PNN October–December 2017

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

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>>>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

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>>>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

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>>>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

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>>>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

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>>>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
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>>>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
Providing news and information about medications and their proper use

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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
Providing news and information about medications and their proper use

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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
Providing news and information about medications and their proper use

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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
Providing news and information about medications and their proper use

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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
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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
Providing news and information about medications and their proper use

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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
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>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

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>>>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

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>>>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

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>>>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
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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
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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
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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
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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
Providing news and information about medications and their proper use

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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

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>>>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

Click here for a PDF of this issue.

>>>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

Click here for a PDF of this issue.

>>>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

Click here for a PDF of this issue.

>>>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

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>>>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%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively.… Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site.” (J. Absalon, judith.absalon@pfizer.com)
Drug Companies’ Liability for the Opioid Epidemic: “Litigation could also help alleviate the opioid epidemic by changing industry practices and building public awareness,” Commentary authors write about legal liability for the opioid epidemic (pp. 2301–5). “Settlement agreements may include commitments to modify particular marketing and distribution practices, as in the case of McKesson. Lawsuits may bring to light harmful, unethical, and even illegal business practices that sour public opinion of opioid companies and prompt patients to ask more questions about what their doctor prescribes. Finally, snowballing litigation helps build the case for greater regulation. Win or lose, lawsuits that very publicly paint the opioid industry as contributing to the worst drug crisis in American history put wind in the sails of agencies and legislatures seeking stronger oversight. Together, litigation and its spillover effects hold real hope for arresting the opioid epidemic.” (R. L. Haffajee)
>>>PNN NewsWatch
FDA yesterday said it will provide online information about bacterial or fungal breakpoints for specific organisms and their susceptibility to specific drugs. This approach is intended to aid health professionals in making more informed prescribing decisions that will both benefit their patients and prevent the spread of resistant bacteria, the agency said.
* Marmex Corp is voluntarily recalling all lots of
 Blue Pearl All Natural Male Enhancement Supplement 500 mg to the consumer level because the product contains sildenafil, FDA said.

PNN Pharmacotherapy Line
Dec. 15, 2017 * Vol. 24, No. 240
Providing news and information about medications and their proper use

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>>>Allergy/Immunology Report
Source:
 Dec. issue of the Journal of Allergy and Clinical Immunology (2017; 140).
Neonatal BCG Vaccination & Recurrent Wheeze: Contrary to studies showing nonspecific beneficial respiratory effects of neonatal BCG vaccination, the Danish Calmette Study concludes that the immunization has no effect on development of recurrent wheeze (RW) before 13 months of age (pp. 1616–21.e3). Of 4,262 newborns of 4,184 included mothers in 2012–15, randomization to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth produced these outcomes: “By 13 months, 211 (10.0%) of 2,100 children in the BCG group and 195 (9.4%) of 2,071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89–1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW.” (L. M. Thøstesen, lmje@dadlnet.dk)
Advances in Therapy of Chronic Rhinosinusitis: Agents in development for treating chronic rhinosinusitis (CRS) “seem likely to have a positive effect” but “will require targeted individualized treatments based on identifying subjects with the relevant endotype” (pp. 1499–508). “The need for individualized definitions of pathogenic mechanisms before initiating therapy extends to virtually all therapeutic considerations,” the authors write. “This is clearly crucial with antibiotics, where, barring an influence from their off-target anti-inflammatory pharmacologic effects, an understanding of the role of the individual biome predicts likelihood of therapeutic benefit. However, this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids. As with asthma, it is recognized that a large minority of patients with CRS have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative because targeted biotherapeutic agents, such as anti-IgE and anti-cytokine antibodies, are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that patient.” (J. Gurrola II, jose.gurrola@ucsf.edu)
>>>Geriatrics Highlights
Source:
 Dec. issue of the Journal of the American Geriatrics Society (2017; 65).
Antipsychotics & Risk of Aspiration Pneumonia: Among hospitalized adults, use of antipsychotic agents was associated with increased risk of aspiration pneumonia in a retrospective cohort study at a large academic medical center (pp. 2580–6). Outcomes were as follows for nonpsychiatric hospitalizations in 2007–13: “Our cohort included 146,552 hospitalizations (median age 56; 39% male). Antipsychotics were used in 10,377 (7.1%) hospitalizations (80% atypical, 35% typical, 15% both). Aspiration pneumonia occurred in 557 (0.4%) hospitalizations. The incidence of aspiration pneumonia was 0.3% in unexposed individuals and 1.2% in those with antipsychotic exposure (odds ratio (OR) = 3.9, 95% confidence interval (CI) = 3.2–4.8). After adjustment, antipsychotic exposure was significantly associated with aspiration pneumonia (adjusted OR = (aOR) = 1.5, 95% CI = 1.2–1.9). Similar results were demonstrated in a propensity-matched analysis and in an analysis restricted to those with delirium or dementia. The magnitude of the association was similar for typical (aOR = 1.4, 95% CI = 0.94–2.2) and atypical (aOR = 1.5, 95% CI = 1.1–2.0) antipsychotics.” (S. J. Herzig, sherzig@bidmc.harvard.edu)
Guideline-Recommended Medications and Physical Function: Community-dwelling adults aged 65 years or older had minimal self-reported decline in physical function that was connected to use of guideline-recommended medications for atrial fibrillation, coronary artery disease, depression, diabetes mellitus, and/or heart failure, researchers report (pp. 2619–26).Data on 3,273 participants in the Medicare Current Beneficiary Survey study showed significant links only for lower risks of decline in patients with heart failure who were treated with ARBs and higher risks in those with diabetes who were taking statins. (G. McAvay, gail.mcavay@yale.edu)

PNN Pharmacotherapy Line
Dec. 18, 2017 * Vol. 24, No. 241
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Dec. 16 issue of Lancet (2017; 390).
Worldwide Trends in Body Mass: The frequency of underweight, overweight, and obesity are tracked in a pooled analysis of data from 2,416 population-based studies of 128.9 million participants (pp. 2627–42). Researchers report that the “rising trends in children’s and adolescents’ BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. The U.S. is among the countries with obesity in more than 20% of its population, results show: “Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0.7% (0.4–1.2) in 1975 to 5.6% (4.8–6.5) in 2016 in girls, and from 0.9% (0.5–1.3) in 1975 to 7.8% (6.7–9.1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9.2% (6.0–12.9) in 1975 to 8.4% (6.8–10.1) in 2016 in girls and from 14.8% (10.4–19.5) in 1975 to 12.4% (10.3–14.5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22.7% (16.7–29.6) among girls and 30.7% (23.5–38.0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44–117) million girls and 117 (70–178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24–89) million girls and 74 (39–125) million boys worldwide were obese.” (NCD Risk Factor Collaboration)
Physical Activity & CVD in Countries of Different Income Levels: Recreational or nonrecreational physical activity is beneficial among people in countries with all levels of income, a study of mortality and cardiovascular disease (CVD) shows (pp. 2643–54). Seeking to confirm the benefits of exercise previously studied primarily in high-income countries, the investigators conclude that “increasing physical activity is a simple, widely applicable, low cost global strategy that could reduce deaths and CVD in middle age.” Results in people age 35–70 years of age showed the following: “Between Jan 1, 2003, and Dec 31, 2010, 168,916 participants were enrolled, of whom 141,945 completed the IPAQ. Analyses were limited to the 130,843 participants without pre-existing CVD. Compared with low physical activity (<600 metabolic equivalents [MET] × minutes per week or <150 minutes per week of moderate intensity physical activity), moderate (600–3000 MET × minutes or 150–750 minutes per week) and high physical activity (>3000 MET × minutes or >750 minutes per week) were associated with graded reduction in mortality (hazard ratio 0.80, 95% CI 0.74–0.87 and 0.65, 0.60–0.71; p <0.0001 for trend), and major CVD (0.86, 0.78–0.93; p <0.001 for trend). Higher physical activity was associated with lower risk of CVD and mortality in high-income, middle-income, and low-income countries. The adjusted population attributable fraction for not meeting the physical activity guidelines was 8.0% for mortality and 4.6% for major CVD, and for not meeting high physical activity was 13.0% for mortality and 9.5% for major CVD. Both recreational and non-recreational physical activity were associated with benefits.” (S. A Lear, slear@providencehealth.bc.ca)
>>>PNN NewsWatch
* Providing more efficient access to targeted therapies is the goal of two draft guidances issued by FDA on Friday that “will provide medical product developers with greater clarity on the FDA’s recommendations for researching and developing the next generation of individualized therapies.” 
>>>PNN JournalWatch
* New Anti-Eosinophil Drugs for Asthma and COPD: Targeting the Trait!, in Chest, 2017; 152: 1276–82. (E. H. Bel, e.h.bel@amc.uva.nl
* Potassium Homeostasis in Health and Disease: A Scientific Workshop Cosponsored by the National Kidney Foundation and the American Society of Hypertension, in 
American Journal of Kidney Diseases, 2017; 70: 244–58. (C. P. Kovesdy, ckovesdy@uthsc.edu)

PNN Pharmacotherapy Line
Dec. 19, 2017 * Vol. 24, No. 242
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Dec. 19 issue of the Annals of Internal Medicine (2017; 167).
Dabigatran v. Warfarin for Atrial Fibrillation: Adults treated in practice with dabigatran had similar incidences of stroke and bleeding as those on warfarin, according to FDA Sentinel data from 2010 to 2014 (pp. 845–54). In a retrospective cohort study, these outcomes were identified for 25,289 patients starting dabigatran therapy and an equal number of matched controls beginning warfarin treatment: “Those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran.” (A. S. Go, Alan.S.Go@kp.org)
OTC Supplements for Cognition: Evidence is lacking for use of OTC dietary supplements for preventing cognitive decline, mild cognitive impairment (MCI), or dementia, according to authors of a systematic review (10.7326/M17-1530): “Thirty-eight trials with low to medium risk of bias compared omega-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or beta-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer-type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of omega-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, beta-carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported.” (M. Butler, butl0092@umn.edu)
Drug Therapy for Cognition: Despite 51 trials of pharmacotherapy for preserving cognition during aging, little positive evidence has accumulated, systematic review authors write (10.7326/M17-1529): “In persons with normal cognition, estrogen and estrogen–progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high-dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen–progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism).” (H. A. Fink, Howard.fink@va.gov)
>>>PNN NewsWatch
FDA yesterday proposed a new, risk-based enforcement approach to drug products labeled as homeopathic. To protect consumers who choose to use homeopathic products, this proposed new approach would update the FDA’s existing policy to better address situations where homeopathic treatments are being marketed for serious diseases and/or conditions but where the products have not been shown to offer clinical benefits. It also covers situations where products labeled as homeopathic contain potentially harmful ingredients or do not meet current good manufacturing practices the agency said.

PNN Pharmacotherapy Line
Dec. 20, 2017 * Vol. 24, No. 243
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Dec. 19 issue of JAMA (2017; 318).
Tumor-Treating Fields for Glioblastoma: In radiochemotherapy-treated patients with glioblastoma, progression-free and overall survival rates were improved by addition of tumor-treating fields (TTFields), researchers report (pp. 2306–16). Final analysis of data from a randomized, open-label trial found these effects of the electric-field intervention: “Of the 695 randomized patients (median age, 56 years; IQR, 48–63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields–temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52–0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53–0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields–temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.” (R. Stupp, roger.stupp@northwestern.edu)
Antibiotics in Pediatric Acute Respiratory Tract Infections: Narrow-spectrum antibiotics proved as effective and safer than broad-spectrum choices in a retrospective cohort study of children aged 6 months to 12 years with acute respiratory tract infections (pp. 2325–36). Experiences of those seen at 31 pediatric practices in Pennsylvania and New Jersey showed similar outcomes regardless of antibiotic choice but fewer adverse effects among narrow-spectrum agents: “Of 30,159 children in the retrospective cohort (19,179 with acute otitis media; 6,746, group A streptococcal pharyngitis; and 4,234, acute sinusitis), 4,307 (14%) were prescribed broad-spectrum antibiotics including amoxicillin-clavulanate, cephalosporins, and macrolides. Broad-spectrum treatment was not associated with a lower rate of treatment failure (3.4% for broad-spectrum antibiotics vs 3.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 0.3% [95% CI, −0.4% to 0.9%]). Of 2,472 children enrolled in the prospective cohort (1,100 with acute otitis media; 705, group A streptococcal pharyngitis; and 667, acute sinusitis), 868 (35%) were prescribed broad-spectrum antibiotics. Broad-spectrum antibiotics were associated with a slightly worse child quality of life (score of 90.2 for broad-spectrum antibiotics vs 91.5 for narrow-spectrum antibiotics; score difference for full matched analysis, −1.4% [95% CI, −2.4% to −0.4%]) but not with other patient-centered outcomes. Broad-spectrum treatment was associated with a higher risk of adverse events documented by the clinician (3.7% for broad-spectrum antibiotics vs 2.7% for narrow-spectrum antibiotics; risk difference for full matched analysis, 1.1% [95% CI, 0.4% to 1.8%]) and reported by the patient (35.6% for broad-spectrum antibiotics vs 25.1% for narrow-spectrum antibiotics; risk difference for full matched analysis, 12.2% [95% CI, 7.3% to 17.2%]).” (J. S. Gerber, gerberj@email.chop.edu)
>>>PNN NewsWatch
* The first directly administered gene therapy that targets a disease caused by specific gene mutations, voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics), has been approved by FDA to treat children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The condition leads to vision loss and may cause complete blindness in certain patients. This one-time gene therapy product is the first adeno-associated virus vector gene therapy approved in the U.S.
FDA said yesterday that it is requiring a new class warning and other safety measures for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) concerning gadolinium remaining in patients’ bodies, including the brain, for months to years after receiving these drugs. Required actions include a new patient Medication Guide, educational information that every patient will be asked to read before receiving a GBCA. FDA is also requiring manufacturers of GBCAs to conduct human and animal studies to further assess the safety of both linear and macrocyclic types of GBCAs.

PNN Pharmacotherapy Line
Dec. 21, 2017 * Vol. 24, No. 244
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 21 issue of the New England Journal of Medicine (2017; 377).
Letermovir for CMV in Hematopoietic-Cell Transplantation: In a placebo-controlled phase 3 trial, the antiviral agent letermovir lowered the risk of clinically significant cytomegalovirus (CMV) in patients who had received allogeneic hematopoietic-cell transplantation (pp. 2433–44). The drug inhibits the CMV–terminase complex; it had these effects based on a primary end point of proportion of those patients without detectable CMV DNA at randomization who had clinically significant CMV infection through week 24 after transplantation: “From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P <0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.” (F. M. Marty, fmarty@bwh.harvard.edu)
Evidence-Based Health Policy: “Having a clear framework for characterizing what is, and isn’t, evidence-based health policy (EBHP) is a prerequisite for a rational approach to making policy choices, and it may even help focus the debate on the most promising approaches,” Perspective authors write in outlining the elements of such a policy (pp. 2413–5). In addition to making sure that policies are well-specified and distinguishing between policies and goals, the authors maintain that “EBHP requires evidence of the magnitude of the effects of the policy, and obtaining such evidence is an inherently empirical endeavor. Introspection and theory are terrible ways to evaluate policy. In some instances, we have clear conceptual models that suggest the direction of the effect a policy is likely to have, but these models never tell us how big the effect is likely to be. For example, economic theory says that, all else being equal, when copayments or deductibles are higher, patients use less care (we’re pretty sure that demand slopes down), but this theory doesn’t tell us by how much. And often even the direction of the effect is unclear without empirical research, with different effects potentially going in opposite directions.” (K. Baicker)
#MeToo in Medicine: “I wish I had brilliant insights about how our society can address the deep-rooted, pervasive causes of [sexual harassment] proactively rather than simply reactively,” a Perspectives author writes of challenges in medicine (10.1056/NEJMp1715962). “Nevertheless, I find it valuable to have the opportunity to participate in this now open conversation and draw from the example of innovators like the astronomy allies.” (R. Jagsi)
>>>PNN NewsWatch
FDA has removed boxed warnings about asthma-related deaths from the drug labels of drug products that contain both an inhaled corticosteroid (ICS) and long-acting beta agonist (LABA). An FDA review of four large clinical safety trials shows that treating asthma with this drug combination does not result in significantly more serious asthma-related adverse effects than treatment with ICS alone. A description of the four trials is now also included in the warnings and precautions section of the drug labels. These trials showed that LABAs, when used with ICS, did not significantly increase the risk of asthma-related hospitalizations, need for intubation, or asthma-related deaths, compared to ICS alone, the agency said.
AuroMedics Pharma LLC is voluntarily recalling one lot of Pantoprazole Sodium for Injection 40 mg per vial to the hospital level because of presence of glass particles in vials.
PNN will not be published on Fri., Dec. 22, and Mon., Dec. 25, in celebration of Christmas.

PNN Pharmacotherapy Line
Dec. 26, 2017 * Vol. 24, No. 245
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Dec. 23 issue of Lancet (2017; 390).
Tight Control of Crohn Disease: Compared with symptom-driven decisions alone, timely escalation with an anti-tumor necrosis factor therapy based on clinical symptoms and biomarkers improves clinical and endoscopic outcomes among patients with early Crohn disease, researchers report (pp. 2779–89). In the phase 3 CALM trial, 244 participants were randomized to tight control or clinical management groups after 8 weeks of prednisone induction therapy, or earlier if they had active disease, with these results: “Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0.9 years [SD 1.7]; tight control group, 1.0 year [2.3]) were randomly assigned to monitoring groups (n = 122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran–Mantel–Haenszel test-adjusted risk difference of 16.1% (95% CI 3.9–28.3; p = 0.010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn’s disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group.” (J-F Colombel, jean-frederic.colombel@mssm.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 358).
Incremental Effects of Antihypertensive Drugs: In a secondary analysis of data from the SPRINT (Systolic Blood Pressure Intervention Trial), addition of a new antihypertensive drug class was associated with large reductions in systolic blood pressure and major cardiovascular events in high-risk patients without diabetes (j5542). Results were as follows for 9,092 participants: “In standard multivariable models not adjusted for confounding by indication, addition of an antihypertensive drug from a new class was associated with modestly lower systolic blood pressure (−1.3 mm Hg, 95% confidence interval −1.6 to −1.0) and no change in major cardiovascular events (absolute risk of events per 1,000 patient years, 0.5, 95% confidence interval −1.5 to 2.3). In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (−14.4 mm Hg, −15.6 to −13.3) and fewer major cardiovascular events (absolute risk −6.2, −10.9 to −1.3). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients. The addition of another antihypertensive drug class was not associated with adverse events in either standard or instrumental variable models.” (A. M. Ryan, amryan@umich.edu)
>>>PNN NewsWatch
FDA on Thursday approved angiotensin II (Giapreza, La Jolla Pharmaceutical Company) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock. Distributive shock is the most common type of shock in the inpatient setting, affecting approximately one-third of intensive care unit patients. There are approximately 800,000 distributive shock cases in the U.S. per year. Of these patients, an estimated 90% have septic shock.
FDA is adding information to product labeling on ways of discontinuing nilotonib (Tasigna, Novartis) in patients with early phase chronic myeloid leukemia who have been taking the drug for 3 years or more, and whose leukemia has responded to treatment according to specific criteria as detected by a test that has received FDA marketing authorization.
>>>PNN JournalWatch
* Review: Metabolic Control of Immune System Activation in Rheumatic Diseases, in Arthritis & Rheumatology, 2017; 69: 2259–70. (A. Perl, perla@upstate.edu)

PNN Pharmacotherapy Line
Dec. 27, 2017 * Vol. 24, No. 246
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Dec. 26 issue of JAMA (2017; 318).
Calcium/Vitamin D Supplements & Fractures in Older Adults: Routine use of calcium and vitamin D supplementation in community-dwelling older adults is not supported by results of a systematic review and meta-analysis of 33 randomized trials of 51,145 participants (pp. 2466–82). Based on a primary outcome of hip fracture and secondary outcomes of nonvertebral fracture, vertebral fracture, and total fracture, results show the following: “There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; [absolute risk differences (ARDs)], 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, −0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, −0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration.” (J-G Zhao, rthopaedic@163.com">orthopaedic@163.com)
Antibiotic Prophylaxis in Below-Knee Surgery: A single-dose of cefazolin failed to improve infection rates following removal of orthopedic implants used in fractures below the knee, researchers report (pp. 2438–45). While surgical site-infections (SSIs) in clean surgeries should be less than 2%, the observed SSI rate after removal of below-knee implants has exceeded 12%. In a clinical trial of 500 adults undergoing removal of orthopedic implants at 19 Dutch hospitals, cefazolin 1000 mg or placebo given I.V. preoperatively produced these changes in a primary outcome of SSI within 30 days: “Among 477 randomized patients (mean age, 44 years [SD, 15]; women, 274 [57%]; median time from orthopedic implant placement, 11 months [interquartile range, 7–16]), 470 patients completed the study. Sixty-six patients developed an SSI (14.0%): 30 patients (13.2%) in the cefazolin group vs 36 in the saline group (14.9%) (absolute risk difference, −1.7 [95% CI, −8.0 to 4.6], P = .60).” (T. Schepers, t.schepers@amc.nl)
Deaths From Low-Level Air Pollution: Commenting on a study of U.S. Medicare beneficiaries linking poor air quality with increased mortality (pp. 2446–56; J. D. Schwartz, jschwrtz@hsph.harvard.edu), an editorialist makes these observations (pp. 2431–2). “[These] findings … may have implications for forecasting and personal monitoring of exposure to [particulate matter (PM2.5)] and ozone, which could allow individuals at increased risk to reduce or mitigate their exposure. The study showed that when PM2.5 or ozone concentration was higher on a particular day, more deaths occurred 2 days later. Predictions of pollutant concentrations for the next few days, such as weather forecasting, can be made readily available to the public. (For example, this has already been done in China.) Individuals can be advised to minimize their outdoor activities when outdoor pollutant levels are projected to be higher. However, staying indoors may be more helpful in avoiding exposure to ozone than to PM2.5 because less than 30% of ambient ozone penetrates indoor spaces when windows and doors are closed, whereas more than 80% of PM2.5 enters the indoor space in the absence of an air cleaning device such as central or room filtration.” (J. Zhang, junfeng.zhang@duke.edu)
>>>PNN NewsWatch
* FDA has approved ertugliflozin (Steglatro) tablets, an oral sodium-glucose cotransporter 2 inhibitor, and the fixed-dose combination ertugliflozin and sitagliptin (Steglujan) tablets, Merck has announced. Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The combination product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both ertugliflozin and sitagliptin is appropriate. The two products are not recommended in type 1 diabetes or diabetic ketoacidosis.

PNN Pharmacotherapy Line
Dec. 28, 2017 * Vol. 24, No. 247
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Dec. 28 issue of the New England Journal of Medicine (2017; 377).
Better-Quality Compounded Drugs: Five years after drug compounding problems killed at least 64 people, FDA provides an update on its activities related to enforcement of the Drug Quality and Security Act (pp. 2509–12). “Since the 2012 meningitis outbreak, the agency has conducted more than 425 inspections of compounding pharmacies,” authors write. “We have observed problematic conditions during the vast majority of these inspections and have overseen more than 140 recalls of compounded drugs.… Examples of observations include dead insects in compounding areas designated for sterile processing, visible mold on ceiling tiles in compounding rooms, and dog beds and dog hairs in close proximity to compounding areas.” (J. Woodcock)
Emergency Legal Authority & the Opioid Crisis: Reviewing the types of emergency legal authority available to respond to the opioid crisis at state and federal levels, Perspective authors conclude, “Although opioid-related morbidity and mortality present a public health challenge different from those in previously declared emergencies, the same underlying principles apply, including the need for due process, ongoing review, and other legal safeguards for vulnerable groups” (pp. 2512–4). They provide these details: “In 2014, shortly after the Food and Drug Administration approved Zohydro, an extended-release opioid, Massachusetts declared the first opioid-related emergency. Virginia followed in 2016. In 2017, Alaska, Arizona, Florida, and Maryland issued emergency declarations, with Alaska and Maryland explicitly citing concerns about synthetic opioids such as fentanyl.
“Five of the six declarations seek to improve access to the opioid antagonist naloxone, either through education and training (e.g., teaching law-enforcement officers to administer it) or through a standing order to allow pharmacists to dispense it without an individual prescription. The Arizona and Massachusetts declarations explicitly address opioid-prescribing practices, through the development of prescribing guidelines, regulations, or requirements for [prescription drug monitoring program] use.” (L. Rutkow)
CAR T Cells in Refractory B-Cell Lymphomas: Two studies published in this issue (pp. 2531–44, S. S. Neelapu, sneelapu@mdanderson.orgpp. 2545–54, S. J. Schuster, stephen.schuster@uphs.upenn.edu) “validate the efficacy of CD19-targeted [chimeric antigen receptor (CAR)] T-cell therapy” in patients with diffuse large B-cell lymphoma or follicular lymphoma that had relapsed or was refractory to previous treatments, editorialists write (pp. 2593–6). “CAR-engineered T cells are a revolutionary treatment for patients with advanced blood cancers,” the authors conclude. “Unfortunately, CAR-engineered T cells have been largely ineffective in patients with metastatic solid cancers, which account for the majority of cancer-related deaths. One major factor contributing to this lack of efficacy is the paucity of suitable cell-surface molecules that are expressed by solid cancers for CARs to target. This roadblock can be overcome by engineering T cells with T-cell receptors that can recognize tumor-specific antigens derived from intracellular proteins, such as neoantigens arising as a consequence of somatic mutations expressed by tumors, which are found in the majority of patients with metastatic epithelial cancers. T cells that are genetically modified to express T-cell receptors targeting mutated neoantigens may represent a new wave of promising and highly personalized gene-engineered T-cell therapies for patients with metastatic solid cancers.” (E. Tran)
Health Professionals & Law Enforcement: “A test of moral courage may arise for any health care professional with little warning, as it did in Utah” for the nurse arrested aggressively by police earlier this year, writes a Perspective author (pp. 2515–7). “Alex Wubbels is an exemplar of the clinician who, in the face of extreme pressure to do otherwise, adhered to her professional ethical principles.” (A. R. Derse)
>>>PNN NewsWatch
AuroMedics Pharma is voluntarily recalling one lot of linezolid injection 600 mg/300 mL flexible bags, NDC 55150–242–51, batch CLZ160007, expiration August 2018, to the hospital level because of white particulate matter identified as mold.

PNN Pharmacotherapy Line
Dec. 29, 2017 * Vol. 24, No. 248
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>The News You Liked in 2017
With PNN’s switch to an HTML format in the spring of this year, data on open and click rates became available. It’s been interesting to learn more about how subscribers use Pharmacy’s Daily Newspaper. Mondays are very popular, but the open rates often go down as the week wears on. Click rates are often high for articles listed in the PNN JournalWatch column, where only the title is listed. 
If you were one of the few who didn’t open the issues with the below articles, or didn’t click on these pearls, here is your lucky second chance. Enjoy and have a great start to the New Year!
Your Brain on Drugs
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The President’s Commission Combating Drug Addiction and the Opioid Crisis
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FDA Requests Removal of Opana ER for Risks Related to Abuse
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Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review, in Pediatrics, 2017; 139: 10.1542/peds.2016-4131.
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Benzodiazepines and Risk of All Cause Mortality in Adults: Cohort Study, in BMJ, 2017; 358: j2941. 
Your Brain on Booze
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Moderate Alcohol Consumption as Risk Factor for Adverse Brain Outcomes and Cognitive Decline: Longitudinal Cohort Study, in BMJ, 2017; 357 j2353.
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Alcohol and Cancer: A Statement of the American Society of Clinical Oncology, in Journal of Clinical Oncology, 2018; 36: 83–93.
Care for Older Adults
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Recent Literature Update on Medication Risk in Older Adults, 2015–2016, in Journal of the American Geriatrics Society, 2017; 65: 1401–5.
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Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care, in Journal of the American Geriatrics Society, 2017; 65: 1578–85.
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Polypharmacy in the Elderly—When Good Drugs Lead to Bad Outcomes: A Teachable Moment, in JAMA Internal Medicine, 2017; 177: 871.
Guidelines & Stewardship
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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.
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Antibiotic Stewardship in Small Hospitals: Barriers and Potential Solutions, in Clinical Infectious Diseases, 2017; 65: 691–6.
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Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults, in JAMA, 2017; 318: 2132–4.
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2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis, in Arthritis & Rheumatology, 2017; 69: 1521–37.
Timely Topics
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Gastrointestinal Safety of Celecoxib Versus Naproxen in Patients With Cardiothrombotic Diseases and Arthritis After Upper Gastrointestinal Bleeding (CONCERN), in Lancet, 2017; 389: 2375–82.
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Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review, in Annals of Internal Medicine, 2017; 167: 256–67.
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Risk of Major Congenital Malformations in Relation to Maternal Overweight and Obesity Severity: Cohort Study of 1.2 Million Singletons, in BMJ, 2017; 357: j2563.
New Drugs 
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FDA Approves a New Vaccine for Shingles That Provides Broad Protection
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FDA Approves Vosevi for Hepatitis C
What Other Pharmacists Want to Know
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ASHP House of Delegates Agenda
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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.
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CDC Yellow Book
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Medication Reconciliation vs Medication Review, in JAMA, 2017; 318: 965–6.
Lagniappe
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The Evolution of the Use of Beta-Blockers to Treat Heart Failure: A Conversation With Finn Waagstein, MD, in Circulation, 2017; 136: 889–93.
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Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock, in Chest, 2017; 151: 1229–38.
>>>PNN NewsWatch
*
FDA yesterday permitted the marketing of the Dermapace System, a medical device for treatment of chronic, full-thickness diabetic foot ulcers with wound areas measuring no larger than 16 cm2 (about the size of a soda can top) and extending through the epidermis, dermis, tendon, or capsule, but without bone exposure. The Dermapace System is an extracorporeal shock wave system that uses pulses of energy to mechanically stimulate the wound. The device is intended for adult patients (22 years or older), presenting with diabetic foot ulcers lasting for more than 30 days, and should be used along with standard diabetic ulcer care.
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PNN will not be published on Mon., Jan. 1, New Year’s Day.

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