GD) and cardiovascular disease (CVD) later in life (pp. 1735–42). Based on 1,161 self-reported occurrences of nonfatal or fatal myocardial infarction or stroke, the investigators determined: “Participants had a mean (SD) age of 34.9 (4.7) years. Adjusting for age, prepregnancy body mass index, and other covariates, GD vs no GD was associated with subsequent CVD (HR, 1.43; 95% CI, 1.12–1.81). Additional adjustment for weight gain since pregnancy and updated lifestyle factors attenuated the association (HR, 1.29; 95% CI, 1.01–1.65). Classifying GD by progression to {type 2 diabetes (T2D)] in relation to CVD risk indicated a positive association for GD with progression to T2D vs no GD or T2D (HR, 4.02; 95% CI, 1.94–8.31), and an attenuated relationship for GD only (HR, 1.30; 95% CI, 0.99–1.71).” (C. Zhang, zhangcu@mail.nih.gov)
Compounded Bioidentical Hormone Therapy: “Clinicians should be cautious about prescribing [compounded bioidentical hormone therapy (cBHT)], and women should be cautious about filling prescriptions,” editorialists write about the unproven products, “and women should be cautious about filling prescriptions” (pp. 1719–20). “State pharmacy boards could take the initiative to request that compounding pharmacists provide a patient package insert when these medications are dispensed, or state legislatures could pass laws mandating that this information is provided to patients. Congress could also provide the FDA with full legal authority over cBHT. In the absence of such measures, clinicians should fully inform their patients. One way or another, let’s tell patients the truth.” (C. A. Stuenkel, castuenkel@ucsd.edu)
>>>PNN NewsWatch
* For the first time, a “follow-on” short-acting insulin product has been approved by FDAAdmelog (insulin lispro injection; Sanofi-Aventis) is indicated for improving control of blood glucose levels in patients aged 3 years or older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus.
* In the newly launched 
“Every Try Counts” campaign, FDA is targeting smokers ages 25–54 who have attempted to quit smoking in the last year but were unsuccessful. Messages will be displayed in and around gas stations and convenience stores – retail locations where smokers face a multitude of triggers and that typically feature cigarette advertisements, the agency said.

PNN Pharmacotherapy Line
Dec. 13, 2017 * Vol. 24, No. 238
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Dec. 12 issue of JAMA (2017; 318).
Pharmacist-Prescribed Contraception in California: In the first year of pharmacist-prescribed contraception in California, only 11.1% of community pharmacies provided this service, according to a research letter (pp. 2253–4). “Most pharmacies offering pharmacist-prescribed contraception required a fee for this service, particularly retail chains,” the author writes. “Even when contraception is available in pharmacies, it may not be economically accessible because of fees.” Based on a telephone audit survey of a representative sample of California pharmacies, these results were identified: “The sampling frame included 5,291 community-based, retail pharmacies. A random sample of 1,058 pharmacies was drawn, with data collected from 1,008 (95.2%). Most pharmacies were urban (85.7%) and affiliated with chains (70.3%). Pharmacist-prescribed contraception was available in 11.1% (95% CI, 9.3%–13.2%) of pharmacies, with no significant availability differences by urbanity or pharmacy type. Among pharmacies offering this service (n = 112), 67.9% (95% CI, 58.5%–75.9%) indicated a specific fee requirement (median, $45 [IQR, $40–$45]). Most chain pharmacies (86.3% [95% CI, 76.2%–92.6%]) had set fees compared with independent pharmacies (33.3% [95% CI, 20.2%–49.7%]) (P <.001). When queried about method availability, contraceptive pills were referenced most frequently (77.7%), followed by rings (40.2%), patches (38.4%), and injections (8.9%).” (A. Manchikanti Gomez, anugomez@berkeley.edu)
Hormonal Therapy for Primary Prevention in Postmenopausal Women: The U.S. Preventive Services Task Force (USPSTF) recommends against use of hormonal therapy for primary prevention of chronic conditions in postmenopausal women in an update of its 2012 statement (pp. 2224–33): “Although the use of hormone therapy to prevent chronic conditions in postmenopausal women is associated with some benefits, there are also well-documented harms. The USPSTF determined that the magnitude of both the benefits and the harms of hormone therapy in postmenopausal women is small to moderate. Therefore, the USPSTF concluded with moderate certainty that combined estrogen and progestin has no net benefit for the primary prevention of chronic conditions for most postmenopausal women with an intact uterus and that estrogen alone has no net benefit for the primary prevention of chronic conditions for most postmenopausal women who have had a hysterectomy.” (D. C. Grossman, david.c.grossman@kp.org)
Hormonal therapy is a story of “unfulfilled expectations,” an editorialist writes in a 
JAMA Cardiology article posted online (10.1001/jamacardio.2017.4575): “Has the last chapter been written on menopausal hormone therapy for chronic disease prevention? The ‘timing hypothesis’ concerning the interval between menopause and initiation of hormone therapy remains incompletely explored. A 2015 Cochrane review reported a decreased relative risk of coronary heart disease (0.52) in randomized clinical trials when hormone use was initiated less than 10 years after menopause. Newer formulations, newer delivery mechanisms, and newer versions of menopausal hormone therapy will likely be studied. The effect of gene polymorphisms is unanswered. Risks and benefits may be modified by concomitant nonhormonal preventive interventions, both pharmacologic and lifestyle.” (N. K. Wenger, nwenger@emory.edu)
>>>PNN NewsWatch
FDA yesterday expanded the approved use of mepolizumab (Nucala, GlaxoSmithKline) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). This new indication provides the first FDA-approved therapy specifically to treat EGPA.
* In a letter to marketers and distributors posted yesterday, 
FDA warns companies about promoting Coco Loko, a snortable chocolate powder, and Legal Lean, a drink, as alternatives to street drugs. The agency explains how the claims made in the promotional materials for Legal Lean Syrup and Coco Loko demonstrate that the products are intended to be used as alternatives to illicit street drugs and that the products, as labeled and marketed, may pose safety concerns. Street drug alternatives are products that claim to mimic the effects of recreational drugs to affect psychological states.

PNN Pharmacotherapy Line
Dec. 14, 2017 * Vol. 24, No. 239
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 14 New England Journal of Medicine (2017; 377).
Sotagliflozin Plus Insulin in Type 1 Diabetes: In a phase 3 trial of an oral inhibitor of sodium–glucose cotransporters 1 and 2 added to pump or injected insulin, sotagliflozin produced better glycemic control than placebo but also more diabetic ketoacidosis among 1,402 patients with type 1 diabetes (pp. 2337–48). Based on a primary end point of glycated hemoglobin level lower than 7.0% at week 24, sotagliflozin produced these results: “A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P <0.001).… The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).” (S. Garg, satish.garg@ucdenver.edu)
“The further development of automated insulin delivery systems is likely to make adjunctive drug therapies for type 1 diabetes unnecessary,” an editorialist writes (
pp. 2390–1). “Improved automated delivery systems should be able to lower the glycated hemoglobin level while resulting in fewer episodes of hypoglycemia than those seen with adjunctive therapies and requiring less effort from the patient. Any added benefits of adjunctive therapies for type 1 diabetes must be carefully balanced against their added risks and costs. Physicians and patients should beware.” (D. M. Nathan)
Bivalent Meningococcal B Vaccine: MenB-FHbp, a licensed meningococcal B vaccine targeting factor H–binding protein, was safe and immunogenic after two or three doses in two phase 3 studies, researchers report (pp. 2349–62). Tested against hepatitis A vaccine and saline, the vaccine yielded these results: “In the modified intention-to-treat population, the percentage of adolescents who had an increase in the [serum bactericidal assays that included human complement] titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%