PNN January–March 2019

PNN Pharmacotherapy Line
Jan. 2, 2019 * Vol. 26, No. 1
Providing news and information about medications and their proper use

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>>>Internal Medicine Highlights
Source:
 Jan. 1 issue of Annals of Internal Medicine (2019; 170).
Statins for Primary Prevention of Cardiovascular Disease: In a quantitative benefit–harm balance modeling study, statins were shown to provide net benefits at higher 10-year risks for cardiovascular disease (CVD) than are reflected in most current guidelines but with differing results for subpopulations, researchers report (pp. 1–10; (M. A. Puhan, miloalan.puhan@uzh.ch).
PICO: Persons aged 40–75 years with no history of CVD; low- or moderate-dose statin versus no statin; 10-year risk for CVD at which statins provide at least a 60% probability of net benefit, with baseline risk, frequencies of and preferences for statin benefits and harms, and competing risk for non-CVD death taken into account. 
Results: “Younger men had net benefit at a lower 10-year risk for CVD than older men (14% for ages 40 to 44 years vs. 21% for ages 70 to 75 years). In women, the risk required for net benefit was higher (17% for ages 40 to 44 years vs. 22% for ages 70 to 75 years). Atorvastatin and rosuvastatin provided net benefit at lower 10-year risks than simvastatin and pravastatin.” Sensitivity analysis showed that most alternative assumptions led to similar findings.
Editorial: “The aggregated clinical trial evidence on statins for primary prevention is finite, so when the same studies lead to 3 different conclusions, which is correct?” editorialists ask in analyzing these results (pp. 62–3; J. S. Ross, joseph.ross@yale.edu). “Perhaps only the patient can say. As others have shown, the CVD risk threshold for initiation of statin therapy for primary prevention is sensitive to patient preferences, including the burden of taking a pill daily. Some patients may favor a risk-averse approach in which harms associated with therapy are given greater weight than potential benefits, but others may prefer to give greater weight to potential benefits. The onus is on physicians to fairly summarize the evidence and guide patients through the decision-making process. [This work] can support that decision making, particularly for older adults or those who are more concerned about harms of treatment. Indeed, primary prevention of CVD must be patient-centered, because healthy patients are asked to assume risk, benefits are experienced only as the absence of disease, and uncertainty lurks beneath every choice.”
Atrial Fibrillation in Patients With Heart Failure: Results from six randomized controlled trials of 775 patients with atrial fibrillation (AF) and heart failure (HF) show that “catheter ablation was superior to conventional drug therapy in improving all-cause mortality, HF hospitalizations, [clinical outcomes], and quality of life, with no statistically significant increase in serious adverse events” (pp. 41–50; V. Y. Reddy, vivek.reddy@mountsinai.org). 
PICO: Adults with AF and HF; randomized controlled trials published in English with at least 6 months of follow-up; comparisons of clinical outcomes of catheter ablation versus drug therapy. 
Results: “Compared with drug therapy, AF ablation reduced all-cause mortality (9.0% vs. 17.6%; risk ratio [RR], 0.52 [95% CI, 0.33 to 0.81]) and HF hospitalizations (16.4% vs. 27.6%; RR, 0.60 [CI, 0.39 to 0.93]). Ablation improved left ventricular ejection fraction (mean difference, 6.95% [CI, 3.0% to 10.9%]), 6-minute walk test distance (mean difference, 20.93 m [CI, 5.91 to 35.95 m]), peak oxygen consumption (mean difference, 3.17 mL/kg per minute [CI, 1.26 to 5.07 mL/kg per minute]), and quality of life (mean difference in Minnesota Living with Heart Failure Questionnaire score, −9.02 points [CI, −19.75 to 1.71 points]). Serious adverse events were more common in the ablation groups, although differences between the ablation and drug therapy groups were not statistically significant (7.2% vs. 3.8%; RR, 1.68 [CI, 0.58 to 4.85]).”
>>>PNN JournalWatch
* Thinking About Schizophrenia in an Era of Genomic Medicine, in American Journal of Psychiatry2019; 176: 12–20. (D. R. Weinberger)
* Impulse Control Disorders in Parkinson’s Disease, in 
American Journal of Psychiatry2019; 176: 5–11. (D. Weintraub)
* Clinical Practice Guidelines for Quality Palliative Care, in 
Pediatrics2019; 143: 10.1542/peds.2018-3310. (American Academy of Pediatrics)

PNN Pharmacotherapy Line
Jan. 3, 2019 * Vol. 26, No. 2
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Jan. 3 issue of the New England Journal of Medicine (2019; 380).
Icosapent Ethyl for Hypertriglyceridemia: The highly purified eicosapentaenoic acid ethyl ester icosapent ethyl lowered patients’ risk of cardiovascular events, including death, in the placebo-controlled, phase 3b Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) (pp. 11–22; D. L. Bhatt, dlbhattmd@post.harvard.edu).
PICO: Patients (n = 8,179) with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had fasting triglyceride levels of 135–499 mg/dL and LDL levels of 41–100 mg/dL; icosapent ethyl 2 g twice daily (total daily dose, 4 g) or placebo; primary end point of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina; key secondary end point of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
Results: “A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P <0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P <0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P = 0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P = 0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P = 0.06).”
Editorial: “After a parade of failed cardiovascular outcome trials of fish oils, REDUCE-IT has shown a substantial benefit with respect to major adverse cardiovascular events,” editorialists write (pp. 89–90; J. J. P. Kastelein). “More data are needed to confirm these effects and to inform an understanding of the mechanism of action, the uniqueness of the compound tested, and the potential influence of mineral oil as the comparator. However, the finding that the risks of several cardiovascular outcomes were significantly and consistently lower with icosapent ethyl than with placebo make us hopeful that the use of icosapent ethyl can substantially improve cardiovascular health in patients with statin-controlled LDL cholesterol levels who have elevated triglyceride levels.”
Supplements for Prevention of Cancer, Heart Disease: Commenting on negative studies of marine n-3 (omega-3) fatty acids (pp. 23–32; J. E. Manson, jmanson@rics.bwh.harvard.edu) and vitamin D (pp. 33–44; J. E. Manson, jmanson@rics.bwh.harvard.edu), editorialists conclude, “Despite the negative findings regarding the primary end points in VITAL, the secondary end points will undoubtedly draw attention. It will be tempting to note the lower incidence of myocardial infarction and of death from myocardial infarction with n−3 fatty acids than with placebo and the lower mortality from cancer with vitamin D than with placebo and then to cite these findings as evidence that these supplements can benefit some patients in preventing coronary heart disease or cancer death” (pp. 91–3; J. F. Keaney, Jr.). “However, these ‘positive’ results need to be interpreted with caution.… The medical literature is replete with exciting secondary end points that have failed when they were subsequently formally tested as primary end points in adequately powered randomized trials. Thus, in the absence of additional compelling data, it is prudent to conclude that the strategy of dietary supplementation with either n−3 fatty acids or vitamin D as protection against cardiovascular events or cancer suffers from deteriorating VITAL signs.”
Other Articles: Tisagenlecleucel produces high rates of durable responses in adults with relapsed or refractory diffuse large B-cell lymphoma (pp. 45–56); RNA-targeting oligonucleotides could play important roles in regulating gene expression and RNA splicing in health and disease, according to a review article (pp. 57–70); authors discuss opioid use, overdose, and suicide (pp. 71–9) and “opioids in the shadow of the HIV epidemic” (pp. 1–3).

PNN Pharmacotherapy Line
Jan. 4, 2019 * Vol. 26, No. 3
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
 Jan. issue of Pediatrics (2019; 143).
Neonatal Head Circumference & Antenatal Opioid Use: Neonates exposed in utero to opioids, including medication-assisted treatment for opioid use disorder, and treated for neonatal abstinence syndrome (NAS) had significantly smaller head circumferences at birth, according to a prospective cohort study from 2014 to 2016 (10.1542/peds.2018-0541; C. V. Towers)
PICO: 429 newborns treated for NAS and delivered from well-dated pregnancies ≥34 weeks’ gestation and 429 nonopioid-exposed newborns matched for race, parity, mode of delivery, and gestational age. Outcome was an increase in the proportion of newborns with HCs at or below the 10th percentile from 10% in controls to a minimum of 20% in NAS newborns with 90% power.
Results: “Mean HC for cases was 33.04 cm (± 1.9 cm) compared with 33.99 cm (± 2.0 cm) for controls (P < .0001). Among the 429 NAS cases, the mothers of 372 (87%) were on opioid medication-assisted treatment. For NAS cases, 30.1% (95% confidence interval: 25.8%–34.7%) had an HC less than or equal to the 10th percentile (129 of 429 neonates), and 8.2% (95% confidence interval: 5.8%–11.2%) had an HC less than or equal to the third percentile (35 of 429 neonates). Multivariate analysis was used and determined that only chronic opioid use during gestation resulting in a neonate who was NAS treated was a significant risk factor for the observed smaller HC.”
Editorial: “The number of newborns with NAS has exploded because the rate of this condition has risen fivefold since 2000,” editorialists write (10.1542/peds.2018-3376; M. L. Hudak). “In some states, >30 infants per 1,000 live births develop NAS, effectively transforming some [neonatal intensive care units] into NAS wards.”
>>>Psychiatry Highlights
Source:
 Jan. issue of the American Journal of Psychiatry (2019; 176).
Schizophrenia Polygenic Risk Score & Antipsychotic Efficacy: Higher polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) are associated with lower efficacy of antipsychotics, researchers report, indicating potential utility of these scores as prognostic biomarkers (pp. 21–8; J-P Zhang).
PICO: Four independent cohorts of participants having first-episode psychosis (n = 150) whose genotypes were determined using standard single-nucleotide polymorphism arrays imputed to the 1000 Genomes Project reference panel. Symptoms were measured with total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout.
Results: “In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r = 0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples).”
>>>PNN NewsWatch
Torrent Pharmaceuticals is expanding its voluntary recall from 2 lots of Losartan Potassium tablets USP to a total of 10 lots to the consumer level because of amounts of N-nitrosodiethylamine above the acceptable daily intake levels released by FDA.
* Use of black tar heroin is likely an underrecognized cause of 
wound botulism, a condition that is treatable with heptavalent botulism antitoxin (BAT), according to an article in this week’s MMWR. The condition “is likely underrecognized because of its rarity and the overlapping signs and symptoms with opioid intoxication, overdose, and other neurologic syndromes including Guillain-Barré syndrome, the Miller Fisher variant of Guillain-Barré syndrome, and myasthenia gravis,” the authors write. “Prompt diagnosis, administration of BAT, and provision of supportive care can help stop the progression of paralysis and be lifesaving.”

PNN Pharmacotherapy Line
Jan. 7, 2019 * Vol. 26, No. 4
Providing news and information about medications and their proper use

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>>>Lancet Report
Source:
 Jan. 5 issue of Lancet (2019; 393).
SGLT2 Inhibitors & Cardiovascular/Renal Outcomes: Patients with type 2 diabetes benefit from use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for both primary and secondary prevention of cardiovascular and renal outcomes, a study shows (pp. 31–9; M. S. Sabatine, msabatine@bwh.harvard.edu).
PICO: Systematic review and meta-analysis of three randomized, placebo-controlled, cardiovascular outcome trials of SGLT2i in 34,322 patients with type 2 diabetes; efficacy outcomes for major adverse cardiovascular events, cardiovascular death or hospitalizations for heart failure, or progression of renal failures; hazard ratios pooled across trials.
Results: “SGLT2i reduced major adverse cardiovascular events by 11% (HR 0.89 [95% CI 0.83–0.96], p = 0.0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0.86 [0.80–0.93]) and not in those without (1.00 [0.87–1.16], p for interaction = 0.0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0.77 [0.71–0.84], p <0.0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0.55 [0.48–0.64], p <0.0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction = 0.0073) and lesser reductions in progression of renal disease (p for interaction = 0.0258) in patients with more severe kidney disease at baseline.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
CRP & Lung Cancer: In former or current smokers, elevated levels of circulating high-sensitivity C reactive protein (hsCRP) were predictive of lung cancer in cohort studies, report researchers who conclude that the marker has value as a prediagnostic indicator of lung cancer risk but not a causal factor (k4981; D. C. Muller, david.muller@imperial.ac.uk). 
PICO: 20 population-based cohort studies on four continents of 5,299 patients with incident lung cancer; tested for circulating hsCRP concentrations in prediagnostic serum/plasma samples; outcome of incident lung cancer diagnosis by smoking status (never, former, and current smokers), and histological subtype.
Results: “A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P <0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.”
>>>PNN NewsWatch
Lupin Pharmaceuticals is recalling numerous lots of Ceftriaxone for Injection, USP, to the hospital/physician level because of visual gray particulate matter resulting from improper piercing of vials and use of needles larger than 21 gauge during reconstitution.
>>>PNN JournalWatch
* Clinically Diagnosing Pertussis-Associated Cough in Adults and Children: CHEST Guideline and Expert Panel Report, in Chest2019; 155: 147–54. (A. Moore, abigail.moore@phc.ox.ac.uk)
* Adult Outpatients With Acute Cough Due to Suspected Pneumonia or Influenza: CHEST Guideline and Expert Panel Report, in 
Chest2019; 155: 155–67. (A. T. Hill, adam.hill318@nhs.net)
* Trends in Outpatient Antibiotic Use in 3 Health Plans, in 
Pediatrics2019; 143: 10.1542/peds.2018-1259. (J. A. Finkelstein)

PNN Pharmacotherapy Line
Jan. 8, 2019 * Vol. 26, No. 5
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from and Jan. issue of JAMA Internal Medicine (2019; 179).
Prescribed Opioids & Community-Acquired Pneumonia: In patients with and without HIV, prescribed opioids are associated with increased risk of community-acquired pneumonia (CAP), researchers report, with the relationship particularly strong for higher doses of opioids and those agents that are immunosuppressive (10.1001/jamainternmed.2018.6101; E. J. Edelman, ejennifer.edelman@yale.edu)
PICO: A nested case–control study of patients in the Veterans Aging Cohort Study (VACS) in 2000–12 who received care in U.S. Veterans Health Administration (VA) medical centers; 4,246 patients hospitalized for CAP were matched 1:5 with 21,146 control individuals without CAP and stratified by HIV status.
Results: “Among the 25,392 VACS participants (98.9% male; mean [SD] age, 55 [10] years), current medium doses of opioids with unknown or no immunosuppressive properties (adjusted odds ratio [AOR], 1.35; 95% CI, 1.13–1.62) and immunosuppressive properties (AOR, 2.07; 95% CI, 1.50–2.86) and current high doses of opioids with unknown or no immunosuppressive properties (AOR, 2.07; 95% CI, 1.50–2.86) and immunosuppressive properties (AOR, 3.18; 95% CI, 2.44–4.14) were associated with the greatest CAP risk compared with no prescribed opioids or any past prescribed opioid with no immunosuppressive (AOR, 1.24; 95% CI, 1.09–1.40) and immunosuppressive properties (AOR, 1.42; 95% CI, 1.21–1.67), especially with current receipt of immunosuppressive opioids. In stratified analyses, CAP risk was consistently greater among people living with HIV with current prescribed opioids, especially when prescribed immunosuppressive opioids (eg, AORs for current immunosuppressive opioids with medium dose, 1.76 [95% CI, 1.20–2.57] vs 2.33 [95% CI, 1.60–3.40]).”
Off-Label Use of Combined Dextromethorphan/Quinidine: The combination product of dextromethorphan hydrobromide and quinidine sulfate — approved by FDA for treatment of pseudobulbar affect and studied in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) — is more often being used in practice in patients with dementia and/or Parkinson disease (PD), a study shows (10.1001/jamainternmed.2018.6112; A. Kesselheim, akesselheim@bwh.harvard.edu).
PICO: Population-based cohort study of 12,858 patients prescribed dextromethorphan-quinidine in 2 commercial insurance databases, with the Medicare Part D Prescription Drug Program data set used to evaluate numbers of prescriptions and total reported CMS spending in Dec. 2017 through Aug. 1, 2018.
Results: “Mean (SD) age was 66.0 (18.5) years, 66.7% were women, and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased 15.3-fold, from 3,296 in 2011 to 50,402 in 2016. Reported spending by Centers for Medicare & Medicaid Services on this medication increased from $3.9 million in 2011 to $200.4 million in 2016.”
Diabetic Benefits of Nutrition Assistance: By increasing medication adherence, participation in the Supplemental Nutrition Assistance Program (SNAP) may improve health outcomes in low-income Americans with diabetes, a study shows (pp. 63–70; J. A. Pooler, jennifer.pooler@outlook.com).
PICO: Repeated cross-sectional, population-based study of 1,302 older adults with diabetes or borderline diabetes who self-reported SNAP benefits and participated in the National Health Interview Survey from 2013 through 2016.
Results: “Participants in SNAP had a moderate decrease in cost-related medication nonadherence compared with eligible nonparticipants (5.3 percentage point reduction; 95% CI, 0.5–10.0 percentage point reduction; P = .03). Similar reductions were observed for subgroups that had prescription drug coverage (5.8 percentage point reduction; 95% CI, 0.6–11.0) and less than $500 in out-of-pocket medical costs in the previous year (6.4 percentage point reduction; 95% CI, 0.8–11.9), but not for older adults lacking prescription coverage or those with higher medical costs. Results remained robust to several sensitivity analyses.”

PNN Pharmacotherapy Line
Jan. 9, 2019 * Vol. 26, No. 6
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Jan. 1/8 issue of JAMA (2019; 321).
Post-MI MACE & P2Y12 Inhibitor Copayment Vouchers: While major adverse cardiovascular events (MACE) remained unchanged in patients in the year following myocardial infarction (MI), provision of vouchers to offset medication copayments for higher-potency P2Y12 inhibitors produced a 3.3% absolute increase in patient-reported persistence with therapy, researchers report (pp. 44–55; T. Y. Wang, tracy.wang@duke.edu).
PICO: Cluster-randomized clinical trial conducted at 301 hospitals where adult patients were enrolled in 2015–16; randomized to copayment vouchers for clopidogrel or ticagrelor for 1 year or usual care; coprimary outcomes were persistence with P2Y12 inhibitor therapy and MACE (death, recurrent MI, stroke) at 1 year.
Results: “Among 11,001 enrolled patients (median age, 62 years; 3,459 [31%] women), 10,102 patients were discharged with prescriptions for clopidogrel or ticagrelor (clopidogrel prescribed to 2,317 [36.0%] in the intervention group and 2497 [54.7%] in the usual care group), 4,393 of 6,135 patients (72%) in the intervention group used the voucher, and follow-up data at 1 year were available for 10,802 patients (98.2%). Patient-reported persistence with P2Y12 inhibitors at 1 year was higher in the intervention group than in the control group (unadjusted rates, 5,340/6,135 [87.0%] vs 3,324/3,967 [83.8%], respectively; P < .001; adjusted difference, 2.3% [95% CI, 0.4% to 4.1%]; adjusted odds ratio, 1.19 [95% CI, 1.02 to 1.40]). There was no significant difference in MACE at 1 year between intervention and usual care groups (unadjusted cumulative incidence, 10.2% vs 10.6%; P = .65; adjusted difference, 0.66% [95% CI, −0.73% to 2.06%]; adjusted hazard ratio, 1.07 [95% CI, 0.93 to 1.25]).”
Editorial: “Given that the co-payment voucher in the ARTEMIS trial (with cost of up to $1,600/patient per year) did not improve outcomes despite modestly improving adherence, eliminating co-pays alone may not be sufficient to improve adherence,” editorialists conclude (pp. 37–9; C. A. Jackevicius, cjackevicius@westernu.edu). “Perhaps combined with other interventions, especially those that also are directed toward patients who may need the voucher most but who had not activated the intervention in this trial (ie, those who were female, nonwhite, had lower income, or had more comorbidities), co-payment vouchers may prove effective, but this remains to be tested. Based on lessons from ARTEMIS and other recent medication adherence trials, key areas of research that need further development include improved ability to target patients at risk of nonadherence, ‘diagnose’ the patient’s individualized nonadherence type, and design and implement multipronged targeted interventions.”
Linagliptin & MACE in Type 2 Diabetes, CV/Renal Disease: Compared with placebo in the CARMELINA noninferiority trial of patients with type 2 diabetes, renal disease, and high risk of cardiovascular (CV) events, linagliptin failed to improve a primary outcome or protect against advances in renal disease (pp. 69–79; J. Rosenstock, julio.rosenstock@dallasdiabetes.com).
PICO: 6,979 patients in 27 countries with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk, and high renal risk; randomized to linagliptin 5 mg once daily or placebo added to usual care; primary outcome of time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke.
Results: “During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3,494 (12.4%) and 420 of 3,485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, −0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3,494 (9.4%) and 306 of 3,485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, −0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2,697 (77.2%) and 2,723 (78.1%) patients in the linagliptin and placebo groups; 1,036 (29.7%) and 1,024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.”

PNN Pharmacotherapy Line
Jan. 10, 2019 * Vol. 26, No. 7
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Jan. 10 issue of the New England Journal of Medicine (2019; 380).
Hydroxyurea for Pediatric Sickle Cell Anemia: In children in sub-Saharan Africa who had sickle cell anemia, “hydroxyurea treatment was feasible and safe,” researchers report based on reduced incidence of vaso-occlusive events, infections, malaria, transfusions, and death (pp. 121–31; R. E. Ware, russell.ware@cchmc.org).
PICO: Children aged 1–10 years with sickle cell anemia in four sub-Saharan countries; hydroxyurea 15–20 mg/kg/d for 6 months, followed by dose escalation; end points of feasibility (enrollment, retention, adherence), safety (dose levels, toxic effects, malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, survival).
Results: “Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient–years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient–years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient–years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient–years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient–years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient–years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).”
Editorial: “Patients with sickle cell disease in Africa ought to have access to the most advanced methods of intervention, but this should go hand in hand with the availability of hydroxyurea therapy on a wide scale,” editorialists write (pp. 187–8; L. Luzzatto). “To this end, a major limiting factor has been affordability. Today in a pharmacy in Tanzania, the mean price for a typical daily dose of hydroxyurea is approximately $1.20 — not a small sum, if you need it every day for a lifetime. Free health care for all is a desirable goal. Until it is attained, we need to explore new avenues for reducing prices and to do so now — for instance, local compounding of galenic hydroxyurea by qualified pharmacies or production of the drug by the local pharmaceutical industry.”
Acute Infection & Myocardial Infarction: Short- and long-term risks of myocardial infarction following acute infections are discussed in a review article (pp. 171–6; D. M. Musher, daniel.musher@va.gov).
PICO: Narrative review of 43 published articles.
Results: “Whether statins and drugs that inhibit platelet activation offer a benefit to all patients with acute infection — even those who do not have known clinical indications for these treatments — is an issue worthy of clinical investigation.… Because the risk of other cardiovascular events — such as heart failure, arrhythmias, and strokes — also increases after acute infection, the mechanisms that account for these associations need to be characterized. This is especially important in the case of heart failure, because after pneumonia the risk of worsening heart failure is even higher than the risk of myocardial infarction. An integrated understanding of the interplay between acute infections and the cardiovascular system should facilitate efforts to reduce the risk of myocardial infarction and other cardiovascular events after acute infections.”
>>>PNN NewsWatch
* With about 40% of FDA staff on furlough because of the federal government shutdown, drug approvals are in limbo and the agency is unable to receive new drug applications. Recalls continue as mission-critical activities. Sun Pharmaceutical is voluntarily recalling four lots of lyophilized Vecuronium Bromide for Injection 10 and 20 mg to the hospital level because of presence of glass particulate matter. Happy Together voluntarily recalled all lots within expiry of the Rhino 5k capsules to the consumer level after FDA analysis found these products tainted with sildenafil and tadalafil.

PNN Pharmacotherapy Line
Jan. 11, 2019 * Vol. 26, No. 8
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Chest Highlights
Source:
 Jan. issue of Chest (2019; 155).
Influenza Vaccination & Severe Outcomes in COPD: In patients with COPD, influenza vaccination significantly reduced influenza-related hospitalizations and related complications, a study shows (pp. 69–78; S. Mulpuru, smulpuru@toh.ca).
PICO: National, prospective, multicenter cohort study of 4,198 patients with COPD hospitalized with any acute respiratory illness or exacerbation in 2011–15; outcome was influenza-related hospitalization.
Results: “The adjusted analysis showed a 38% reduction in influenza-related hospitalizations in vaccinated vs unvaccinated individuals. Influenza-positive patients (n = 1,833 [38.5%]) experienced higher crude mortality (9.7% vs 7.9%; P = .047) and critical illness (17.2% vs 12.1%; P < .001) compared with influenza-negative patients.…”
GERD & Idiopathic Pulmonary Fibrosis: The link between gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remains controversial, authors write, and a new meta-analysis indicates the conditions may be related but the association is confounded by smoking (pp. 33–43; Y. Lacasse, yves.lacasse@fmed.ulaval.ca).
PICO: Meta-analysis of 18 case–control studies of 3,206 patients with IPF and 9,368 control participants; confidence in the estimate of association is low because only case–control studies were used in the calculation.
Results: “The meta-analysis indicated that GERD is associated with IPF (OR, 2.94 [95% CI, 1.95–4.42]; P homogeneity < .0001). Overall, the results remained consistent whatever the data source (clinical studies vs databases) or the type of control subject (healthy volunteers, patients with respiratory diseases other than interstitial lung disease, or patients with non-IPF interstitial lung disease). In a meta-regression, after controlling for smoking, GERD and IPF were not related.”
Editorial: “[This study has] demonstrated how misunderstanding the relationship between GERD and IPF (spurious and indirect) has propagated misunderstanding and overtreatment with PPIs,” (pp. 5–6; P. J. Kahrilas, p-kahrilas@northwestern.edu). “Magnify this by analogy to the numerous other syndromes ‘associated’ with GERD and no wonder that an estimated 8% to 9% of the US adult population is using PPIs. Thoughtful utilization of PPIs has revolutionized the treatment of acid-related disorders, but indiscriminate use has only exposed the population to unopposed risk. Indeed, lack of statistical literacy and the proliferation/acceptance of flawed studies of risk and benefit have overwhelmed proper critical analysis of PPI treatment.”
De-escalating Therapy for MRSA in Culture-Negative Nosocomial Pneumonia: In culture-negative nosocomial pneumonia, de-escalation (DE) from broad-spectrum empirical antimicrobials to narrower-spectrum agents produced similar mortality rates, shorter lengths of stay (LOS), and a lower incidence of acute kidney injury (AKI), researchers report (pp. 53–9; S. T. Micek, scott.micek@stlcop.edu).
PICO: Retrospective cohort study of 279 adult patients in intensive care units (ICUs) in 2012–17 with nosocomial pneumonia and a negative respiratory culture; DE was defined as anti-MRSA agent discontinuation within 4 days of initiation.
Results: “Patients who were not de-escalated [NDE] received 5 more days of MRSA coverage than patients who were de-escalated; however, there was no difference in 28-day mortality (NDE group, 28% vs DE group, 23%; difference, −5.5%; 95% CI, −16.1 to 6.5). Patients who were de-escalated had shorter hospital (DE group, 15 days vs NDE group, 20 days; difference, 3.2 days; 95% CI, 0.1-6.4) and ICU (DE group, 10 days vs NDE group, 13 days; difference, 2.2 days; 95% CI, −0.3 to 4.9) LOSs after the index date. The incidence of AKI was significantly higher in patients who were not de-escalated (DE group, 36% vs NDE group, 50%; difference, −13.8%; 95% CI, −26.9 to −0.4).”
>>>PNN NewsWatch
Drug overdose deaths among American women aged 30–64 years increased by 260% in the 1999–2017 time period, the CDC reports in this week’s MMWR (2019; 68: 1–5; ; K. A. Mack, kmack@cdc.gov). Mortality from drug overdoses increased for all drug classes, with deaths from prescription opioids climbing steadily and synthetic opioids spiking in 2015 and beyond.

PNN Pharmacotherapy Line
Jan. 14, 2019 * Vol. 26, No. 9
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Jan. 12 issue of Lancet (2019; 393).
Two-Drug Antiretroviral Regimen: As initial antiretroviral therapy (ART) in patients with HIV, dolutegravir plus lamivudine proved noninferior to a guideline-recommended three-drug regimen at 48 weeks, GEMINI-1 and -2 investigators conclude, supporting its use in ART-naive adults (pp. 143–55; J. Sievers, jorg.x.sievers@viivhealthcare.com).
PICO: 1,441 adults participating in two identical multicenter phase 3 trials who had HIV-1 infection and screening HIV-1 RNA of ≤500,000 copies/mL and who were naive to ART; once-daily dolutegravir 50 mg plus lamivudine 300 mg or once-daily dolutegravir 50 mg plus tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg; proportion of participants with HIV-1 RNA of <50 copies/mL at week 48 in the intention-to-treat-exposed population, using noninferiority margin of −10%.
Results: “At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
HRT & Venous Thromboembolism Risk: While underused, transdermal hormone-replacement therapy appears to be safer than oral preparations, studies show (k4810; Y. Vinogradova, Yana.Vinogradova@nottingham.ac.uk).
PICO: Two nested case–control studies of 80,936 women aged 40–79 years with primary diagnosis of venous thromboembolism in 1998–2017 and 391,494 matched control women in the the QResearch or Clinical Practice Research Datalink (CPRD) databases.
Results: “Overall, 5,795 (7.2%) women who had venous thromboembolism and 21,670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4,915 (85%) and 16,938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).”
>>>PNN JournalWatch
* Long-Term Mortality and Early Valve Dysfunction According to Anticoagulation Use: The FRANCE TAVI Registry, in Journal of the American College of Cardiology2019; 73: 10.1016/j.jacc.2018.08.1045. (P. Overtchouk)
* New Concepts in Sudden Cardiac Arrest to Address an Intractable Epidemic: 
JACC State-of-the-Art Review, in Journal of the American College of Cardiology2019; 73: 10.1016/j.jacc.2018.09.083. (S. M. Narayan)
* Refining Prediction of Atrial Fibrillation–Related Stroke Using the P
2-CHA2DS2-VASc Score, in Circulation2019; 139: 180–91. (A. Maheshwari, ankit.maheshwari@uphs.upenn.edu)

PNN Pharmacotherapy Line
Jan. 15, 2019 * Vol. 26, No. 10
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from and Jan. 15 issue of Annals of Internal Medicine (2019; 170).
Mental Illness & Hospitalization in Young-Onset Type 2 Diabetes: Mental health is an important aspect of care in young adults with young-onset type 2 diabetes (T2D) (YOD), according to authors who found excess hospitalizations across the lifespans of those with this condition (10.7326/M18-1900; J. C. N. Chan, jchan@cuhk.edu.hk).
PICO: Population-based (n = 422,908) and registry-based (n = 20,866) adults aged 20–75 years in Hong Kong with type 2 diabetes; prospective cohort study; all-cause and cause-specific hospitalization rates.
Results: “Patients with YOD had the highest hospitalization rates by attained age. In the registry cohort, 36.8% of YOD bed-days before age 40 years were due to mental illness. The adjusted rate ratios showed increased hospitalization in YOD versus usual-onset T2D (onset at age ≥40 years) (all-cause, 1.8 [95% CI, 1.7 to 2.0]; renal, 6.7 [CI, 4.2 to 10.6]; diabetes, 3.7 [CI, 3.0 to 4.6]; cardiovascular, 2.1 [CI, 1.8 to 2.5]; infection, 1.7 [CI, 1.4 to 2.1]; P < 0.001 for all). Models estimated that intensified risk factor control in YOD (hemoglobin A1c level <6.2%, systolic blood pressure <120 mm Hg, low-density lipoprotein cholesterol level <2.0 mmol/L [<77.3 mg/dL], triglyceride level <1.3 mmol/L [<115.1 mg/dL], waist circumference of 85 cm [men] or 80 cm [women], and smoking cessation) was associated with a one-third reduction in cumulative bed-days from onset to age 75 years (97 to 65 bed-days).”
Commentaries on Cannabinoids, Marijuana: In a series of brief commentaries selected from among those submitted by readers in response to a call for papers, authors provide perspectives on six marijuana-related topics:
Cannabinoid Dosing for Chronic Pain Management
Marijuana and Cardiovascular Disease—What Should We Tell Patients?
Advocating for Blunt Policy
Marijuana Use During Gestation and Lactation—Harmful Until Proved Safe
Treating Pain—The Cannabis Conundrum
Consequences of Marijuana—Observations From the Emergency Department
“Absent the requisite data and an attendant FDA sanction, marijuana use in pregnant and lactating women should be discouraged,” write authors of the commentary on marijuana use during pregnancy and lactation (E. Y. Adashi, 
eli_adashi@brown.edu). “Several professional associations, erring on the side of caution, strongly discourage perinatal marijuana use. Ongoing use that is deemed therapeutic should be replaced with a drug that has a pregnancy-specific safety record. Doing no harm requires that uncompromising vigilance not be allowed to lapse. Doing anything less is to ignore the well-being of would-be progeny.”
American College of Physicians Ethics Manual: In a supplement on medical ethics, new or expanded information is provided on electronic communications, telemedicine ethics, electronic health records, precision medicine and genetics, caring for oneself and special categories of patients (close personal relations and “very important persons&rdquoWinking, social media, and other topics. (suppl 2; L. Snyder Sulmasy, lsnyder@acponline.org). “Medicine, law, and social values are not static,” the authors write. “Reexamining the ethical tenets of medicine and their application in new circumstances is a necessary exercise. The seventh edition of the American College of Physicians Ethics Manual covers emerging issues in medical ethics and revisits older ones that are still very pertinent. It reflects on many of the ethical tensions in medicine and attempts to shed light on how existing principles extend to emerging concerns. In addition, by reiterating ethical principles that have provided guidance in resolving past ethical problems, the Manual may help physicians avert future problems. The Manual is not a substitute for the experience and integrity of individual physicians, but it may serve as a reminder of the shared duties of the medical profession.”
Editorial: “The American College of Physicians Ethics Manual is a tremendous resource to physicians,” editorialists write (pp. 133–4; J. S. Blumenthal-Barby, jsswinde@bcm.edu). “As professionals who are dedicated to lifelong learning, physicians should build on the manual to address the ethical issues confronting them in clinical practice.”

PNN Pharmacotherapy Line
Jan. 16, 2019 * Vol. 26, No. 11
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Jan. 15 JAMA (2019; 321).
Preventing Progression of Relapsing-Remitting Multiple Sclerosis: Two research studies examine interventions for preventing disease progression of relapsing-remitting multiple sclerosis (MS). A preliminary study shows that nonmyeloblative autologous hematopoietic stem cell transplantation (HSCT) may be more effective than disease-modifying therapy (pp.165–74; R. K. Burt, rburt@northwestern.edu). A cohort study demonstrates a lower risk of conversion to secondary progressive MS with the disease-modifying treatments (DMTs) fingolimod, alemtuzumab, or natalizumab than with glatiramer acetate or interferon beta (pp. 175–87; T. Kalincik, tomas.kalincik@unimelb.edu.au).
Editorial: “As is often the case in science, the information provided by these studies lead to more questions,” an editorialist in considering next steps (pp. 153–5; H. Atkins, hatkins@ohri.ca). “When in the course of MS is HSCT most optimally used? How many DMTs should fail in a patient before considering HSCT? What is the optimal transplant conditioning regimen that balances toxicity and efficacy in controlling MS? And should HSCT be more liberally applied, for instance, for patients with less frequent relapses? Careful ongoing study, through clinical trials and registry-based databases, will be required to optimize the timing and sequence of DMT and HSCT, as the use of HSCT moves into the realm of potential treatment options for patients with MS.”
Fecal Microbiota Transplantation in Ulcerative Colitis: Short-duration fecal microbiota transplantation (FMT) using anaerobically prepared pooled donor product may be more effective than autologous FMT for producing remission at 8 weeks in patients with mild-to-moderate ulcerative colitis (UC), researchers report (pp. 156–64; S. P. Costello, sam.costello@sa.gov.au).
PICO: 73 participants with mild to moderately active UC at three Australian tertiary referral centers; anaerobically prepared pooled donor FMT or autologous FMT via colonoscopy followed by 2 enemas over 7 days; primary outcome of steroid-free remission of UC at week 8.
Results: “The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%–42%]; odds ratio, 5.0 [95% CI, 1.2–20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.”
Editorial: “A main finding [of this and] other trials of FMT in UC is that broad microbial restoration is effective in only one-third of patients, which is similar in efficacy to trials of systemic immunosuppression,” editorialists write (pp. 151–2; C. R. Kelly, colleen_r_kelly@brown.edu). “Rather than stand-alone therapy, manipulation of the microbiome in UC is likely to be most effective when used in combination with agents, such as immunomodulators and biologics, which target the immune dysregulation underlying the disorder. Given the signal of benefit seen so far, larger multicenter trials are an important next step and should be designed to answer questions about FMT delivery methods, mechanisms of action, and long-term durability of effects. In parallel, the right patient population must also be defined to clarify whether FMT has a role as monotherapy or adjunct and in mild or severe disease. Finally, regulatory agencies must provide a reasonable pathway for approval of microbial-based therapeutics.…”
Using “4 Moments” to Rethink Antibiotic Prescribing: In a Viewpoint article, authors describe an approach to prescribing antibiotic prescribing in the acute care setting (pp. 139–40; P. D. Tamma, ptamma1@jhmi.edu). The 4 moments framework was developed by the Agency for Healthcare Research and Quality Safety Program for Improving Antibiotic Use:
* Does this patient have an infection that requires antibiotics?
* Have I ordered appropriate cultures before starting antibiotics? What empirical antibiotic therapy should I initiate?
* A day or more has passed. Can I stop antibiotics? Can I narrow therapy? Can I change from intravenous to oral therapy?
* What duration of antibiotic therapy is needed for this patient’s diagnosis?

PNN Pharmacotherapy Line
Jan. 17, 2019 * Vol. 26, No. 12
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Jan. 17 issue of the New England Journal of Medicine (2019; 380).
Tafenoquine for Preventing Relapse of Plasmodium vivax Malaria: Two studies show promise for use of tafenoquine for safe prevention of Plasmodium vivax malaria when used with appropriate host glucose-6-phosphate dehydrogenase (G6PD) deficiency testing. Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity (pp. 215–28; G. C. K. W. Koh, gavin.c.koh@gsk.com). While noninferiority was not demonstrated, a phase 3 trial comparing tafenoquine with primaquine showed efficacy for radical cure of P. vivax malaria (pp. 229–41; J. A. Green, justin.a.green@gsk.com).
Editorial: “In the two current studies, which included follow-up periods of 6 months, the efficacy of tafenoquine in preventing recurrence of P. vivax malaria was similar to that of the standard 14-day regimen of primaquine in South America and the Horn of Africa, but efficacy was lower with tafenoquine than with primaquine in Southeast Asia,” writes an editorialist (pp. 285–6; N. J. White). “Earlier studies of single adult doses of tafenoquine of up to 600 mg showed a clear dose–response relationship. The rates of relapse among patients with P. vivax infections in East Asia and Oceania are generally higher than elsewhere, and these patients require higher doses of primaquine to attain the maximum radical curative efficacy. The lower efficacy of tafenoquine in Southeast Asia is therefore perhaps not surprising, and it suggests that a higher dose should be evaluated in that region. The requirement for accurate quantitative G6PD assessments and the current prescribing restrictions (pregnancy, lactation, or age younger than 16 years) will limit the potential deployment of tafenoquine, at least in the immediate future. The developers of tafenoquine deserve credit for persevering with this potentially valuable antimalarial drug, despite the difficulties, but it is too early to say whether tafenoquine can be used safely on a large scale in routine practice and thus fulfill its promise as a radical improvement in the treatment of malaria.”
Steering CAR T Cells into Solid Tumors: The methods and results of recently published preclinical trial illustrate possible ways that chimeric antigen receptor (CAR) T cells can be mobilized for use in the solid tumor glioblastoma (pp. 289–91; M. H. Brown). In hematologic cancers, CAR T-cell therapy have been “strikingly successful,” the authors write. “[In a recent Nature study], investigators engineered a CAR T cell to express a homing molecule (an adhesion molecule), which allows it to tether to and then migrate through the endothelial cells that make up the vasculature perfusing a mouse model of glioblastoma. Their approach is built on the detailed study of tumor endothelial phenotypes and adhesion pathways that affect T-cell endothelial transmigration.”
Climate Change & Health: “Climate change is causing injuries, illnesses, and deaths, with the risks projected to increase substantially with additional climate change, threatening the health of many millions of people if there are not rapid increases in investments in adaptation and mitigation,” review article authors write (pp. 263–73; A. Haines, andy.haines@lshtm.ac.uk). “They can support health systems in developing effective adaptation to reduce the health risks of climate change, promote healthy behaviors and policies with low environmental impact, support intersectoral action to reduce the environmental footprint of society in general and the health care system specifically, and undertake research and education on climate change and health. The pervasive threats to health posed by climate change demand decisive actions from health professionals and governments to protect the health of current and future generations.”
>>>PNN NewsWatch
FDA yesterday granted to Teva marketing rights for the first generic version of vigabatrin (Sabril) 500 mg tablets for treating refractory complex partial seizures (focal seizures) as an adjunctive therapy in patients 10 years and older.
* The “surge in 
cell and gene therapy products entering early development” will change FDA’s focus within a few years, wrote Commissioner Scott Gottlieb, MD, in a statement issued this week. “By 2025, we predict that the FDA will be approving 10 to 20 cell and gene therapy products a year based on an assessment of the current pipeline and the clinical success rates of these products,” Gottlieb noted.

PNN Pharmacotherapy Line
Jan. 18, 2019 * Vol. 26, No. 13
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
 Feb. 1 issue of Clinical Infectious Diseases (2019; 68).
Vancomycin Monotherapy in Children With MRSA, Severe Influenza: Pediatric patients with coinfections of influenza critical illness and methicillin-resistant Staphylococcus aureus (MRSA) have a high fatality rate, and vancomycin monotherapy may be insufficient for these patients, a study shows (pp. 365–72A. G. Randolphadrienne.randolph@childrens.harvard.edu).
PICO: 170 patients younger than 18 years of age (127 with influenza A, 43 with influenza B) in 34 pediatric intensive care units in 2008–16; comparisons of baseline characteristics, clinical courses, and treatments.
Results: “Children with influenza–MRSA pneumonia (N = 30, 87% previously healthy) were older than those with non-MRSA (N = 61) or no (N = 79) bacterial coinfections. Influenza–MRSA was associated with increased leukopenia, acute lung injury, vasopressor use, extracorporeal life support, and mortality than either group (P ≤ .0001). Influenza-related mortality was 40% with MRSA compared to 4.3% without (relative risk [RR], 9.3; 95% confidence interval [CI], 3.8–22.9). Of 29/30 children with MRSA who received vancomycin within the first 24 hours of hospitalization, mortality was 12.5% (N = 2/16) if treatment also included a second anti-MRSA antibiotic compared to 69.2% (N = 9/13) with vancomycin monotherapy (RR, 5.5; 95% CI, 1.4, 21.3; P = .003). Vancomycin dosing did not influence initial trough levels; 78% were <10 µg/mL.”
Influenza Vaccination Antibody Responses in HCWs: Antibody responses in health care workers (HCWs) to the AS03-adjuvanted H1N1pdm09 pandemic vaccine in 2009 and later seasonal vaccines supports inclusion of the adjuvant and supports annual vaccination of this target population, researchers report (pp. 382–92; R. J. Cox, rebecca.cox@uib.no).
PICO: HCWs who received the pandemic vaccine (n = 250) and were subsequently vaccinated with seasonal vaccines with the pdm09 antigen for 4, 1–3, or no seasons (repeated, occasional, and single groups, respectively); H1N1pdm09-specific antibodies measured by hemagglutination inhibition (HI).
Results: “Pandemic vaccination robustly induced HI antibodies that persisted above the 50% protective threshold (HI titers ≥ 40) over 12 months post-vaccination. Previous seasonal vaccination and the duration of adverse events after the pandemic vaccination influenced the decision to vaccinate in subsequent seasons. During 2010/2011–2013/2014, antibodies were boosted after each seasonal vaccination, although no significant difference was observed between the repeated and occasional groups. In the single group without seasonal vaccination, 32% of HCWs seroconverted (≥4-fold increase in HI titers) during the 4 subsequent years, most of whom had HI titers <40 prior to seroconversion. When excluding these seroconverted HCWs, HI titers gradually declined from 12 to 60 months post–pandemic vaccination.”
Antimicrobial Lock Solutions for Preventing Central Line Septicemia: For reducing the incidence of central line–associated bloodstream infection (CLABSI), antimicrobial lock solutions are an effective strategy in a variety of care situations, a cost analysis shows (pp. 419–25; E. Mylonakis, emylonakis@lifespan.org).
PICO: Decision-analytic model comparing antimicrobial lock solutions to heparin locks in hemodialysis, cancer treatment, and home parenteral nutrition; cost-effectiveness calculated based on CLABSIs prevented and incremental cost-effectiveness ratios.
Results: “In probabilistic analysis, at a willingness to pay of $50,000, antimicrobial lock solutions had a 96.24% chance of being cost-effective, compared with heparin locks in the hemodialysis setting, an 88.00% chance in the cancer treatment setting, and a 92.73% chance in the home parenteral nutrition setting. In base-case analysis, antimicrobial lock solutions resulted in savings of $68,721.03 for the hemodialysis setting, $85,061.41 for the cancer setting, and $78,513.83 for the home parenteral nutrition setting per CLABSI episode prevented.”
>>>PNN NewsWatch
* A higher prevalence of gastroschisis among infants born to mothers on opioid prescriptions supports the need for further research on the effects of opioid exposure during pregnancy (MMWR. 2019;68:31–6).
PNN will not be published on Mon., Jan. 21, MLK Day.

PNN Pharmacotherapy Line
Jan. 22, 2019 * Vol. 26, No. 14
Providing news and information about medications and their proper use

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>>>Lancet Report
Source:
 Jan. 19 issue of Lancet (2019; 393).
A+CHP v. CHOP in CD30 Peripheral T-Cell Lymphomas: In the ECHELON-2 trial, replacement of vincristine in the CHOP regimen with brentuximab vedotin increased progression-free survival and overall survival in patients with CD30-positive peripheral T-cell lymphomas (pp. 229–40; S. Horwitz, horwitzs@mskcc.org).
PICO: 452 adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma); double-blind, double-dummy, randomized, placebo-controlled, active comparator phase 3 study; brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); intent-to-treat progression-free survival.
Results: “Median progression-free survival was 48.2 months (95% CI 35.2–not evaluable) in the A+CHP group and 20.8 months (12.7–47.6) in the CHOP group (hazard ratio 0.71 [95% CI 0.54–0.93], p = 0.0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.”
Ixazomib Maintenance After Stem Cell Transplantation: For posttransplant maintenance therapy in newly diagnosed multiple myeloma, ixazomib maintenance therapy extends progression-free survival compared with placebo, researchers report (pp. 253–61; M. A. Dimopoulos, mdimop@med.uoa.gr).
PICO: 656 patients with a confirmed diagnosis of symptomatic multiple myeloma in the phase 3 TOURMALINE-MM3 study at 167 clinical or hospital sites in 30 countries; oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and autologous stem cell transplantation; intent-to-treat PFS, safety.
Results: “With a median follow-up of 31 months (IQR 27.3–35.7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26.5 months [95% CI 23.7–33.8] vs 21.3 months [18.0–24.7]; hazard ratio 0.72, 95% CI 0.58–0.89; p = 0.0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Outpatient Antibiotic Prescribing: A 2016 study shows that 1 in 7 Americans received questionable antibiotic prescriptions (k5092; K-P Chua, chuak@med.umich.edu).
PICO: 19.2 million Americans aged 0–64 years; cross-sectional study of the MarketScan Commercial Claims and Encounters database, 2016; proportion of antibiotic prescription fills categorized by appropriateness based on ICD-10 codes.
Results: “Among 15,455,834 fills, 1,973,873 (12.8%) were appropriate, 5,487,003 (35.5%) were potentially appropriate, 3,592,183 (23.2%) were inappropriate, and 4,402,775 (28.5%) were not associated with a recent diagnosis code. Among the 3,592,183 inappropriate fills, 2,541,125 (70.7%) were written in office based settings, 222,804 (6.2%) in urgent care centers, and 168,396 (4.7%) in emergency departments. In 2016, 2,697,918 (14.1%) of the 19,203,264 enrollees filled at least one inappropriate antibiotic prescription, including 490,475 out of 4,631,320 children (10.6%) and 2,207,173 out of 14,571,944 adults (15.2%).”
>>>PNN JournalWatch
* Tools for Deprescribing in Frail Older Persons and Those with Limited Life Expectancy: A Systematic Review, in the Journal of the American Geriatrics Society2019; 67: 172–80. (W. Thompson, wthomp01@gmail.com)
* Controversies in Drug Allergy: In Vitro Testing, in the 
Journal of Allergy and Clinical Immunology2019; 143: 56–65. (C. Mayorga, lina.mayorga@ibima.eu)

PNN Pharmacotherapy Line
Jan. 23, 2019 * Vol. 26, No. 1
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Jan. 22 issue of JAMA (2019; 321).
Aspirin Use for Primary Cardiovascular Prevention: In individuals without cardiovascular disease, aspirin use was associated with a lower risk of cardiovascular events and an increased risk of major bleeding in a systematic review and meta-analysis (pp. 277–87; S. L. Zheng, sean.zheng@nhs.net).
PICO: 13 randomized clinical trials enrolling at least 1,000 participants with no known cardiovascular disease and a follow-up of at least 12 months; 164,225 participants with 1,050,511 participant–years of follow-up; primary composite outcome of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke; primary safety outcome of any major bleeding. 
Results: “The median age of trial participants was 62 years (range, 53–74), 77,501 (47%) were men, 30,361 (19%) had diabetes, and the median baseline risk of the primary cardiovascular outcome was 9.2% (range, 2.6%–15.9%). Aspirin use was associated with significant reductions in the composite cardiovascular outcome compared with no aspirin (57.1 per 10,000 participant-years with aspirin and 61.4 per 10,000 participant-years with no aspirin) (hazard ratio [HR], 0.89 [95% credible interval, 0.84–0.95]; absolute risk reduction, 0.38% [95% CI, 0.20%–0.55%]; number needed to treat, 265). Aspirin use was associated with an increased risk of major bleeding events compared with no aspirin (23.1 per 10,000 participant-years with aspirin and 16.4 per 10,000 participant-years with no aspirin) (HR, 1.43 [95% credible interval, 1.30-1.56]; absolute risk increase, 0.47% [95% CI, 0.34%–0.62%]; number needed to harm, 210).”
Editorial: “[This analysis] demonstrates a general consistency of the newer studies with the previous studies of aspirin for primary prevention of cardiovascular events,” (pp. 253–5; J. M. Gaziano, jmgaziano@partners.org). “When applying these results to an individual patient, clinicians must consider other interventions in addition to aspirin, such as smoking cessation and control of blood pressure and lipid levels, to lower risk. In places of the world in which CVD risk is rising or where other preventive strategies, such as statins, are less available, aspirin as a low-cost intervention may have a more important role. Aspirin remains an important medication for acute management of vascular events; for use after certain procedures; for secondary prevention; and, after careful selection of the right patients, for primary prevention.”
Breast Cancer Treatment: The distinct risk profiles and treatment strategies for three major breast tumor subtypes are summarized in a narrative review (pp. 287–300; E. P. Winer, eric_winer@dfci.harvard.edu).
Results: “Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerly HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15%–20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%).… For [the more than 90% of] people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive and ERBB2 positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor–positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients with ERBB2-positive tumors receive ERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation.…”
>>>PNN NewsWatch
Torrent Pharmaceuticals is expanding its NDEA-related recall to include 6 lots of Losartan Potassium and Hydrochlorothiazide Tablets, USP.

PNN Pharmacotherapy Line
Jan. 24, 2019 * Vol. 26, No. 16
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Jan. 24 New England Journal of Medicine (2019; 380).
Delayed-Start Levodopa in Parkinson Disease: Delaying levodopa treatment of patients with early Parkinson disease had no effect on outcomes, the LEAP Study Group reports (pp. 315–24; R. M. A. de Bie, r.m.debie@amc.uva.nl).
PICO: 445 patients with early Parkinson disease randomized to levodopa 100 mg plus carbidopa 25 mg three times daily for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa plus carbidopa for 40 weeks (delayed-start group); primary outcome of between-group difference in mean change from baseline to week 80 in total score on the Unified Parkinson’s Disease Rating Scale (UPDRS).
Results: “The change in UPDRS score from baseline to week 80 was −1.0 ± 13.1 points and −2.0 ± 13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], −1.5 to 3.5; P = 0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04 ± 0.23 in the early-start group and 0.06 ± 0.34 in the delayed-start group (difference, −0.02; 95% CI, −0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10 ± 0.25 and 0.03 ± 0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.”
Editorial: “Trials of disease-modifying agents for the treatment of Parkinson’s disease are entering a new era that addresses the heterogeneity of the disease, facilitating the identification of disease processes and consequent targeted development and testing of therapies” editorialists write (pp. 389–90; S. Bressman). “Populations enriched for clinical features that may relate to differing underlying disease mechanisms may improve trial efficiency. Trials that are based on genotype are also under way, and other factors such as imaging patterns and inflammatory markers may need to be considered in future trials. The potential for identifying effective disease-modifying agents and for advancing the field beyond the conundrum of early use as compared with later use of levodopa is promising.”
Dapagliflozin & Cardiovascular Outcomes in Type 2 Diabetes: Compared with placebo, the selective SGLT-2 inhibitor dapagliflozin lowered rates of cardiovascular death and hospitalization for heart failure in patients with type 2 diabetes, DECLARE–TIMI 58 researchers report (pp. 347–57; S. D. Wiviott, swiviott@bwh.harvard.edu).
PICO: 17,160 patients with type 2 diabetes (10,186 without atherosclerotic disease) followed a median of 4.2 years; ; primary safety outcome of a composite of major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or ischemic stroke); primary efficacy outcomes of MACE and a composite of cardiovascular death or hospitalization for heart failure.
Results: “In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P <0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P = 0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P = 0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P = 0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P <0.001).”

PNN Pharmacotherapy Line
Jan. 25, 2019 * Vol. 26, No. 17
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
 Jan. issue of and early-release articles from the Journal of the American Geriatrics Society (2019; 67).
Clinical Pharmacists & Deprescribing in Older Adults: In adults aged 80 years or older, a Geriatric Patient-Aligned Care Team (GeriPACT) produced significantly more deprescribing of potentially inappropriate medications (PIMs) (pp. 115–8; C. A. Ammerman, catherine.ammerman@va.gov).
PICO: Retrospective cohort study at the Lexington, KY, VA center of patients aged 80 years or oder who filled a PIM at least 90 days before a GeriPACT or primary care appointment in 2015–17; primary outcome of deprescribing of PIMs for older adults by an interdisciplinary team (IDT) including a clinical pharmacy specialist (CPS) compared with usual care (UC).
Results: “One hundred twenty-one (26.8%) PIMs were deprescribed in GeriPACT, compared with 73 (16.1%) in UC (p = <.001). Of PIMs not deprescribed, 9.7% (n = 32) were dose reduced in GeriPACT, versus 2.8% (n = 11) in UC (p < .001). Documentation of risk versus benefit discussion between a provider and participant or pharmacist and participant occurred with 65.2% (n = 215) of PIMs not deprescribed in GeriPACT and 0.003% (n = 1) in UC (p < .001).”
Deprescribing of Agents for Delirium in Intensive Care: In the intensive care units (ICUs) of three large hospitals with state-of-the-art clinical services, addition of a deprescribing intervention had no significant impact on use of anticholinergics or benzodiazepines in adults with delirium, researchers report (10.1111/jgs.15751; N. L. Campbell, campbenl@iupui.edu).
PICO: 200 adults admitted to ICUs with delirium based on the Richmond Agitation–Sedation Scale and the Confusion Assessment Method for the ICU (CAM-ICU) and a contraindication or preference against haloperidol; randomization to deprescribing intervention or usual care; primary outcome of delirium duration based on the Delirium Rating Scale Revised-98 (DRS-R-98) and the CAM-ICU-7.
Results: “Participants had a mean age of 61.8 (SD = 14.3) years, 59% were female, and 52% were African American, with no significant differences in baseline characteristics between groups. No differences between groups were identified in the number exposed to anticholinergics (P = .219) or benzodiazepines (P = .566), the median total anticholinergic score (P = .282), or the median total benzodiazepine dose in lorazepam equivalents (P = .501). Neither median delirium/coma-free days (P = .361) nor median change in delirium severity scores (P = .582 for DRS-R-98; P = .333 for CAM-ICU-7) were different between groups. No differences in adverse events or mortality were identified.”
>>>Vaccine Highlights
Source:
 Jan. issues of Vaccine (2019; 37).
Rx Requirements & Pharmacist Zoster Vaccinations: States without a requirement for prescription orders for pharmacist administration of zoster vaccine have higher vaccination rates, data show (pp. 631–6; C. R. Tak).
PICO: 50-state law review of statutes and regulations regarding pharmacists’ ability to administer the zoster vaccine with/without a prescription order; data for adults aged 60 years or older from 2014 Behavioral Risk Factor Surveillance System.
Results: “Of the 50 states, 39 and the District of Columbia did not require a prescription order. After propensity score matching, zoster vaccination rates for adults ages 60 and older were significantly higher in states that did not require a prescription order (23.0% vs 21.1%, p = 0.0022). The propensity score-matched multilevel logistic regression model for adults aged 60+ found modestly higher odds of HZ vaccination for states that removed the prescription order requirement (OR 1.17, 95% CI 1.01–1.35). Similar estimates were found across other methodologies employed and age strata, although statistical significance varied.”
>>>PNN NewsWatch
FDA has released two draft guidances to help improve the agency’s ability to ensure that risk mitigation programs for certain drugs and biologics are working.
* On the 
verywell.com site, “An Overview of Gastroesophageal Reflux Disease (GERD)” provides information for consumers regarding symptoms, causes, diagnosis, treatment, and caregiving for GERD.

PNN Pharmacotherapy Line
Jan. 28, 2019 * Vol. 26, No. 18
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Comparative Effectiveness of Non-TNF Inhibitors in Rheumatoid Arthritis: Compared with abatacept, rituximab and tocilizumab produced better outcomes at 2 years in adult patients with refractory cases of rheumatoid arthritis, researchers report (l67; J-E Gottenberg, jacques-eric.gottenberg@chru-strasbourg.fr).
PICO: Population-based prospective study of 3,162 adults with rheumatoid arthritis in a French Society of Rheumatology registry with no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.
Results: “Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab ([life expectancy difference without failure] 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (−0.7, −1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.”
>>>Lancet Report
Source:
 Jan. 26 issue of Lancet (2019; 393).
Perinatal Calcium Supplementation & Pre-eclampsia: Parous women with previous pre-eclampsia had similar outcomes when randomized to prepregnancy and early pregnancy calcium supplements or placebo, a parallel-arm study shows (pp. 330–9; T. A. Lawrie, tess@lawrie.com).
PICO: In South Africa, Zimbabwe, and Argentina, 1,355 women with prior pre-eclampsia or eclampsia and who intended to become pregnant received calcium 500 mg or placebo daily from enrollment during prepregnancy until 20 weeks’ gestation; primary outcome of pre-clampsia (gestational hypertension and proteinuria).
Results: “331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks’ gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks’ gestation (risk ratio [RR] 0.80, 95% CI 0.61–1.06; p = 0.121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks’ gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0.66, CI 0.44–0.98; p = 0.037). There were no serious adverse effects of calcium reported.”
>>>PNN NewsWatch
* Reviewing the history of the genotoxic impurity in valsartan produced by the Zhejiang Huahai Pharmaceutical Co. Ltd. (ZHP) — the root cause of numerous recent recalls — FDA Commissioner Scott Gottlieb, MD, writes: “Our investigation into ZHP’s process identified that a change made to the manufacturing process likely led to this impurity, and that the impurity went undetected by global regulators, including the FDA, for a period of time. Before we undertook this analysis, neither regulators nor industry fully understood how [N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA)] could form during this particular manufacturing process. This is troubling to us and we know it’s troubling to the public. This concern is appropriate. Among other steps, we need to take actions that would prevent a similar situation from occurring. We are making important strides at understanding how these impurities occurred, mitigating the risk to patients, and learning what steps need to be taken to prevent this from occurring again in the future.”
>>>PNN JournalWatch
* Opioid Tolerance in Critical Illness, in the New England Journal of Medicine2019; 380: 365–78. (J. A. J. Martyn, jmartyn@mgh.harvard.edu)
* Medication Treatment For Opioid Use Disorders In Substance Use Treatment Facilities, in 
Health Affairs2019; 38: 14–23. (R. Mojtabai)
* Genetics Coming of Age in Type 1 Diabetes, in 
Diabetes Care2019; 42: 189–91. (C. J. Greenbaum, cjgreen@benaroyaresearch.org)
* Provider Time and Costs to Vaccinate Adult Patients: Impact of Time Counseling Without Vaccination, in 
Vaccine2019; 37: 792–7. (B. Yarnoff, byarnoff@rti.org)

PNN Pharmacotherapy Line
Jan. 29, 2019 * Vol. 26, No. 19
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
 Feb. issue of Diabetes Care (2019; 42).
Consistent Benefits Across the SGLT2 Inhibitor Class: Benefits of the sodium–glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin extend to dapagliflozin, researchers report, suggesting classwide benefits of these agents (pp. 318–26; L. E. Clegg, lindsay.clegg1@astrazeneca.com).
PICO: Data from 786 participants with type 2 diabetes who received SGLT2i in the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) were examined for effects on the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and estimated glomerular filtration rate (eGFR).
Results: “In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49–1.28]), as did dapagliflozin users (0.55 [0.26–1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27–0.95]; dapagliflozin: 0.66 [0.25–1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87–2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01–3.54] mL/min/1.73 m2 per year).”
Proinsulin Secretion in Type 1 Diabetes: Even in patients with long-duration type 1 diabetes who have low or no detectable serum C-peptide, the ability to secrete proinsulin persists, questioning some underlying assumptions about the disease (pp. 258–64; E. K. Sims, eksims@iu.edu).
PICO: 319 subjects with long-standing type 1 diabetes (≥3 years) and 12 control subjects without diabetes; using longitudinal samples at 1, 2, and 4 years, C-peptide and proinsulin were measured in fasting and stimulated sera to identify three categories of stimulated C-peptide: (1) C-peptide positive, with high stimulated values ≥0.2 nmol/L; (2) C-peptide positive, with low stimulated values ≥0.017 but <0.2 nmol/L; and (3) C-peptide <0.017 nmol/L.
Results: “Of individuals with long-standing type 1 diabetes, 95.9% had detectable serum proinsulin (>3.1 pmol/L), while 89.9% of participants with stimulated C-peptide values below the limit of detection (<0.017 nmol/L; n = 99) had measurable proinsulin. Proinsulin levels remained stable over 4 years of follow-up, while C-peptide decreased slowly during longitudinal analysis. Correlations between proinsulin with C-peptide and mixed-meal stimulation of proinsulin were found only in subjects with high stimulated C-peptide values (≥0.2 nmol/L). Specifically, increases in proinsulin with mixed-meal stimulation were present only in the group with high stimulated C-peptide values, with no increases observed among subjects with low or undetectable (<0.017 nmol/L) residual C-peptide.”
Editorial: “There is long-standing evidence that at the time of diagnosis and subsequently, individuals with type 1 diabetes have beta-cells still capable of synthesizing proinsulin, and many can process it to C-peptide and insulin,” editorialists write (pp. 183–5; S. E. Kahn, skahn@uw.edu). “The current study and others, some going back decades, now strongly support the hypothesis that type 1 diabetes is more than just a destructive disease. By probing the meaning of persistent propeptide release, we hope greater insights into beta-cell dysfunction in type 1 diabetes will result.”
Metabolic Surgery for Type 2 Diabetes: Based on benefits demonstrated with bariatric surgery, which is intended to produce weight loss, nonbariatric types of metabolic surgery are being developed, authors of a “personal perspective review” write (pp. 331–40; H. Buchwald, buchw001@umn.edu): “Metabolic surgery can cause amelioration, resolution, and possible cure of type 2 diabetes. Bariatric surgery is metabolic surgery. In the future, there will be metabolic surgery operations to treat type 2 diabetes that are not focused on weight loss. These procedures will rely on neurohormonal modulation related to the gut as well as outside the peritoneal cavity. Metabolic procedures are and will always be in flux as surgeons seek the safest and most effective operative modality; there is no enduring gold standard operation. Metabolic bariatric surgery for type 2 diabetes is more than part of the clinical armamentarium, it is an invitation to perform basic research and to achieve fundamental scientific knowledge.”

PNN Pharmacotherapy Line
Jan. 30, 2019 * Vol. 26, No. 20
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Jan. 29 issue of JAMA (2019; 321).
Estimating Coronary Heart Disease Risks: The clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in apolipoprotein B (ApoB), researchers report (pp. 364–73; B. A. Ference, baf29@medschl.cam.ac.uk).
PICO: Randomization analyses of genetic scores based on triglyceride-lowering variants in key genes for people in 63 cohort and case–control studies in 1948–2017.
Results: “In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965–1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967–1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723–0.798], P = 7.51 × 10−20).…”
Editorial: “Hypertriglyceridemia should not be considered as a single entity but rather multiple conditions that vary in CHD risk based on overall particle number and composition,” an editorialist writes in reaction to this study (pp. 347–9; A. M. Navar, ann.navar@duke.edu). “A simple diagnostic algorithm using total cholesterol level, TG level, and ApoB, a measure of the number of VLDL and LDL particles in circulation, can be used to categorize phenotypes of hypertriglyceridemia. Elevations in TG levels that are associated with greater particle number are associated with greater CHD risk, and the relative potential benefits of TG lowering and LDL-C lowering (via genetics at least) are similar when standardized for their effects on ApoB. Barring off-target effects, treatments that lower LDL-C or TG levels should lead to reductions in CHD risk proportional to their reduction in ApoB. Given the growing body of evidence supporting the importance of ApoB, the guidelines should consider including broader measurement of ApoB as part of routine clinical care.”
Hydrocortisone Therapy in Ventilated Very Preterm Infants: Mortality and pulmonary outcomes were not improved through the common practice of giving hydrocortisone to very preterm infants on mechanical ventilation at 7–14 days of age (pp. 354–63; A. H. van Kaam, a.h.vankaam@amc.uva.nl).
PICO: Preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1,250 g who were ventilator dependent between 7 and 14 days of life; primary outcome of composite of death or bronchopulmonary dysplasia (BPD) assessed at 36 weeks’ postmenstrual age.
Results: “Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, −3.6% [95% CI, −12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54–1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks’ postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, −8.2% [95% CI, −16.2% to −0.1%]; odds ratio, 0.59 [95% CI, 0.35–0.995]; P = .048).…”
Economic Factors, Clinician Supply & Neonatal Abstinence Syndrome: Higher long-term unemployment, higher mental health clinician shortage areas, and higher county-level rates of neonatal abstinence syndrome (NAS) are associated in an ecological study of 8 U.S. states (pp. 385–93; S. W. Patrick, stephen.patrick@vanderbilt.edu).
PICO: Cross-sectional study of FL, KY, MA, MI, NY, NC, TN, and WA in 2009–15; economic data for 2000–15 and county-level 10-year unemployment rate and mental health/primary care clinician supply.
Results: “…The 10-year unemployment rate was associated with higher rates of NAS (unadjusted rate in highest unemployment quartile of 20.1 per 1,000 births vs 7.8 per 1,000 births in lowest unemployment quartile; adjusted IRR, 1.11 [95% CI, 1.00–1.23]) occurring primarily in rural remote counties (adjusted IRR, 1.34 [95% CI, 1.05–1.70]; P = .04 for test of equivalence between metropolitan counties and rural remote counties).”
Editorial: “When clinical, community, and policy efforts align to address structural factors that shape health crises like the opioid epidemic, the fabric of society is strengthened, building resiliency to encounter the next epidemic in a way that honors the role mothers play in shaping the health of their families,” editorialists write (pp. 352–3; K. B. Kozhimannil, kbk@umn.edu).

PNN Pharmacotherapy Line
Jan. 31, 2019 * Vol. 26, No. 21
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Early-release articles and Jan. 31 issue of the New England Journal of Medicine (2019; 380).
E-Cigarettes v. Nicotine-Replacement Therapy: For smoking cessation, e-cigarettes are more effective than nicotine-replacement therapy (10.1056/NEJMoa1808779; D. Przulj, d.przulj@qmul.ac.uk).
PICO: 886 U.K. smokers were randomized to the nicotine-replacement therapy of their choice, provided for 3 months, or an e-cigarette starter pack with a recommendation to purchase further e-liquids of the flavor and strength of their choice; primary outcome of sustained abstinence at 1 year.
Results: “The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P <0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath.”
Editorial: “A consensus has emerged that e-cigarettes are safer than traditional combustible cigarettes, but it remains controversial whether e-cigarettes should be recommended as a first-line treatment to assist smoking cessation, alongside FDA-approved treatments,” editorialists conclude (10.1056/NEJMe1816406; B. Borrelli). “The appropriate duration of e-cigarette ‘treatment’ for smokers trying to quit is also uncertain. We recommend that e-cigarettes be used only when FDA-approved treatments (combined with behavioral counseling) fail, that patients be advised to use the lowest dose needed to manage their cravings, and that there be a clear timeline and ‘off ramp’ for use. Use of e-cigarettes should be monitored by health care providers, like other pharmacologic smoking-cessation treatments. The efficacy and safety of e-cigarettes need to be evaluated in high-risk subgroups, and further research on the health consequences of long-term e-cigarette use is needed.”
Oral Antibiotics for Osteomyelitis and Endocarditis: Reacting to studies showing noninferiority of partial oral antibiotic therapy for osteomyelitis (pp. 415–24; H. Bundgaard, henning.bundgaard@regionh.dk) and oral antibiotic therapy for endocarditis (pp. 425–36; M. Scarborough) in comparison with intravenous therapies, an editorialist writes (pp. 487–9; H. W. Boucher): “On the basis of these data, targeted oral therapy may have a role in the treatment of selected patients who have osteomyelitis or infective endocarditis on the left side of the heart and the health care infrastructure to support close monitoring. At this time, it is premature to recommend a widespread early switch to oral therapy for bone and joint infection or step down to combination oral antibiotic therapy for infective endocarditis on the left side of the heart. Subsequent trials might benefit from standardization of either antibiotic therapy or surgery, accepting that this may affect the ease of enrollment. Further studies are needed to confirm these findings and will further inform these strategies and advance stewardship to decrease antimicrobial resistance.”
>>>PNN NewsWatch
FDA yesterday approved Mylan’s fluticasone propionate/salmeterol inhalation powder, the first generic of Advair Diskus, for twice-daily treatment of asthma in patients aged 4 years and older and in patients with chronic obstructive pulmonary disease.
Kaiser Permanente Colorado Pharmacy Department has been named the 2019 recipient of the Warren E. Weaver/Richard P. Penna Award in the organization category by the Board of Pharmacy Specialties. Receiving individual awards are Dick R. Gourley, PharmD, and Peter H. Vlasses, PharmD, DSc(Hon), FCCP.

PNN Pharmacotherapy Line
Feb. 1, 2019 * Vol. 26, No. 22
Providing news and information about medications and their proper use

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>>>Nephrology Report
Source:
 Feb. American Journal of Kidney Diseases (2019; 73).
Protein Restriction & RAAS Inhibitors in CKD: A large-scale clinical trial is needed to determine the effectiveness of protein restriction combined with renin-angiotensin-aldosterone system (RAAS) inhibitors to slow the progression of chronic kidney disease (CKD), researchers report (pp. 248–57; D. Fouque, denis.fouque@chu-lyon.fr). Authors of a Perspective article write: “RAAS activity contributes to increased blood pressure, fluid retention, and positive sodium balance, but also to kidney damage by enhancing glomerular capillary filtration pressure and synthesis of profibrotic molecules such as transforming growth factor beta. It has been well established that [a low-protein diet (LPD)] decreases glomerular hyperfiltration and the generation of uremic toxins, as well as the burden of acid load, phosphorus, and sodium. In different animal CKD models, a significant reduction in proteinuria and glomerulosclerosis has been achieved when an RAAS inhibitor and LPD were combined. To date, high-quality intervention trials investigating this combined strategy are lacking. We summarize the experimental and clinical studies that have examined a potential additive action of these therapies on CKD progression. We outline potential mechanisms of action and additive efficacy of an LPD and RAAS inhibitors in CKD, with a particular emphasis on phosphate levels, uremic toxin production, acid load, and salt intake. Finally, although the evidence is inadequate to recommend combining RAAS inhibitors and an LPD to slow the progression of CKD, we provide a perspective to support a large-scale randomized clinical trial to study this combination.”
Risk Factors for Recurrent Acute Kidney Injury: Heart failure, acute coronary syndrome, diabetes, and chronic liver disease were predictors of recurrent acute kidney injury (AKI) following episodes during hospitalizations in a large managed care plan (pp. 163–73; K. D. Liu, kathleen.liu@ucsf.edu).
PICO: 38,659 hospitalized patients who had AKI in 2006–13.
Results: “In multivariable analyses, older age, black race, and Hispanic ethnicity were associated with recurrent AKI, along with lower estimated glomerular filtration rate, proteinuria, and anemia.…”
Quality Indicators for Conservative Kidney Management: Patients/caregivers and providers differed greatly in the quality indicators they felt were important regarding holistic patient-centered care for patients with kidney failure (pp. 174–83; C. M. Thomas, chandra.thomas@ahs.ca).
PICO: Nominal group technique study of 16 patients and caregivers from Calgary, Canada, yielded prioritized quality indicators; 91 multidisciplinary health care professionals from 10 countries ranked these in a 4-round Delphi process.
Results: “The most highly rated quality indicator in the Delphi process was the ‘percentage of patients that die in the place they desire.’ There was significant discordance between priorities of the nominal groups with that of the Delphi survey, with only 1 quality indicator being shared on each groups’ top 10 list of quality indicators.”
Editorial: Drawing an analogy between quality indicators and the need for doughnuts to have holes to ensure even cooking, editorialists conclude (pp. 153–5; A. H. Moss, amoss@hsc.wvu.edu): “In the end, prioritizing patients’ values will require changing the culture of care of patients with advanced CKD to make it less dialysis driven and more focused on conversations with patients to identify what is most important to them. Because they can drive the care provided, quality measures are needed for both the processes clinicians think contribute to good care (the hole in the donut) and the aspects that patients believe are important (the whole donut). This is a tall order, but the goal is worth achieving for the sake of our patients’ [quality of life] and experience of care.”
>>>PNN NewsWatch
* Adverse events in a postlicensure safety study of recombinant zoster vaccine were as expected, with percentages and types of adverse effects consistent with prelicensure studies. The report, published in this week’s MMWR (2019; 68:91–4), included 230 reports of vaccination errors, including incorrect routes of administration (RZV given subcutaneously rather than intramuscularly), administration of the adjuvant vial alone, and mixing of the lyophilized antigen with incorrect diluents.

PNN Pharmacotherapy Line
Feb. 4, 2019 * Vol. 26, No. 23
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Feb. 2 issue of Lancet (2019; 393).
Statin Therapy in Older People: Older people in all age ranges have significant reductions in major vascular events with statin therapy, researchers report, but evidence for primary therapy of those older than 75 years is less conclusive (pp. 407–15; Cholesterol Treatment Trialists’ Collaboration).
PICO: Meta-analysis of 28 randomized trials of statin therapy with 1,000 or more participants and a scheduled treatment duration of at least 2 years; six age groups were considered, starting at 55 years of age.
Results: “Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0.79, 95% CI 0.77–0.81) proportional reduction in major vascular events per 1.0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend = 0.06). Overall, statin or more intensive therapy yielded a 24% (RR 0.76, 95% CI 0.73–0.79) proportional reduction in major coronary events per 1.0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend = 0.009). We observed a 25% (RR 0.75, 95% CI 0.73–0.78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1.0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend = 0.6).…”
Editorial: “When statins are used in people with low cardiovascular risk, the risks and benefits need to be weighed against each other,” editorialists write (pp. 379–80; B. M. Y. Cheung, mycheung@hku.hk). “Statins have been associated with a slight increase in incidence of muscle pain, diabetes, and haemorrhagic stroke, but their benefits in prevention of major vascular events are shown to be much greater. The present meta-analysis that includes people older than standard trial populations echoes this conclusion. The challenge for the health-care profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice.”
Carbohydrate Quality & Human Health: All-cause and cardiovascular-related mortality, and the incidence of coronary heart disease, stroke and related mortality, type 2 diabetes, and colorectal cancer are improved through increased intake of higher-quality dietary fiber and whole grains, according to a series of systematic reviews and meta-analyses of prospective studies (pp. 434–45; J. Mann, jim.mann@otago.ac.nz).
PICO: 135 million person–years of data from 185 prospective studies and 58 clinical trials with 4,635 adult participants.
Results: “Observational data suggest a 15–30% decrease in all-cause and cardiovascular-related mortality, and incidence of coronary heart disease, stroke incidence and mortality, type 2 diabetes, and colorectal cancer when comparing the highest dietary fibre consumers with the lowest consumers Clinical trials show significantly lower body weight, systolic blood pressure, and total cholesterol when comparing higher with lower intakes of dietary fibre. Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer. Similar findings for whole grain intake were observed.…”
>>>PNN NewsWatch
* Terrific Care/Medex Supply LLC last month issued a class I recall of certain Roche Diagnostics test strip lots used with CoaguChek test meter devices, FDA said.
>>>PNN JournalWatch
* Youth and the Opioid Epidemic, in Pediatrics2019; 143: 10.1542/peds.2018-2752. (S. Levy)
* Survival and Impairment of Extremely Premature Infants: A Meta-analysis, in 
Pediatrics2019; 143: 10.1542/peds.2018-0933. (H. T. Myrhaug)
* Arterial Stiffness in CKD: A Review, in 
American Journal of Kidney Diseases2019; 73: 240–7. (R. R. Townsend, townsend@upenn.edu)
* Heart Disease and Stroke Statistics — 2019 Update: A Report From the American Heart Association, in 
Circulation2019; 10.1161/CIR.0000000000000659. (E. J. Benjamin)

PNN Pharmacotherapy Line
Feb. 5, 2019 * Vol. 26, No. 24
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Feb. 5 issue of Annals of Internal Medicine (2019; 170).
2019 Adult Immunization Schedule: Approved by the CDC Advisory Committee on Immunization Practices at its Oct. meeting, the 2019 Adult Immunization Schedule is now available (pp. 182–92; D. K. Kim, ddk5@cdc.gov). Changes include restoration of the intranasal live attenuated influenza vaccination (LAIV; FluMist Quadrivalent, AstraZeneca) for adults through age 49; addition of the two-dose, single-antigen recombinant hepatitis B vaccine with a novel cytosine-phosphate-guanine 1018 oligodeoxynucleotide adjuvant (Heplisav-B, Dynavax) for prevention of hepatitis B virus infection in adults aged 18 years or older; and addition of homelessness as an indication for routine hepatitis A vaccination with a 2-dose series of single-antigen hepatitis A vaccine (Havrix, GlaxoSmithKline; Vaqta, Merck) or a 3-dose series of combination hepatitis A and B vaccine (Twinrix, GlaxoSmithKline). The schedule has undergone major changes in its format and graphics to improve usability.
Fracture Risk After Initiation of Canagliflozin Therapy: Among middle-aged patients with type 2 diabetes and relatively low fracture risk, use of canagliflozin was not associated with increased risk for fracture compared with other GLP-1 agonists (pp. 155–63; M. Fralick, mif823@mail.harvard.edu).
PICO: Population-based new-user cohort study of two U.S. commercial health databases with records of 70 million patients in 2013–15; primary outcomes of composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention.
Results: “79,964 patients initiating use of canagliflozin were identified and matched to 79,964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1,000 person–years) and GLP-1 agonists (2.3 events per 1,000 person–years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1,000 person–years) and GLP-1 agonists (16.1 events per 1,000 person–years) (overall HR, 0.92 [CI, 0.83 to 1.02]).”
Editorial: “Although these data may reassure health care providers that prescribing canagliflozin will not increase fracture risk in their patients with diabetes, caution may still be appropriate when this agent is used in older patients who have high fracture risk, with particular attention given to hydration status and fall risk,” editorialists write (pp. 201–2; W. D. Leslie, bleslie@sbgh.mb.ca). “For example, SGLT2 inhibitors may predispose persons to dehydration and increased risk for falls, and older populations at higher fracture risk may be more susceptible to this than the populations captured in the Optum and MarketScan databases. Real-world observational data from administrative data sets and electronic health records are well suited to provide this needed pharmacovigilance, provided that rigorous methods are used to control for selection bias.”
Compounded Topical Creams for Local Chronic Pain: Compounded topical pain creams were no more effective than placebo creams in a study of 399 patients at a military treatment facility with localized chronic pain, and authors conclude that given their cost and lack of efficacy, their use should be curtailed (10.7326/M18-2736; S. P. Cohen, scohen40@jhmi.edu).
PICO: Randomization to products specific for neuropathic, nociceptive, or mixed pain.
Results: No differences in average pain scores 1 month after treatment for any pain type; 36% and 28% of participants on active and placebo cream, respectively, had positive outcomes.
>>>PNN NewsWatch
* The updated Beers criteria have been released by the American Geriatrics Society. An accompanying editorial reminds readers of key principles that guide optimal use of these criteria.
* Because of mislabeling on the primary container, 
Dr. Reddy’s Laboratories is continuing its voluntary nationwide recall of lot ABD807 of Levetiracetram in 0.54% Sodium Chloride Injection, 1,500 mg/100 mL (15 mg/mL) single-dose infusion bags to the hospital level in the U.S.

PNN Pharmacotherapy Line
Feb. 6, 2019 * Vol. 26, No. 25
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Feb. 5 issue of JAMA (2019; 321).
MRI-Guided Rheumatoid Arthritis Therapy: Compared with a conventional treat-to-target approach to management of rheumatoid arthritis (RA), therapy guided by magnetic resonance imaging (MRI) was no more beneficial, IMAGINE-RA researchers report (pp. 461–72; S. Møller-Bisgaard, s.moeller.bisgaard@gmail.com).
PICO: 200 patients at 9 Danish hospitals whose RA was in remission (disease activity score in 28 joints–C-reactive protein [DAS28-CRP] <3.2 and no swollen joints); randomly allocated to an MRI-guided vs a conventional treat-to-target strategy using clinical remission as the goal.
Results: “Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde–modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, −4.8% [1-sided 95% CI, −13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, −7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events.”
Editorial: “The findings of Møller-Bisgaard et al that patients in clinical remission exhibit no or only minimal progression of joint damage as shown by x-ray or MRI confirm previous observations that subclinical inflammation does not signify progression of joint damage during sustained clinical remission,” editorialists conclude (pp. 457–8; D. Aletaha, daniel.aletaha@meduniwien.ac.at). “In addition, the trial demonstrated that maintaining remission was achievable with [conventional synthetic disease-modifying antirheumatic drug (csDMARD)] monotherapy for most patients with RA. The study findings also demonstrated the importance of clinical assessment using composite disease activity measures in follow-up, including clinical remission. Based on results of the trial by Møller-Bisgaard et al, existing treatment strategies should not change. Rather, results of the trial by Møller-Bisgaard et al support current RA management recommendations. Specifically, csDMARD should be initial therapy, with [biologic] DMARDs added if csDMARDs fail to achieve the treatment target using a treat-to-target approach. These recommendations should be closely followed.”
Reducing P&T Expert Halo Effect: Recommending strategies for reducing the “expert halo effect” when physicians present their own formulary requests to pharmacy and therapeutics committees, Viewpoint authors write (pp. 453–4; J. P. Austin, austinja@ohsu.edu): “Typically, the expert discusses the mechanistic explanation of the new medication and explains why it is desired for patients. Even in the absence of high-quality evidence, experts may provide compelling supporting arguments. Furthermore, the presence of expert specialists at pharmacy and therapeutics committees may introduce significant power dynamics. Taught directly or indirectly through the ‘hidden curriculum’ and reinforced by inequitable reimbursement models within institutions, specialists may wield greater power than generalists, and procedure-based specialists may wield greater power than cognitive-based specialists. These factors reinforce the expert halo effect and have the potential to exert undue influence on the decision-making process of committee members.”
Postoperative Delirium Among Older Adults: “The choice of anesthetic dose remains critically important in the context of an aging surgical patient population, and the role of good-quality, safe anesthesia is as important as ever,” write editorialists (pp. 459–60; R. Pearse, r.pearse@qmul.ac.uk) in reaction to a study of EEG-guided surgical anesthesia in older adults (pp. 473–83; M. S. Avidan, avidanm@wustl.edu)
>>>PNN NewsWatch
* In an update to a 2017 recall, Smiths Medical is recalling select serial and lot numbers of sterile saline and sterile water products for inhalation because of potential exposure to Bacillus infantis and Staphylococcus epidermidis.

PNN Pharmacotherapy Line
Feb. 7, 2019 * Vol. 26, No. 26
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Feb. 7 issue of the New England Journal of Medicine (2019; 380).
Omadacycline, the “Newest Tetracycline”: In a pair of clinical trials, a recently approved, once-daily aminomethylcycline antibiotic was safe and effective for treatment of community-acquired bacterial pneumonia (pp. 517–27) and acute bacterial skin and skin-structure infections (pp. 528–38; L. Garrity-Ryan, lynne.garrity-ryan@paratekpharma.com), compared with commonly used alternative agents.
PICO: Adult participants were randomized to I.V. omadacycline or I.V. moxifloxacin for community-acquired bacterial pneumonia (n = 774) and I.V. omadacycline or I.V. linezolid for acute bacterial skin and skin-structure infections (n = 627); I.V. dosing was continued for 3 days, followed by transitions to oral doses of the same drugs for a total duration of therapy of 7–14 days.
Results: For pneumonia, omadacycline was noninferior to moxifloxacin (81.1% versus 82.7% early response rates; adverse events in 41.1% and 48.5% of patients). For skin infections, omadacycline was noninferior to linezolid with a similar safety profile (84.8% versus 85.5% early response rates; adverse events in 48.3% and 45.7%).
Editorial: “So what is the role of omadacycline for treatment of infections caused by multiple-drug–resistant pathogens?,” an editorialist asks (pp. 588–9; H. F. Chambers). “It is a question desperately in need of an answer. Omadacycline does not have cross-resistance with beta-lactam antibiotics, aminoglycosides, polymyxins, and fluoroquinolones and is active against organisms expressing tetracycline efflux and ribosomal protection genes. It is many times more active than doxycycline and minocycline against Enterobacteriaceae and Acinetobacter baumannii, with minimum inhibitory concentrations (MICs) less than or equal to 4 μg per milliliter for 90% of strains, the FDA breakpoint MIC for susceptibility of K. pneumoniae to omadacycline. Two other advanced-spectrum tetracyclines — tigecycline and eravacycline, the latter of which was recently approved by the FDA for the treatment of intraabdominal infections — have similar properties. Results with tigecycline in the treatment of carbapenem-resistant gram-negative infections have been disappointing. The FDA label warns of higher all-cause mortality with tigecycline than with comparators in clinical trials and specifically states that it is not indicated for the treatment of hospital-acquired pneumonia. Eravacycline failed in phase 3 trials evaluating its use in complicated urinary tract infections, a stated limitation of use in the label. With respect to in vitro activity as a predictor of in vivo efficacy, the MIC breakpoints vary according to species and cannot be generalized, and the MICs for drug-resistant strains often are higher than those for susceptible strains.”
Sacubitril–Valsartan in Acute Decompensated Heart Failure: In the PIONEER-HF trial, patients with acute decompensated heart failure benefited from angiotensin-neprilysin inhibition (pp. 539–48; E. J. Velazquez, eric.velazquez@yale.edu).
PICO: 881 patients hospitalized with heart failure with reduced ejection fraction hospitalized for acute decompensated heart failure at 129 U.S. sites were randomized to sacubitril–valsartan or enalapril.
Results: Time-averaged proportional change in the N-terminal pro–B-type natriuretic peptide concentration from baseline through weeks 4 and 8 was significantly lower with combination therapy (–46.7% versus –25.3%).
Editorial: “The PIONEER-HF trial provides the best evidence available to guide the initiation of sacubitril–valsartan in patients with acute decompensated heart failure,” concludes an editorialist (pp. 590–1; J. Jarcho). “One would anticipate that, if this treatment is initiated in-hospital as described in this report, and if the patient remains adherent to the treatment after hospital discharge, the long-term benefits on clinical outcomes that were seen in the PARADIGM-HF trial should be attainable. These findings may help to increase the adoption of this important addition to the heart-failure armamentarium.”
>>>PNN NewsWatch
FDA yesterday approved caplacizumab-yhdp (Cablivi, Ablynx) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura.

PNN Pharmacotherapy Line
Feb. 8, 2019 * Vol. 26, No. 27
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
 Feb. issue of Pediatrics (2019; 143).
LAIV v. IIV Effectiveness: Consistent with other studies in the 2013–14 through 2015–16 influenza seasons, pooled data confirm reduced effectiveness of the quadrivalent live attenuated influenza vaccine (LAIV4) in comparison with the inactivated influenza vaccine (IIV) among children and adolescents (e20182094; J. R. Chung).
PICO: Data from 5 U.S. studies were pooled to assess vaccine effectiveness (VE) in children and adolescents aged 2–17 years who had medically attended, laboratory-confirmed influenza.
Results: “Of 17,173 patients aged 2 to 17 years, 4,579 received IIV, 1,979 received LAIV4, and 10,615 were unvaccinated. Against influenza A/H1N1pdm09, VE was 67% (95% confidence interval [CI]: 62% to 72%) for IIV and 20% (95% CI: −6% to 39%) for LAIV4. Results were similar when stratified by vaccination in the previous season. LAIV4 recipients had significantly higher odds of influenza A/H1N1pdm09 compared with IIV recipients (odds ratio 2.66; 95% CI: 2.06 to 3.44). LAIV4 and IIV had similar effectiveness against influenza A/H3N2 and B. Our overall findings were consistent when stratified by influenza season and age group.”
Pediatric Antibiotic Prescribing in the ED: Pediatric antibiotic stewardship efforts need to be expanded into nonpediatric emergency departments (EDs), authors conclude based on data showing that children receive nearly 7 million antibiotic prescriptions in EDs annually in the U.S., many of them for inappropriate uses (e20181056; N. M. Poole).
PICO: 2009–2014 National Hospital Ambulatory Medical Care Survey ED data for discharged patients aged 0–17 years.
Results: “In 2009–2014, of the 29 million mean annual ED visits by children, 14% (95% confidence interval [CI]: 10%–20%) occurred at pediatric EDs. Antibiotics overall were prescribed more frequently in nonpediatric than pediatric ED visits (24% vs 20%, P < .01). Antibiotic prescribing frequencies were stable over time. Of all antibiotics prescribed, 44% (95% CI: 42%–45%) were broad spectrum, and 32% (95% CI: 30%–34%, 2.1 million per year) were generally not indicated. Compared with pediatric EDs, nonpediatric EDs had a higher frequency of prescribing macrolides (18% vs 8%, P < .0001) and a lower frequency of first-line, guideline-concordant prescribing for the respiratory conditions studied (77% vs 87%, P < .001).”
>>>Psychiatry Highlights
Source:
 Feb. issue of the American Journal of Psychiatry (2019; 176).
Substance Use & Adolescent Cognitive Development: Adolescent use of marijuana may produce more pronounced cognitive changes than alcohol use, with implications that go beyond the role of cognition in substance use, researchers report (pp. 98–106; J-F. G. Morin).
PICO: Population-based sample of 3,826 seventh-grade students in 2012–13 in Montreal; assessed annually for 4 years on alcohol and cannabis use and other measures.
Results: “Common vulnerability effects were detected for cannabis and alcohol on all domains. Cannabis use, but not alcohol consumption, showed lagged (neurotoxic) effects on inhibitory control and working memory and concurrent effects on delayed memory recall and perceptual reasoning (with some evidence of developmental sensitivity). Cannabis effects were independent of any alcohol effects.”
>>>PNN NewsWatch
* CDC is calling for a multifaceted approach to increase Americans’ awareness of the five common signs and symptoms of heart attack and the appropriate emergency response. A study published in this week’s MMWR shows sociodemographic disparities in knowledge persist despite improved overall awareness of this topic.
* FDA is launching a 
new pilot project in which participants representing manufacturers, repackagers, and other stakeholders in the drug supply chain can pilot the use of innovative and emerging approaches for enhanced tracing and verification of prescription drugs in the U.S., the agency said yesterday. Eligible entities may apply to participate in the program. The pilot will inform the development of the enhanced electronic, interoperable track-and-trace system for industry set to go into effect in 2023 as part of the Drug Supply Chain Security Act.

PNN Pharmacotherapy Line
Feb. 11, 2019 * Vol. 26, No. 28
Providing news and information about medications and their proper use

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>>>Lancet Report
Source:
 Feb. 9 issue of Lancet, a theme issue on advancing women in science, medicine, and global health (2019; 393).
Sex-Related Reporting in Medical Research: Greater diversity in medical research is needed from cell lines to rodents to humans, authors conclude, and the effort will need to include addressing gender disparities in the scientific workforce and the lack of sex-related reporting policies at journals and in institutions (pp. 550–9; V. Lariviere, vincent.lariviere@umontreal.ca).
PICO: Sex-related reporting in medical research as reported in 11.5 million articles published between 1980 and 2016; gender of first and last authors and other variables.
Results: “Between Jan 1, 1980, and Dec 31, 2016, sex-related reporting increased from 59% to 67% in clinical medicine and from 36% to 69% in public health research. But for biomedical research, sex remains largely under-reported (31% in 2016). Papers with female first and last authors had an increased probability of reporting sex, with an odds ratio of 1.26 (95% CI 1.24 to 1.27), and sex-related reporting was associated with publications in journals with low journal impact factors. For publications in 2016, sex-related reporting of both male and female is associated with a reduction of −0.51 (95% CI −0.54 to −0.47) in journal impact factors.”
Editorial: “It is well established that women are under-represented in positions of power and leadership, undervalued, and experience discrimination and gender-based violence in scientific and health disciplines across the world,” the journal editors write (p. 493The Lancet). “Intersectional approaches have provided insights into how other categories of difference such as ethnicity, class, geography, disability, and sexuality interact with gender to compound inequalities. Most submissions to this theme issue came from high-income countries, highlighting the need to support scholarship from the Global South. Geordan Shannon and colleagues provide a global overview of gender inequality in science, medicine, and global health, and discuss the evidence for the substantial health, social, and economic gains that could be achieved by addressing this inequality. Indeed, some studies, including [the above report], show that more diverse and inclusive teams lead to better science and more successful organisations.”
Gender Gaps in Grant Peer Review: Less favorable assessments of women as principal investigators, not the quality of the proposed research, result in gender gaps in grant funding, according to an analysis of peer review of applications to the Canadian Institutes of Health Research (pp. 531–40; H. O. Witteman, holly.witteman@fmed.ulaval.ca).
PICO: 23,918 grant applications from 7,093 principal investigators in 2011–16; comparison of differences in application success between male and female principal investigators under different review criteria.
Results: “Overall application success across competitions was 15.8%. After adjusting for age and research domain, the predicted probability of success in traditional programmes was 0.9 percentage points lower for female applicants than male applicants (95% CI 2.0 lower–0.2 higher; odds ratio 0.934, 95% CI 0.854–1.022). In the new programme, in which review focused on the proposed science, the gap remained 0.9 percentage points (3.2 lower–1.4 higher; 0.998, 0.794–1.229). In the new programme with an explicit review focus on the calibre of the principal investigator, the gap was 4.0 percentage points (6.7 lower–1.3 lower; 0.705, 0.519–0.960).”
>>>PNN JournalWatch
* Bezlotoxumab, in Clinical Infectious Diseases2019; 68: 699–704. (S. Johnson, stuart.johnson2@va.gov)
* Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update, in 
Journal of Clinical Oncology2019; 37: 423–38. (H. J. Burstein, guidelines@asco.org)
* Clinical Cancer Advances 2019: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology, in 
Journal of Clinical Oncology2019; 37: 10.1200/JCO.18.02037. (M. J. Miller, wendy.stokes@asco.org)
* Does Platinum-Based Chemotherapy Still Have a Role in First-Line Treatment of Advanced Non–Small-Cell Lung Cancer?, in 
Journal of Clinical Oncology2019; 37: 10.1200/JCO.18.01534. (E. B. Garon, egaron@mednet.ucla.edu)
* Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review, in 
Journal of the American College of Cardiology2019; 73: 10.1016/j.jacc.2018.11.033. (K. McHugh)

PNN Pharmacotherapy Line
Feb. 12, 2019 * Vol. 26, No. 29
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from JAMA Internal Medicine (2019; 179).
Racial & Geographic Differences in U.S. Opioid Prescribing: Two studies and an editorial examine opioid prescribing in the U.S. 
Study 1: In California in 2011–15, controlled medications were significantly more likely to be prescribed to residents of majority-white areas, and this “may have shielded nonwhite communities from the brunt of the prescription opioid epidemic but also represent[s] disparities in treatment and access to all medications,” investigators conclude (10.1001/jamainternmed.2018.6721; D. L. Schriger, schriger@ucla.edu).
PICO: Longitudinal population-based study tracking all 29.7 million patients receiving controlled substance prescriptions in California from 2011 to 2015.
Results: “A nearly 300% difference in opioid prescription prevalence across the race/ethnicity–income gradient was observed in California, with 44.2% of adults in the quintile of [zip code tabulation areas (ZCTAs)] with the lowest-income/highest proportion–white population receiving at least 1 opioid prescription each year compared with 16.1% in the quintile with the highest-income/lowest proportion–white population and 23.6% of all individuals 15 years or older. Stimulant prescriptions were highly concentrated in mostly white high-income areas, with a prevalence of 3.8% among individuals in the quintile with the highest-income/highest proportion–white population and a prevalence of 0.6% in the quintile with the lowest-income/lowest proportion–white population. Benzodiazepine prescriptions did not have an income gradient but were concentrated in mostly white areas, with 15.7% of adults in the quintile of ZCTAs with the highest proportion–white population receiving at least 1 prescription each year compared with 7.0% among the quintile with the lowest proportion–white population.”
Study 2: The decrease in opioid prescribing in the U.S. is accelerating, according to 2015–17 county-level data, but the per-capita use of these drugs remains 3 times higher than in 1999, researchers report (10.1001/jamainternmed.2018.6989; G. P. Guy Jr., irm2@cdc.gov).
PICO: 2015–17 prescriptions from 50,400 community pharmacies.
Results: “From 2015 to 2017, the amount of opioids prescribed in the United States decreased 20.1%, from 641.4 to 512.6 [morphine milligram equivalent (MME)] per capita; opioid prescribing rates decreased 16.9%, from 70.7 to 58.7 per 100 persons; high-dose prescribing rates decreased 25.3%, from 6.7 to 5.0 per 100 persons; and the average daily MME per prescription decreased 6.0%, from 48.1 to 45.2 MME. Meanwhile, average and median duration of opioid prescriptions increased by 3.4% (17.7 to 18.3 days) and 33.3% (15.0 to 20.0 days), respectively.
“In 2017, the amount of opioids prescribed per capita varied substantially at the county level. The average amount of opioids prescribed in the highest quartile (1061.0 MME per capita) was 5.8 times the amount in the lowest quartile (182.8 MME per capita). Substantial variation between the highest and lowest prescribing counties was also observed for overall prescribing rates (4.6 times higher) and high-dose prescribing rates (7.1 times higher). From 2015 to 2017, the majority of counties experienced a reduction in the amount of opioids prescribed (2,204 [74.7%]), overall prescribing rates (2,251 [76.3%]), and high-dose prescribing rates (2,259 [76.6%]).”
Editorial: “Although health care professionals have many ways to respond to the opioid crisis, we must also acknowledge that the problem cannot be solved by medical interventions alone,” federal officials write (10.1001/jamainternmed.2018.7934; J. M. Adams, jerome.adams@hhs.gov). “Stopping the epidemic requires a public health approach that recognizes substance misuse and addiction are the result of interrelated individual, environmental, and societal factors, requiring diverse stakeholder cooperation to prevent, mitigate, and reverse. As patient touchpoints, influencers, and integrators of various health interventions, health care professionals are uniquely positioned to be catalysts of the cross-sector collaborations that are required to comprehensively address opioid misuse.”
>>>PNN NewsWatch
FDA yesterday posted warnings to companies it said are illegally selling 58 dietary supplements and other products with claims to prevent, treat, or cure Alzheimer’s disease and other serious health conditions.

PNN Pharmacotherapy Line
Feb. 13, 2019 * Vol. 26, No. 30
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Feb. 12 issue of JAMA (2019; 321).
Acetaminophen + Ibuprofen After Total Hip Arthroplasty: Morphine consumption was significantly reduced in patients who had undergone total hip arthroplasty (THA) through scheduled doses of paracetamol (acetaminophen) plus ibuprofen, compared with paracetamol alone, PANSAID Randomized Clinical Trial investigators conclude (pp. 562–71; K. H. Thybo, khty@regionsjealland.dk).
PICO: At six Danish hospitals, 556 postsurgical patients received oral paracetamol 1000 mg plus ibuprofen 400 mg every 6 hours for 24 hours (PCM + IBU), beginning 1 hour after surgery; comparisons made with paracetamol alone (PCM), ibuprofen alone (IBU), or half-strength paracetamol/ibuprofen (HS–PCM + IBU). Coprimary outcomes were 24-hour morphine consumption using patient-controlled analgesia and proportion of patients with 1 or more serious adverse events (SAEs) during 90 days’ follow-up.
Results: “Median 24-hour morphine consumption was 20 mg (99.6% CI, 0–148) in the PCM + IBU group, 36 mg (99.6% CI, 0–166) for PCM alone, 26 mg (99.6% CI, 2–139) for IBU alone, and 28 mg (99.6% CI, 2–145) for HS–PCM + IBU. The median difference in morphine consumption between the PCM + IBU group vs PCM alone was 16 mg (99.6% CI, 6.5 to 24; P < .001); for the PCM-alone group vs HS–PCM + IBU, 8 mg (99.6% CI, −1 to 14; P = .001); and for the PCM + IBU group vs IBU alone, 6 mg (99.6% CI, −2 to 16; P = .002). The difference in morphine consumption was not statistically significant for the PCM + IBU group vs HS–PCM + IBU (8 mg [99.6% CI, −2 to 16]; P = .005) or for the PCM-alone group vs IBU alone (10 mg [99.6% CI, −2 to 16]; P = .004) after adjustment for multiple comparisons and 2 coprimary outcomes. There was no significant difference between the IBU-alone group vs HS–PCM + IBU (2 mg [99.6% CI, −10 to 7]; P = .81). The proportion of patients with SAEs in groups receiving IBU was 15%, and in the PCM-alone group, was 11%. The relative risk of SAE was 1.44 (97.5% CI, 0.79 to 2.64; P = .18).”
CMS Opioid Overutilization Criteria: By relying on prescription opioid data and failing to capture illicit opioid use, CMS criteria for overutilization of opioids miss the majority of patients with opioid use disorder (OUD) and inaccurately flag more than half of opioid prescription users as high risk, researchers report (pp. 609–11; Y-J J. Wei, jenny.wei@cop.ufl.edu).
PICO: In 2011 through 2014, 142,036 to 190,320 eligible Medicare Parts A, B, and D beneficiaries were prescribed opioids during 6-month time periods; CMS overuse criteria (receiving prescription opioids with a mean daily morphine equivalent dose ≥90 mg and from >3 prescribers and >3 pharmacists or receiving a prescription of opioids with a mean daily morphine equivalent dose of ≥90 mg by >4 prescribers) were applied and results matched with diagnoses of OUD or overdose in that period or within the following 12 months.
Results: “The proportion of beneficiaries who met CMS overutilization criteria during any 6-month cycle ranged from 0.37% to 0.58%. The proportion who had a diagnosis of OUD or overdose during the 18-month follow-up increased from 3.91% in the first cycle to 7.55% in the last. We observed low sensitivity of the criteria, ranging from 4.96% (95% CI, 4.42%–5.58%) at the beginning of the study period to 2.52% (95% CI, 2.26%–2.81%) at the end (P for trend <.001) and positive predictive values ranged from 35.20% (95% CI, 32.14%–38.38%) to 50.94% (95% CI, 47.00%–54.86%; P for trend <.001). Specificity was greater than 99% in all cycles.”
Medicare Part D Buprenorphine Coverage: Despite its importance in treating individuals with opioid use disorder (OUD), buprenorphine is often placed in restricted categories by Medicare Part D plans (pp. 607–9; D. M. Hartung, hartungd@ohsu.edu).
PICO: Buprenorphine coverage as shown in Medicare Part D prescription drug plan formulary files in Jan. 2007, 2012, and 2018.
Results: “The proportion of plans covering any buprenorphine product without restriction declined from 89% (95% CI, 87%–91%) in 2007 to 35% (95% CI, 31%–39%) in 2018 (P < .001). By comparison, 93% to 100% of plans covered the most frequently used prescription opioid analgesics without coverage restrictions during the study period.”

PNN Pharmacotherapy Line
Feb. 14, 2019 * Vol. 26, No. 31
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Feb. 14 issue of the New England Journal of Medicine (2019; 380).
Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer: Adjuvant trastuzumab emtansine (T-DM1; an antibody–cytotoxic drug combination) lowered the risk of recurrence of invasive breast cancer by 50%, compared with transtuzumab alone, in patients with human epidermal growth factor receptor 2 (HER2)–positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, KATHERINE investigators report (pp. 617–28; G. von Minckwitz, vonminckwitz@gbg.de).
PICO: Phase 3, open-label trial of patients with HER2-positive early breast cancer with residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab; randomly assigned to adjuvant T-DM1 or trastuzumab for 14 cycles; primary end point was invasive disease–free survival (freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).
Results: “At the interim analysis, among 1,486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P <0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.”
Editorial: “The trial by von Minckwitz and colleagues is a game changer,” writes an editorialist (pp. 676–7; D. F. Hayes). “It suggests that neoadjuvant chemotherapy with trastuzumab, with or without pertuzumab, is the standard of care for patients with newly diagnosed HER2-positive breast cancer, especially those with stage II or III disease. This approach has the ability to reduce the extent of local treatment. More important, it will guide postoperative systemic therapy. If patients do not have a pathological complete response with such a regimen, postoperative treatment with T-DM1 offers a major opportunity to improve long-term outcomes. Caveat emptor: doctors and patients need to be aware that the side effects of this regimen are more common than with trastuzumab alone, and occasional severe toxic effects need to be considered. Therefore, T-DM1 should not be used in patients with a pathological complete response or in those with stage I disease; these patients have a very favorable outcome with adjuvant paclitaxel and trastuzumab alone. Nonetheless, this trial is one more step toward personalized medicine and reduced mortality among patients with early-stage breast cancer.”
Perspective: In a Perspective article, authors assess the current status of research into management of hormone receptor–positive breast cancer and use of the pathological complete response rate as a new regulatory end point to expedite development of drugs for high-risk early breast cancer: “Although there has been recent progress in risk stratification in hormone receptor–positive breast cancer, we need more sophisticated prognostic-biomarker testing to identify high-risk patients in time to intervene and improve outcomes. The availability of resected residual disease tissue provides opportunities to explore biomarker correlates that may be predictive of response to new agents. With a greater understanding of which patients derive benefit from the new agent, subsequent trials could evaluate the drug preoperatively in a more targeted population. Meanwhile, residual disease after neoadjuvant treatment should be considered an important biomarker for patient selection in clinical trials in early breast cancer. Its use will increase both efficiency and the likelihood of success in developing new agents for patients with the greatest unmet need.”

PNN Pharmacotherapy Line
Feb. 15, 2019 * Vol. 26, No. 32
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
 Mar. 1 issue of Clinical Infectious Diseases (2019; 68).
Antimicrobial Stewardship & ICU Mortality: Antimicrobial stewardship programs (ASP) have not affected mortality rates in intensive care units, according to results of a systematic review of 11 studies (pp. 748–65; M. P. Muller, mullerm@smh.ca).
Results: “Although a variety of study designs were used to assess reductions in antibiotic use, mortality was analyzed using an uncontrolled before-after study design in all studies. Five studies directed audit and feedback to all or most ICU patients receiving antibiotics and measured overall ICU mortality. In the meta-analysis of these studies, the pooled relative risk of ICU mortality was 1.03 (95% confidence interval, .93–1.14). A second meta-analysis of 3 smaller studies that evaluated mortality only in patients directly assessed by the ASP found a pooled relative risk of ICU mortality of 1.06 (95% confidence interval, .80 to 1.4). Three studies were not appropriate for meta-analysis, but their results were consistent with our overall findings.”
qHPV Vaccine Efficacy in Women Living With HIV: Girls and women living with HIV (WLWH) have higher vaccine failure rates following receipt of the quadrivalent human papillomavirus (qHPV) vaccine, compared with girls and women without the infection, researchers report (pp. 788–94; D. Money, deborah.money@ubc.ca).
PICO: 420 girls and women aged 9 to 65 years living with HIV; vaccine failure defined as incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher (CIN2+), or genital warts; vaccine failure rates compared with historical figures from published rates in vaccinated and unvaccinated women without HIV.
Results: “In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person–years (/100PY) (95% confidence interval [CI], 1.1–4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2–4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3–2.6) and of genital warts was 1.0/100PY (95% CI, 0.3–2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02–0.03), 1.5 (95% CI, 1.1–2.0), and 1.2 (95% CI, 0.2–3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY).”
>>>PNN NewsWatch
* In an interim report of effectiveness of the 2018–19 influenza vaccines, the CDC yesterday reported an adjusted VE figure of 46% in the current relatively mild season among patients with medically attended acute respiratory illness and cough. Overall, 43% of patients with ARI had received the influenza vaccine, and all age groups had positive VEs except those aged 50 years or older (VE 8, 95% CI –59 to 46). The MMWR report noted that VE estimates based on influenza vaccine production method (egg, cell culture, recombinant antigen) are not yet available. In a second MMWR report, the CDC says 28 laboratory-confirmed pediatric deaths have occurred in 21 states and New York City. During the 2017–18 season, vaccination averted an estimated 7.1 million illnesses, 3.7 million medical visits, 109,000 influenza-associated hospitalizations, and 8,000 influenza-associated deaths, CDC estimates. Pediatric deaths last season set a record of 185.
FDA yesterday permitted marketing of the Tandem Diabetes Care t:Slim X2 insulin pump (Tandem Diabetes Care) with interoperable technology (interoperable t:Slim X2) for delivering insulin under the skin for children and adults with diabetes. This new type of insulin pump, referred to as an alternate controller enabled (ACE) infusion pump, is the first interoperable pump (can be used with different components that make up diabetes therapy systems), allowing patients to tailor their diabetes management to their individual device preferences. Diabetes therapy systems may comprise an ACE insulin pump and other compatible medical devices, including automated insulin dosing systems, continuous glucose monitors, blood glucose meters, or other electronic devices used for diabetes management, FDA said.
PNN will not be published on Mon., Feb. 18, Presidents Day.

PNN Pharmacotherapy Line
Feb. 19, 2019 * Vol. 26, No. 33
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Feb. 19 issue of the Annals of Internal Medicine (2019; 170).
Cost-Effectiveness of Alirocumab: Based on data from the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the U.S. price of alirocumab would have to be reduced considerably to be cost-effective compared with ezetimibe, researchers report (pp. 221–9; K. Bibbins-Domingo, Kirsten.Bibbins-Domingo@ucsf.edu).
PICO: Cost-effectiveness analysis of interventions in U.S. adults with a recent first myocardial infarction (MI) and a baseline low-density lipoprotein cholesterol level of ≥1.81 mmol/L (70 mg/dL); lifetime horizon; U.S. health system perspective; alirocumab or ezetimibe added to statin therapy.
Results: “Compared with a statin alone, the addition of ezetimibe cost $81,000 (95% uncertainty interval [UI], $51,000 to $215,000) per QALY. Compared with a statin alone, the addition of alirocumab cost $308,000 (UI, $197,000 to $678,000) per QALY. Compared with the combination of statin and ezetimibe, replacing ezetimibe with alirocumab cost $997,000 (UI, $254,000 to dominated) per QALY.… The price of alirocumab would have to decrease from its original cost of $14,560 to $1,974 annually to be cost-effective relative to ezetimibe.”
Editorial: “Newer biologic agents can target disease pathways more precisely and promise to improve the outcomes of many diseases, including cancer, infectious diseases, and autoimmune disorders,” (pp. 264–5; M.A. Hlatky, hlatky@stanford.edu). “The price tags of up to $100,000 a year for these new drugs, however, pose a major challenge to health care systems. Expensive new treatments that cure a fatal disease or eliminate disabling symptoms may well provide sufficient value to justify their high prices. Preventive therapies that slow the progression of atherosclerosis neither cure the disease nor reduce its symptoms, so their potential benefits are more limited; therefore, spending $5,000 or more a year to lower cholesterol levels is harder to justify. The economics of PCSK9 inhibitors are a cautionary tale, because the price point that yields good value for patients and society is well below what manufacturers are charging. We need to find policies that reward the development of breakthrough drugs without breaking the bank.”
>>>Lancet Report
Source:
 Feb. 16 issue of Lancet (2019; 393).
Lomustine-Temozolomide in Glioblastoma With Methylated MGMT Promoter: In patients with newly diagnosed glioblastoma with methylated MGMT promoter, lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy, according to findings from the CeTeG/NOA-09 trial (pp. 678–88; U. Herrlinger, ulrich.herrlinger@ukbonn.de).
PICO: Open-label, randomized, phase 3 trial of 141 adult patients at 17 German hospitals who were newly diagnosed glioblastoma with methylated MGMT promoter and had a Karnofsky Performance Score of 70% and higher; primary endpoint was overall survival in the modified intention-to-treat population.
Results: “Median overall survival was improved from 31.4 months (95% CI 27.7–47.1) with temozolomide to 48.1 months (32.6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0.60, 95% CI 0.35–1.03; p = 0.0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n = 141, HR 0.60, 95% CI 0.35–1.03; p = 0.0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths.”
>>>PNN JournalWatch
* Effectiveness and Safety of Electronically Delivered Prescribing Feedback and Decision Support on Antibiotic Use for Respiratory Illness in Primary Care: REDUCE Cluster Randomised Trial, in BMJ, 2019; 364: l236. (M. C. Gulliford, martin.gulliford@kcl.ac.uk)
* Assessing the Scope and Appropriateness of Prescribing Cascades, in 
Journal of the American Geriatrics Society, 2019; 10.1111/jgs.15800. (L. M. McCarthy, lisa.mccarthy@utoronto.ca)
* Treatment of Urticarial Vasculitis: A Systematic Review, in 
Journal of Allergy and Clinical Immunology, 2019; 143: 458–66. (M. Maurer, marcus.maurer@charite.de)

PNN Pharmacotherapy Line
Feb. 20, 2019 * Vol. 26, No. 34
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Feb. 19 issue of JAMA (2019; 321).
REMS for Transmucosal Immediate-Release Fentanyl: High levels of knowledge among pharmacists, prescribers, and patients were documented after implementation of FDA’s Risk Evaluation and Mitigation Strategy (REMS) for transmucosal immediate-release fentanyls (TIRFs) (pp. 676–85; G. C. Alexander, galexan9@jhmi.edu).
PICO: Qualitative analysis of 6 annual REMS assessment reports (2012–17) and related documents, reports, and correspondence.
Results: “Twelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing.”
Editorial: “For REMS to ensure safe use of clinically useful prescription drugs with potentially significant adverse effects, the FDA will need to be more assertive in requesting specific analyses pertaining to the performance of REMS programs and in restructuring [elements to assure safe use (ETASU)] in response to concerns the analyses raise,” editorialists write (pp. 621–3; A. Sarpatwari, asarpatwari@bwh.harvard.edu). The writers note that documents contained no instances of any instances of inappropriate prescribing or corrective actions involving the 8,100 physicians in the program and that 1 of the 8 companies whose products was covered by the REMS was involved in a “nationwide conspiracy to bribe physicians to prescribe its fentanyl spray (Subsys) for off-label use.” They add, “These findings highlight not just deficiencies with the structure and administration of the TIRF REMS, but problems with the REMS system more generally. Although the FDA has taken steps to improve this system in recent years, including efforts to standardize, integrate, and evaluate REMS programs, additional action is needed.”
Opioid Prescribing Limits for Acute Pain: Examining the appropriate limits on opioid prescribing for management of acute pain, Viewpoint authors write, “To mitigate the potential for unintended effects, states, insurers, pharmacies, and pharmacy benefit managers could implement a coordinated set of prescribing limits that could help minimize conflicts and confusion” (pp. 643–4; K-P Chua, chuak@med.umich.edu). “To prevent both excessive and inadequate opioid prescribing, clinicians could use data on patient-reported opioid consumption to develop condition-specific prescribing guidelines. Early studies suggest that such guidelines may reduce prescribing to levels that better reflect the need of the typical patient without increasing the need for refills of opioid prescriptions. Moreover, guidelines for opioid prescribing that are informed by patient experience may secure more clinician agreement than prescribing limits designed mostly in the absence of data, potentially decreasing the motivation for gaming behavior. Thus, guidelines could prevent excessive prescribing in a manner that is more clinically nuanced, patient-centered, and evidence-based than blunt regulatory approaches alone.”
Replacing Opioids With Cannabis: Viewpoint authors ask, “Should physicians recommend replacing opioids with cannabis?” (pp. 639–40; R. Saitz, richard.saitz@jamanetwork.org). Cannabis and its derivatives need more research, the authors conclude, adding, “For the opioid addiction crisis, clearly efficacious medications such as methadone and buprenorphine are underprescribed. Without convincing evidence of efficacy of cannabis for this indication, it would be irresponsible for medicine to exacerbate this problem by encouraging patients with opioid addiction to stop taking these medications and to rely instead on unproven cannabis treatment.”

PNN Pharmacotherapy Line
Feb. 21, 2019 * Vol. 26, No. 35
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Feb. 21 New England Journal of Medicine (2019; 380).
DOAC Thromboprophylaxis in Ambulatory Patients With Cancer: Research studies and an editorialist look at use of apixaban and rivaroxaban in managing venous thromboembolism risk in ambulatory patients with cancer. 
First Study: Among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy, apixaban significantly lowered rates of venous thromboembolism compared with placebo, AVERT investigators report (pp. 720–8; A. K. Khorana, khorana@ccf.org).
PICO: Randomized, placebo-controlled, double-blind clinical trial of apixaban 2.5 mg twice daily; primary efficacy outcome of objectively documented venous thromboembolism over 180 days; main safety outcome of major bleeding episode.
Results: “Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P <0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24).”
Second Study: In the CASSINI trial, high-risk ambulatory patients with cancer had statistically similar incidences of venous thromboembolism or death over a 180-day trial period; events were reduced during a prespecified intervention period (first to last dose plus 2 days). 
PICO: Randomized, placebo-controlled, double-blind trial of rivaroxaban 10 mg for up to 180 days with screening every 8 weeks; primary efficacy end point of a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, or death from venous thromboembolism.
Results: “Of 1,080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).”
Editorial: “Although the evidence provided by the two trials is quite compelling, some clinicians could still be reluctant to change their practice,” writes an editorialist in addressing the “will these studies change practice” question (pp. 781–3; G. Agnelli). “Indeed, some of the most common cancers, such as colorectal, breast, and prostate cancers, were underrepresented in the two trials. The Khorana score, the cornerstone of the two trials, has been shown to perform poorly in some cancer types, such as lung cancer, which accounts for 13% of all cancers and 24% of cancer deaths in the United States. Furthermore, this score does not take into account the chemotherapy regimen. All these considerations may limit the generalizability of the AVERT and CASSINI trials, and some clinicians may consider that data on individual cancer types or individual chemotherapy agents are required before prophylaxis can be generally accepted.”
Other Studies: Also in this issue of NEJM are research studies showing that once-daily plazomicin is noninferior to meropenem for treatment of complicated UTIs and acute pyelonephritis (pp. 729–40; F. M. E. Wagenlehner, florian.wagenlehner@chiru.med.uni-giessen.de); sacituzumab govitecan-hziy is effective in metastatic triple-negative breast cancer (pp. 741–51; A. Bardia, bardia.aditya@mgh.harvard.edu), and low-dose methotrexate did not prevent atherosclerotic events (pp. 752–62; P. M. Ridker, pridker@bwh.harvard.edu).

PNN Pharmacotherapy Line
Feb. 22, 2019 * Vol. 26, No. 36
Providing news and information about medications and their proper use

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>>>Geriatrics Highlights
Source:
 Feb. issue of the Journal of the American Geriatrics Society (2019; 67).
Pharmacotherapy in Older Adults with CVD: “The needs and circumstances of older adults with [cardiovascular disease (CVD)] differ from those that the current medical system has been designed to meet,” concludes a report of a workshop sponsored by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society (pp. 371–80; J. B. Schwartz, janice.schwartz@ucsf.edu). The report, previously reported in PNN (see Dec. 21, 2018), also notes: “Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person-centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices.”
Editorial: “Multispecialty efforts to transform care of older adults to a seamless, patient-centered focus are igniting in a broadening array of disciplines,” editorialists conclude (pp. 205–7; D. E. Forman). Commenting on the workshop report, the authors write: “Polypharmacy may be reduced through prescribing consistent with specific patients’ current goals of care and cognizant of the dynamic impact of aging on the changing status of baseline function, comorbidities, time to benefit/time to harm, and life expectancy. Additional strategies targeting ‘too many drugs’ include deprescribing, personalized and precision medicine tactics, and enhanced monitoring of drug regimens and patient goals. Improvements in meaningful outcomes-based evidence to support ideal prescribing in older adults and methods augmenting adherence could address ‘too little medication.’ Rapidly evolving technology that facilitates communication, monitoring, personalized decision making, and goal setting could prove especially useful.”
>>>Allergy/Immunology Report
Source:
 Feb. issue of the Journal of Allergy and Clinical Immunology (2019; 143).
School-Supervised Inhaled Corticosteroids: School-supervised use of a once-daily inhaled corticosteroid regimen (supervised therapy) had no significant effect on asthma control in elementary school students (pp. 755–64; J. K. Gerald, geraldj@email.arizona.edu).
PICO: Cluster randomized trial of 20 elementary schools with a disproportionate enrollment of low-income Latino students; 9 months of supervised therapy with mometasone furoate or usual care; Asthma Control Questionnaire (ACQ) was interviewer administered quarterly at school.
Results: “Of 393 enrolled students, 189 students receiving immediate intervention and 143 students receiving delayed intervention provided 1 or more ACQ data points, were between 6 and 10 years of age, and were included in the primary analysis. At baseline, 39% of students reported taking a controller medication, and 24% had well-controlled asthma. Eighty percent of students receiving immediate intervention were prescribed mometasone. Schools administered 98% of prescribed doses when students attended school. Absences, weekends, and holidays reduced calendar adherence to 53%. During the first year, the mean ACQ score for students receiving immediate and delayed intervention was 1.55 (95% CI, 1.41–1.70) and 1.64 (95% CI, 1.47–1.80), respectively. The estimated treatment effect was −0.08 (95% CI, −0.31 to 0.14).”
>>>PNN NewsWatch
FDA yesterday issued a proposed rule that would update regulatory requirements for most sunscreen products to better ensure consumers have access to safe and effective preventive sun care options. Among its provisions, the proposal addresses sunscreen active ingredient safety, dosage forms, and sun protection factor and broad-spectrum requirements. It also proposes updates to how products are labeled to make it easier for consumers to identify key product information.
FDA has also issued a draft guidance“Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products.” It provides a framework for new potential clinically relevant outcomes for smoking cessation products, such as reducing the long-term risks of a smoker going back to using cigarettes.

PNN Pharmacotherapy Line
Feb. 25, 2019 * Vol. 26, No. 37
Providing news and information about medications and their proper use

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>>>Lancet Report
Source:
 Feb. 23 issue of Lancet (2019; 393).
Monthly Buprenorphine Depot Injection for OUD: Availability of a monthly depot buprenorphine formulation (BUP-XR) “represents an advance in treatment for opioid use disorder that enhances the benefits of buprenorphine by delivering sustained, optimal exposure, while reducing risks of current buprenorphine products,” conclude authors of a multicenter study (pp. 778–90; M. K. Greenwald, mgreen@med.wayne.edu).
PICO: Randomized, double-blind, placebo-controlled trial of 504 patients with moderate or severe opioid use disorder at 36 U.S. treatment centers; participants received BUP-XR 300 mg/300 mg, BUP-XR 300 mg/100 mg, or placebo every 28 days, and weekly individual drug counselling; primary efficacy endpoint of participants’ percentage abstinence from opioid use based on negative urine samples and self-reports of illicit opioid use from week 5 to week 24.
Results: “Mean participants’ percentage abstinence was 41.3% (SD 39.7) for BUP-XR 300 mg/300 mg and 42.7% (38.5) for 300 mg/100 mg, compared with 5.0% (17.0) for placebo (p <0.0001 for both BUP-XR regimens). No compensatory non-opioid drug use was observed during BUP-XR treatment. The most common adverse events were headache (17 [8%] participants in the BUP-XR 300 mg/300 mg group vs 19 [9%] participants in the BUP-XR 300 mg/100 mg group vs six [6%] participants in the placebo group), constipation (16 [8%] vs 19 [9%] vs 0), nausea (16 [8%] vs 18 [9%] vs five [5%]), and injection-site pruritis (19 [9%] vs 13 [6%] vs four [4%]). The BUP-XR safety profile was consistent with other buprenorphine products for treatment of opioid use disorder, except for injection-site reactions, which were reported in more than 5% of all participants who received BUP-XR, but were mostly mild and not treatment-limiting.”
Drug Treatments for Generalized Anxiety Disorder: For treating patients with generalized anxiety disorder, clinicians have several effective treatment choices, researchers report, and “failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy” (pp. 768–77; N. Freemantle, nicholas.freemantle@ucl.ac.uk).
PICO: Systematic review and network meta-analysis of 89 trials of 29,441 participants.
Results: “Duloxetine ([mean difference (MD) in change in Hamilton Anxiety Scale Score] −3.13, 95% credible interval [CrI] −4.13 to −2.13), pregabalin (MD −2.79, 95% CrI −3.69 to −1.91), venlafaxine (MD −2.69, 95% CrI −3.50 to −1.89), and escitalopram (MD −2.45, 95% CrI −3.27 to −1.63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD −3.60 95% CrI −4.83 to −2.39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1.44, 95% CrI 1.16–1.80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias.”
>>>PNN NewsWatch
FDA on Friday added a boxed warning to the product labeling of febuxostat (Uloric, Takeda) cautioning of an increased mortality risk with the antigout drug compared with allopurinol. The action was based on data from a safety study published last March showing significant increases in all-cause and cardiovascular mortality among those on the drug. The action pushes febuxostat to a second-line position, with use only in patients who have failed or do not tolerate allopurinol, FDA said. Patients should watch for chest pain, shortness of breath, rapid or irregular heartbeat, one-sided numbness or weakness, dizziness, trouble talking, or sudden severe headache.
>>>PNN JournalWatch
* Proceedings of the American College of Rheumatology/Association of Physicians of Great Britain and Ireland Connective Tissue Disease–Associated Interstitial Lung Disease Summit: A Multidisciplinary Approach to Address Challenges and Opportunities, in Arthritis & Rheumatology2019; 71: 182–95. (A. Fischer, aryeh.fischer@ucdenver.edu)
* Hospital Prices Grew Substantially Faster Than Physician Prices for Hospital-Based Care In 2007–14, in 
Health Affairs2019; 38: 184–9. (Z. Cooper, zack.cooper@yale.edu)

PNN Pharmacotherapy Line
Feb. 26, 2019 * Vol. 26, No. 38
Providing news and information about medications and their proper use

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>>>Diabetes Highlights
Source:
 Mar. issue of Diabetes Care (2019; 42).
T2D, Insulins & Breast Cancer: In a Dutch study, type 2 diabetes but not therapy with insulin or its analogues is linked to increased risk of a more aggressive type of breast cancer (pp. 434–42; J. A. Overbeek, jetty.overbeek@pharmo.nl).
PICO: Nested case-control study of 33,377 women with breast cancer diagnosed in 2002–14 in the linked Netherlands Cancer Registry–PHARMO Database Network; two or more dispensings of noninsulin blood glucose–lowering drugs prior to breast cancer diagnosis defined T2M; comparisons made using multivariable ordinal logistic regression.
Results: “Women with T2D (n = 1,567) were more often diagnosed with a more advanced tumor stage (odds ratio 1.28 [95% CI 13–1.44]) and a higher grade (1.22 [1.08–1.39]) though less often with a PR-negative breast tumor (0.77 [0.67–0.89]) than women without diabetes (n = 6,267). No associations were found for the other breast cancer characteristics. Women with T2D using insulin (n = 388) were not diagnosed with different breast cancer characteristics compared with women with T2D not using insulin (n = 1,179).”
Exenatide for Inpatient Management of Type 2 Diabetes: For management of hospitalized general medical and surgical patients with type 2 diabetes (T2D), exenatide alone or in combination with basal insulin is safe and effective, researchers report (pp. 450–6; G. E. Umpierrez, geumpie@emory.edu).
PICO: 150 patients with blood glucose (BG) of 140–400 mg/dL, treated at home with diet, oral agents, or insulin at a total daily dose <0.5 units/kg; randomized to exenatide 5 μg twice daily, exenatide plus basal insulin, or basal-bolus insulin; primary end point of difference in mean daily BG concentration among groups.
Results: “Mean daily BG was similar between patients treated with exenatide plus basal and a basal-bolus regimen (154 ± 39 vs. 166 ± 40 mg/dL, P = 0.31), and exenatide plus basal resulted in lower daily BG than did exenatide alone (177 ± 41 mg/dL, P = 0.02). Exenatide plus basal resulted in a higher proportion of BG levels in target range between 70 and 180 mg/dL compared with exenatide and basal-bolus (78% vs. 62% vs. 63%, respectively, P = 0.023). More patients in the exenatide and exenatide plus basal groups experienced nausea or vomiting than in the basal-bolus group (10% vs. 11% vs. 2%, P = 0.17), with three patients (6%) discontinued exenatide owing to adverse events. There were no differences in hypoglycemia <54 mg/dL (2% vs. 0% vs. 4%, P = 0.77) or length of stay (5 vs. 4 vs. 4 days, P = 0.23) among basal plus exenatide, exenatide, and basal-bolus groups.”
Metformin for Gestational Diabetes Mellitus: Authors review the evidence for use of metformin in management of gestational diabetes (pp. 396–9; L. A. Barbour, lynn.barbour@ucdenver.edu): “Given the rapidly growing population of women diagnosed with gestational diabetes mellitus (GDM), approximating 1 in 7 pregnancies globally, in conjunction with the rising cost of insulins and lack of affordability, the popularity of using an oral agent such as metformin is expanding enormously. In fact, a number of organizations have supported its use as an alternative to insulin. However, recent long-term studies on offspring have provided conflicting results, with two of three studies recently published on the 4- to 9-year-old children of mothers with GDM or polycystic ovarian syndrome (PCOS) suggesting some long-term metabolic programming effects on the offspring. This has given some clinical investigators and organizations pause in embracing metformin as equivalent to insulin ”
>>>Kidney Diseases Report
Source:
 Mar. American Journal of Kidney Diseases (2019; 73).
Calcimimetics & Bundled Reimbursement: Changes in CMS reimbursement policies resulting from marketing of an injectable calcimimetic (etelcalcetide) have the potential to create poor transitions from injectable to oral-only agents covered only under Medicare Part D, review authors write (pp. 385–90; E. Lin, eugeneli@usc.edu): “The complexity of bone-mineral management in conjunction with the paucity of evidence-based recommendations in this area makes it difficult to predict the impact of this transition.… To ensure that patients are not adversely affected, it is critical that Medicare incorporate these medications into the bundle carefully, with close monitoring of outcomes.”

PNN Pharmacotherapy Line
Feb. 27, 2019 * Vol. 26, No. 39
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Feb. 26 issue of JAMA (2019; 321).
Managing Blood Cholesterol: “Pharmacologically lowering low-density lipoprotein cholesterol (LDL-C) consistently reduces [atherosclerotic cardiovascular disease (ASCVD)] events (myocardial infarction, stroke, and cardiovascular death), and the principle that lower LDL-C is better was reaffirmed by trials that added ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to statin therapy,” write authors of a JAMA Clinical Guidelines Synopsis article discussing the 2018 Guideline on the Management of Blood Cholesterol from the American Heart Association (AHA) and American College of Cardiology (ACC) (pp. 800–1; A. M. Davis, amd@uchicago.edu).
Summary: “The current guideline is the first from the AHA/ACC to suggest selected use of ezetimibe and PCSK9 inhibitors based on information from high-quality clinical trials. Those trials support the ‘LDL hypothesis’ that LDL-C is a major atherogenic factor and that lowering it, even to very low levels, reduces ASCVD events across a spectrum of risk. This has led to the resurrection of LDL-C goals. The new guideline also includes special sections for pediatric, young adult, and elderly populations and risk-enhancing factors beyond basic risk percentage for clinician-patient risk discussion, such as metabolic syndrome, chronic kidney disease, family history of early ASCVD (in men, age <55 years; in women, age <65 years), premature menopause, inflammatory conditions, some biomarkers, and South Asian ancestry.”
Editorial: “The 2018 lipid guideline represents a significant and positive step forward for cardiovascular disease prevention,” write editorialists (pp. 749–50; E. Peterson, eric.peterson@duke.edu). “While no guideline is perfect, if the algorithms in these new guidelines were followed, thousands if not millions of people worldwide each year would be able to avoid CVD events. However, the uptake and translation of guidelines into practice has been historically poor. Even in the United States, which spends more on health care than any other country, more than half of all residents did not meet the 2013 less stringent lipid management guidelines recommendations. Moving forward, the United States will need to do better to improve individual and population health. Ideally, the increased use of electronic medical records, computer-aided clinical decision support, and team-based care models could assist in the appropriate application of these algorithms for management of cholesterol levels in community practice.”
Patient-Centered Transitional Care Services for HF: In Ontario, patients with heart failure (HF) overall fared no better following implementation of a patient-centered transitional care model compared with usual care (pp. 753–61; H. G. C. Van Spall, harriette.vanspall@phri.ca).
PICO: Stepped-wedge cluster randomized trial of 2,494 adults hospitalized for HF in 2015–16; intervention of nurse-led self-care education, structured hospital discharge summary, family physician follow-up appointment less than 1 week after discharge, and, for high-risk patients, structured nurse homevisits and heart function clinic care were provided to patients, or usual care; primary outcomes of composite all-cause readmission, emergency department (ED) visit, or death at 3 months; and composite all-cause readmission or ED visit at 30 days.
Results: “There was no significant difference between the intervention and usual care groups in the first primary composite outcome (545 [49.4%] vs 698 [50.2%] events, respectively; hazard ratio [HR], 0.99 [95% CI, 0.83–1.19]) or in the second primary composite outcome (304 [27.5%] vs 408 [29.3%] events, respectively; HR, 0.93 [95% CI, 0.73–1.18]). There were significant differences between the intervention and usual care groups in the secondary outcomes of mean B-PREPARED score at 6 weeks (16.6 vs 13.9; difference, 2.65 [95% CI, 1.37–3.92]; P < .001); mean [3-Item Care Transitions Measure] score at 6 weeks (76.5 vs 70.3; difference, 6.16 [95% CI, 0.90-11.43]; P = .02); and mean [quality of life] score at 6 weeks (0.7 vs 0.7; difference, 0.06 [95% CI, 0.01 to 0.11]; P = .02) and 6 months (0.7 vs 0.6; difference, 0.06 [95% CI, 0.01-0.12]; P = .02). There was no significant difference in mean [quality-adjusted life-years] between groups at 6 months (0.3 vs 0.3; difference, 0.00 [95% CI, −0.02 to 0.02]; P = .98).”

PNN Pharmacotherapy Line
Feb. 28, 2019 * Vol. 26, No. 40
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Feb. 28 issue of the New England Journal of Medicine (2019; 380).
PADI3 Mutations in Central Centrifugal Cicatricial Alopecia: Researchers studying the most common form of scarring alopecia among women of African ancestry identify mutations affecting a hair-shaft formation protein, peptidyl arginine deiminase, type III (PADI3), that are associated with central centrifugal cicatricial alopecia (CCCA) (pp. 833–41; E. Sprecher, elisp@tlvmc.gov.il).
PICO: Exome sequencing in women with alopecia (discovery set) were compared with results from a public repository and filtered to identify candidate genes; direct sequencing used to identify associated factors; replication set of women with CCCA used for confirmation.
Results: “In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3 in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.).… All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity — findings that support their pathogenicity.…”
Editorial: “[These observations] suggest that PADI3 mutations predispose persons to CCCA, which is then clinically manifested when hairstyling practices damage the hair,” (pp. 873–6; J. Uitto). “Thus, in the familial setting, such practices should be discouraged in both symptomatic and asymptomatic family members. Although PADI3 mutations would appear to predispose women to CCCA, the screening of asymptomatic women for pathogenic mutations in PADI3 would be premature. Perhaps, once the association is tested in larger groups of women and the effect on risk is better understood and there is a comprehensive genomic landscape of CCCA (i.e., other risk variants and genes are identified and their effect on risk delineated), genotyping of asymptomatic women would be warranted. The presence of variants in PADI3 in both CCCA and uncombable hair syndrome suggests that this gene has a pleiotropic effect on the determination of hair texture, and the finding holds implications for future development of therapy, such as the restoration of PADI3 activity.”
Bag-Mask Ventilation During Tracheal Intubation: Bag-mask ventilation of critically ill patients during tracheal intubation produced significantly higher oxygen saturation and fewer severe hypoxemia events in a comparison with no ventilation (pp. 811–21; J. D. Casey, jonathan.d.casey@vumc.org).
PICO: Multicenter, randomized trial in seven U.S. intensive care units of adults undergoing tracheal intubation comparing ventilation with a bag-mask device or no ventilation between induction and laryngoscopy; primary outcome of the lowest oxygen saturation observed during the interval between induction and 2 minutes after tracheal intubation.
Results: “Among the 401 patients enrolled, the median lowest oxygen saturation was 96% (interquartile range, 87 to 99) in the bag-mask ventilation group and 93% (interquartile range, 81 to 99) in the no-ventilation group (P = 0.01). A total of 21 patients (10.9%) in the bag-mask ventilation group had severe hypoxemia, as compared with 45 patients (22.8%) in the no-ventilation group (relative risk, 0.48; 95% confidence interval [CI], 0.30 to 0.77). Operator-reported aspiration occurred during 2.5% of intubations in the bag-mask ventilation group and during 4.0% in the no-ventilation group (P=0.41). The incidence of new opacity on chest radiography in the 48 hours after tracheal intubation was 16.4% and 14.8%, respectively (P=0.73).”
Editorial: “In the eyes of all clinicians managing airways in the ICU, the results of this rigorous, multicenter trial may not settle the question of the safety of bag-mask ventilation during rapid-sequence intubation,” (pp. 870–1; P. A. Kritek). “However, the findings provide a strong suggestion that the practice is not harmful. More important, they show the feasibility of conducting a well-designed trial with the goal of questioning one of the long-standing dogmas that too often restrict our clinical practice.”

PNN Pharmacotherapy Line
Mar. 1, 2019 * Vol. 26, No. 41
Providing news and information about medications and their proper use

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>>>Pediatrics Report
Source:
 Mar. issue of Pediatrics (2019; 143).
Palivizumab in Young Infants With RSV Bronchiolitis: Used for treating acute respiratory syncytial virus (RSV)–positive bronchiolitis, “intravenous palivizumab did not appear to help or harm young infants,” researchers report (10.1542/peds.2018-2308; K. Alansari). The monoclonal antibody is recommended for prophylaxis during bronchiolitis seasons; the study was conducted to assess efficacy in treatment.
PICO: 413 infants 3 months of age or younger (median age 49 days) presenting to a pediatric emergency service with RSV-positive bronchiolitis requiring inpatient admission were randomized to single-dose I.V. palivizumab 15 mg/kg or placebo; primary efficacy outcome of inpatient readmission in the 3 weeks after discharge. 
Results: “Readmission during follow-up was needed for 23 (11%) patients on palivizumab and 19 (9.3%) patients in the placebo group (difference 1.8%; 95% confidence interval −4.4% to 7.7%; P = .51). Geometric mean time to readiness for discharge was 29.5 hours for the palivizumab group and 30.2 hours for the placebo group (ratio 0.98; 95% confidence interval 0.81 to 1.20). No safety issues were reported.”
Nonmedical Rx Opioid Use by U.S. Parents, Adolescents: When targeting nonmedical prescription opioid (NMPO) in adolescents, parental NMPO use and smoking need to be addressed along with positive parenting, according to a U.S. study of intergenerational patterns of NMPO use (10.1542/peds.2018-2354; P. C. Griesler).
PICO: 35,000 parent-child dyads with an adolescent aged 12–17 years from the 2004–12 National Surveys on Drug Use and Health; multivariable logistic regression models used to assess association between self-reported parental and adolescent lifetime NMPO use and attitudes about drug use, parental and adolescent psychosocial risk factors, and sociodemographic characteristics.
Results: “Controlling for other factors, parental NMPO use was associated with adolescent NMPO use (adjusted odds ratio [aOR] 1.30; 95% confidence interval [CI] 1.09–1.56). Mothers’ use had a stronger association with adolescent use than fathers’ use (aOR 1.62 [95% CI 1.28–2.056] versus aOR 0.98 [95% CI 0.74–1.24]). Associations between parental and adolescent NMPO use did not differ by adolescent sex or race and/or ethnicity. Parental lifetime smoking, low monitoring, and parent-adolescent conflict were uniquely associated with adolescent NMPO use (aOR 1.19–1.24) as were adolescent smoking, marijuana use, depression, delinquency, and perceived schoolmates’ drug use (aOR 1.25–1.71). Perceived risk of drug use and religiosity were associated with lower rates of adolescent NMPO use (aOR 0.77–0.93). Use among older adolescents was higher than among younger adolescents (aOR 1.27; 95% CI 1.21–1.34).”
Sleep Problems & Autism, Developmental Delays: “Pediatricians and health care providers who see children with [autism spectrum disorder or a neurodevelopmental disorder should] make sure that sleep is discussed with families and, if there are difficulties, to move beyond brief advice to either carrying out systematic interventions themselves or referring families to get appropriate help,” an editorialist writes (10.1542/peds.2018-2629) in reaction to a study of sleep problems in children with these conditions.
>>>PNN NewsWatch
* A safety clinical trial found an increased risk of pulmonary emboli and death when tofacitinib 10 mg twice daily (Xeljanz, Xeljanz XR) was used in patients with rheumatoid arthritis (RA). FDA has not approved this dose for RA; it is approved only in the dosing regimen for patients with ulcerative colitis, the agency warned this week.
* In 2015 in Oklahoma and Texas, 7.0% of women with a recent live birth reported using 
electronic vapor products (EVPs) shortly before, during, or after pregnancy, with 1.4% reporting use during pregnancy, authors report in this week’s MMWR. Among prenatal EVP users, 38.4% reported using EVPs containing nicotine, and 26.4% did not know if the EVPs they used contained nicotine.
Camber Pharmaceuticals is recalling 87 lots of Losartan Tablets USP 25 mg, 50 mg, and 100 mg to consumer level because of presence of the NMBA contaminant.

PNN Pharmacotherapy Line
Mar. 4, 2019 * Vol. 26, No. 42
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Antibiotic Management of UTIs in Older Adults: Among patients 65 or older with a diagnosis of urinary tract infection (UTI) in U.K. primary care practices, immediate treatment with antibiotics was associated with significantly lower rates of sepsis and all-cause mortality, compared with no antibiotics and deferred antibiotics (l525; P. Aylin, p.aylin@imperial.ac.uk).
PICO: Retrospective population based cohort analysis of 1.5 million older adults in the Clinical Practice Research Database for 2007–15 with links to English hospital and mortality records.
Results: “Among 312,896 UTI episodes (157,264 unique patients), 7.2% (n = 22,534) did not have a record of antibiotics being prescribed and 6.2% (n = 19,292) showed a delay in antibiotic prescribing. 1,539 episodes of bloodstream infection (0.5%) were recorded within 60 days after the initial UTI. The rate of bloodstream infection was significantly higher among those patients not prescribed an antibiotic (2.9%; n = 647) and those recorded as revisiting the general practitioner within seven days of the initial consultation for an antibiotic prescription compared with those given a prescription for an antibiotic at the initial consultation (2.2% v 0.2%; P = 0.001). After adjustment for covariates, patients were significantly more likely to experience a bloodstream infection in the deferred antibiotics group (adjusted odds ratio 7.12, 95% confidence interval 6.22 to 8.14) and no antibiotics group (8.08, 7.12 to 9.16) compared with the immediate antibiotics group. The number needed to harm (NNH) for occurrence of bloodstream infection was lower (greater risk) for the no antibiotics group (NNH = 37) than for the deferred antibiotics group (NNH = 51) compared with the immediate antibiotics group.… Men older than 85 years were particularly at risk for both bloodstream infection and 60 day all cause mortality.”
Editorial: “Prompt treatment should be offered to older patients, men (who are at higher risk than women), and those living in areas of greater socioeconomic deprivation who are at the highest risk of bloodstream infections,” writes an editorialist (l780; A. D. Hay, alastair.hay@bristol.ac.uk). “Further research is needed to establish whether treatment should be initiated with a broad or a narrow spectrum antibiotic and to identify those in whom delaying treatment (while awaiting investigation) is safe.”
Antibiotic Treatment Durations for Common Infections: “Substantial reductions in antibiotic exposure can be accomplished by aligning antibiotic prescription durations with guidelines,” conclude authors of a study of primary-care prescribing in the U.K. (l440; K. B. Pouwels, k.b.pouwels@gmail.com).
PICO: Cross-sectional study of 931,015 consultations in which antibiotics were prescribed in The Health Improvement Network database during 2013–15.
Results: “Antibiotic treatments for upper respiratory tract indications and acute cough and bronchitis accounted for more than two thirds of the total prescriptions considered, and 80% or more of these treatment courses exceeded guideline recommendations. Notable exceptions were acute sinusitis, where only 9.6% (95% confidence interval 9.4% to 9.9%) of prescriptions exceeded seven days and acute sore throat where only 2.1% (2.0% to 2.1%) exceeded 10 days (recent guidance recommends five days). More than half of the antibiotic prescriptions were for longer than guidelines recommend for acute cystitis among females (54.6%, 54.1% to 55.0%). The percentage of antibiotic prescriptions exceeding the recommended duration was lower for most non-respiratory infections. For the 931,015 included consultations resulting in antibiotic prescriptions, about 1.3 million days were beyond the durations recommended by guidelines.”
>>>PNN NewsWatch
* Implications of finding a third carcinogenN-nitroso-N-methyl-4-aminobutyric acid (NMBA), in ARB products are discussed in an FDA news release issued on Friday. 
FDA has posted a warning letter to CanaRx for facilitating the distribution of unapproved new drugs and misbranded drugs to U.S. consumers.
>>>PNN JournalWatch
* Antibiotic Stewardship in the Neonatal Intensive Care Unit: Lessons From Oxygen, in Pediatrics2019; 143: 10.1542/peds.2018-3902. (A. L. Hersh, adam.hersh@hsc.utah.edu)

PNN Pharmacotherapy Line
Mar. 5, 2019 * Vol. 26, No. 43
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from Annals of Internal Medicine (2019; 170).
MMR Vaccine & Autism: In a national study, no relationship was found between measles, mumps, rubella (MMR) vaccine and autism (10.7326/M18-2101; A. Hviid, aii@ssi.dk). “The study strongly supports that MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination,” the investigators conclude. “It adds to previous studies through significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases.”
PICO: Nationwide cohort study using population registries of 657,461 children born in Denmark in 1999–2010, with follow-up from 1 year of age and through Aug. 31, 2013.
Results: “During 5,025,754 person–years of follow-up, 6,517 children were diagnosed with autism (incidence rate, 129.7 per 100,000 person–years). Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). Similarly, no increased risk for autism after MMR vaccination was consistently observed in subgroups of children defined according to sibling history of autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination.”
Editorial: For addressing myths regarding vaccines and autism, the approach proposed in The Debunking Handbook by Cook and Lewandowsky could be useful, editorialists write (10.7326/M19-0596; S. B. Omer, somer@emory.edu): “First, any myth should be clearly labeled as such. For example, there is evidence that a misleading headline can induce a reader to remember the inaccurate information while discounting the correct information presented subsequently. Second, while confronting the erroneous information, the focus should be on a few key facts; it is not essential to rebut every piece of misinformation. Finally, an alternative explanation of the perceived phenomenon should be provided. Otherwise, the individual can revert to their original erroneous belief.…”
Low-Dose Aspirin & Prostate Cancer Mortality: In a study limited by lack of OTC drug use data, researchers report that starting low-dose aspirin after diagnosis of incident prostate adenocarcinoma is not associated with decreased prostate cancer mortality (10.7326/M17-3085; C. Skriver, skriver@cancer.dk). However, “low-dose aspirin use might be inversely associated with prostate cancer mortality after 5 years from cancer diagnosis,” the group concludes.
PICO: Nationwide cohort study using registries of tumor characteristics, drug use, primary prostate cancer therapy, comorbidity, and socioeconomic parameters in Denmark.
Results: “Of 29,136 patients (median age, 70 years), 7,633 died of prostate cancer and 5,575 died of other causes during a median follow-up of 4.9 years (interquartile range, 3.1 to 7.2 years), through 2015. Postdiagnosis low-dose aspirin use was associated with adjusted hazard ratios (HRs) of 0.95 (95% CI, 0.89 to 1.01) for prostate cancer–specific mortality and 1.12 (CI, 1.05 to 1.20) for other-cause mortality. The secondary analyses showed that prostate cancer mortality was slightly reduced with low-dose aspirin use after the 5-year (HR, 0.91 [CI, 0.83 to 1.01]) and 7.5-year (HR, 0.84 [CI, 0.72 to 0.97]) postdiagnosis exposure periods, notably among patients filling prescriptions for a large quantity of low-dose aspirin tablets during the 7.5-year period.”
Fecal Immunochemical Testing & Colorectal Cancer: Commenting on a review article on use of fecal immunochemical tests (FITs) for colorectal cancer (CRC) detection showing that “sensitivity of 1-time testing for advanced adenomas is low, regardless of the threshold” (10.7326/M18-2390; T. F. Imperiale, timperia@iu.edu), an editorialist writes, “Physicians in the United States must understand the advantages of FITs as screening tests for CRC and educate and advocate to increase screening rates, especially in vulnerable populations” (10.7326/M19-0301; J. Allison, james.allison@ucsf.edu). “If we hope to achieve national goals for CRC screening, we must learn as much as we can about the screening tests and advocate for funding of comparative studies of available tests and insurance coverage not only for screening colonoscopies but for those done after a positive FIT result.”

PNN Pharmacotherapy Line
Mar. 6, 2019 * Vol. 26, No. 44
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Mar. 5 issue of JAMA (2019; 321).
The End of the HIV? On the heels of reports of a second patient with HIV being cured, HHS officials project the impact of federal efforts to end an epidemic that has gripped the world since the early 1980s (pp. 844–5; A. S. Fauci, afauci@niaid.nih.gov): “[The Health Resources and Services Administration (HRSA)] will accelerate its efforts working with state and county health departments and community and faith-based organizations to play a major role in the HHS initiative to end the US HIV epidemic. … 
“The NIH’s Centers for AIDS Research will inform HHS partners in this initiative on best practices, based on state-of-the-art biomedical research findings, and by collecting and disseminating data on the effectiveness of approaches used in this initiative. In addition to syringe services programs, access to FDA-approved medication-assisted treatment for substance use disorders, in concert with counseling/behavioral services, is critically important. [The Substance Abuse and Mental Health Services Administration] efforts to increase providers of medication-assisted treatment, particularly in the hotspots, will help control the spread of HIV, providing access for intravenous drug users with substance use disorder and HIV to receive the treatment they need.”
Next-Generation Sequencing of Infectious Pathogens: “High-throughput technologies and bioinformatics can provide new insights into disease transmission, virulence, and antimicrobial resistance,” according to authors of a JAMA Insights article focusing on genomics and precision health (pp. 893–4; M. Gwinn, MGwinn@cdc.gov). “Next-generation sequencing is a versatile technology, broadly applicable to viruses, bacteria, fungi, parasites, animal vectors, and human hosts. Choosing among available methods depends on sequencing objectives and involves tradeoffs in accuracy, efficiency, and cost. For routine sequencing, most US clinical and public health microbiology laboratories use short-read sequencing platforms, which produce sequence fragments up to 1,000 base-pairs long. Although microbial genomes are generally smaller and less complex than human genomes, long-read sequencing technologies (such as single-molecule real-time sequencing) are useful for constructing complete, highly accurate genomes and sorting out plasmids, repeats, and other complex regions.”
>>>PNN NewsWatch
FDA Commissioner Scott Gottlieb, MD, abruptly resigned yesterday, citing family factors in a departure note to FDA staff. During nearly 2 years in the role Gottlieb was an activist commissioner, focusing on tobacco and the emerging vaping industry in communications and regulations. He shifted the agency’s PR effort from one built around typical news releases to nearly daily “statements” that were often attributed to Gottlieb and tended to be long summaries of the issue and related FDA actions. “Gottlieb targeted drug industry tactics used to maintain sky-high prices on older drugs, calling them ‘shenanigans’ and ‘deceptions,’” reports the Washington Post. “For decades, FDA commissioners steered clear of the issue, noting that the FDA has no direct role in regulating U.S. medicine prices, which are set by drugmakers. But Gottlieb said the agency could help spur competition and reshuffled its review procedures to speed up approvals of lower-cost generic drugs.”
FDA yesterday approved a nasally administered agent, esketamine (Spravato, Janssen), for treatment-resistant depression in adults. The Schedule III agent is used in conjunction with orally administered antidepressants and is available only through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS). Product labeling contains a boxed warning of risks for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. Because of the risk of sedation and dissociation, patients must be monitored by a health care provider for at least 2 hours after receiving their esketamine dose. Approved under FDA’s fast-track and breakthrough regulations, the agent is the s-enantiomer of ketamine, which was approved by FDA in 1970 and is marketed as an injectable anesthetic induction agent.

PNN Pharmacotherapy Line
Mar. 7, 2019 * Vol. 26, No. 45
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Mar. 7 New England Journal of Medicine (2019; 380).
Treatments for Actinic Keratosis: In a trial of four field-directed treatments for patients with five or more actinic keratosis lesions on their heads, 5% fluorouracil cream was the most effective, researchers report (pp. 935–46; M. H. E. Jansen, maud.jansen@mumc.nl).
PICO: At four Dutch hospitals, patients were randomized to 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel; primary outcome of the proportion of patients with a reduction of 75% or more in the number of actinic keratosis lesions from baseline to 12 months after the end of treatment.
Results: “A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumulative probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confidence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the hazard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P ≤0.001 for all comparisons). No unexpected toxic effects were documented.”
Medicines From DNA Editing: A review article describes the development of genome editing and its potential for creation of new medicines (pp. 947–59; M. H. Porteus, mporteus@stanford.edu): “Genome editing represents a transformative means of generating medicines and gives the engineering of the genome a precision that has not previously been possible. Nonetheless, it is a nascent technology, and it is prudent to first apply it in patients with serious conditions. In early phase 1 and phase 2 clinical trials in humans, it will be important to pay attention to details that cannot be explored in preclinical studies and that may facilitate an iterative approach to improving the molecular process involved in genome editing. Once this process has been established as safe and efficacious, its application to less serious diseases could be considered.”
Scientific/Social Consensus on Gene Editing: Jennifer Doudna of U. Calif., Berkeley, “had long worried that CRISPR-related research was leaping ahead of the consensus necessary to support its ethical use,” writes the author of a Medicine and Society article (pp. 971–5; L. Rosenbaum). In light of the experiment of Chinese scientist He Jiankiu to create the world’s first “CRISPR babies,” the words of Doudna are especially prescient: “That we are unprepared for such colossal responsibility, I have no doubt. But we cannot avoid it.” Based partially on an interview with Ethan Weiss of the U. Calif., San Francisco, a cardiologist who is also the father of a 12-year-old with a genetic disease, the article concludes: “We will no doubt spend decades debating whether and how to use germline editing ethically and safely. In the meantime, Weiss’s sense that there’s no such thing as an ‘informed decision’ for parents who are offered such emerging technologies may be as true for life as it is for the science: ‘You can’t know,’ he said, ‘until you know.’”
A Responsible Path for Genome Editing: Furthering examination the implications of the above CRISPR research, Perspective authors write, “Jiankui may claim priority for the first use of CRISPR-Cas9 genome editing in human embryos, but he will forever be remembered for his reckless flouting of widely articulated scientific, clinical, and ethical standards.” (pp. 897–9; G. Q. Daley). The authors conclude, “The prospect of genome editing to prevent genetic disease, if determined to be safe, enjoys widespread public support, as shown by published opinion polls and engagement activities. There is, however, robust opposition to editing genomes to enhance human traits, which suggests that applications of any methods deemed permissible will have to be regulated to protect against misuse. In the long run, our greatest protection against inappropriate genome editing may be the implausibility of influencing traits such as intelligence, which emerge from complex interactions among multiple genes and environments. Our ignorance regarding such complexity may ultimately save us from the hazards of humanity’s hubris.”

PNN Pharmacotherapy Line
Mar. 8, 2019 * Vol. 26, No. 46
Providing news and information about medications and their proper use

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>>>Circulation Report
Source:
 Mar. 5 issue of Circulation (2019; 139).
Sleep Apnea & Blood Pressure Control Among Blacks: In the Jackson Heart Sleep Study, the risk of resistant hypertension was significantly higher in blacks with moderate or severe obstructive sleep apnea (OSA), researchers report (pp. 1275–84; D. A. Johnson, dayna.johnson@emory.edu). “These results suggest that untreated OSA may contribute to inadequate [blood pressure (BP)] control in blacks,” the group concludes.
PICO: 913 participants underwent an in-home Type 3 sleep apnea study, clinic BP measurements, and anthropometry; cut points of 130 and 80 mm Hg used to define hypertension and controlled BP.
Results: “The analytic sample with hypertension (N = 664) had a mean age of 64.0 (SD,10.6) years, and were predominately female (69.1%), obese (58.6%), and college educated (51.3%). Among the sample, 25.7% had OSA, which was untreated in 94% of participants. Overall, 48% of participants had uncontrolled hypertension and 14% had resistant hypertension. After adjustment for confounders, participants with moderate or severe OSA had a 2.0 times higher odds of resistant hypertension (95% confidence interval [CI], 1.14–3.67). Each standard deviation higher than <90% oxyhemoglobin saturation was associated with an adjusted odds ratio for resistant hypertension of 1.25 (95% CI 1.01–1.55). OSA and <90% oxyhemoglobin saturation were not associated with uncontrolled BP.”
Editorial: “Given the devastating, disproportionate toll of high BP in blacks, identifying and eradicating sources of inequality in hypertension risk and consequences are a national priority,” editorialists write (pp. 1285–8; V. K. Somers, somers.virend@mayo.edu). “As also advocated by the American Heart Association, it is time to bring to center stage the role of sleep in these disparities. Johnson and colleagues take an important step toward answering this call to action. Understanding the contribution of sleep disorders and sleep habits in the excessive cardiovascular risk experienced by blacks, as well as the potential benefits of normalizing sleep, could go a long way toward mitigating such disparities.”
Canakinumab for Prevention of Hospitalization in HF: Hospitalizations for heart failure (HHFs) and a composite of HHF and heart failure–related morbidity were reduced by treatment with the interleukin-1-beta inhibitor canakinumab in patients with established heart failure (pp. 1289–99; B. M. Everett, beverett@bwh.harvard.edu).
PICO: 10,061 patients with heart failure at baseline and prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L were randomized to canakinumab 50, 150, or 300 mg or placebo subcutaneously once every 3 months; 385 patients had an HHF event during a median follow-up of 3.7 years.
Results: “Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P <0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79–1.36) for 50 mg, 0.86 (95% CI, 0.65–1.13) for 150 mg, and 0.76 (95% CI, 0.57–1.01) for 300 mg (P for trend = 0.025). The composite of HHF or heart failure–related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78–1.29) for 50 mg, 0.88 (95% CI, 0.68–1.13) for 150 mg, and 0.78 (95% CI, 0.60–1.02) for 300 mg (P for trend = 0.042).”
>>>PNN NewsWatch
* “Despite reductions in incidence of [methicillin-resistant Staphylococcus aureus (MRSA)] bloodstream infections since 2005, S. aureus infections account for significant morbidity and mortality in the United States,” conclude authors of an epidemiologic analysis in this week’s MMWR (2019; 68: 214–9; “To reduce the incidence of these infections further, health care facilities should take steps to fully implement CDC recommendations for prevention of device- and procedure-associated infections and for interruption of transmission. New and novel prevention strategies are also needed.

PNN Pharmacotherapy Line
Mar. 11, 2019 * Vol. 26, No. 47
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Genetically Predicted Adverse Events With Testosterone: Based on data showing that endogenous testosterone is “positively associated with thromboembolism, heart failure, and myocardial infarction in men,” investigators conclude that this represents a modifiable risk factor controllable with existing treatments (l476; C. M. Schooling, cms1@hku.hk).
PICO: Genomewide association study of 3,225 men of European ancestry aged 50–75 in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomized controlled trial; validated using data on 392,038 white British men and women aged 40–69 from the UK Biobank and 171,875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation.
Results: “Of the UK Biobank participants, 13,691 had thromboembolism (6,208 men; 7,483 women), 1,688 had heart failure (1,186; 502), and 12,882 had myocardial infarction (10,136; 2,746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes.”
Postmenopausal Hormone Therapy & Alzheimer Disease: A small but significant increase in risk of Alzheimer disease is identified among postmenopausal women in Finland who were long-term users of systemic hormonal therapy, researchers report (l665; T. S. Mikkola, tomi.mikkola@hus.fi).
PICO: Nationwide case–control study of the Finnish national population and drug register in 1999–2013; all 84,739 postmenopausal women who received a diagnosis of Alzheimer’s disease and 84,739 age- and hospital district–matched control women without an Alzheimer disease diagnosis.
Results: “In 83,688 (98.8%) women, a diagnosis for Alzheimer’s disease was made at the age of 60 years or older, and 47,239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9–17% increased risk of Alzheimer’s disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen–progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen–progestogen therapy were not related to different progestogens (norethisterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer’s disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01).”
>>>PNN NewsWatch
American Health Packaging is voluntarily recalling one lot of Valsartan Tablets, USP, 160 mg to the consumer level due to the detection of trace amounts of N-Nitrosodiethylamine (NDEA) found in the finished drug product.
>>>PNN JournalWatch
* State Gun Laws, Gun Ownership, and Mass Shootings in the US: Cross Sectional Time Series, in BMJ2019; 364: :l542. (P. Reeping, pmr2149@cumc.columbia.edu)
* A New Beginning for Triglyceride Lowering Therapies, in 
Circulation2019;139: 10.1161/CIRCULATIONAHA.119.038770. (A. D. Pradhan, apradhan@bwh.harvard.edu)
* The Clinical Biology of Cystic Fibrosis Transmembrane Regulator Protein: Its Role and Function in Extrapulmonary Disease, in 
Chest2019; 155: 605–16. (T. G. Liou, ted.liou@utah.edu)
* Alcohol Use Disorder: A Pediatric-Onset Condition Needing Early Detection and Intervention, in 
Pediatrics, 2019; 143: 10.1542/peds.2018-3654. (S. E. Hadland, scott.hadland@bmc.org)

PNN Pharmacotherapy Line
Mar. 12, 2019 * Vol. 26, No. 48
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>>>Internal Medicine Report
Source:
 Early-online articles from and Mar. issue of JAMA Internal Medicine (2019; 179).
Prescribed Opioids, CAP & HIV: Community-acquired pneumonia (CAP) was more common among veterans who received prescribed opioids, a study shows, and the relationship was not influenced by HIV status (pp. 297–304; E. J. Edelman, ejennifer.edelman@yale.edu).
PICO: In the Veterans Aging Cohort Study (VACS) from 2000–12, participants with CAP requiring hospitalization (n = 4,246) were matched with controls (n = 21,146) based on prescription opioid exposure (timing, dose, opioid immunosuppression).
Results: “Among the 25,392 VACS participants (98.9% male; mean [SD] age, 55 [10] years), current medium doses of opioids with unknown or no immunosuppressive properties (adjusted odds ratio [AOR], 1.35; 95% CI, 1.13–1.62) and immunosuppressive properties (AOR, 2.07; 95% CI, 1.50–2.86) and current high doses of opioids with unknown or no immunosuppressive properties (AOR, 2.07; 95% CI, 1.50–2.86) and immunosuppressive properties (AOR, 3.18; 95% CI, 2.44–4.14) were associated with the greatest CAP risk compared with no prescribed opioids or any past prescribed opioid with no immunosuppressive (AOR, 1.24; 95% CI, 1.09–1.40) and immunosuppressive properties (AOR, 1.42; 95% CI, 1.21–1.67), especially with current receipt of immunosuppressive opioids. In stratified analyses, CAP risk was consistently greater among people living with HIV with current prescribed opioids, especially when prescribed immunosuppressive opioids (eg, AORs for current immunosuppressive opioids with medium dose, 1.76 [95% CI, 1.20–2.57] vs 2.33 [95% CI, 1.60–3.40]).”
Adverse Effects of Aspirin When Added to Warfarin Therapy: Increased bleeding and similar observed rates of thrombosis are noted in a study of patients who were on aspirin therapy for no apparent clinical reason during warfarin therapy (10.1001/jamainternmed.2018.7816; G. D. Barnes, gbarnes@umich.edu).
PICO: Registry-based cohort study of adults at 6 Michigan anticoagulation clinics in 2010–17; patients on warfarin therapy for atrial fibrillation or venous thromboembolism without documentation of a recent myocardial infarction or history of valve replacement were assessed for aspirin use without therapeutic indication.
Results: “Of the study cohort of 6,539 patients (3,326 men [50.9%]; mean [SD] age, 66.1 [15.5] years), 2,453 patients (37.5%) without a clear therapeutic indication for aspirin were receiving combination warfarin and aspirin therapy. Data from 2 propensity score–matched cohorts of 1,844 patients were analyzed (warfarin and aspirin vs warfarin only). At 1 year, patients receiving combination warfarin and aspirin compared with those receiving warfarin only had higher rates of overall bleeding (cumulative incidence, 26.0%; 95% CI, 23.8%–28.3% vs 20.3%; 95% CI, 18.3%–22.3%; P < .001), major bleeding (5.7%; 95% CI, 4.6%–7.1% vs 3.3%; 95% CI, 2.4%–4.3%; P < .001), emergency department visits for bleeding (13.3%; 95% CI, 11.6%–15.1% vs 9.8%; 95% CI, 8.4%–11.4%; P = .001), and hospitalizations for bleeding (8.1%; 6.8%–9.6% vs 5.2%; 4.1%–6.4%; P = .001). Rates of thrombosis were similar, with a 1-year cumulative incidence of 2.3% (95% CI, 1.6%–3.1%) for those receiving combination warfarin and aspirin therapy compared with 2.7% (95% CI, 2.0%–3.6%) for those receiving warfarin alone (P = .40). Similar findings persisted during 3 years of follow-up as well as in sensitivity analyses.”
Communicating Nonefficacy Benefits of New Drugs: “Novelty alone carries no intrinsic therapeutic value, is known before initiation of studies, and neither explains added benefits for patients of new interventions nor justifies harms to participants enrolled in trials,” authors write in a study of language used by FDA and drug sponsors based on noninferiority studies conducted to support product approval (10.1001/jamainternmed.2018.7040; P. Doshi, pdoshi@rx.umaryland.edu). “We found that some nonefficacy benefits were based on assumptions not evaluated in trials themselves (eg, reduced nondrug costs).”
>>>PNN NewsWatch
* Advancing medical product innovation and safety of compounded drugs are two goals of proposed increases in the FDA budget for fiscal year 2020, Commissioner Scott Gottlieb, MD, said in a statement released yesterday.

PNN Pharmacotherapy Line
Mar. 13, 2019 * Vol. 26, No. 49
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Mar. 12 issue of JAMA (2019; 321).
Tramadol & Mortality in Osteoarthritis: Given an initial prescription for tramadol for osteoarthritis, patients aged 50 years or older have a higher risk of all-cause mortality over the following year, compared with similar patients treated with commonly prescribed NSAIDs, researchers report (pp. 969–82; G. Lei, lei_guanghua@csu.edu.cn).
PICO: Sequential, propensity score-matched cohort study of 88,902 U.K. adults at least 50 years old given initial prescriptions for tramadol, naproxen, diclofenac, celecoxib, etoricoxib, or codeine.
Results: “During the 1-year follow-up, 278 deaths (23.5/1,000 person–years) occurred in the tramadol cohort and 164 (13.8/1,000 person–years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1,000 person–years [95% CI, 6.3–13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41–2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1,000 vs 19.2/1,000 person–years; HR, 1.88 [95% CI, 1.51–2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1,000 vs 18.4/1,000 person–years; HR, 1.70 [95% CI, 1.33–2.17]) and etoricoxib (25.7/1,000 vs 12.8/1,000 person–years; HR, 2.04 [95% CI, 1.37–3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1,000 vs 34.6/1,000 person–years; HR, 0.94 [95% CI, 0.83–1.05]).”
Prenatal High-Dose Vitamin D Supplements & Childhood Asthma: High doses of vitamin D provided to mothers during pregnancy failed to affect rates of asthma in their children during the first 6 years of life, compared with standard doses of the nutrient (pp. 1003–5; H. Bisgaard, bisgaard@copsac.com).
PICO: In Denmark, women were randomized to vitamin D 2400 IU/d or placebo plus vitamin D 400 IU/d at week 24 of pregnancy; follow-up of 545 offspring through age 6 years with respiratory assessments.
Results: “Asthma was diagnosed in 23 of 274 children (8%) in the high-dose vitamin D group compared with 18 of 268 children (7%) in the placebo group (odds ratio [OR], 1.27 [95% CI, 0.67–2.42], P = .46; adjusted OR, 1.21 [95% CI, 0.63–2.32], P = .57). An analysis of the yearly prevalence of persistent wheeze or asthma through the age of 6 years also showed no effect of the supplementation (OR, 0.87 [95% CI, 0.59–1.28], P = .48).
“No significant differences were observed for lung function outcomes, bronchial reactivity, fractional exhaled nitric oxide concentration, allergic sensitization, or rhinitis by the age of 6 years.”
Optimal Vaccine Timing During Pregnancy: Given the increasing recognition of the advantages to both mother and child of vaccines administered during pregnancy, the optimal timing for this intervention needs to be studied and strategies developed, write authors of a Viewpoint article (pp. 935–6; B. Abu-Raya, baburaya@bcchr.ubc.ca). “Time-dependent safety, vaccine effectiveness, maternal and infant immune responses, and vaccine uptake should be considered by policy makers when making recommendations about the timing of vaccination in pregnancy,” the writers conclude. “As the strategy of vaccination in pregnancy is gaining support and has the potential to be expanded to new vaccines, maximizing the strategy will ensure the highest benefit for pregnant women and their infants.”
>>>PNN NewsWatch
FDA yesterday granted priority approval for a new valsartan generic product (Alkem Laboratories). The agency said it prioritized the review of this product to help relieve recent shortages of generic valsartan and other ARB products because of nitrosamine impurities. For this approval, the FDA evaluated the company’s manufacturing processes and also made sure the sponsor was using appropriate testing methods to demonstrate that this valsartan product does not contain NDMA or NDEA. The agency’s assessment of the manufacturing processes for the product determined that there is no known risk for the formation of other nitrosamine impurities.
* Texas-based 
Guardian Pharmacy Services has been ordered by a federal judge to stop producing compounded drug products intended to be sterile until it complies with relevant federal laws and quality control and labeling regulations, FDA said yesterday.

PNN Pharmacotherapy Line
Mar. 14, 2019 * Vol. 26, No. 50
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Mar. 14 issue of the New England Journal of Medicine (2019; 380).
Isoniazid for Preventing HIV-Related Tuberculosis: Compared with 9 months of isoniazid monotherapy, a 1-month course of rifapentine plus isoniazid was noninferior for prevention of tuberculosis among patients living with HIV (pp. 1001–11; R. E. Chaisson, rchaiss@jhmi.edu).
PICO: Randomized, open-label, phase 3 noninferiority trial in patients with HIV living in areas with high tuberculosis prevalence or with possible latent tuberculosis infections; primary end point of first diagnosis of tuberculosis or death from tuberculosis or an unknown cause.
Results: “A total of 3,000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1,488 patients (2%) in the 1-month group and in 33 of 1,498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person–years and 0.67 per 100 person–years, respectively (rate difference in the 1-month group, −0.02 per 100 person–years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P <0.001).”
Editorial: “[Preventive] therapy has to be considered in the context that several billion people — between a quarter and a third of the world’s population — are believed to have asymptomatic latent tuberculosis infection and thus are at risk for progression to symptomatic tuberculosis disease,” (pp. 1073–4; M. J. Saunders). “Attempts to prevent tuberculosis are likely to be most efficient, and also most socially just, if they are integrated with interventions to strengthen the diagnosis and cure of tuberculosis. Furthermore, the studies that are described above demonstrating that tuberculosis programs have not had any detectable effect on tuberculosis incidence have also shown how predictably tuberculosis incidence increases when countries get poorer and decreases when poverty decreases. Socioeconomic poverty-reduction interventions such as cash transfers have reduced tuberculosis rates regionally and globally and have improved tuberculosis outcomes. Thus, attempts to increase the quality of preventive therapy should be integrated with socioeconomic interventions to facilitate equitable access to health care while also addressing the social determinants that drive the tuberculosis epidemic.”
Initial Opioid Prescriptions: Analysis of prescribing patterns for commercially insured U.S. patients shows a decline in initial opioid prescriptions as the opioid crisis progressed in 2012–17, even as “a subgroup of providers continued to write high-risk initial opioid prescriptions,” investigators conclude (pp. 1043–52; N. Maestas, maestas@hcp.med.harvard.edu).
PICO: Incidence of initial opioid prescriptions in each month between July 2012 and Dec. 2017 using U.S. administrative-claims data; percentage of nearly 64 million enrollees initiating opioid therapy who received a long-duration or high-dose initial opioid prescription in each month; trends in initial duration/dose opioid amounts for prescriber and patient subgroups.
Results: “The monthly incidence of initial opioid prescriptions among enrollees who had not used opioids declined by 54%, from 1.63% in July 2012 to 0.75% in December 2017. This decline was accompanied by a decreasing number of providers (from 114,043 in July 2012 to 80,462 in December 2017) who initiated opioid therapy in any patient who had not used opioids. Nonetheless, among the shrinking subgroup of physicians who initiated opioid therapy in such patients, high-risk prescribing (i.e., prescriptions for more than a 3-day supply or for a dose of 50 morphine milligram equivalents per day or higher) persisted at a monthly rate of 115,378 prescriptions per 15,897,673 enrollees who had not used opioids.”
>>>PNN NewsWatch
* Stokes Healthcare is voluntarily recalling 1 lot of Pilocarpine 0.1% Ophthalmic Solution to the consumer and veterinarian office levels because of higher-than-normal levels of benzalkonium chloride.

PNN Pharmacotherapy Line
Mar. 15, 2019 * Vol. 26, No. 51
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 Mar. 15 issue of Clinical Infectious Diseases (2019; 68).
IDSA Guidelines on Seasonal Influenza: In a 2018 update to clinical practice guidelines from 2009, the Infectious Diseases Society of America makes 58 recommendations for the diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza (pp. 895–902; T. M. Uyeki, tuyeki@cdc.gov), including these for institutions:
* Outbreak control measures should be implemented as soon as possible, including antiviral chemoprophylaxis of residents/patients, and active surveillance for new cases, when 2 cases of healthcare-associated laboratory-confirmed influenza are identified within 72 hours of each other in residents or patients of the same ward or unit.
* Empiric antiviral treatment should be administered as soon as possible to any resident or patient with suspected influenza during an influenza outbreak without waiting for the results of influenza diagnostic testing.
* Clinicians should administer antiviral chemoprophylaxis for 14 days and continue for at least 7 days after the onset of symptoms in the last case identified during an institutional influenza outbreak.
Addition of Azithromycin to Ivermectin Mass Administration for Scabies/Impetigo Control: Used for mass drug administration (MDA) in scabies or impetigo outbreaks, coadministration of azithromycin with ivermectin provided no additional benefit and increased the proportion of macrolide-resistant microbial strains, researchers report, compared with ivermectin alone (pp. 927–33; M. Marks, michael.marks@lshtm.ac.uk).
PICO: Six communities randomized to ivermectin-based MDA or ivermectin-based MDA coadministered with azithromycin; scabies and impetigo prevalence at baseline and 12 months; antimicrobial resistance in impetigo lesions swabs at baseline, 3, and 12 months.
Results: “At baseline, scabies and impetigo prevalences were 11.8% and 10.1% in the ivermectin-only arm and 9.2% and 12.1% in the combined treatment arm. At 12 months, the prevalences had fallen to 1.0% and 2.5% in the ivermectin-only arm and 0.7% and 3.3% in the combined treatment arm. The proportion of impetigo lesions containing Staphylococcus aureus detected did not change (80% at baseline vs 86% at 12 months; no significant difference between arms) but the proportion containing pyogenic streptococci fell significantly (63% vs 23%, P <.01). At 3 months, 53% (8/15) of S. aureus isolates were macrolide-resistant in the combined treatment arm, but no resistant strains (0/13) were detected at 12 months.”
>>>Vaccine Report
Source:
 Mar. 22 issue of Vaccine (2019; 37).
Pregnancy Outcomes With Seasonal Influenza Vaccine: Addressing concerns over seasonal influenza vaccinations of pregnant women, investigators report no safety concerns and fewer adverse outcomes among vaccinated than unvaccinated mothers (pp. 1785–91; D. Getahun, arios.T.Getahun@kp.org">Darios.T.Getahun@kp.org). “The lack of increased adverse outcomes associated with influenza vaccination suggests that the benefits of vaccination during pregnancy to the woman and her child far outweigh any risk, if there is one, from the vaccination,” the group concludes.
PICO: Kaiser Permanente medical and vaccination records from 2008–16; women pregnant with singletons; odds ratios for immunization status and prenatal/postnatal outcomes. 
Results: “Of the 247,036 women in these analyses, 53% were vaccinated during their pregnancy. No association between influenza vaccination during pregnancy and adverse prenatal and neonatal outcomes were observed. Influenza vaccination is associated with reduced risk of influenza (OR: 0.49, 95% CI: 0.39–0.62), maternal fever (OR: 0.40, 95% CI: 0.35–0.45), preeclampsia (OR: 0.93, 95% CI: 0.90–0.96), placental abruption (OR: 0.89, 95% CI: 0.82–0.96), stillbirth (OR: 0.88, 95% CI: 0.78–0.99), and NICU admission (OR: 0.89, 95% CI: 0.87–0.92). Both active and inactive vaccines were found to be safe in vaccinated pregnant women regardless of timing of vaccination.”
>>>PNN NewsWatch
FDA yesterday allowed marketing of a new device, ClearMate (Thornhill Research), intended to be used in the emergency department to help treat patients with carbon monoxide poisoning.

PNN Pharmacotherapy Line
Mar. 18, 2019 * Vol. 26, No. 52
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Mar. 16 issue of Lancet (2019; 393).
Preventing Coronary Artery Abnormalities in Kawasaki Disease: For optimizing favorable coronary artery outcomes in patients with Kawasaki disease, preventive therapy with intravenous immunoglobulin (IVIG) plus cyclosporine is safe and effective, researchers report (pp. 1128–37; A. Hata, ahata@faculty.chiba-u.jp).
PICO: At 22 Japanese hospitals, randomized, open-label treatment with higher-risk patients with Kawasaki disease received IVIG plus cyclosporine 5 mg/kg/d for 5 days (study treatment) or IVIG alone (conventional treatment) for 12 weeks in 2014–16; primary endpoint of incidence of coronary artery abnormalities using Japanese criteria.
Results: “We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0.46; 95% CI 0.25–0.86; p = 0.010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p = 0.78).”
Automated Insulin Dosing Guidance in Type 2 Diabetes: Compared with support from health professionals alone, the combination of automated insulin titration guidance plus support from health professionals produced better glycemic outcomes, according to a study of 181 patients with types 2 diabetes (pp. 1138–48; R. M. Bergenstal, richard.bergenstal@parknicollet.com).
PICO: Adult patients with type 2 diabetes and a glycosylated hemoglobin (HbA 1c) between 7.5% and 11% while on stable therapy were block randomized to use of the d-Nav Insulin Guidance System (Hygieia) and health-care professional support (intervention group) or health-care professional support alone (control group); both groups contacted seven times through three face-to-face and four phone visits during 6 months of follow-up; primary objective of average change in HbA 1c from baseline to 6 months; safety assessed by frequency of hypoglycemic events.
Results: “236 patients were screened for eligibility, of whom 181 (77%) were enrolled and randomly assigned to the intervention (n = 93) and control (n = 88) groups. At baseline, mean HbA 1c was 8.7% (SD 0.8; 72 mmol/mol [SD 8.8]) in the intervention group and 8.5% (SD 0.8; 69 mmol/mol [SD 8.8]) in the control group. The mean decrease in HbA 1c from baseline to 6 months was 1.0% (SD 1.0; 11 mmol/mol [SD 11]) in the intervention group, and 0.3% (SD 0.9; 3.3 mmol/mol [9.9]) in the control group (p <0.0001). The frequency of hypoglycaemic events per month was similar between the groups (0.29 events per month [SD 0.48] in the intervention group vs 0.29 [SD 1.12] in the control group; p = 0.96).”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Urinary Na/K Excretion & Cardiovascular Outcomes: The WHO advice for low sodium and high potassium intake is rarely followed, investigators found, while a simultaneous target of moderate sodium intake (3–5 g/d) with high potassium intake (>3.5 g/d) “is associated with the lowest risk of mortality and cardiovascular events” (l772; M. O’Donnell, donnm@mcmaster.ca">odonnm@mcmaster.ca).
PICO: International prospective cohort study in 18 countries and 103,570 people who provided morning fasting urine samples.
Results: “Compared with [a] reference group [of moderate sodium and high potassium intake], the combinations of low potassium with low sodium excretion (hazard ratio 1.23, 1.11 to 1.37; 7.4% of cohort) and low potassium with high sodium excretion (1.21, 1.11 to 1.32; 13.8% of cohort) were associated with the highest risk, followed by low sodium excretion (1.19, 1.02 to 1.38; 3.3% of cohort) and high sodium excretion (1.10, 1.02 to 1.18; 29.6% of cohort) among those with potassium excretion greater than the median. Higher potassium excretion attenuated the increased cardiovascular risk associated with high sodium excretion (P for interaction = 0.007).”
>>>PNN JournalWatch
* Delafloxacin: A New Anti–methicillin-resistant Staphylococcus aureus Fluoroquinolone, in Clinical Infectious Diseases2019; 68: 1058–62. (L. D. Saravolatz, louis.saravolatz@stjohn.org)

PNN Pharmacotherapy Line
Mar. 19, 2019 * Vol. 26, No. 53
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from and Mar. 19 issue of Annals of Internal Medicine (2019; 170).
Bleeding Risk Prediction as Aspirin Primary Prevention Guide: In patients requiring primary prevention of cardiovascular disease (CVD), prognostic bleeding risk models can be used to estimate the absolute bleeding harms of aspirin use, a study shows (pp. 357–68; V. Selak, v.selak@auckland.ac.nz).
PICO: Prospective study of a New Zealand primary care cohort of 385,191 persons aged 30–79 years whose CVD risk was assessed in 2007–16; those with aspirin contraindications or prior use of antiplatelet/anticoagulant therapy excluded; Cox proportional hazards models used to predict major bleeding risks.
Results: “During 1,619,846 person–years of follow-up, 4,442 persons had major bleeding events (of which 313 [7%] were fatal). The main models predicted a median 5-year bleeding risk of 1.0% (interquartile range, 0.8% to 1.5%) in women and 1.1% (interquartile range, 0.7% to 1.6%) in men. Plots of predicted-against-observed event rates showed good calibration throughout the risk range.”
Editorial: This study offers “a major step toward more evidence-based, individualized decision making about aspirin use to prevent CVD (and perhaps colorectal cancer),” editorialists write (pp. 411–3; E. P. Whitlock, ewhitlock@pcori.org). “This research has several strengths. First and foremost, it directly responds to a key evidence gap identified by a major guideline developer, the U.S. Preventive Services Task Force. The predictive models’ development followed recommendations for valid prognostic research and built on a substantially expanded evidence base for understanding expected bleeding risks, and thus net benefit, in real-world candidates for aspirin primary prevention. These types of data are essential to clarify current uncertainties and should help eventually reduce variation in clinical decision making and current guidelines.”
CEA of Herpes Zoster Vaccine: In a study designed to provide input for national recommendations on use of the newer recombinant zoster vaccine (RZV), researchers report “cost-effectiveness ratios lower than those for many recommended adult vaccines, including [zoster vaccine live (ZVL) that] are robust over a wide range of plausible values” (pp. 380–8; L. A. Prosser, lisapros@umich.edu).
PICO: Simulation (state-transition) model using published U.S. epidemiologic, clinical, and cost data for a hypothetical cohort of immunocompetent U.S. adults aged 50 years or older; lifetime horizon; societal and health care sector perspective; primary outcome measure of incremental cost-effectiveness ratio (ICER) for each of three interventions (RZV [recommended 2-dose regimen], vaccination with ZVL, and no vaccination).
Results: “For vaccination with RZV compared with no vaccination, ICERs ranged by age from $10,000 to $47,000 per quality-adjusted life–year (QALY), using a societal perspective and assuming 100% completion of the 2-dose RZV regimen. For persons aged 60 years or older, ICERs were less than $60,000 per QALY. Vaccination with ZVL was dominated by vaccination with RZV for all age groups 60 years or older.… Results were most sensitive to changes in vaccine effectiveness, duration of protection, herpes zoster incidence, and probability of postherpetic neuralgia. Vaccination with RZV after previous administration of ZVL yielded an ICER of less than $60,000 per QALY for persons aged 60 years or older. In probabilistic sensitivity analyses, RZV remained the preferred strategy in at least 95% of simulations, including those with 50% completion of the second dose.”
Checklist for Initial Anthrax Mass Exposure Triage: “A brief checklist covering symptoms and signs can distinguish anthrax from other conditions with minimal need for diagnostic testing after known or suspected population exposure,” authors conclude based on analysis of published anthrax case reports in 1880–2013, including patients with suspected cases during the 2001 attacks in the U.S. (10.7326/M18-1817; K. Hendricks, kah1@cdc.gov).
>>>PNN NewsWatch
FDA recallsHospira 8.4% Sodium Bicarbonate Injection, USP, 50 mEq/50 mL (1 mEq/mL), to the hospital/institution level; Mylan Institutional Levoleucovorin Injection 250 mg/25 mL to the consumer/user level; and Legacy Pharmaceutical Packaging repackaged lots of Losartan Tablets to the consumer level.

PNN Pharmacotherapy Line
Mar. 20, 2019 * Vol. 26, No. 54
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Early-online articles from and Mar. 19 issue of JAMA (2019; 321).
AF Interventions & QOL: In the CAPTAF (Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation) study, quality of life at 12 months was improved for those treated with catheter ablation compared with antiarrhythmic medication in patients with symptomatic atrial fibrillation despite use of antiarrhythmic medication (pp. 1059–68; C. Blomström-Lundqvist, carina.blomstrom.lundqvist@akademiska.se).
PICO: At 5 hospitals in Sweden and Finland, 155 patients aged 30–70 years with more than 6 months of atrial fibrillation and treatment failure with 1 antiarrhythmic drug or beta-blocker were randomized to pulmonary vein isolation ablation or previously untested antiarrhythmic drugs; primary outcome of the General Health subscale score (Medical Outcomes Study 36-Item Short-Form Health Survey) at 0 and 12 months.
Results: “Among 155 randomized patients (mean age, 56.1 years; 22.6% women), 97% completed the trial. Of 79 patients randomized to receive ablation, 75 underwent ablation, including 2 who crossed over to medication and 14 who underwent repeated ablation procedures. Of 76 patients randomized to receive antiarrhythmic medication, 74 received it, including 8 who crossed over to ablation and 43 for whom the first drug used failed. General Health score increased from 61.8 to 73.9 points in the ablation group vs 62.7 to 65.4 points in the medication group (between-group difference, 8.9 points; 95% CI, 3.1-14.7; P = .003). Of 26 secondary end points, 5 were analyzed; 2 were null and 2 were statistically significant, including decrease in atrial fibrillation burden (from 24.9% to 5.5% in the ablation group vs 23.3% to 11.5% in the medication group; difference –6.8% [95% CI, –12.9% to –0.7%]; P = .03). Of the Health Survey subscales, 5 of 7 improved significantly. Most common adverse events were urosepsis (5.1%) in the ablation group and atrial tachycardia (3.9%) in the medication group.”
Editorial: Reacting to similar results from the CABANA trial released in conjunction with last weekend’s American College of Cardiology meeting (10.1001/jama.2019.0693, D. L. Packer, packer@mayo.edu10.1001/jama.2019.0692, D. B. Mark, daniel.mark@duke.edu), editorialists ask, “Where does this leave the patient with AF?” (10.1001/jama.2018.17478; C. M. Albert, calbert@bwh.harvard.edu). “Shared decision making between the cardiologist and the patient is the best answer and is critical in determining treatment. The CABANA trial provides a wealth of additional data regarding the comparative benefits and risks of catheter ablation vs drug therapy to inform this process. This approach may be well positioned to occur in comprehensive AF management centers that offer the full range of anticoagulation options, antiarrhythmic drug therapy, and percutaneous and surgical procedures, coupled with lifestyle modification, such as weight loss, that may further augment the success of ablation, medical therapies, or both.”
>>>PNN NewsWatch
* Following a priority review, FDA yesterday approved the breakthrough GABA modulator brexanolone (Zulresso, Sage Therapeutics) injection for intravenous use for the treatment of postpartum depression (PPD) in adult women. This is the first drug approved specifically for PPD. The product, which media reports indicate will cost $20,000 for each 60-hour continuous infusion, is expected to be available in late June following scheduling by DEA. Brexanolone will be available only through a Zulresso REMS Program that requires the drug to be administered by a health care provider in a certified health care facility. In three trials, brexanolone achieved the primary endpoint, a significant mean reduction from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score at 60 hours compared with placebo. A reduction of depressive symptoms was also seen as early as 24 hours, and brexanolone maintained effect through the 30-day follow-up. The most common adverse events in the studies were sleepiness, dry mouth, loss of consciousness, and flushing.
FDA yesterday posted a warning letter to Nutra Pharma Corp. for illegally marketing unapproved products labeled as homeopathic with claims about their ability to treat addiction and chronic pain, including pain associated with cancer, diabetes, shingles, and fibromyalgia.

PNN Pharmacotherapy Line
Mar. 21, 2019 * Vol. 26, No. 55
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Mar. 21 issue of the New England Journal of Medicine (2019; 380).
First-Line Combination Therapy for Metastatic RCC: A pair of programmed death ligand 1 (PD-L1) inhibitors plus axitinib showed superiority over sunitinib in progression-free survival and objective response rates in patients with metastatic renal-cell carcinoma in two large, phase 3 trials.
Study 1: The first trial included 886 previously untreated patients with advanced renal-cell carcinoma and showed significantly longer progression-free survival in those receiving avelumab plus axitinib than with sunitinib (pp. 1103–15; R. J. Motzer, motzerr@mskcc.org).
PICO: 6-week cycles of I.V. avelumab plus oral axitinib or oral sunitinib; primary end points of progression-free survival and overall survival among 560 patients with PD-L1–positive tumors.
Results: “The median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P <0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P <0.001). Among the patients with PD-L1–positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively.… ”
Study 2: Similar patients had significantly longer overall survival and progression-free survival, as well as a higher objective response rate, with pembrolizumab plus axitinib than with sunitinib (pp. 1116–7; B. I. Rini, rinib2@ccf.org).
PICO: 6-week cycles in 861 patients of I.V. pembrolizumab plus oral axitinib or oral sunitinib; primary end points of overall survival and progression-free survival. 
Results: “After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab–axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P <0.0001). Median progression-free survival was 15.1 months in the pembrolizumab–axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P <0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab–axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P <0.001).…”
Editorial: Discussing questions raised by these trials, an editorialist writes, “Both combinations [avelumab or pembrolizumab plus axitinib] are expected to become new standards of care and to be incorporated into future guidelines,” (pp. 1176–8; B. Escudier). “[One] question [these studies raise] is whether inhibition of PD-1 and PD-L1 synergizes with axitinib and what the role of axitinib is in these combinations. Axitinib was shown to be a potent and selective VEGF inhibitor with excellent antitumor activity in a large phase 2 trial involving 213 patients with metastatic renal-cell carcinoma. In that trial, the median progression-free survival was 14.5 months and the objective response rate was 48%. It would have been very informative to have a control group with axitinib monotherapy in the current trials to ensure that avelumab and pembrolizumab made a clinically significant contribution to the observed results.”
Psychosis With Stimulants in ADHD: “Despite uncertainties regarding causal mechanisms, [a] study by Moran and colleagues provides important data on the incidence of psychosis observed in routine practice among patients with ADHD,” an editorialist writes (pp. 1178–80; S. Cortese) in reaction to a report showing that 1 in 660 patients on stimulants for this condition develops new-onset psychosis (pp. 1128–38; L. V. Moran, lmoran4@partners.org). “These figures could inform decision making among patients, families, and physicians when stimulants are prescribed for ADHD, and a balance is desirable between the safety and the effectiveness of a drug for ADHD core symptoms. The ostensible benefits of stimulants with respect to problems related to ADHD (such as a reduction in criminality, as suggested in a previous study) should also be considered before treatment is initiated.”

PNN Pharmacotherapy Line
Mar. 22, 2019 * Vol. 26, No. 56
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Rheumatology Report
Source:
 Mar. issue of Arthritis & Rheumatology (2019; 71).
Rheumatic Syndromes With Immune Checkpoint Inhibitors: Patients who experienced rheumatic immune-related adverse effects (Rh-irAEs) associated with immune checkpoint inhibitor (ICI) therapy rarely required drug discontinuation despite lengthy treatment courses, researchers report (pp. 468–75; U. Thanarajasingam, thanarajasingam.uma@mayo.edu).
PICO: Retrospective analysis of the Mayo Clinic database for Rh-irAEs.
Results: “Of the 1,293 patients who received any ICI, Rh-irAEs were clinically diagnosed in 43. Eighteen patients with Rh-irAEs who received ICI therapy elsewhere were also analyzed. Clinical syndromes included inflammatory arthritis (n = 34 [prevalence 2%]), myopathy (n = 10), and other rheumatic syndromes (n = 17). Inflammatory arthritis was most commonly polyarticular, and glucocorticoid treatment was required in 26 patients (76%). The mean ± SD duration of treatment was 18 ± 18 weeks. Five patients (15%) also received disease-modifying antirheumatic drugs, and ICI therapy had to be discontinued in 3 patients (9%). Myopathy was treated with glucocorticoids in all cases (mean ± SD treatment duration 15 ± 17 weeks) and led to 2 deaths and permanent ICI discontinuation in 9 patients (90%). Other syndromes included connective tissue diseases, vasculitis, polymyalgia rheumatica–like syndrome, and flare of preexisting rheumatic disease. Most (71%) were treated with immunosuppression, with 12% requiring ICI discontinuation.”
Serum S100 in Polyarticular Juvenile Idiopathic Arthritis: In patients with polyarticular forms of juvenile idiopathic arthritis (JIA), serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare, and S100A12 levels were moderately and inversely correlated with the time to disease flare (pp. 451–9; C. H. Hinze, claas.hinze@ukmuenster.de).
PICO: 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti–tumor necrosis factor (anti-TNF) therapy; initial 6-month phase of continued anti-TNF treatment followed by anti-TNF withdrawal. 
Results: “Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the [receiver operating characteristic] analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = −0.36).”
>>>Allergy/Immunology Report
Source:
 Mar. issue of the Journal of Allergy and Clinical Immunology (2019; 143).
Novel Vaccine Technology: A review focuses “on how new and more rational approaches to vaccine development use novel biotechnology, target new mechanisms, and shape the immune system response, with an emphasis on discoveries that have direct translational relevance to the treatment of allergic diseases” (pp. 844–51; S. U. Patil, sarita.patil@mgh.harvard.edu).
>>>PNN NewsWatch
FDA has approved for marketing the Optimizer Smart system (Impulse Dynamics) for treating patients with chronic, moderate-to-severe heart failure who are not suited for treatment with other heart failure devices such as cardiac resynchronization therapy for restoration of sinus rhythms.
FDA recalls: All lots within expiry of Ata Int. Inc.’s Bluefusion Capsules to the consumer level because FDA analysis shows the product is tainted with sildenafil, tadalafil, and other compounds; lot KL180157 of Kingston Pharma’s 59-mL bottles of DG/health Naturals baby Cough Syrup + Mucus because of possible Bacillus spp.

PNN Pharmacotherapy Line
Mar. 25, 2019 * Vol. 26, No. 57
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Data-Sharing Practices of Medication-Related Apps: Sharing of data about users of apps for medication prescribing and related activities is common among app owners and developers, a study shows; authors provide this conclusion: “Clinicians should be conscious of privacy risks in their own use of apps and, when recommending apps, explain the potential for loss of privacy as part of informed consent” (l920; Q. Grundy, quinn.grundy@utoronto.ca).
PICO: 24 top-rated medication-related apps for the Android mobile platform available in the Medical store category of Google Play in the U.K., U.S., Canada, and Australia; apps pertained to medication information, dispensing, administration, prescribing, or use, and were interactive; laboratory-based traffic analysis of each app downloaded onto a smartphone, simulating real world use with four dummy scripts.
Results: “19/24 (79%) of sampled apps shared user data. 55 unique entities, owned by 46 parent companies, received or processed app user data, including developers and parent companies (first parties) and service providers (third parties). 18 (33%) provided infrastructure related services such as cloud services. 37 (67%) provided services related to the collection and analysis of user data, including analytics or advertising, suggesting heightened privacy risks. Network analysis revealed that first and third parties received a median of 3 (interquartile range 1–6, range 1–24) unique transmissions of user data. Third parties advertised the ability to share user data with 216 ‘fourth parties’; within this network (n = 237), entities had access to a median of 3 (interquartile range 1–11, range 1–140) unique transmissions of user data. Several companies occupied central positions within the network with the ability to aggregate and re-identify user data.”
>>>Lancet Report
Source:
 Mar. 23 issue of Lancet (2019; 393).
Smartphone-Enabled, Video-Observed TB Treatment: Compared with directly observed treatment (DOT), video-observed therapy (VOT) using smartphones proved a more effective means of observing daily and more frequent administrations of antitubercular therapy, researchers report (pp. 1216–24; A. C. Hayward, a.hayward@ucl.ac.uk).
PICO: Randomized superiority trial at 22 U.K. clinics; patients aged 16 years or older with access to a smartphone and charging capability; DOT by trained health care or lay workers in the home, community, or clinic 3 to 5 times per week; VOT used patient-recorded videos of all doses administered with viewing by trained treatment observers; primary outcome of completion of 80% or more scheduled treatment observations over the first 2 months following enrollment; intention-to-treat (ITT) and restricted analyses; superiority determined by 15% difference in the primary outcome.
Results: “Overall, 131 (58%) patients had a history of homelessness, imprisonment, drug use, alcohol problems or mental health problems. In the ITT analysis, 78 (70%) of 112 patients on VOT achieved ≥80% scheduled observations successfully completed during the first 2 months compared with 35 (31%) of 114 on DOT (adjusted odds ratio [OR] 5.48, 95% CI 3.10–9.68; p <0.0001). In the restricted analysis, 78 (77%) of 101 patients on VOT achieved the primary outcome compared with 35 (63%) of 56 on DOT (adjusted OR 2.52; 95% CI 1.17–5.54; p = 0.017). Stomach pain, nausea, and vomiting were the most common adverse events reported (in 16 [14%] of 112 on VOT and nine [8%] of 114 on DOT).”
>>>PNN JournalWatch
* Allergic Rhinitis and Its Impact on Asthma (ARIA) Phase 4 (2018): Change Management in Allergic Rhinitis and Asthma Multimorbidity Using Mobile Technology, in Journal of Allergy and Clinical Immunology2019; 143: 864–79. (J. Bousquet, jean.bousquet@orange.fr)
* Comparative Effectiveness of Medication Therapy Management Eligibility Criteria Across Racial/Ethnic Groups, in the 
Journal of the American Geriatrics Society2019; 67: 581–7. (J. Wang, jwang26@uthsc.edu)
* Patient-Centered Care, Yes; Patients As Consumers, No, in 
Health Affairs2019; 38: 368–73. (M. K. Gusmano, gusmanom@thehastingscenter.org)
* Regional and Rural-Urban Differences in the Use of Direct-Acting Antiviral Agents for Hepatitis C Virus: The Veteran Birth Cohort, in 
Medical Care2019; 57: 279–85. (B. Njei)

PNN Pharmacotherapy Line
Mar. 26, 2019 * Vol. 26, No. 58
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
 Mar. issue of the Journal of the American Geriatrics Society (2019; 67).
Psychoactive Meds & Adverse Events in Hemodialysis: Among older U.S. adults receiving hemodialysis, use of anticholinergic antidepressants is associated with adverse outcomes, a study shows (pp. 449–54; J. H. Ishida, julie.ishida@ucsf.edu). Sedative–hypnotics were not associated with increased risks, but the authors advise “further investigation of the harms of this class of agents … before their recommendation as a treatment option for insomnia in this population.”
PICO: Observational cohort study of a national registry of 60,007 older patients (≥65 years of age) on Medicare Part D and receiving hemodialysis (US Renal Data System) in 2011.
Results: “Overall, 17% and 6% used sedative–hypnotics and anticholinergic antidepressants, respectively, in 2011. In multivariable-adjusted Cox regression, anticholinergic antidepressant use was associated with a 25%, 27%, and 39% higher hazard of altered mental status, fall, and fracture, respectively, compared with no use. Use of sedative–hypnotics was not associated with adverse outcomes.”
Chronic Is Polypharmacy in Older Adults: While older adults on five or more medications most often are using the agents chronically, substantial numbers of patients experience short, recurring episodes of polypharmacy, researchers report (pp. 455–62; J. W. Wastesson, jonas.wastesson@ki.se).
PICO: Longitudinal cohort study using Swedish registry data for 711,432 adults aged 65 years or older with five or more prescribed drugs in 2010–13; monthly changes in exposure to polypharmacy as reported in the Swedish Prescribed Drugs Register.
Results: “Overall, 82% were continuously exposed to polypharmacy for 6 months or longer, and 74% for 12 months or longer. The proportion of individuals who remained exposed until the end of the study was 55%. Among the 21,361 individuals who had not been exposed to polypharmacy during the 6-month period before baseline (ie, with a new episode of polypharmacy), only 30% remained exposed for 6 months or longer. The proportion of older adults who spent at least 80% of their follow-up time with polypharmacy was substantially higher among prevalent polypharmacy users at baseline than among those with a new polypharmacy episode (80% vs 24%; P < .01). Factors associated with chronic polypharmacy included higher age, female sex, living in an institution, chronic multimorbidity, and multidose dispensing.”
Comprehensive Dementia Management in End-of-Life Care: People enrolled “in a comprehensive dementia care comanagement program had high engagement in advance care planning, high rates of hospice use, and low acute care utilization near the end of life,” investigators conclude (pp. 443–8; L. A. Jennings, lee-jennings@ouhsc.edu).
PICO: 322 persons enrolled in dementia care management in 2012 who died before July 1, 2016; nurse practitioners partnered with primary care providers and community organizations to provide comprehensive dementia care, including advance care planning; outcomes of advance care preferences, use of Physician Orders for Life Sustaining Treatment (POLST), hospice enrollment, and hospitalizations and emergency department (ED) visits in the last 6 months of life.
Results: “Nearly all decedents (99.7%, N = 321) had a goals-of-care conversation documented (median = 3 conversations; interquartile range = 2–4 conversations), and 64% had advance care preferences recorded. Among those with recorded preferences, 88% indicated do not resuscitate, 48% limited medical interventions, and 35% chose comfort-focused care. Most patients (89%) specified limited artificial nutrition, including withholding feeding tubes. Over half (54%) had no hospitalizations or ED visits in the last 6 months of life, and intensive care unit stays were rare (5% of decedents). Overall, 69% died on hospice. Decedents who had completed a POLST were more likely to die in hospice care (74% vs 62%; P = .03) and die at home (70% vs 59%; P = .04).”
>>>PNN NewsWatch
* Gaps in HIV testing and treatment are hindering efforts to stop new infections, U.S. Surgeon General Jerome M. Adams said last week during a CDC media briefing at a national HIV prevention conference.

PNN Pharmacotherapy Line
Mar. 27, 2019 * Vol. 26, No. 59
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Mar. 26 issue of JAMA (2019; 321).
Costs of Measles Outbreaks: In the postelimination era of vaccine hesitancy and refusal, responding to a single case of measles can cost as much as $142,000, Viewpoint authors write, “depending on the number and location of contacts that must be traced, the amount of postexposure prophylaxis that must be administered, and the number of people quarantined,” (pp. 1155–6; S. B. Omer, somer@emory.edu). “In 2011, the estimated total cost of measles outbreaks in the United States ranged from $2.7 million to $5.3 million. These costs include postexposure prophylaxis (including postexposure vaccination and immunoglobulin), laboratory testing for suspected cases, compensating health care providers and other staff members for their increased work time and overtime, public outreach regarding measles risk and prevention, and establishing quarantine for exposed susceptible individuals.”
The authors conclude, “Evaluation of the true clinical implications and economic cost of measles outbreaks in the United States requires a broader epidemiological approach than the mere reporting of case counts. Policy makers must consider the long-term immunologic effects measles infection has on the individual, the complete financial cost associated with outbreak response, and the associated strain on health system infrastructure when resources are diverted at the individual, hospital, and community level.”
In-Hospital Cardiac Arrest: Limited evidence is available to guide clinicians in responding to an estimated 290,000 in-hospital cardiac arrests that occur annually in the U.S., according to a review of the topic (pp. 1200–10; L. W. Andersen, lwandersen@clin.au.dk). “Cohort data from the United States indicate that the mean age of patients with in-hospital cardiac arrest is 66 years, 58% are men, and the presenting rhythm is most often (81%) nonshockable (ie, asystole or pulseless electrical activity). The cause of the cardiac arrest is most often cardiac (50%–60%), followed by respiratory insufficiency (15%–40%). Efforts to prevent in-hospital cardiac arrest require both a system for identifying deteriorating patients and an appropriate interventional response (eg, rapid response teams). The key elements of treatment during cardiac arrest include chest compressions, ventilation, early defibrillation, when applicable, and immediate attention to potentially reversible causes, such as hyperkalemia or hypoxia. There is limited evidence to support more advanced treatments. Post–cardiac arrest care is focused on identification and treatment of the underlying cause, hemodynamic and respiratory support, and potentially employing neuroprotective strategies (eg, targeted temperature management). Although multiple individual factors are associated with outcomes (eg, age, initial rhythm, duration of the cardiac arrest), a multifaceted approach considering both potential for neurological recovery and ongoing multiorgan failure is warranted for prognostication and clinical decision-making in the post–cardiac arrest period. Withdrawal of care in the absence of definite prognostic signs both during and after cardiac arrest should be avoided. Hospitals are encouraged to participate in national quality-improvement initiatives.”
>>>PNN NewsWatch
FDA yesterday approved siponimod (Mayzent, Novartis) tablets to treat adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive MS (SPMS). The phase 3 EXPAND trial showed that siponimod significantly reduced the risk of SPMS progression, including impact on physical disability and cognitive decline. The product must be dispensed with a patient Medication Guide that warns of increased risk of infections, macular edema, transient bradycardia, and a decline in lung function. Liver enzymes should be monitored before and during therapy.
“Strategies to Expand Value-Based Pharmacist-Provided Care” identifies 15 actions pharmacists and payers can take to foster adoption of pharmacist-provided care. A 50-member Pharmacy Quality Alliance task force sought to show how pharmacist-provided care can transform the pharmacist’s role from a medication dispenser to an indispensable clinical care team member providing affordable, accessible, and high-quality health care services that improve patient outcomes.

PNN Pharmacotherapy Line
Mar. 28, 2019 * Vol. 26, No. 60
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Mar. 28 New England Journal of Medicine (2019; 380).
Shorter Regimen for Rifampin-Resistant Tuberculosis: In persons with rifampin-resistant tuberculosis, an abbreviated regimen of high-dose moxifloxacin was noninferior to a long regimen based on a primary efficacy outcome and was similar to the long regimen in terms of safety, STREAM Study investigators report (pp. 1201–13; A. J. Nunn, a.nunn@ucl.ac.uk).
PICO: Phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides; short regimen (9–11 months) that included high-dose moxifloxacin or a long regimen (20 months); primary efficacy outcome of cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion; noninferiority defined as between-group difference of 10 percentage points or less.
Results: “Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group — a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], −7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, –0.7 percentage points; 95% CI, −10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia’s formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.”
Editorial: “We can look forward to continued improvements in the treatment of multidrug-resistant and rifampin-resistant tuberculosis as new chemical entities enter the development pipeline, which will allow for the development of shorter, safer, more efficacious all-oral regimens,” writes an editorialist (pp. 1279–80; G. J. Churchyard). “Mathematical modeling suggests that scaling up the administration of more efficacious regimens for multidrug-resistant and rifampin-resistant tuberculosis when they become available could substantially reduce the incidence of and mortality from these conditions and contribute to ending the multidrug-resistant and rifampin-resistant tuberculosis epidemic. The STREAM study is an early and useful step toward vanquishing drug-resistant tuberculosis, but we have a long way to go to turn back the tide.”
Opioid Use Disorder & Incarceration: For avoiding treatment interruptions in patients with opioid use disorder (OUD) before jail stays for pending or new charges, a Nov. 2018 Massachusetts court case “may help accelerate the adoption of medications for OUD in jails,” a Perspectives author writes (pp. 1193–5; I. A. Binswanger). “The basis of the lawsuit … was that discontinuing treatment during a planned jail stay violates both the prohibition against cruel and unusual punishment in the Eighth Amendment to the U.S. Constitution and the Americans with Disabilities Act. This case is atypical in that most people who are put in jail don’t have the opportunity to prepare for incarceration, and most are not already receiving treatment for OUD. Yet the case illustrates the complex web of legal, policy, and structural barriers to obtaining effective treatment for OUD in correctional facilities.”
>>>PNN NewsWatch
Testosterone undecanoate (Jatenzo, Clarus Therapeutics), an oral testosterone capsule, has been approved by FDA for treatment of men with low testosterone levels caused by specific conditions such as genetic disorders or tumors that have damaged the pituitary gland. The product should not be used to treat men with age-related hypogonadism in which testosterone levels decline due to aging, even if these men have symptoms that appear to be related to low testosterone, as benefits of use in this situation do not outweigh risks.

PNN Pharmacotherapy Line
Mar. 29, 2019 * Vol. 26, No. 61
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
 Apr. issue of Diabetes Care (2019; 42).
Long-term Metformin & Diabetes Prevention: Metformin reduces the risk of developing diabetes during at least 15 years of preventive therapy, according to data from the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS) (pp. 601–8; M. Temprosa, ella@bsc.gwu.edu). People with higher baseline fasting glucose or A1c levels and women with a history of gestational diabetes mellitus (GDM) benefit the most.
PICO: High-risk adults randomly assigned to masked metformin 850 mg twice daily during DPP (1996–2001) continued on unmasked metformin in the DPPOS (2002–present); those originally on placebo could participate in DPPOS but received only lifestyle education; fasting or 2-h glucose levels after an oral glucose tolerance test or HbA1c levels; hazard ratio (HR) and rate differences (RDs) with metformin versus placebo.
Results: “During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA1c levels, respectively. Metformin’s effect on the development of glucose-defined diabetes was greater for women with a history of prior [GDM] (HR 0.59, RD −4.57 cases/100 person–years) compared with parous women without GDM (HR 0.94, RD −0.38 cases/100 person–years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA1c, metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD −1.03 cases/100 person–years with baseline HbA1c <6.0% (42 mmol/mol) and −3.88 cases/100 person–years with 6.0–6.4% (P = 0.0001).”
Editorial: “Despite a clear need for better means of preventing diabetes, the lack of a formal prevention-related indication for metformin is and will remain a significant barrier to more widespread use,” (pp. 499–501; W. T. Cefalu, wcefalu@diabetes.org). “Perhaps we are now ready to surmount this hurdle. We fully expect that, in the near future, discussion will resume as to when, for whom, and how metformin should be deployed as preventive therapy. Let the arguments begin!”
Real-World Costs of Insulin Pump v. Injection Therapy of T1D: Costs of insulin pump therapy, compared with multiple daily injection (MDI) therapy, were higher during 9 years of treatment for type 1 diabetes, leading researchers to call for increased “identification of tangible and intangible benefits of pump therapy over time” (pp. 545–52; K. S. Carlsson, katarina.steen_carlsson@ihe.se).
PICO: Mean annual costs of pump or MDI therapy in 14,238 individuals the Swedish National Diabetes Register since 2002.
Results: “Mean age at baseline was 34 years, with 21 years of diabetes duration and a mean HbA1c of 8.1% (65 mmol/mol). We had 73,920 person–years of observation with a mean follow-up of 5 years per participant. Mean annual costs were higher for pump therapy than for MDI therapy ($12,928 vs. $9,005, respectively; P <0.001; mean difference $3,923 [95% CI $3,703–$4,143]). Health care costs, including medications and disposables, accounted for 73% of the costs for pump therapy and 63% of the costs for MDI therapy. Regression analyses showed higher costs for low education, low disposable income, women, and older age.”
>>>PNN NewsWatch
Certolizumab pegol (Cimzia, UCB) injection has been approved by FDA for the additional indication of treatment of adults with nonradiographic axial spondyloarthritis (nr-axSpA) who have objective signs of inflammation. This is the first time that FDA has approved a treatment for nr-axSpA. Originally approved in 2008, certolizumab pegol is also indicated for adults with Crohn’s disease, moderate-to-severe rheumatoid arthritis, active ankylosing spondylitis, and moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
* Starting in April, 
artesunate, the WHO-recommended first-line treatment of severe malaria, will become first-line treatment for severe malaria in the U.S., CDC said yesterday. This change is needed because the only FDA-approved I.V. antimalarial drug in the U.S., quinidine, has been discontinued by the manufacturer. Clinicians must call CDC’s Malaria Hotline at 770/488-7788 to obtain I.V. artesunate.


PNN October–December 2018

PNN Pharmacotherapy Line
Oct. 1, 2018 * Vol. 25, No. 189
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Sept. 29 issue of Lancet (2018; 392).
Long-Term Outcomes With BP/Lipid Therapy in Hypertension: After 16 years of follow-up in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study, researchers report “long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin” among patients initially diagnosed with hypertension and total cholesterol levels below 6.5 mmol/L (250.97 mg/dL) (pp. 1127–37). “Patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure,” the authors conclude. “Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes.” (P. Sever, p.sever@imperial.ac.uk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Hormonal Contraception & Ovarian Cancer: Use of contemporary combined hormonal contraception — but not progestin-only products — may have prevented 21% of cases of ovarian cancer among younger women over a 20-year period, a study estimates (k3609). A cohort analysis of nationwide data from Denmark shows these patterns of contraception use and ovarian cancer for women aged 15–49 years in 1995–2014: “During 21.4 million person years, 1,249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13,344,531 person years. Never users had 771 ovarian cancers during 8,150,250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (relative risk 0.58 (95% confidence interval 0.49 to 0.68) and 0.77 (0.66 to 0.91), respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82 (0.59 to 1.12) with ≤1 year use to 0.26 (0.16 to 0.43) with >10 years’ use; P <0.001 for trend). Similar results were achieved among women followed up to their first switch in contraceptive type. Little evidence of major differences in risk estimates by tumour type or progestogen content of combined oral contraceptives was seen. Use of progestogen-only products were not associated with ovarian cancer risk. Among ever users of hormonal contraception, the reduction in the age standardised absolute rate of ovarian cancer was 3.2 per 100,000 person years. Based on the relative risk for the never use versus ever use categories of hormonal contraception (0.66), the population prevented fraction was estimated to be 21%—that is, use of hormonal contraception prevented 21% of ovarian cancers in the study population.” (L. Iversen, l.iversen@abdn.ac.uk)
>>>PNN NewsWatch
FDA on Friday approved cemiplimab-rwlc (Libtayo, Regeneron Pharmaceuticals) injection for treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Approval of this intravenous agent is the first of a drug specifically for advanced CSCC.
Amikacin liposome inhalation suspension (Arikayce, Insmed) was approved by FDA on Friday for treatment of refractory pulmonary infections of Mycobacterium avium complex.
* Two lots of Endo’s 
Robaxin (methocarbamol tablets, USP) 750 mg tablets in 100-count bottle packs are being recalled to the consumer level because of incorrect daily dosing information on the label.
>>>PNN JournalWatch
Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation, in Annals of Internal Medicine, 2018; 10.7326/M17-2762. (S. J. Shah, sachin.shah@ucsf.edu)
CKD and Sedentary Time: Results From the Canadian Health Measures Survey, in American Journal of Kidney Diseases, 2018; 72: 529–37. (C. Bohm, cbohm@hsc.mb.ca)
Social Determinants of Health: Addressing Unmet Needs in Nephrology, in American Journal of Kidney Diseases, 2018; 72: 582–91. (Y. N. Hall, ynhall@kri.washington.edu)
Alcohol Use in Patients with Chronic Liver Disease, in New England Journal of Medicine, 2018; 379: 1251–61. (J. H. Samet, jsamet@bu.edu)

PNN Pharmacotherapy Line
Oct. 2, 2018 * Vol. 25, No. 190
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online article from and Oct. 2 issue of Annals of Internal Medicine (2018; 169).
Cost Drivers Among Dual Eligibles: The high cost of care of dual-eligible Medicare and Medicaid beneficiaries comes primarily from long-term care and not preventable hospitalizations and other ambulatory care–sensitive conditions, according to results of an observational study (10.7326/M18-0085). Medicare–Medicaid Linked Enrollee Analytic Data Source data for 2008 to 2010 show these patterns among 1.9 million dual-eligible beneficiaries who were alive all 3 years: “In the first year, 192,835 patients were high-cost. More than half (54.8%) remained high-cost across all 3 years. These patients were younger than transiently high-cost patients, with fewer medical comorbidities and greater intellectual impairment. Persistently high-cost patients spent $161,224 per year compared with $86,333 per year for transiently high-cost patients and $22,352 per year for non–high-cost patients. Most of the spending among persistently high-cost patients (68.8%) was related to long-term care, and very little (<1%) was related to potentially preventable hospitalizations for ambulatory care–sensitive conditions.” (A. K. Jha, ajha@hsph.harvard.edu)
Chronic Pain Among Suicide Decedents: Chronic pain may be an important contributor to suicide, authors of a retrospective analysis conclude based on data from 18 states participating in the National Violent Death Reporting System (NVDRS) in the U.S. (pp. 448–55). “Access to quality, comprehensive pain care and adherence to clinical guidelines may help improve pain management and patient safety,” the investigators conclude based on these data from 2003 through 2014: “Of 123,181 suicide decedents included in the study, 10,789 (8.8%) had evidence of chronic pain, and the percentage increased from 7.4% in 2003 to 10.2% in 2014. More than half (53.6%) of suicide decedents with chronic pain died of firearm-related injuries and 16.2% by opioid overdose.” (E. Petrosky, xfq7@cdc.gov)
E-Cigarette Use Among U.S. Adults: A 2016 survey shows that 4.5% of adults in the U.S. were using e-cigarettes, with higher numbers in some states and among younger adults, LGBT persons, current cigarette smokers, and persons with comorbid conditions (pp. 429–38). Data from the Behavioral Risk Factor Surveillance System show that 10.8 million adults used e-cigarettes during that year: “The prevalence of current e-cigarette use was highest among persons aged 18 to 24 years (9.2% [95% CI, 8.6% to 9.8%]), translating to approximately 2.8 million users in this age range. More than half the current e-cigarette users (51.2%) were younger than 35 years. In addition, the age-standardized prevalence of e-cigarette use was high among men; lesbian, gay, bisexual, and transgender (LGBT) persons; current combustible cigarette smokers; and those with chronic health conditions. The prevalence of e-cigarette use varied widely among states, with estimates ranging from 3.1% (CI, 2.3% to 4.1%) in South Dakota to 7.0% (CI, 6.0% to 8.2%) in Oklahoma.” (M. J. Blaha, mblaha1@jhmi.edu)
Effectiveness of Fecal Immunochemical Test Screening Programs: Comparing detection rates for proximal versus distal colorectal neoplasia with the fecal immunochemical test (FIT), researchers report that a “multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round” (10.7326/M18-0855). The retrospective study of a screening program in the Venato region of Italy produced these results for 123,347 people with 441,647 FITs: “Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1,000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed.” (M. Zorzi, manuel.zorzi@azero.veneto.it)
>>>PNN NewsWatch
* October is American Pharmacists Month! Resources and ideas for celebrating are available online from APhA.

PNN Pharmacotherapy Line
Oct. 3, 2018 * Vol. 25, No. 191
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Oct. 2 issue of JAMA (2018; 320).
Diagnosis and Management of Rheumatoid Arthritis: “Scientific advances have improved therapies that prevent progression of irreversible joint damage in up to 90% of patients with [rheumatoid arthritis (RA)],” conclude authors of a review article that summarizes recent studies of HLA-DRB1 haplotypes in RA and use of non-TNF and anti-TNF treatments (pp. 1360–72). “The development of novel instruments to measure disease activity and identify the presence or absence of remission have facilitated new treatment strategies to arrest RA before joints are damaged irreversibly. Outcomes have been improved by recognizing the benefits of early diagnosis and early therapy with disease-modifying antirheumatic drugs (DMARDs). The treatment target is remission or a state of at least low disease activity, which should be attained within 6 months. Methotrexate is first-line therapy and should be prescribed at an optimal dose of 25 mg weekly and in combination with glucocorticoids; 40% to 50% of patients reach remission or at least low disease activity with this regimen. If this treatment fails, sequential application of targeted therapies, such as biologic agents (eg, [TNF] inhibitors) or Janus kinase inhibitors in combination with methotrexate, have allowed up to 75% of these patients to reach the treatment target over time. New therapies have been developed in response to new pathogenetic findings. The costs of some therapies are considerable, but these costs are decreasing with the advent of biosimilar drugs (drugs essentially identical to the original biologic drugs but usually available at lower cost).” (D. Aletaha, daniel.aletaha@meduniwien.ac.at)
“Although [such] findings … may not have immediate clinical implications, identification of the precise HLA variants that influence disease course is of great interest,” editorialists write (pp. 1623–4). “These observations open the door to further research, including replication for this haplotype and discovery related to its combination with other determinants of disease development and progression. Such discoveries will prove helpful both to understand and predict the variable disease course and response to therapy that occurs in patients with rheumatoid arthritis.” (D. T. Felson, 
dfelson@bu.edu)
Aging, Cell Senescence, Disease & the Healthspan: Use of medications for altering the aging process is reviewed in the first of three related Viewpoint articles (pp. 1319–20): “If senolytic drugs are effective across a range of disorders, provided they are safe, clinical trials of senolytics might move toward studies in presymptomatic individuals to delay or prevent age-related conditions.” (J. L. Kirkland, kirkland.james@mayo.edu)
“One major challenge for improving human health by treating aging processes is that from a regulatory perspective (eg, the US Food and Drug Administration) there is no indication that is similar to targeting aging,” authors write (
pp. 1321–2). “Even if safe and effective drugs are available, health care payers will be reluctant to pay for such treatment without regulatory approval. Consequently, for now, drug companies are reluctant to invest in treatments targeting aging.” (N. Barzilai, nir.barzilai@einstein.yu.edu)
“The longer people live, the more important aging biology becomes as a primary risk factor in determining both length and quality of life,” Viewpoint authors write in discussing the lifespan versus the healthspan (
pp. 1323–4). “In long-lived populations, a substantial part of life, and certainly most deaths, now occur in a period in the life-span when the risk for frailty and disability increases exponentially. In this period, which could be called the red zone, it becomes increasingly more difficult to intervene using conventional disease-oriented approaches; the further into this period that humans venture, the more resistant diseases become.” (S. J. Olshansky, sjayo@uic.edu)
>>>PNN NewsWatch
* FDA yesterday issued a revised draft guidance on use of 505(q) petitions, which can be misused by companies to block or delay marketing of generic drugs. “We know there’s no easy or single solution to the challenges posed by high drug development costs and the high prices,” Commissioner Scott Gottlieb, MD, writes. But “we can make additional, new headway in helping to promote competition, reduce prices, and enable more patients to have access to medicines.”

PNN Pharmacotherapy Line
Oct. 4, 2018 * Vol. 25, No. 192
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Oct. 4 New England Journal of Medicine (2018; 379).
Rivaroxaban in Heart Failure & Coronary Disease: In the COMMANDER-HF trial, rivaroxaban did not improve outcomes in 5,022 patients with chronic heart failure, left ventricular ejection fraction of 40% or less, coronary artery disease, and elevated plasma concentrations of natriuretic peptides and who did not have atrial fibrillation (pp. 1332–42). The study concept was based on activation of thrombin-related pathways in heart failure, the researchers report, noting that “treatment with rivaroxaban, a factor Xa inhibitor, could reduce thrombin generation and improve outcomes for patients with worsening chronic heart failure and underlying coronary artery disease.” Compared with placebo in patients who also received standard care after treatment of episodes of worsening heart failure, the study showed: “Over a median follow-up period of 21.1 months, the primary end point occurred in 626 (25.0%) of 2,507 patients assigned to rivaroxaban and in 658 (26.2%) of 2,515 patients assigned to placebo (hazard ratio, 0.94; 95% confidence interval [CI], 0.84 to 1.05; P = 0.27). No significant difference in all-cause mortality was noted between the rivaroxaban group and the placebo group (21.8% and 22.1%, respectively; hazard ratio, 0.98; 95% CI, 0.87 to 1.10). The principal safety outcome occurred in 18 patients who took rivaroxaban and in 23 who took placebo (hazard ratio, 0.80; 95% CI, 0.43 to 1.49; P = 0.48).” (F. Zannad, f.zannad@chru-nancy.fr)
“Clinical trials in heart failure must strive for a better match of the patient to the therapy,” editorialists write (
pp. 1372–4). “Future trials testing this ‘precision’ approach will require greater specificity of phenotyping, genotyping, or both, with more screening hurdles for the trialists and a smaller target population for the sponsors. In the meantime, the results of COMMANDER HF support the position that oral anticoagulation is not indicated for patients with heart failure and reduced ejection fraction in the absence of atrial fibrillation.” (M. A. Pfeffer)
Tyrosine Kinase 2 Inhibition in Psoriasis: A phase 2 trial of the oral agent BMS-986165 demonstrates greater clearing of psoriasis over a 12-week period with 3 mg or higher doses of the tyrosine kinase 2 inhibitor, compared with placebo (pp. 1313–21). Study participants were adults with moderate-to-severe psoriasis; exclusion criteria included lack of prior response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Based on a primary end point of 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12, results were as follows: “A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P <0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P <0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P <0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P <0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment.” (K. Papp, kapapp@probitymedical.com)
Next-Generation Sequencing for Genetic Testing: “Genomic data are a potential component of precision medicine, and exome and genome sequences have been described as a lifelong clinical resource,” write authors of a review of genetic testing with next-generation sequencing (pp. 1353–62). “These data can potentially produce refinement of risk estimates for common diseases, pharmacogenomic data, and diagnoses for late-onset disorders. Exome-sequencing studies detect one to seven carrier variants on average, and one trial showed that 2% of studies produce potentially actionable pathogenic or likely pathogenic variants in at least one [gene]. Approximately 130 pharmacogenomic biomarkers are included in current drug labeling, but the literature regarding the usefulness of pharmacogenomic data for individual variants has been mixed. Most persons have one or more such variants…. However, studies of genotype-guided warfarin dosing — arguably one of the best-known pharmacogenomic examples — have not yielded clear guidance.” (D. R. Adams, david.adams@nih.gov)

PNN Pharmacotherapy Line
Oct. 5, 2018 * Vol. 25, No. 193
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
 Oct. issue of the American Journal of Psychiatry (2018; 175).
Medications for Alcohol and Opioid Use Disorders: Suicidality and crime were reduced during pharmacotherapy of patients with alcohol and opioid use disorders, researchers report (pp. 970–8). Among a population cohort of 21,281 individuals with records in Swedish registries, rates of suicidal behaviors, accidental overdoses, and crime were compared during periods of medication treatment and no treatment, with these results: “No significant associations with any of the primary outcomes were found for acamprosate. For naltrexone, there was a reduction in the hazard ratio for accidental overdoses during periods when individuals received treatment compared with periods when they did not (hazard ratio = 0.82, 95% CI = 0.70, 0.96). Buprenorphine was associated with reduced arrest rates for all crime categories (i.e., violent, nonviolent, and substance-related) as well as reduction in accidental overdoses (hazard ratio = 0.75, 95% CI = 0.60, 0.93). For methadone, there were significant reductions in the rate of suicidal behaviors (hazard ratio = 0.60, 95% CI = 0.40–0.88) as well as reductions in all crime categories. However, there was an increased risk for accidental overdoses among individuals taking methadone (hazard ratio = 1.25, 95% CI = 1.13, 1.38).” (Y. Molero)
Molecular Genetics & New Strategies for Opioid Addiction: Molecular-based genetics could provide direction for new medication strategies for management of opioid addiction, write authors of a review article (pp. 935–42): “The opioid epidemic is at the epicenter of the drug crisis, resulting in an inconceivable number of overdose deaths and exorbitant associated medical costs that have crippled many communities across the socioeconomic spectrum in the United States. Classic medications for the treatment of opioid use disorder predominantly target the opioid system and thus have been underutilized, in part due to their own potential for abuse and heavy regulatory burden for patients and clinicians. Opioid antagonists are now evolving in their use, not only to prevent acute overdoses but as extended-use treatment options. Strategies that target specific genetic and epigenetic factors, along with novel nonopioid medications, hold promise as future therapeutic interventions for opioid abuse. Success in increasing the treatment options in the clinical toolbox will, hopefully, help to end the historical pattern of recurring opioid epidemics.” (Y. L. Hurd)
>>>Pediatrics Highlights
Source:
 Oct. issue of Pediatrics (2018; 142).
Alcohol Use & Interactions Among Medically Vulnerable Youth: Many youth with chronic medical conditions use alcohol at rates similar to other young people, a study shows, making it important to counsel them on the risks of alcohol in general and its interactions with other medications (10.1542/peds.2017-4026). An electronic survey of adolescents with type 1 diabetes, juvenile idiopathic arthritis, moderate persistent asthma, cystic fibrosis, attention-deficit/hyperactivity disorder, or inflammatory bowel disease showed the following: “Of 396 youth, 86.4% were on [alcohol-interactive (AI)] medications, of whom, 35.4% reported past-year alcohol use (46.3% among those who were not on AI medications). AI medication use was associated with 43% lower odds of past-year alcohol use (adjusted odds ratio: 0.57; 95% confidence interval: 0.39–0.85) and lower total consumption (beta = −.43; SE = 0.11; P < .001). Perceptions of alcohol-medication interference partially mediated the relationship between AI medication exposure and past-year alcohol use (Sobel test P = .05).” (E. R. Weitzman)
>>>PNN NewsWatch
* In New York City in 2010–16, congenital syphilis occurred mostly in babies of women whose infections were detected too late during pregnancy, a study in this week’s Morbidity and Mortality Weekly Report shows (2018; 67: 1088–93). “Provider and public health systems play a critical role in preventing congenital syphilis through screening and treating pregnant women for syphilis; these systems need to be maintained and strengthened,” the authors write.
Silver Star Brands is voluntarily recalling four Native Remedies, two Healthful Naturals, and two PetAlive products.
PNN will not be published on Mon., Oct. 8, Columbus Day.

PNN Pharmacotherapy Line
Oct. 9, 2018 * Vol. 25, No. 194
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online articles from JAMA Internal Medicine (2018; 178). 
Drug Safety in Real-World Studies: Articles examine safety indicators of NSAIDs and allopurinol in large-scale studies of real-world data. 
Among 814,049 older adults with 2.4 million primary care visits for musculoskeletal conditions, NSAID use was frequent among those at high risk for chronic kidney disease (CKD) but not linked to adverse, short-term outcomes, researchers report (
10.1001/jamainternmed.2018.4273). Administrative claims databases in Ontario yielded these insights into prescription NSAID dispensing within 7 days of a primary care visit: “The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%–16.7%) among 7,365 primary care physicians. Within a sample of 35,552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, −0.001 to 0.002; P = .74).” (R. S. Bhatia, sacha.bhatia@wchospital.ca)
Similarly, concerns about drug-associated renal function decline in patients taking allopurinol for gout may be unfounded, an analysis shows (
10.1001/jamainternmed.2018.4463). In a large cohort of patients newly diagnosed with gout who had records in a U.K. general practitioner database, “allopurinol initiation of at least 300 mg/d was associated with a lower risk of renal function deterioration,” the authors write. “Because allopurinol does not appear to be associated with renal function decline, clinicians should consider evaluating other potential causes when patients with gout experience renal function decline.” (T. Neogi, tneogi@bu.edu)
“The bigger issue is how these studies should influence practice, if at all,” editorialists write (
10.1001/jamainternmed.2018.5766). “Clinicians already recognize that many patients with heart failure, kidney disease, or hypertension tolerate a short course of NSAIDs without obvious harm, and that in many patients with gout, higher doses of allopurinol can be prescribed without concerns about progression of CKD. On balance, these studies help soften our stance on the use of NSAIDs and allopurinol in patients with relative contraindications.
“Done well, observational studies can provide valuable information about the real-world safety of drugs. Moving forward, detailed real-world data will be increasingly available in electronic health records and registries. In response to initiatives such as the 21st Century Cures Act, the National Evaluation System for Health Technology, and the US Food and Drug Administration’s Sentinel Initiative, we can expect to see more observational studies testing longstanding assumptions about treatments, along with new uses for old therapies. Yes, the findings will need to be contextualized and viewed with more skepticism than [randomized controlled trials], but in some instances, they can be thoughtfully integrated into our treatment decisions.” (D. N. Juurlink, 
dnj@ices.on.ca)
>>>PNN NewsWatch
* Two FDA decisions announced on Friday have implications for vaccine-administering pharmacists and those in community settings. Gardasil 9 (Human Papillomavirus (HPV) 9-valent Vaccine, Recombinant) is now licensed for use in women and men aged 27 through 45 years, and the Bose Hearing Aid will be available for self-use in adults with perceived mild-to-moderate hearing impairment.
>>>PNN JournalWatch
Amoxicillin–Clavulanate Versus Azithromycin for Respiratory Exacerbations in Children with Bronchiectasis (BEST-2): A Multicentre, Double-Blind, Non-Inferiority, Randomised Controlled Trial, in Lancet, 2018; 392: 1197–206. (V. Goyal, drvikasgoyal@gmail.com)
Long Term Adjuvant Endocrine Therapy and Risk of Cardiovascular Disease in Female Breast Cancer Survivors: Systematic Review, in BMJ, 2018; 363: k3845. (A. Matthews, anthony.matthews@lshtm.ac.uk)
Discoveries on the Genetics of ADHD in the 21st Century: New Findings and Their Implications, in the American Journal of Psychiatry, 2018; 175: 943–50. (A. Thapar)

PNN Pharmacotherapy Line
Oct. 10, 2018 * Vol. 25, No. 195
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Oct. 9 issue of JAMA (2018; 320).
Targeted Polymyxin B Hemoperfusion in Septic Shock: In the EUPHRATES trial, patients with septic shock and high endotoxin activity had similar mortality outcomes after randomization to polymyxin B therapy or sham treatments, researchers report (pp. 1455–63). A total of 450 adult critically ill patients participated in the study at 55 North American tertiary hospitals; all had septic shock and an endotoxin activity assay level of 0.60 or higher when they were enrolled in 2010–16. Standard therapy plus two polymyxin B hemoperfusion treatments or sham therapy completed within the first 24 hours of enrollment produced these results: “Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0–71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a [multiple organ dysfunction score] of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, −10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).” (R. P. Dellinger, dellinger-phil@cooperhealth.edu)
Antibiotics for Sepsis: Responding to recommendations made previously as part of the Surviving Sepsis Campaign, authors write, “The time has come to balance the recommendation for early and aggressive antibiotics for all patients with possible sepsis with the diagnostic uncertainty regarding sepsis and the possible harm associated with unnecessary antibiotics” (pp. 1433–4). “The Surviving Sepsis Campaign and similar quality improvement initiatives have helped improve quality of care by focusing much-needed attention on sepsis and emphasizing the importance of early diagnosis and optimal management. The good that these initiatives have done could be further enhanced by encouraging and permitting clinicians to gather more data to confirm infection in patients without shock before prescribing antibiotics when the evidence for infection is equivocal.” (M. Klompas, mklompas@bwh.harvard.edu)
Chronic Wound Management: “Effective care for chronic wounds requires a multimodal approach, including wound bed optimization, management of chronic medical conditions, and consistent follow-up,” conclude authors of an update article that includes an analysis of wound bed preparation and adjunctive therapies such as antimicrobial dressings and bariatric therapy (pp. 1481–2). “Advanced wound therapies, such as [negative-pressure wound therapy (NPWT)], can benefit some patients, but evidence to support the use of one specific advanced dressing type over another is limited. Cost-effectiveness is a key consideration given the expense of many advanced dressings. However, some of these products decrease dressing change frequency and may improve healing, which can lead to overall cost reductions. Dressing selection can generally be based on wound assessment, physician and patient familiarity with the products, availability, and affordability.” (M. T. Longaker, longaker@stanford.edu)
>>>PNN NewsWatch
* FDA yesterday released revised draft “guidance documents that will advance the development of generic transdermal and topical delivery systems (TDS),” FDA Commissioner Scott Gottlieb, MD, wrote on the agency website. “Assessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs” provides updated advice for the design and conduct of studies evaluating the adhesive performance of a proposed generic TDS. “Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs” provides recommendations for the design and conduct of studies to evaluate the in vivo skin irritation and sensitization potential of a proposed generic TDS.

PNN Pharmacotherapy Line
Oct. 11, 2018 * Vol. 25, No. 196
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Oct. 11 New England Journal of Medicine (2018; 379).
DNA Sequencing to Determine TB Drug Susceptibility: Testing the feasibility of predicting susceptibility of Mycobacterium tuberculosis isolates to first-line drugs using DNA sequencing, investigators find that genotypic results correlate well with phenotypic sensitivities (pp. 1403–15). Whole-genome sequences and associated phenotypes of resistance or susceptibility to isoniazid, rifampin, ethambutol, and pyrazinamide showed these associations for 10,209 isolates from 16 countries on six continents: “The largest proportion of phenotypes was predicted for rifampin (9,660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8,794 [89.8%] of 9,794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7,516 isolates with complete phenotypic drug-susceptibility profiles, 5,865 (78.0%) had complete genotypic predictions, among which 5,250 profiles (89.5%) were correctly predicted. Among the 4,037 phenotypic profiles that were predicted to be pansusceptible, 3,952 (97.9%) were correctly predicted.” (T. Walker, timothy.walker@ndm.ox.ac.uk)
Using this approach to bring individualized therapy “to patients in high-burden, resource-limited settings will be challenging, to say the least,” editorialists write (
pp. 1474–5). “Globally, only 22% of the 6.3 million people with newly diagnosed tuberculosis in 2016 had access to rifampin drug-susceptibility testing. However, previous programmatic failures, while underscoring the challenges, should not preclude us from aiming to provide the same standard of care for all patients with tuberculosis regardless of where they reside. Our goals should include the provision of universal drug-susceptibility testing as a key requirement for meeting the WHO End TB targets. At the time of the first-ever United Nations General Assembly High-Level Meeting on the Fight to End Tuberculosis, there is hope that renewed political will for mobilizing the resources needed to capitalize on advances such as that reported [in this study] will be brought to bear on this formidable global health challenge.” (H. Cox)
Personalized Prognosis in Myeloproliferative Neoplasms: Genomic classification of myeloproliferative neoplasms — including polycythemia vera, essential thrombocythemia, and myelofibrosis— could enable “personalized predictions of patients’ outcomes and … treatment,” conclude authors of a study of 69 myeloid cancer genes (pp. 1416–30). Genomic classification of myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients showed these results: “A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy.” (A. R. Green, arg1000@cam.ac.uk)
>>>PNN NewsWatch
Pregnant women who received influenza vaccinations were 40% less likely to be hospitalized for laboratory-confirmed influenza, according to a large CDC-coauthored study released today by Clinical Infectious Diseases. Data for more than 2 million pregnant women from four countries showed that 80% of pregnancies overlapped with the influenza season and the vaccine was equally protective across comorbidities and all trimesters.

PNN Pharmacotherapy Line
Oct. 12, 2018 * Vol. 25, No. 197
Providing news and information about medications and their proper use

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>>>Circulation Highlights
Source:
 Oct. 9 issue of Circulation (2018; 138).
Sacubitril/Valsartan v. Irbesartan in Chronic Kidney Disease: In the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial, 12 months of sacubitril/valsartan showed similar effects on kidney function and albuminuria as irbesartan but with additional beneficial effects on blood pressure and cardiac biomarkers in 414 people with chronic kidney disease (pp. 1505–14). Participants had glomerular filtration rates (GFRs) of 20–60 mL/min/1.73 sq m at study entry. Sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily had these effects on GFR: “At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 sq m among those assigned irbesartan; difference, –0.1 (0.7) mL/min/1.73 sq m. Effects were similar in all prespecified subgroups. There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, –9%; 95% CI, –18 to 1). However, compared with irbesartan, allocation to sacubitril/valsartan reduced study average systolic and diastolic blood pressure by 5.4 (95% CI, 3.4–7.4) and 2.1 (95% CI, 1.0–3.3) mm Hg and levels of troponin I and N terminal of prohormone brain natriuretic peptide (tertiary end points) by 16% (95% CI, 8–23) and 18% (95% CI, 11–25), respectively. The incidence of serious adverse events (29.5% versus 28.5%; rate ratio, 1.07; 95% CI, 0.75–1.53), nonserious adverse reactions (36.7% versus 28.0%; rate ratio, 1.35; 95% CI, 0.96–1.90), and potassium ≥5.5 mmol/L (32% versus 24%, P = 0.10) was not significantly different between randomized groups.” (R. Haynes, harp3@ndph.ox.ac.uk)
“For the majority of patients with CKD who do not have reduced ejection fraction and yet remain at high cardiovascular risk, a larger clinical trial designed to examine the effect of sacubitril/valsartan on clinical end points of cardiovascular mortality and events will be required to determine whether this therapy is effective for reducing cardiovascular risk and improving patient outcomes in the broader CKD population,” editorialists write (
pp. 1515–8). “When one considers that the price of sacubitril/valsartan is >15-fold higher than generic valsartan, understanding whether this new therapy is effective and offers value for money (ie, that higher medication costs are offset by reductions in the cost of hospitalizations for heart disease) in the current setting of constrained healthcare resources seems particularly important.” (B. Manns, Braden.Manns@albertahealthservices.ca)
Apixaban Use in End-Stage Kidney Disease & Atrial Fibrillation: Effectiveness and safety measures were better with apixaban than warfarin in 25,523 Medicare beneficiaries with end-stage kidney disease and atrial fibrillation (AF) who received one of the drugs in 2010–15 (pp. 1519–29). In the dataset, too few patients received dabigatran or rivaroxaban for inclusion of those drugs in the analysis. Based outcomes of survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death, results for apixaban or warfarin were as follows among this older population: “An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P = 0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P <0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n = 1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n = 1317; HR, 0.61; 95% CI, 0.37–0.98; P = 0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45–0.92; P = 0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42–0.97; P = 0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46–0.85; P = 0.003 for death).” (K. C. Siontis, siontis.konstantinos@mayo.edu)
If these results are confirmed, “standard dose apixaban will be the preferred anticoagulant for stroke prevention in AF among patients dependent on dialysis,” an editorialist concludes (
pp. 1534–6; E. M. Hylek, ehylek@bu.edu).

PNN Pharmacotherapy Line
Oct. 15, 2018 * Vol. 25, No. 198
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Oct. 13 issue of Lancet (2018; 392).
Predictive Value of Baseline/On-Statin Lipoprotein(a) Levels: Support for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials comes from a meta-analysis of individual-patient data from seven statin studies of 26,069 people (pp. 1311–20). Hazard ratios (HRs) for cardiovascular events within each trial were estimated using predefined lipoprotein(a) levels in four ranges, as follows: “Initiation of statin therapy reduced LDL cholesterol (mean change −39% [95% CI −43 to −35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex ( vs <15 mg/dL) were 1.04 (95% CI 0.91–1.18) for 15 mg/dL to less than 30 mg/dL, 1.11 (1.00–1.22) for 30 mg/dL to less than 50 mg/dL, and 1.31 (1.08–1.58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0.94 (0.81–1.10), 1.06 (0.94–1.21), and 1.43 (1.15–1.76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p = 0.010) and was more pronounced at younger ages (interaction p = 0.008) without effect-modification by any other patient-level or study-level characteristics.” (P. Willeit, peter.willeit@i-med.ac.at)
Ustekinumab in SLE: The interleukin (IL)-12 and IL-23–targeting monoclonal antibody ustekinumab was effective and safe in a phase 2, placebo-controlled trial of 102 patients with systemic lupus erythematosus, researchers report (pp. 1330–9): “The addition of ustekinumab to standard-of-care treatment resulted in better efficacy in clinical and laboratory parameters than placebo in the treatment of active systemic lupus erythematosus and had a safety profile consistent with ustekinumab therapy in other diseases. The results of this study support further development of ustekinumab as a novel treatment in systemic lupus erythematosus.” (R. F. van Vollenhoven, r.vanvollenhoven@vumc.nl)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Standing More at Work: In the multicomponent intervention Stand More AT (SMArT) Work trial, provision of a height-adjustable work station with educational and motivational sessions reduced sitting times of desk-based workers in the U.K. National Health Service trust over 3, 6, and 12 months (k3870). A primary outcome of occupational sitting time measured with a thigh-worn accelerometer showed the following: “A significant difference between groups (in favour of the intervention group) was found in occupational sitting time at 12 months (−83.28 min/workday, 95% confidence interval −116.57 to −49.98, P = 0.001). Differences between groups (in favour of the intervention group compared with control) were observed for occupational sitting time at three months (−50.62 min/workday, −78.71 to −22.54, P <0.001) and six months (−64.40 min/workday, −97.31 to −31.50, P <0.001) and daily sitting time at six months (−59.32 min/day, −88.40 to −30.25, P <0.001) and 12 months (−82.39 min/day, −114.54 to −50.26, P = 0.001).” (C. L. Edwardson, ce95@le.ac.uk)
>>>PNN JournalWatch
Evaluation of the Diet Wide Contribution to Serum Urate Levels: Meta-Analysis of Population Based Cohorts, in BMJ, 2018; 363: k3951. (T. R. Merriman, tony.merriman@otago.ac.nz)
Classification, Ontology, and Precision Medicine, in New England Journal of Medicine, 2018; 379: 1452–62. (P. N. Robinson, peter.robinson@jax.org)
Provider Specialty, Anticoagulation, and Stroke Risk in Patients With Atrial Fibrillation and Cancer, in the Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.07.077. (W. T. O’Neal)
Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention, in the Journal of the American College of Cardiology, 2018; 72: 10.1016/j.jacc.2018.07.079. (M. Inouye)
P2Y12-ADP Receptor Blockade in Chronic Kidney Disease Patients With Acute Coronary Syndromes: Review of the Current Evidence, in Circulation, 2018; 138: 1582–96. (L. Bonello, laurent.bonello@ap-hm.fr)

PNN Pharmacotherapy Line
Oct. 16, 2018 * Vol. 25, No. 199
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-release articles from and Oct. 16 issue of Annals of Internal Medicine (2018; 169).
Beta-Blockers During Pregnancy: Beyond known effects of underlying chronic hypertension and associated conditions, use of beta-blockers during the first trimester of pregnancy “is not associated with a large increase in the risk for overall malformations or cardiac malformations,” conclude authors who analyzed health registries of five Nordic countries and the U.S. Medicaid database (10.7326/M18-0338). “Of 3,577 women with hypertensive pregnancies in the Nordic cohort and 14,900 in the U.S. cohort, 682 (19.1%) and 1,668 (11.2%), respectively, were exposed to beta-blockers in the first trimester,” the investigators report. “The pooled adjusted relative risk (RR) and risk difference per 1,000 persons exposed (RD1000) associated with beta-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, −6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, −4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, −0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, −2.0 to 4.0) (based on U.S. cohort data only).” (B. T. Bateman, bbateman@bwh.harvard.edu)
“There is little reason to believe that daily use of an oral beta-antagonist in the first trimester of pregnancy heightens risk for congenital malformations,” writes an editorialist (
10.7326/M18-2500). “There is reason, however, why the fetus of a woman prescribed this class of medication might be at higher risk for a structural birth defect: Women with chronic hypertension are more likely than women without hypertension to have higher body mass index, older age, and prepregnancy diabetes mellitus, factors which are themselves risk factors for birth defects. In fact, chronic hypertension itself, whether treated or not, is associated with slightly higher odds of fetal cardiac malformation. The study by Bateman and colleagues reinforces these observations, which some of the same authors have previously described.” (J. G. Ray, rayj@smh.ca)
Statins & Noncardiovascular Outcomes: Available observational and controlled trials do not support broad use of statins for noncardiovascular outcomes, a review article concludes (pp. 543–53). This supports “leaving the current recommendations unchanged,” the authors write. The umbrella review considered 278 unique noncardiovascular outcomes from 112 meta-analyses of observational studies and 144 meta-analyses of randomized controlled trials (RCTs). Two observational trials provided highly suggestive (class II) evidence of benefits in cancer mortality and COPD, while RCTs showed decreased all-cause mortality in chronic kidney disease. (E. Theodoratou, E.Theodoratou@ed.ac.uk)
>>>PNN NewsWatch
* In remarks to the National Academy of Medicine yesterday, HHS Secretary Alex Azar proposed requiring pharmaceutical companies to provide drug costs in television advertising. “Patient empowerment and transparency are at the core of the President’s drug-pricing blueprint that was released five months ago,” Azar said in a statement released in response to an industry proposal for creating websites providing pricing information. “Our vision for a new, more transparent drug-pricing system does not rely on voluntary action. The drug industry remains resistant to providing real transparency around their prices, including the sky-high list prices that many patients pay. So while the pharmaceutical industry’s action today is a small step in the right direction, we will go further and continue to implement the President’s blueprint to deliver new transparency and put American patients first.” 
* FDA yesterday issued 
new guidance documents providing “drug developers greater clarity and direction as they pursue the next generation of therapies and treatments for patients” in the areas of hematologic malignancies and targeted therapies for rare genetic variants of diseases. “Using more sophisticated approaches to learn about the safety and efficacy of treatments, we can reduce the barriers to bringing new science forward and make sure more patients can benefit sooner from improved treatments,” FDA Commissioner Scott Gottlieb, MD, said in announcing the actions.
* Fat Burners Zone is voluntarily recalling a lot of 
Zero Xtreme capsules to the consumer level. FDA said it has found Zero Xtreme to be tainted with sibutramine.

PNN Pharmacotherapy Line
Oct. 17, 2018 * Vol. 25, No. 200
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Oct. 16 issue of JAMA (2018; 320).
Adjunctive Theophylline in COPD: In a 1-year study of high-risk adults with COPD, addition of low-dose theophylline to an inhaled corticosteroid regimen produced no additional reductions in exacerbations, researchers report (pp. 1548–59). The TWICS (theophylline with inhaled corticosteroids) trial included 1,567 participants with reduced pulmonary function (FEV1/FVC <0.7) and at least two exacerbations over the prior year. For 1 year following randomization in 2014–16, participants in the theophylline 200 mg once or twice daily group had a mean of 2.24 exacerbations compared with 2.23 in the placebo group. “Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%),” the authors write. (D. Price, dprice@opri.sg)
“It is somewhat disappointing that low-dose theophylline did not result in a reduction in exacerbation risk because the drug is relatively inexpensive, and its rationale was based on sound preclinical and human mechanistic studies,” write editorialists (
pp. 1541–2). “Perhaps future formulations that can deliver theophylline to the airway via the inhaled route or pharmacological analogues that can mimic its effect on increasing [histone deacetylase] levels with a better safety profile are possible approaches that can help in the development of targeted therapies for patients with COPD who are at increased risk for exacerbation despite use of current best inhaled agents.” (G. J. Criner, gerard.criner@tuhs.temple.edu)
Bariatric Surgery & Macro-vascular Disease Outcomes: “Even though there appears to be relatively weak evidence supporting aggressive medical management of type 2 diabetes for reducing CV events and mortality, evidence for the benefits of bariatric surgery for improving these outcomes is increasing,” write editorialists responding to a retrospective cohort study (pp. 1570–82; D. Arterburn, david.e.arterburn@kp.org) of macrovascular (coronary artery disease and cerebrovascular diseases) events in 5,301 patients with severe obesity and type 2 diabetes who underwent bariatric surgery (pp. 1545–7). “Yet, access to bariatric surgery is limited by stringent private insurance requirements, lack of Medicaid coverage in some states, and high out-of-pocket costs. [These authors] provide additional evidence that bariatric surgery is associated with lower rates of macrovascular events. Given the benefits of bariatric surgery for patients with type 2 diabetes, including potentially greater long-term benefits than most pharmaceuticals, insurance coverage for weight loss operations should be expanded for appropriate patients.” (S. Ikramuddin, ikram001@umn.edu)
Influenza Pandemic Vulnerability: “I think people believe that because you can go on the internet and order something from Amazon and it’s here tomorrow, that anything we need in the medical care field will be available in equal speed,” says Michael Osterholm, PhD, MPH, of U. Minn. in a JAMA interview on the threat of an influenza pandemic (pp. 1523–5). “We don’t have stockpiles of anything beyond a limited supply the U.S. government has of some medical products, which would be quickly exhausted if we are in a real pandemic. We have to anticipate these things, and we have to have plans. Right now, anticipation is the word that probably applies to the next 12 hours. What we need to understand is that it has to apply to the next 10 to 15 years.” 
Asked to rank influenza in terms of all the microbes that could cause widespread harm, Osterholm says, “There really are only 2 disease categories today that really have the ability to wreak havoc on the global society, both in terms of number of severe cases and deaths as well as economic disruption. That’s influenza and pandemic influenza and its antimicrobial resistance, which is coming too.…” (R. Voelker)
>>>PNN NewsWatch
Cybersecurity of medical devices is the focus of a new framework between FDA and the Dept. of Homeland Security (DHS). DHS continues to serve as the central medical device vulnerability coordination center, and FDA continues to engage in regular, ad hoc, and emergency coordination calls with DHS and advise DHS regarding the risk to patient health and potential harms of identified threats and vulnerabilities.

PNN Pharmacotherapy Line
Oct. 18, 2018 * Vol. 25, No. 201
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Oct. 18 issue of the New England Journal of Medicine (2018; 379).
Aspirin for Prevention in the Poststatin Era: In four research articles and an editorial, the contemporary place of prophylactic aspirin is examined. 
Compared with placebo in older adults, enteric-coated aspirin 100 mg used for primary prevention failed to prolong disability-free survival over 5 years but produced a significantly higher rate of major hemorrhage, report investigators in the Aspirin in Reducing Events in the Elderly (ASPREE) trial (
pp. 1499–508). Participants (n = 19,114) in Australia and the U.S. were age 70 years or older (65 for blacks and Hispanics in the U.S.) and did not have cardiovascular disease, dementia, or physical disability when randomized in 2010–14. Before early termination of the study for futility, results showed: “The rate of the composite of death, dementia, or persistent physical disability was 21.5 events per 1000 person–years in the aspirin group and 21.2 per 1000 person–years in the placebo group (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P = 0.79).… The rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%; hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P <0.001).” (J. J. McNeil, john.mcneil@monash.edu)
In two additional analyses of this group of “healthy elderly,” the ASPREE investigators find no benefits of aspirin on primary prevention of cardiovascular disease (
pp. 1509–18) and an unexpected increase in all-cause mortality among those on the drug (pp. 1519–28). Rates of fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure during a median of 4.7 years of aspirin or placebo produced rates of 10.7 and 11.3 events per 1,000 person–years for aspirin and placebo, respectively (not significantly different), but rates of major hemorrhage of 8.6 and 6.2 events per 1,000 person–years for the respective drugs (P <.0.001). In the all-cause mortality analysis, “cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1,000 person–years,” the authors write. “Cancer-related death occurred in 3.1% of the participants in the aspirin group and in 2.3% of those in the placebo group (hazard ratio, 1.31; 95% CI, 1.10 to 1.56).” (J. J. McNeil, john.mcneil@monash.edu)
Patients with diabetes and no evident cardiovascular diseases at entry into the ASCEND (A Study of Cardiovascular Events in Diabetes) randomized trial had significantly fewer serious vascular events with enteric-coated aspirin, but major bleeding events “largely counterbalanced” benefits of the drug, investigators conclude (
pp. 1529–39). During a mean of 7.4 years of follow-up in 15,480 participants, enteric-coated aspirin 100 mg produced rates of serious vascular events in 8.5% versus 9.6% (P = 0.01), major bleeding events of 4.1% versus 3.2% (P = 0.003), gastrointestinal tract cancers of 2.0% versus 2.0%, and all cancers of 11.6% versus 11.5%. (J. Armitage, ascend@ndph.ox.ac.uk)
“What can we conclude about the use of aspirin for prophylaxis 150 years after its chemical synthesis?” asks an editorialist (
pp. 1572–4). “For secondary prevention, in which risk is determined largely by the extent of atherosclerotic disease, the benefits of aspirin outweigh the risks of bleeding. In contrast, for primary prevention, in which risk is determined largely by age and the presence or absence of diabetes, the benefit–risk ratio for prophylactic aspirin in current practice is exceptionally small. Thus, beyond diet maintenance, exercise, and smoking cessation, the best strategy for the use of aspirin in the primary prevention of cardiovascular disease may simply be to prescribe a statin instead.” (P. M. Ridker)
Fatty Acid Supplements in Diabetes: ASCEND investigators also looked at effects on n-3 fatty acids in their population of 15,480 participants with diabetes and no evident cardiovascular disease, finding no significant difference in serious vascular events with use of the supplement (pp. 1540–50). Capsules containing 1 g of n-3 fatty acids or olive oil produced no significant differences in rates of nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death (excluding confirmed intracranial hemorrhage), all-cause mortality, or rates of nonfatal serious events during a mean follow-up period of 7.4 years. (L. Bowman, ascend@ndph.ox.ac.uk)

PNN Pharmacotherapy Line
Oct. 19, 2018 * Vol. 25, No. 202
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 Nov. 1 issue of Clinical Infectious Diseases (2018; 67).
HPV Vaccine in HIV-Infected Adults Older Than 26 Years: In a phase 3 study, use of the quadrivalent human papillomavirus (HPV) vaccine in patients living with HIV who are aged 27 years or older is not supported for prevention of new anal HPV infections or improving outcomes with biopsied anal high-grade squamous intraepithelial lesions (bHSIL) (pp. 1339–46). A role for the vaccine in preventing oral HPV infections is suggested by the trial, as noted in these results: “A total of 575 participants were randomized. The Data and Safety Monitoring Board stopped the study early due to futility. Vaccine efficacy was 22% (95.1% confidence interval [CI], −31%, 53%) for prevention of persistent anal infection or single detection at the final visit, 0% (95% CI −44%, 31%) for improving bHSIL outcomes and 88% (95.1% CI 2%, 98%) for preventing persistent oral HPV infection, but was 32% (95.1% CI −80%, 74%) for 6-month persistent oral HPV infection or single detection at the final visit.” The 9-valent HPV vaccine was recently approved by FDA for use in patients aged 27–45 years, but the CDC’s Advisory Committee on Immunization Practices has not addressed use of the vaccine in patients living with HIV. (T. J. Wilkin, w2001@med.cornell.edu)
Influenza Infection in Transplant Recipients: Influenza vaccination and early antiviral therapy are important interventions in patients with transplants, according to a study of 616 participants with confirmed influenza infections (pp. 1322–9). The multicountry study found these results for recipients of solid organ grafts and hematopoietic stem cells: “Antiviral therapy was given to 94.1% for a median of 5 days (range, 1–42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21–.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26–.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively).” (D. Kumar, deepali.kumar@uhn.ca)
>>>Vaccine Highlights
Source:
 Oct. 1, 8, 15, and 22 issues of Vaccine (2018; 36); the Oct. 22 issue has a vaccine hesitancy theme.
Statins & Influenza Vaccine: In Taiwan, influenza-vaccinated older adults had higher risks of medically attended acute respiratory illness (MAARI) when they were taking statins — particularly simvastatin and lovastatin (pp. 6133–7). A retrospective cohort study of 440,180 adults aged 66 years or older showed the following for the 2007–08 through 2012–13 influenza seasons: “In general, the risk of MAARI was higher in statin users than non-statin users (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.02–1.05). Statin exposure after vaccination was associated with a higher risk of MAARI (OR: 1.05, 95% CI: 1.02–1.07). Among different statin agents, simvastatin and lovastatin use was associated with a significant increase in the risk of MAARI (ORsimvastatin: 1.14, 95% CI: 1.10–1.18; ORlovastatin: 1.18, 95% CI: 1.12–1.25).” (H-T Chiu, r04451001@ntu.edu.tw)
Using Motivational Interviewing to Address Vaccine Hesitancy: Using motivational interviewing with new mothers is a “promising tool to address vaccine hesitancy,” according to authors of a Commentary article (pp. 6553–5): “PromoVac is delivered to parents during their postpartum stay at the maternity ward by research nurses who are trained in MI theory and techniques. This educational intervention lasts approximately 15–20 min and is carried out in simple and understandable language in order to allow discussion and questions from parents rather than to provide prescriptive and direct information. The MI intervention is oriented according to Prochaska’s stages of change, a model proposing that people pass through several stages when they want to change a behavior. Thus, each MI intervention is adapted to the parents’ readiness to vaccinate their child.” (A. Gagneur, Arnaud.Gagneur@USherbrooke.ca)

PNN Pharmacotherapy Line
Oct. 22, 2018 * Vol. 25, No. 203
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Oct. 20 issue of Lancet (2018; 392).
Nurse-Led Gout Care: Compared with usual care provided by general practitioners in the U.K., nurse-led care of patients with gout was efficacious and cost-effective over a 2-year period, researchers report (pp. 1403–12). “Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes,” the authors conclude, based on a primary outcome of percentage of participants who achieved serum urate concentrations less than 360 μmol/L (6 mg/dL) at 2 years: “517 patients were enrolled, of whom 255 were assigned nurse-led care and 262 usual care. Nurse-led care was associated with high uptake of and adherence to urate-lowering therapy. More patients receiving nurse-led care had serum urate concentrations less than 360 μmol/L at 2 years than those receiving usual care (95% vs 30%, RR 3.18, 95% CI 2.42–4.18, p <0.0001). At 2 years all secondary outcomes favoured the nurse-led group. The cost per [quality-adjusted life–year] gained for the nurse-led intervention was £5066 at 2 years.” (M. Doherty, michael.doherty@nottingham.ac.uk)
Corticosteroid Injections for Carpal Tunnel Syndrome: In primary care patients with mild or moderate carpal tunnel syndrome, a single corticosteroid injection should be the treatment of choice for rapid symptom response, a study concludes, based on evidence of superior clinical effectiveness compared with night-resting splints (pp. 1423–33). In this randomized, open-label, pragmatic trial of adults with this condition, methylprednisolone acetate 20 mg injections or night-resting splints showed these results based on a primary outcome of overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks: “Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2.02 [SD 0.81]) than the night splint group (2.29 [0.75]; adjusted mean difference −0.32; 95% CI −0.48 to −0.16; p = 0.0001). No adverse events were reported.” (E. Roddy, e.roddy@keele.ac.uk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
n3-PUFA Levels & Healthy Ageing: In the Cardiovascular Health Study, increased dietary consumption of n-3 polyunsaturated fatty acids (n3-PUFAs) from seafood but not plants was associated with better outcomes regarded as indicators of healthy ageing (k4067). The study defined healthy ageing as survival without chronic diseases (cancer or cardiovascular, lung, and severe chronic kidney disease), absence of cognitive and physical dysfunction, or death from other causes not part of the healthy ageing outcome after age 65. Findings were as follows: “Higher levels of long chain n3-PUFAs were associated with an 18% lower risk (95% confidence interval 7% to 28%) of unhealthy ageing per interquintile range after multivariable adjustments with time-varying exposure and covariates. Individually, higher eicosapentaenoic acid and docosapentaenoic acid (but not docosahexaenoic acid) levels were associated with a lower risk: 15% (6% to 23%) and 16% (6% to 25%), respectively. Alpha-linolenic acid from plants was not noticeably associated with unhealthy ageing (hazard ratio 0.92, 95% confidence interval 0.83 to 1.02).” (H Lai, Heidi.Lai@tufts.edu)
>>>PNN JournalWatch
Acinetobacter Pneumonia: Improving Outcomes With Early Identification and Appropriate Therapy, in Clinical Infectious Diseases, 2018; 67: 1455–62. (M. H. Kollef, kollefm@wustl.edu)
Pneumococcal Vaccination in Adult Solid Organ Transplant Recipients: A Review of Current Evidence, in Vaccine, 2018; 42: 6253–61. (C. Dendle, claire.dendle@monash.edu)
Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2018; 36: 3043–54. (R. A. Taplitz)
Medical Marijuana in the United States: Historical Perspectives, Legal Considerations, and Professional Obligations of the Pharmacist, in Journal of the American College of Clinical Pharmacy, 2018; 1: 10.1002/jac5.1014. (J. S. Wheeler, jwheele4@uthsc.edu)

PNN Pharmacotherapy Line
Oct. 23, 2018 * Vol. 25, No. 204
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Early-release articles from the New England Journal of Medicine (2018; 379).
Antipsychotic Management of ICU Delirium: Compared with placebo, neither haloperidol nor ziprasidone significantly altered the duration of delirium in 1,183 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in ICU, researchers report (10.1056/NEJMoa1808217). In the MIND-USA trial, the Confusion Assessment Method for the ICU was used to detect the presence or absence of delirium at 12-hour intervals; drug doses were then halved or doubled up to haloperidol 20 mg daily or ziprasidone 40 mg daily. Based on a primary end point of the number of days alive without delirium or coma during the 14-day intervention period, the investigators found: “The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P = 0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.” (E. W. Ely, wes.ely@vumc.org)
“Why did [this] trial fail to show benefit?” asks an editorialist (
10.1056/NEJMe1813382). “It is likely that our concept of delirium is flawed. The neurochemistry of sudden alteration in mentation is complex and involves several neurotransmitters as well as structural, immunologic, and network alterations and possible brain infection that is not clinically evident. The investigators deserve credit for conducting a difficult trial, but it would have been astounding if there were a single magic bullet for the restitution of normal brain function in ICU patients with delirium.” (T. P. Bleck)
>>>Internal Medicine Report
Source:
 Early-online articles from Annals of Internal Medicine (2018; 169).
Rethinking Buprenorphine in Opioid Use Disorder: Clinicians may need to rethink the way they treat opioid use disorder with buprenorphine, according to a review showing that many current practices are too restrictive and in conflict with science (10.7326/M18-1652). The research focused on the following seven areas: location of buprenorphine induction; combining buprenorphine with a benzodiazepine; relapse during buprenorphine treatment; requirements for counseling; uses of drug testing; use of other substances during buprenorphine treatment; and duration of buprenorphine treatment. Results suggest a more progressive approach to treating opioid use disorder that minimizes barriers in the Opioid Treatment Cascade of Care, including linkage, initiation, and maintenance of buprenorphine therapy. In addition to allowing home induction of buprenorphine, the researchers suggest that the old practice of requiring counseling with buprenorphine use may do more harm than good. The authors also challenge previous practices of discharging patients for relapse or use of other substances. They note that nearly all evidence guiding current practice was found before the lethality of heroin and illicitly produced fentanyl appeared at scale, making updated, evidence-based treatment all the more critical. (S. Martin, stmartin@gmail.com)
Editorialists strongly agree that the magnitude of the opioid epidemic calls for a reexamination of the conservative approaches to buprenorphine use (
10.7326/M18-2722): “The influx of fentanyl and fentanyl analogues has changed the way we calculate the risk of withholding access to this life-saving medication because of concomitant use of benzodiazepines or other drugs or opioid-positive results on urine tests during treatment. A reduction in opioid use should be viewed as a step forward rather than treatment failure.” (G. D’Onofrio, gail.donofrio@yale.edu)
>>>PNN NewsWatch
Promise Pharmacy is voluntarily recalling one lot of Prednisolone and Gatifloxacin Ophthalmic Solution 1%/0.5% sterile, 3-ml vials, to the patient level because of unidentified small particulate matter.

PNN Pharmacotherapy Line
Oct. 24, 2018 * Vol. 25, No. 205
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Oct. 23/30 issue of JAMA (2018; 320).
SNPs & Bleeding in Blacks Taking Warfarin: A preliminary case–control, genomewide association study of patients of African descent taking warfarin identifies four single-nucleotide polymorphisms (SNPs) in linkage disequilibrium on chromosome 6 that are associated with an increased risk of major bleeding at INRs of less than 4 (pp. 1670–7). While requiring confirmation in a prospective cohort, the study demonstrates in those of African descent these significantly increased risks of bleeding in discovery (31 cases) and replication (40 cases) cohorts associated with the SNPs rs115112393, rs16871327, rs78132896, and rs114504854: “Four SNPs in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding in a discovery cohort of 215 patients (odds ratio [OR], 8.3) and a replication cohort of 188 patients (OR, 8.2), and reached genome-wide significance when the cohorts were combined using meta-analysis (OR, 8.3).” (M. A. Perera, minoli.perera@northwestern.edu)
Myo-inositol on Type 1 Retinopathy of Prematurity: In a study of 638 infants of less than 28 weeks’ gestational age, treatment of myo-inositol for up to 10 weeks failed to improve rates of type 1 retinopathy of prematurity (ROP) or mortality (pp. 1649–58). Prior research had suggested a benefit of the compound, which is present in breast milk but not some formulas. The study was terminated early because of increased mortality among infants receiving myo-inositol. Results for myo-inositol 40 mg/kg intravenous or enteral doses or placebo every 12 hours were as follows: “Death or type 1 ROP occurred more often in the myo-inositol group vs the placebo group (29% vs 21%, respectively; adjusted risk difference, 7% [95% CI, 0%-13%]; adjusted relative risk, 1.41 [95% CI, 1.08-1.83], P = .01). All-cause death before 55 weeks’ postmenstrual age occurred in 18% of the myo-inositol group and in 11% of the placebo group (adjusted risk difference, 6% [95% CI, 0%–11%]; adjusted relative risk, 1.66 [95% CI, 1.14–2.43], P = .007). The most common serious adverse events up to 7 days of receiving the ending dose were necrotizing enterocolitis (6% for myo-inositol vs 4% for placebo), poor perfusion or hypotension (7% vs 4%, respectively), intraventricular hemorrhage (10% vs 9%), systemic infection (16% vs 11%), and respiratory distress (15% vs 13%).” (D. L. Phelps, dale_phelps@urmc.rochester.edu)
Immune Checkpoint Inhibitor Toxicity: Used in treatment of metastatic cancer, immune checkpoint inhibitors (ICIs) “frequently cause immunologic toxicity with variable clinical manifestations and severity,” authors of a JAMA Insights article conclude (pp. 1702–3). By altering the actions of T cells, ICIs “may expose preexisting organ-specific inflammation, a genetic propensity for autoimmunity, or shared antigens between self and malignant cells,” the authors write, adding that the increasingly used drugs have been linked with colitis, pneumonitis, skin adverse effects, endocrine dysfunction, hepatitis, myocarditis, and neurotoxicities. “Prompt initiation of steroids in collaboration with the treating oncologist is essential for managing toxicity,” conclude the authors. “Rigorous studies are needed to better understand the pathophysiology of [adverse effects] associated with ICIs, to identify patients at highest risk of severe outcomes, and to develop evidence-based therapies to manage toxicity.” (J. A. Sosman, jeffrey.sosman@nm.org)
>>>PNN NewsWatch
FDA will hold a 2-day advisory committee meeting on Dec. 17–18 to solicit input and advice on strategies to increase the availability of naloxone products intended for use in the community. Comments filed by Dec. 3 will be provided to the committee.
* A 
federal court has ordered Tennessee-based Keystone Laboratories to stop selling OTC drug products until the company complies with the Federal Food, Drug, and Cosmetic Act and other requirements listed in a consent decree.
* As part of the 11th annual International Internet Week of Action (IIWA), 
FDA acted yesterday in partnership with international agencies to target 465 websites that illegally sell potentially dangerous, unapproved versions of opioid, oncology, and antiviral prescription drugs to U.S. consumers.

PNN Pharmacotherapy Line
Oct. 25, 2018 * Vol. 25, No. 206
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Oct. 25 issue of the New England Journal of Medicine (2018; 379).
Triple CFTR Modulation in Cystic Fibrosis: In two research articles, investigators provide evidence supporting use of the next-generation cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-659 and VX-445, in triple combination with tezacaftor and ivacaftor, in patients with cystic fibrosis and one or two specific CFTR mutations.
In vitro and clinical activity of VX-659 is demonstrated in the first trial, which combined the agent with tezacaftor–ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype) (
pp. 1599–611). Pulmonary, sweat chloride, and Cystic Fibrosis Questionnaire–Revised respiratory domain scores improved in both genotypic populations. (S. M. Rowe, smrowe@uab.edu)
A similar corrector, VX-445, also yielded positive results in patients with one or both of these mutations (
pp. 1612–20). As with the first study, authors conclude that “this approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients.” (J. L. Taylor-Cousar, taylor-cousarj@njhealth.org)
These promising results could be a “major breakthrough” if confirmed in larger clinical trials, an editorialist writes (pp. 1671–2): “[These trials] show that triple-combination therapy in patients with a Phe508del–Phe508del CFTR mutation improved the percentage of predicted FEV
1 more than double-combination therapy. Both trials also reported efficacy in patients with a Phe508del–MF CFTR mutation, and neither reported dose-limiting side effects or toxicity. Only three patients in the VX-445 trial discontinued treatment owing to severe adverse events. These reports represent a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common CFTR mutation. It is unclear whether the effects on lung function can be sustained for longer periods of treatment or whether these compounds will effectively reduce exacerbation rates and address other meaningful outcomes, such as weight gain. These questions should soon be answered in the ongoing phase 3 trials of these regimens.” (F. Holguin)
M72/AS01E Vaccine to Prevent Tuberculosis: In a phase 2b trial of a new tuberculosis vaccine, safety and efficacy were demonstrated in a cohort of infected adults with active pulmonary disease and those meeting a primary case definition (pp. 1621–34): “The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P = 0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P = 0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups.” (O. Van Der Meeren, livier.x.van-der-meeren@gsk.com">olivier.x.van-der-meeren@gsk.com)
Noting that “all vaccine development has been an iterative process,” an editorialist concludes (
pp. 1672–4): “The work presented represents an important step forward toward developing an effective immunization against tuberculosis; it is probably not the final iteration. The results reinforce the importance of international collaborations, set the stage for testing additional candidates, and offer renewed hope that effective new vaccines can be developed for tuberculosis.” (B. R. Bloom)
>>>PNN NewsWatch
* Commenting on yesterday’s signing of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities ActFDA Commissioner Scott Gottlieb, MD, said that the law provides the agency with “important new tools to work more effectively across all four broad domains”: interdiction and enforcement, mandatory recall orders for controlled substances, requiring packaging, such as unit dose blister packs, for opioids and other drugs that pose a risk of abuse or overdose, and supporting development of nonaddictive drugs.

PNN Pharmacotherapy Line
Oct. 26, 2018 * Vol. 25, No. 207
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
 Early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Cognition & Vitamin D: Monitored over a 3-year period, older black women had no changes in rates of cognitive decline during a placebo-controlled trial of vitamin D supplements, researchers report (10.1111/jgs.15607). Participants were healthy postmenopausal women age 65 years or older (mean, 68.2 years; 46% had college education or higher) when they were randomized to vitamin D in doses adjusted to achieve a serum concentration above 30 ng/mL. Results showed: “The average dose of vitamin D3 was 3,490 ± 1,465 IU per day, and average serum 25(OH)D at 3 years was 46.8 ± 1.2 ng/mL in the active group and 20.7 ± 1.1 ng/mL in the placebo group. Serum 25(OH)D concentration was maintained at greater than 30 ng/mL in 90% of the active group. Over the 3-year period, [Mini-Mental State Examination] scores increased in both groups (p < .001), although change over time was not significantly different between the groups. No adverse events associated with vitamin D were observed.” (J. F. Aloia, jaloia@nyumc.org)
Addressing Prescribing Cascades: Prescribing cascades — misrecognition of adverse drug effects as new conditions requiring additional medications — are the topic of a scoping review (10.1111/jgs.15543): “Of 369 resources identified, 58 met inclusion criteria; 29 of these were categorized as preventing, 20 as detecting, and 9 as reversing prescribing cascades. Resources originated from 14 countries and mostly focused on older adults. The goal of preventing resources was to educate and increase general awareness of the concept of prescribing cascades as a way to prevent inappropriate prescribing and to illustrate application of the concept to specific drugs (e.g., anticholinergics) and conditions (e.g., inflammatory bowel disease). Detecting resources included original investigations or case reports that identified prescribing cascades using health administrative data, patient cohorts, and novel sources such as social media. Reversing prescribing cascade resources focused on the medication review process and deprescribing initiatives.” (P. A. Rochon, paula.rochon@wchospital.ca)
>>>Health Affairs Report
Source:
 Oct. issue of Health Affairs (2018; 37).
Generic Drug Price Hikes: Relevant to yesterday’s announcement of an HHS initiative to lower drug costs under Medicare Part B, a study changes in patient spending caused by sudden Part D price increases for generics (pp. 1578–86): “The fraction of drugs that at least doubled in price increased from 1.00 percent of generic products in 2007 to 4.39 percent in 2013. Almost all were initially low- or medium-price medications and not among the most widely used generics. Changes in out-of-pocket spending for these drugs were modest. However, the elevated prices persisted for two to five years. Data for 2011–15 showed similar trends. Potential steps to ensure that generic markets remain strong include fast-tracking new generic drug applications when competition is limited, allowing temporary importation of off-patent drugs, and implementing greater oversight of drug company mergers and takeovers.” (G. Joyce, gjoyce@usc.edu)
>>>PNN NewsWatch
Influenza vaccination in the U.S. remains low at about 4 in 10 adults, the CDC reports in a FluVaxView article posted yesterday. With a national average of 37.1% during the 2017–18 season, the 6.2 percentage point decline in vaccination rates may have contributed to the season’s severity, the Washington Post adds. “That’s huge. It’s a striking inflection down from the previous year,” influenza expert William Schaffner says in the Post article. On a state-by-state basis, vaccination rates ranged from 29.2% in Louisiana to 46.3% in West Virginia; populous states Texas (30.7%), Florida (33.1%), New York (33.9%), Georgia (34.8%), and California (35.0%) all fell below the national average. CDC authors called on “healthcare providers … to strongly recommend and offer flu vaccination to all of their patients” to prevent a repeat of the morbidity and mortality in the 2018–19 season.
FDA earlier this week approved the first-in-class polymerase acidic endonuclease inhibitor baloxavir marboxil (Xofluza, Shionogi & Co.; Genentech/Roche) for treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours.

PNN Pharmacotherapy Line
Oct. 29, 2018 * Vol. 25, No. 208
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 362).
ACE Inhibitors & Lung Cancer: Compared with angiotensin receptor blockers, use of ACE inhibitors (ACEIs) — particularly among those treated for 5 years or more — is associated with an increased risk of lung cancer, researchers report (k4209). Data from the U.K. Clinical Practice Research Datalink show these relationships in a cohort of 992,061 patients newly treated with antihypertensive medications in 1995–2015 who were followed until the end of 2016: “The cohort was followed for a mean of 6.4 (SD 4.7) years, generating 7,952 incident lung cancer events (crude incidence 1.3 (95% confidence interval 1.2 to 1.3) per 1,000 person years). Overall, use of ACEIs was associated with an increased risk of lung cancer (incidence rate 1.6 v 1.2 per 1,000 person years; hazard ratio 1.14, 95% confidence interval 1.01 to 1.29), compared with use of angiotensin receptor blockers. Hazard ratios gradually increased with longer durations of use, with an association evident after five years of use (hazard ratio 1.22, 1.06 to 1.40) and peaking after more than 10 years of use (1.31, 1.08 to 1.59). Similar findings were observed with time since initiation.” (L. Azoulay, laurent.azoulay@mcgill.ca)
“Although a 14% relative increase in lung cancer incidence might not translate to a large absolute risk, the findings are important given the considerable use of ACEIs worldwide,” an editorialist writes. “Nonetheless, in an individual patient, concerns about the long term risk of lung cancer should be balanced against gains in life expectancy associated with use of ACEIs. As Hicks and colleagues point out, further studies with long term follow-up are now needed to enhance the scientific evidence on the long term safety of these drugs.” (D. Cronin-Fenton, 
dc@clin.au.dk)
Safety of Zoster Vaccines in Older Adults: Compared with the older live attenuated zoster vaccine, the adjuvant recombinant subunit product has a greater risk of injection site reactions in adults aged 50 years or older, concludes a systematic review with bayesian/network meta-analyses of 2 million patients in 27 studies (k4029): “Network meta-analysis of 11 randomised controlled trials showed the adjuvant recombinant subunit vaccine to be associated with statistically more adverse events at injection sites than the live attenuated vaccine (relative risk 1.79, 95% credible interval 1.05 to 2.34; risk difference 30%, 95% credible interval 2% to 51%) and placebo (5.63, 3.57 to 7.29 and 53%, 30% to 73%, respectively). Network meta-analysis of nine randomised controlled trials showed the adjuvant recombinant subunit vaccine to be associated with statistically more systemic adverse events than placebo (2.28, 1.45 to 3.65 and 20%, 6% to 40%, respectively).” (A. C. Tricco, triccoa@smh.ca)
>>>Lancet Highlights
Source:
 Oct. 27 issue of Lancet (2018; 392).
Albiglutide & CVD Prevention: Compared with placebo for prevention of major cardiovascular events (death, myocardial infarction, or stroke), the glucagon-like peptide 1 receptor agonist albiglutide proved significantly effective, according to Harmony Outcomes investigators (pp. 1519–29). “Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes,” the group concludes. (J. J. V. McMurray, john.mcmurray@glasgow.ac.uk)
>>>PNN JournalWatch
Sleep Apnea Morbidity: A Consequence of Microbial-Immune Cross-Talk?, in Chest, 2018; 154: 754–9. (D. Gozal, dgozal@uchicago.edu)
Sleep Disorders and Atopic Dermatitis: A 2-Way Street?, in Journal of Allergy and Clinical Immunology, 2018; 142: 1033–40. (B-L Chiang, gicmbor@ntu.edu.tw)
Clockwork Allergy: How the Circadian Clock Underpins Allergic Reactions, in Journal of Allergy and Clinical Immunology, 2018; 142: 1021–31. (A. Nakao, anakao@yamanashi.ac.jp)
“Planting the Seed”: Perceived Benefits of and Strategies for Discussing Long-Term Prognosis with Older Adults, in Journal of the American Geriatrics Society, 2018; 66: 10.1111/jgs.15524. (A. K. Smith, aksmith@ucsf.edu)
An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity, in Arthritis & Rheumatism, 2018; 70: 1557–64. (M. G. Moghadam, m.ghiti@hotmail.com)
New Medicare Diabetes Prevention Coverage May Limit Beneficiary Access and Widen Health Disparities, in Medical Care, 2018; 56: 908–11. (N. D. Ritchie)

PNN Pharmacotherapy Line
Oct. 30, 2018 * Vol. 25, No. 209
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
 Nov. issue of Diabetes Care (2018; 41).
GMI: New Tool for Estimating A1C During CGM: A Perspective article describes the need for and use of a glucose control term in patients with diabetes on continuous glucose monitoring (CGM) (pp. 2275–80): “Estimated A1C (eA1C) is a measure converting the mean glucose from CGM or self-monitored blood glucose readings, using a formula derived from glucose readings from a population of individuals, into an estimate of a simultaneously measured laboratory A1C. Many patients and clinicians find the eA1C to be a helpful educational tool, but others are often confused or even frustrated if the eA1C and laboratory-measured A1C do not agree. In the U.S., the Food and Drug Administration determined that the nomenclature of eA1C needed to change. This led the authors to work toward a multipart solution to facilitate the retention of such a metric, which includes renaming the eA1C the glucose management indicator (GMI) and generating a new formula for converting CGM-derived mean glucose to GMI based on recent clinical trials using the most accurate CGM systems available. The final aspect of ensuring a smooth transition from the old eA1C to the new GMI is providing new CGM analyses and explanations to further understand how to interpret GMI and use it most effectively in clinical practice. This Perspective will address why a new name for eA1C was needed, why GMI was selected as the new name, how GMI is calculated, and how to understand and explain GMI if one chooses to use GMI as a tool in diabetes education or management.” (R. M. Bergenstal, richard.bergenstal@parknicollet.com)
Comparing Hypertension Guidelines: High percentages of Americans with diabetes are categorized and treated similarly based on 2017 blood pressure (BP) guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) and American Diabetes Association (ADA), researchers report (pp. 2322–9). Using the U.S. National Health and Nutrition Examination Survey (NHANES) for 2011–16, the group found these diagnostic and treatment results for 2,266 individuals with diabetes: “The prevalence (95% CI) of hypertension among U.S. adults with diabetes was 77.1% (73.9, 80.0) and 66.3% (63.4, 69.1) according to the ACC/AHA and ADA definitions, respectively. Also, 22.9% (20.0, 26.1) did not have hypertension according to either definition, and the concordance in hypertension status was 89.2% (87.2, 91.0). Among U.S. adults with diabetes not taking antihypertensive medication, 52.8% (47.7, 57.8) were not recommended to initiate antihypertensive medication by either the ACC/AHA or the ADA document and 22.4% (19.2, 25.9) were recommended to initiate it by both documents (overall concordance 75.2% [70.4, 79.4]). Among those taking antihypertensive medication, 45.3% (41.3, 49.4) and 50.4% (46.5, 54.2) had BP above the goal in neither and both documents, respectively (overall concordance 95.7% [93.4, 97.2]).” (P. Muntner, pmuntner@uab.edu)
Gut Microbiota in Type 1 Diabetes: Modulation of gut microbiota should be studied further in patients at high risk of type 1 diabetes, conclude authors who found taxonomic and functional differences in healthy participants and those with nonautoimmune diabetes or type 1 diabetes (pp. 2385–95). The case–control study showed that 15 children with maturity-onset diabetes of the young 2 (MODY2) had “significantly higher Prevotella abundance and a lower Ruminococcus and Bacteroides abundance,” and 15 children with type 1 diabetes had “lower microbiota diversity” and “significantly higher relative abundance of BacteroidesRuminococcusVeillonellaBlautia, and Streptococcus genera,” compared with healthy participants. (J. Carlos Fernández-García, josecarlosfdezgarcia@hotmail.com)
Emerging Drugs & Regimens: In 24-hour study, fixed-ratio pramlintide and regular human insulin improved postprandial hyperglycemia and glycemic variability among patients with type 1 diabetes (pp. 2346–52; R. Nahra, rajaa.nahra@astrazeneca.com).
In a cohort study of patients with confirmed insulin receptor autoantibodies, combined immunosuppression using rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine, changed the natural course of the disease (
pp. 2353–60; J. Klubo-Gwiezdzinska, joanna.klubo-gwiezdzinska@nih.gov).

PNN Pharmacotherapy Line
Oct. 31, 2018 * Vol. 25, No. 210
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>>>Nephrology Report
Source:
 Nov. issue of the American Journal of Kidney Diseases (2018; 72).
Oral Anticoagulants for Nonvalvular AF in CKD: Because of the complexities of managing nonvalvular atrial fibrillation (AF) in patients with advanced chronic kidney diseases (CKD), nephrologists should be “active members of the multidisciplinary [care] team,” according to authors presenting pragmatic considerations for the clinician (pp. 717–27): “During the past few years, 4 non–vitamin K–dependent oral anticoagulant (NOAC) agents have supplemented warfarin in the therapeutic armamentarium for the prevention of systemic thromboembolism in nonvalvular AF. However, the use of NOACs in CKD specifically mandates a nuanced understanding due to their varying dependence on renal clearance, with resultant safety implications related to either underdosing (thromboembolism) or excessive drug exposure (bleeding). This pragmatic review highlights unique considerations pertaining to accurate estimation and temporal monitoring of kidney function in the context of NOAC use with specific clinical deliberations and variables when determining whether an NOAC is appropriate for a patient with CKD. The dependence of NOACs on renal clearance and several troubling safety signals in the published literature suggest that it is vital for nephrologists to be active members of a multidisciplinary team caring for these high-risk patients with CKD and AF.” (G. R. Shroff, shrof010@umn.edu)
Immunosuppressives in Proliferative Lupus Nephritis: Authors summarize findings of a Cochrane review on use of mycophenolate mofetil (MMF) and intravenous cyclophosphamide in the management of systemic lupus erythematosus (pp. 756–7). “MMF provides equivalent disease remission and probably avoids drug-related toxicity compared to intravenous cyclophosphamide, supporting the use of MMF in addition to corticosteroids as first-line induction therapy for proliferative lupus nephritis. MMF is appropriate as first-line maintenance therapy, providing the greatest efficacy for prevention of disease relapse after induction with fewer adverse events.
“Lower dose MMF combined with tacrolimus may induce complete remission to a greater extent than intravenous cyclophosphamide. However, the generalizability of these findings may be limited. The safety and effectiveness of biologics is uncertain.” (D. J. Tunnicliffe, 
david.tunnicliffe@health.nsw.gov.au)
“Improving the evidence base is an obvious first step in addressing all the deficits highlighted in this updated Cochrane Review,” an editorialist concludes (
pp. 758–60). “Unfortunately, some of the largest ongoing clinical trials in lupus nephritis still rely on a proteinuria-based remission end point, exemplified by the current studies of voclosporin, a novel [calcineurin inhibitor], and belimumab, a monoclonal antibody directed against B lymphocyte stimulator (BLyS; ClinicalTrials.gov identifiers NCT03021499 and NCT01639339, respectively). Lupus nephritis trials should be designed to be large enough and with sufficient duration of follow-up to evaluate non–proteinuria-based outcomes, such as doubling of serum creatinine level, progression to [end-stage kidney disease], and all-cause mortality. Also, these trials should be designed to specifically address questions about doses and duration of therapy, requirements for concomitant corticosteroid use, and toxicity profiles that our patients continue to ask and that, unfortunately, we continue to answer with low-certainty evidence (to borrow a phrase from these Cochrane authors).” (A. S. Bomback, asb68@cumc.columbia.edu)
Smoking & Hemodialysis: Mortality and hospitalization risks are elevated among patients on hemodialysis when they also smoke, a study shows (pp. 673–81). The relationship was especially strong for younger patients and those with diabetes. Second-hand smoke had no effect. (N. J. Ofsthun, norma.ofsthun@fmc-na.com)
CVD Risk Factors in CKD: A review article details management of traditional cardiovascular risk factors in patients with chronic kidney diseases (pp. 728–44; L. P. Gregg, lucile.gregg@utsouthwestern.edu).
>>>PNN NewsWatch
FDA yesterday issued a final rule repealing the regulation that allows use of lead acetate as a color additive in hair coloring products. FDA took the action in response to a color additive petition. citing potential lead exposure.

PNN Pharmacotherapy Line
Nov. 1, 2018 * Vol. 25, No. 211
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 1 issue of the New England Journal of Medicine (2018; 379).
Health Care–Associated Infections in U.S. Hospitals: Prevention strategies against Clostridioides difficile and pneumonia are needed to continue progress in prevention of health care–associated infections in U.S. hospitals, point-prevalence surveys from 2011 and 2015 show (pp. 1732–44). Through the Emerging Infections Program sites in 10 sites, up to 25 hospitals in each area provided data on a random sample of health care–associated infections on a self-selected day, with these results: “In 2015, a total of 12,299 patients in 199 hospitals were surveyed, as compared with 11,282 patients in 183 hospitals in 2011. Fewer patients had health care–associated infections in 2015 (394 patients [3.2%; 95% confidence interval {CI}, 2.9 to 3.5]) than in 2011 (452 [4.0%; 95% CI, 3.7 to 4.4]) (P <0.001), largely owing to reductions in the prevalence of surgical-site and urinary tract infections. Pneumonia, gastrointestinal infections (most of which were due to Clostridium difficile [now Clostridioides difficile]), and surgical-site infections were the most common health care–associated infections. Patients’ risk of having a health care–associated infection was 16% lower in 2015 than in 2011 (risk ratio, 0.84; 95% CI, 0.74 to 0.95; P = 0.005), after adjustment for age, presence of devices, days from admission to survey, and status of being in a large hospital.” (S. S. Magill, smagill@cdc.gov)
CD47 Blockade in Non-Hodgkin’s Lymphoma: In a phase 1b trial of 22 patients who also received rituximab, Hu5F9-G4 CD-47 blocking antibody showed “promising activity in patients with aggressive and indolent lymphoma” with no clinically significant safety events (pp. 1711–21). “Adverse events were predominantly of grade 1 or 2,” researchers report. “The most common adverse events were anemia and infusion-related reactions. Anemia (an expected on-target effect) was mitigated by the strategy of 5F9 prime and maintenance dosing. Dose-limiting side effects were rare. A selected phase 2 dose of 30 mg of 5F9 per kilogram led to an approximate 100% CD47-receptor occupancy on circulating white and red cells. A total of 50% of the patients had an objective (i.e., complete or partial) response, with 36% having a complete response. The rates of objective response and complete response were 40% and 33%, respectively, among patients with [diffuse large B-cell lymphoma (DLBCL)] and 71% and 43%, respectively, among those with follicular lymphoma. At a median follow-up of 6.2 months among patients with DLBCL and 8.1 months among those with follicular lymphoma, 91% of the responses were ongoing.” (R. Advani, radvani@stanford.edu)
“If confirmed and extended, the results reported by Advani et al. pave the way to macrophage checkpoint blockade as a new immunotherapy strategy,” editorialists write (
pp. 1777–9). “The development of macrophage checkpoint strategies goes back to the very roots of cancer immunology and immunotherapy. In applying macrophage activation in cancer treatment, we are in a sense going back to the future.” (A. Mantovani)
Sildenafil in Idiopathic Pulmonary Fibrosis: Addition of sildenafil to nintedanib treatment of idiopathic pulmonary fibrosis (IPF) yielded no further benefit, researchers report (pp. 1722–31). Among 274 patients with IPF and low lung diffusion capacity, “nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone,” the authors conclude. “No new safety signals were identified with either treatment regimen in this population of patients.” (G. Raghu, graghu@uw.edu)
>>>PNN NewsWatch
FDA yesterday permitted marketing, with special controls, of the 23andme Personal Genome Service Pharmacogenetic Reports test as a direct-to-consumer test. FDA is authorizing the test to detect 33 variants for multiple genes affecting patient responses to more than 50 prescription and OTC medications. This is the first authorization of a direct-to-consumer report on pharmacogenetics; itcame through the FDA’s de novo classification process. With this authorization, the FDA has classified these direct-to-consumer pharmacogenetic reports as moderate risk that have special controls to ensure safety, effectiveness, and accuracy. The tests are available without a prescription.

PNN Pharmacotherapy Line
Nov. 2, 2018 * Vol. 25, No. 212
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>>>Pediatrics Report
Source:
 Nov. issue of Pediatrics (2018; 142).
Medical Exemptions & Vaccine Exemption Policy: Experiences with medical exemptions in California following passage of that state’s Senate Bill 227 (SB277) — which eliminated nonmedical vaccine exemptions for school entry — are documented through semistructured telephone interviews of health officers and immunization staff at local health jurisdictions (e20181051): “Four main themes emerged related to experiences with medical exemptions: (1) the role of stakeholders, (2) reviewing medical exemptions received by schools, (3) medical exemptions that were perceived as problematic, and (4) frustration and concern over medical exemptions. Generally, local health jurisdictions described a narrow role in providing support and technical assistance to schools. Only 5 jurisdictions actively tracked medical exemptions received by schools, with 1 jurisdiction facing a lawsuit as a result. Examples were provided of medical exemptions that listed family history of allergies and autoimmune diseases as contraindications for immunization and of physicians charging steep fees for medical exemptions. Participants also reported concerns about the increase in medical exemptions after the implementation of SB277.” (S. Mohanty)
“Vaccines are safe, >1000 times safer than the diseases they prevent,” editorialists remind readers (
e20182009). “Protection from vaccines extends beyond individuals when vaccination rates are high enough to confer community immunity.…
“Vaccines are one of the greatest public health successes in history. Mandating vaccination for school is an effective strategy to prevent outbreaks. This protection is undermined when unscrupulous physicians monetize their license and abuse the authority delegated to them from the state by granting unwarranted [medical exemptions (MEs)]. Public health officers need the information to identify these physicians and the authority to withdraw their ability to grant MEs and to invalidate unwarranted MEs to protect children and public health. Pediatricians can partner with public health advocates and proscience parents to pass laws that empower public health officers to protect our children and community. Every child needs community immunity.” (R. J. Pan)
>>>Psychiatry Highlights
Source:
 Nov. issue of the American Journal of Psychiatry (2018; 175).
White Matter & Antipsychotics: “Long-term antipsychotic treatment does not adversely affect white matter tracts over the longer-term course of illness and may confer benefits,” conclude authors who looked at white matter deficits in schizophrenia (pp. 1129–36). In 31 never-treated and 46 antipsychotic-treated patients with long-term schizophrenia and 58 healthy comparison participants, the authors found: “Fractional anisotropy significantly differed among the three groups in 14 of 20 white matter tracts defined in the Johns Hopkins University white matter template. Never-treated patients displayed greater reduction of fractional anisotropy than antipsychotic-treated patients in the left anterior thalamic radiation, the left cingulum-hippocampus pathway, the splenium and genu of the corpus callosum, and the left superior longitudinal fasciculus, and greater fractional anisotropy in the right uncinate fasciculus. Both patient groups showed multiple reductions relative to healthy comparison subjects. Never-treated patients showed an accelerated and clinically relevant age-related reduction of fractional anisotropy in the genu of the corpus callosum.” (Y. Xiao)
“While the results of this study present additional pieces of the larger puzzle, they still should be interpreted with caution,” editorialists write, citing the study size and possible type I and II errors (
pp. 1056–7). “Drug-naive patients are more likely (although not explicitly measured) to have lower socioeconomic status, less family support, lack of physical activity, and a possible substance abuse disorder, as well as a higher likelihood of malnutrition. Nonetheless, the findings are still very intriguing and will no doubt provide renewed energy to the debate about the impact of antipsychotic medications.” (M. Kubicki)
>>>PNN NewsWatch
Roche Diagnostics is recalling certain test strip lots used with its CoaguChek test meter by providers and patients to monitor warfarin.

PNN Pharmacotherapy Line
Nov. 5, 2018 * Vol. 25, No. 213
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 362).
Mirtazapine in Treatment-Resistant Depression: Added to a serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressant for treatment-resistant depression in primary care settings, mirtazapine was of no added clinically important benefit, researchers report (k4218). The assessment included 480 adults who were randomized to mirtazapine or placebo after depression symptoms remained despite 6 weeks of SNRI or SSRI treatment. Results for 431 participants included in the 12-week analysis were as follows: “Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means −1.83 (95% confidence interval −3.92 to 0.27); P = 0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug.” (D. S. Kessler, david.kessler@bristol.ac.uk)
Maternal–Fetal Zika Virus Transmission & Outcomes: The frequencies of congenital Zika virus transmission and resulting severe perinatal complications are quantified in a study from French Guiana, with investigators concluding, “The burden of [congenital Zika syndrome (CZS)] might be lower than initially described in South America and may not differ from other congenital infections” (k4431). Prospective enrollment of 300 pregnant women and their 305 fetuses/newborns showed these patterns of infection and outcomes: “Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed.” (D. Baud, david.baud@chuv.ch)
>>>PNN NewsWatch
* Despite concerns expressed by an FDA advisory committee chair and U.S. Senators, FDA on Friday approved AcelRx’s formulation of sufentanil sublingual tablet 30 mcg, Dsuvia. “To address concerns about the potential risks associated with Dsuvia, this product will have strong limitations on its use,” FDA Commission Scott Gottlieb, MD, said in a statement. “It can’t be dispensed to patients for home use and should not be used for more than 72 hours. And it should only be administered by a health care provider using a single-dose applicator. That means it won’t be available at retail pharmacies for patients to take home. These measures to restrict the use of this product only within a supervised health care setting, and not for home use, are important steps to help prevent misuse and abuse of Dsuvia.…”
Janssen Pharmaceuticals is recalling three lots of its norethindrone/ethinyl estradiol product to the pharmacy level because they do not include the appropriate instructions for the Veridate® dispenser: one lot of Ortho-Novum Tablets and two lots of Ortho-Novum 7/7/7.
>>>PNN JournalWatch
Antibiotic Shortages in Pediatrics, in Pediatrics, 2018; 142: e20180858. (R. Banerjee)
Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective, in American Journal of Psychiatry, 2018; 175: 1073–83. (A. S. Brown)
Ejection Fraction Pros and Cons: JACC State-of-the-Art Review, in Journal of the American College of Cardiology, 2018; 72: 2360 ff. (T. H. Marwick)
Management of Pharyngitis: Should America Fall in Line With the Rest of the Developed World?, in Circulation, 2018; 138: 1920–2. (J. Berkley, berkley_j@meuhedet.co.il)

PNN Pharmacotherapy Line
Nov. 6, 2018 * Vol. 25, No. 214
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Nov. 6 issue of Annals of Internal Medicine (2018; 169).
Overlapping Opioid & Benzodiazepines in Veterans: Dual-eligible veterans receiving prescriptions from both the VA system and Medicare Part D were significantly more likely to have overlapping medication orders for benzodiazepines and opioids in 2013, researchers report (pp. 593–601). Simultaneous use of drugs in the two categories is associated with increased risk for overdose. In a cross-sectional analysis of data for 2013 from the VA and Medicare systems, the authors found these outcomes based on the Pharmacy Quality Alliance (PQA) measure of opioid–benzodiazepine overlap (≥2 filled prescriptions for benzodiazepines with ≥30 days of overlap with opioids) and the proportion of patients with high-dose opioid–benzodiazepine overlap (≥30 days of overlap with a daily opioid dose >120 morphine milligram equivalents): “Of 368,891 eligible veterans, 18.3% received prescriptions from the VA only, 30.3% from Medicare only, and 51.4% from both VA and Medicare. The proportion with PQA opioid–benzodiazepine overlap was larger for the dual-use group than the VA-only group (23.1% vs. 17.3%; adjusted risk ratio [aRR], 1.27 [95% CI, 1.24 to 1.30]) and Medicare-only group (23.1% vs. 16.5%; aRR, 1.12 [CI, 1.10 to 1.14]). The proportion with high-dose overlap was also larger for the dual-use group than the VA-only group (4.7% vs. 2.3%; aRR, 2.23 [CI, 2.10 to 2.36]) and Medicare-only group (4.7% vs. 2.9%; aRR, 1.06 [CI, 1.02 to 1.11]).” (W. F. Gellad, walid.gellad@va.gov)
Medicine & Marijuana: “Regardless of whether individual practitioners are for or against [medical marijuana (MM)], we must acknowledge that it has become a clinical reality,” authors write in an attempt to reconcile “the discrepancies in medicine’s relationship to MM” (pp. 646–7). “Individual providers and professional organizations should unite in advocating reclassification of cannabis from Schedule I, defined by federal drug enforcement authorities as drugs with no currently accepted medical use and a high potential for abuse, to Schedule II, defined as drugs with a high potential for abuse (including cocaine). This rescheduling would loosen restrictions on biomedical research; without it, daunting administrative hurdles to the study of MM will likely persist. Our team, for instance, has labored a year to obtain a Schedule I license enabling MM clinical trials. Once this license is in hand, our study drug will likely come from a federally authorized field in Mississippi whose typically low-tetrahydrocannabinol crop approximates neither products available on the street nor those found at registered MM dispensaries.” (I. Braun, ibraun@partners.org)
Public Health Response to Opioid Crisis: Authors propose a six-element response of the U.S. public health system to the ongoing opioid crisis (10.7326/M18-1757). “The comprehensive approach presented here builds on successful efforts by states and territories,” the authors write. “It incorporates national ‘roadmaps’ and ‘frameworks’ that have been developed individually to guide government responses to the opioid crisis but have not fully addressed all of the tactical approaches to ending it.” Elements of the proposed response are as follows (M. Levine, Mark.Levine@vermont.gov):
Leadership, with key leaders in government and nongovernment agencies and in communities statewide, establishes a shared vision for comprehensively addressing opioid use disorder throughout the jurisdiction.
Partnership and collaboration promote the cross-cutting, multisector work needed to comprehensively address opioid use disorder. 
Epidemiology and surveillance [are used] to improve prevention, treatment, and recovery response by using real-time public health data for decision making and to inform the development and implementation of programs and policies.
Education and prevention include building individual and community resilience, addressing health-related social needs, implementing evidence-based campaigns to educate and build awareness, and engaging communities in addressing the root causes of addiction.
Treatment and recovery may or may not be part of a public health agency’s purview. 
Harm reduction and overdose prevention efforts (such as syringe services programs) provide opportunities to intervene and refer individuals to treatment.

PNN Pharmacotherapy Line
Nov. 7, 2018 * Vol. 25, No. 215
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 6 issue of JAMA, a theme issue on global hypertension (2018; 320).
High Blood Pressure in Young Adults: In four studies and related commentaries, guideline-defined blood pressure (BP) elevations are young adults is examined. 
Young adults with high BPs as defined in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines have significantly higher risk for subsequent cardiovascular disease (CVD) events, a study shows (
pp. 1774–82). In 4,851 adults in the prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) study, those with elevated BP, stage 1 hypertension, or stage 2 hypertension before age 40 had these outcomes: “Over a median follow-up of 18.8 years, 228 incident CVD events occurred ([coronary heart disease (CHD)], 109; stroke, 63; heart failure, 48; [peripheral artery disease], 8). CVD incidence rates for normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension were 1.37 (95% CI, 1.07–1.75), 2.74 (95% CI, 1.78–4.20), 3.15 (95% CI, 2.47–4.02), and 8.04 (95% CI, 6.45–10.03) per 1,000 person–years, respectively. After multivariable adjustment, hazard ratios for CVD events for elevated BP, stage 1 hypertension, and stage 2 hypertension vs normal BP were 1.67 (95% CI, 1.01–2.77), 1.75 (95% CI, 1.22–2.53), and 3.49 (95% CI, 2.42–5.05), respectively.” (Y. Yano, yyano@jichi.jp)
A similar analysis of young adults covered by the Korean National Insurance Service reaches the same conclusion for those with stage 1 or stage 2 hypertension (
pp. 1783–92).Among nearly 2.5 million people, risks of CVD events were increased among both men and women with stage 1 or 2 hypertension as defined in the 2017 ACC/AHA criteria. (S. M. Park, smpark.snuh@gmail.com)
“Studies are needed to elucidate the developmental origins of higher blood pressure levels in children and the impact of social determinants of health, acculturation, and allostatic load on blood pressure trajectories in youth,” writes an editorialist (
pp. 1760–3). “Greater clarity is needed regarding the potential use of individual characteristics (eg, geographic residence in the stroke belt, black race with apolipoprotein L1 risk alleles, or a positive family history of CVD), long-term CVD risk, and blood pressure–mediated target organ damage to guide treatment decisions for high blood pressure levels in young adults. Optimal blood pressure targets in relation to plausible clinical benefit vs possible harm due to long-term blood pressure–lowering treatments need to be clearly delineated for young adults with nonnormal blood pressure levels according to the ACC/AHA classification. Bridging these critical knowledge gaps may help define how, when, and what measures could be implemented to maintain an optimal blood pressure profile from childhood through young adulthood and beyond. Answers to these questions will be a public health legacy to the current generation of children and young adults and to their future offspring.” (R. S. Vasan, vasan@bu.edu)
Focusing on hypertension as a “public health challenge of global proportions,” authors of a second editorial make these recommendations (
pp. 1757–9): “The traditional health care model of office visits for the control of blood pressure must be replaced. The control rate of hypertension in the United States has been hovering at a disconcerting 50%. Innovative systems of health care delivery are needed to improve quality of care and reduce costs. Inventive solutions will involve new technologies and models like algorithmic, non–physician-based treatment plans that rely on the automatic transmission of home blood pressure measurements, or hypertensive care delivered in unconventional settings. The management of hypertension on the population level must continue to strengthen as a team effort. More ambitious, innovative thinking should mobilize the international health care community to create sustainable solutions for controlling the problem of high blood pressure, one of the most deleterious health risk factors in nearly every country around the world.” (G. Curfman, gregory.curfman@jamanetwork.org)
Nitrites in Heart Failure: Compared with placebo in 105 patients with heart failure with preserved ejection fraction, inhaled inorganic nitrite failed to improve exercise capacity in a 4-week trial (pp. 1764–73; B. A. Borlaug, borlaug.barry@mayo.edu).

PNN Pharmacotherapy Line
Nov. 8, 2018 * Vol. 25, No. 216
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Nov. 8 New England Journal of Medicine (2018; 379).
Triple-Drug Treatment for Lymphatic Filariasis: Compared with single or three annual doses of a two-drug regimen, a three-drug combination proved superior for clearing microfilariae in participants in Papua New Guinea with lymphatic filariasis, researchers report (pp. 1801–10). The World Health Organization has a 2020 goal of eliminating this condition through mass drug administration. In this study of the optimal regimen for clearing Wuchereria bancrofti microfilaremia, ivermectin plus diethylcarbamazine plus albendazole produced rates of 96% at 1, 2, and 3 years, compared with rates ranging from 32% to 83% for a single dose of a two-drug regimen of diethylcarbamazine plus albendazole and 34% to 98% for three annual doses of the two-drug regimen. (C. L. King, cxk21@case.edu)
“The widespread use of the triple-drug treatment will further facilitate the public health success of the global filariasis elimination efforts, accelerating the reduction of transmission, particularly in what have previously been residual hotspots,” writes an editorialist (
pp. 1871–2). “It will bring additional health benefits with the incorporation of ivermectin into national programs, thus reducing the transmission of scabies as well as intestinal helminths.” (D. H. Molyneux)
Elotuzumab in Multiple Myeloma: The immunostimulatory monoclonal antibody elotuzumab plus pomalidomide and dexamethasone produced significantly lower rates of progression or death among 117 patients with multiple myeloma, compared with pomalidomide plus dexamethasone alone, a study shows (pp. 1811–22). Patients had refractory or relapsed multiple myeloma that was refractory to lenalidomide and a proteasome inhibitor. “After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group,” the investigators write. “The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P = 0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11).” (M. A. Dimopoulos, mdimop@med.uoa.gr)
Energy-Dense Enteral Nutrition in Critically Ill Patients: Among 3,957 patients undergoing mechanical ventilation, use of energy-dense enteral nutrition provided no benefits over routine products, according to authors at 46 intensive care units in Australia and New Zealand (pp. 1823–34). In addition to lack of improvement in a primary outcome of all-cause mortality at 90 days, the authors report, “Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events.” (S. L. Peake, sandra.peake@sa.gov.au)
Single-Dose Zoliflodacin for Urogenital Gonorrhea: While effective for treating most uncomplicated cases of urogenital and rectal gonococcal infections, oral zoliflodacin was less useful in patients with pharyngeal infections in a phase 2 trial of the DNA biosynthesis inhibitor (pp. 1835–45). Participants were men or women with signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea, or who were untreated after potentially infectious sexual contact within 14 days. “Among the 141 participants in the [microbiologic intention-to-treat] population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone,” results show. “All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively.” (S. N. Taylor, staylo2@lsuhsc.edu)
>>>PNN NewsWatch
Kadesh, Inc. is voluntarily recalling all lots of the OTC product Puriton Eye Relief Drops, 15-mL bottle, to the consumer level because of a lack of sterility assurance.

PNN Pharmacotherapy Line
Nov. 9, 2018 * Vol. 25, No. 217
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
 Nov. issue of Chest (2018; 154).
Lower Glucose Target in Critically Ill Patients: Tight glycemic control in critically ill patients is supported by mortality data from a cohort of 1,809 patients, most of them in cardiac units, researchers report (pp. 1044–51). Patients receiving intravenous insulin were treated to target glucose levels of 80–110 or 90–140 mg/dL, with these results: “Median glucose was lower in the 80–110 mg/dL group (104 vs 122 mg/dL, P < .001). Severe hypoglycemia occurred at very low rates in both groups (1.16% vs 0.35%, P = .051). Unadjusted 30-day mortality was lower in the 80–110 mg/dL group (4.3% vs 9.2%, P < .001). This remained after propensity score-adjusted regression (OR, 0.65; 95% CI, 0.43–0.98; P = .04).” (A. M. Hersh, Andrew.m.hersh.mil@mail.mil)
Reflecting on the current practice of using higher blood glucose (BG) targets in critical care, an editorialist writes, “The widespread adoption of the ‘moderate’ BG target of 140 to 180 mg/dL in the critically ill reflected the principle of ‘first, do no harm’” (
pp. 1004–5). “However, the study by Hersh et al. has shown that dedicated clinical teams using standardized protocols that include high frequency of BG measurement can safely achieve ‘tight’ and ‘moderately tight’ levels of mean ICU glycemia. Optimal glucose control includes safety (low rates of hypoglycemia) and efficacy (appropriate BG targets based on patient characteristics). These principles are achievable and should prompt reassessment of BG targets in the critically ill.” (J. S. Krinsley, jkrinsley@stamhealth.org)
>>>Cardiology Report
Source:
 Nov. 6 issue of the Journal of the American College of Cardiology (2018; 72).
sST2 Biomarker in HF: The soluble suppression of tumorigenesis-2 (sST2) biomarker provides strong predictive value in patients with chronic heart failure (HF), a study reports (10.1016/j.jacc.2018.08.2165). Used with N-terminal pro−B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT), sST2 “deserves consideration to be part of a multimarker panel,” the authors conclude, based on these individual-level data from prior studies: “Among the 4,118 patients (96%) with available data, 1,029 (24%) were hospitalized at least once for worsening HF over 2.2 years. The best sST2 cutoff for the prediction of all-cause and cardiovascular death and HF hospitalization was 28 ng/ml, with good performance at Kaplan–Meier analysis (log-rank: 117.6, 61.0, and 88.6, respectively; all p <0.001). In a model that included age, sex, body mass index, ischemic etiology, LVEF, New York Heart Association functional class, glomerular filtration rate, HF medical therapy, NT-proBNP, and hs-TnT, the risk of all-cause death, cardiovascular death, and HF hospitalization increased by 26%, 25%, and 30%, respectively, per each doubling of sST2. sST2 retained its independent prognostic value across most population subgroups.” (M. Emdin)
Ejection Fraction in “Modern Cardiology”: In a review article, the continued place in cardiology of ejection fraction (EF) is assessed based on availability of new ly available biomarkers (10.1016/j.jacc.2018.08.2162): “EF reflects both cardiac function and remodeling, and is widely recognized as a valuable diagnostic and prognostic tool. Its use in a variety of settings, ranging from heart failure and myocardial infarction to valvular heart disease, has made it a cornerstone of modern cardiology, pervading guidelines and practice. However, the development of the test was in another era, with younger patients and a lower prevalence of heart failure with preserved EF. The performance expectations of EF in the current era are also demanding—in relation to detection of subclinical LV dysfunction, and especially relating to recognition of changes in LV function on sequential testing—for example in patients taking cardiotoxic drugs. This review discusses whether the impressive evidence base for EF justifies its ongoing use in the context of newer markers of LV function, and the sophisticated questions posed by modern cardiology.” (T. H. Marwick)
>>>PNN NewsWatch
FDA yesterday allowed remarketing of OTC Primatene Mist inhaler, still containing the problematic agent epinephrine.
CDC is reporting the lowest level of use of cigarette/nicotine/tobacco products ever recorded among Americans — 14% in 2017, a decline from 15.5% in 2016.

PNN Pharmacotherapy Line
Nov. 12, 2018 * Vol. 25, No. 218
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 Nov. 10 issue of Lancet (2018; 392).
Global Burden of Disease — The Past: “Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health,” conclude collaborators in the Global Burden of Diseases 2017 project (pp. 1736–88). “Improvements in global health have been unevenly distributed among populations,” the authors add, based on cause-specific mortality data from 195 countries and territories for 1980 through 2017. “For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for [noncommunicable diseases], and the death rate for selected causes has increased in the past decade.” (GBD 2017 Causes of Death Collaborators)
Predictions for Future Causes of Global Mortality: Forecasting mortality causes for 2016 to 2040 in 195 countries and territories, investigators predict “global life expectancy [will] increase by 4.4 years (95% UI 2.2 to 6.4) for men and 4.4 years (2.1 to 6.4) for women by 2040, but based on better and worse health scenarios, trajectories could range from a gain of 7.8 years (5.9 to 9.8) to a non-significant loss of 0.4 years (–2.8 to 2.2) for men, and an increase of 7.2 years (5.3 to 9.1) to essentially no change (0.1 years [–2.7 to 2.5]) for women” (pp. 2052–90). “Our reference forecast points to overall improvements through 2040 in most countries, yet the range found across better and worse health scenarios renders a precarious vision of the future—a world with accelerating progress from technical innovation but with the potential for worsening health outcomes in the absence of deliberate policy action. For some causes of [years of life lost], large differences between the reference forecast and alternative scenarios reflect the opportunity to accelerate gains if countries move their trajectories toward better health scenarios—or alarming challenges if countries fall behind their reference forecasts. Generally, decision makers should plan for the likely continued shift toward [noncommunicable diseases] and target resources toward the modifiable risks that drive substantial premature mortality. If such modifiable risks are prioritised today, there is opportunity to reduce avoidable mortality in the future. However, [communicable, maternal, neonatal, and nutritional] causes and related risks will remain the predominant health priority among lower-income countries. Based on our 2040 worse health scenario, there is a real risk of HIV mortality rebounding if countries lose momentum against the HIV epidemic, jeopardising decades of progress against the disease.…” (C. J. L. Murray, cjlm@uw.edu)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 363) report:
* Comparative safety data for immune checkpoint inhibitors used for treating cancers (
k4226; J. Ma, majun2@mail.sysu.edu.cn).
* Gender-specific risk factors for myocardial infarction, including several more common in women (
k4247; S. A. E. Peters, sanne.peters@georgeinstitute.ox.ac.uk).
* Better outcomes with triple therapy for COPD, compared with one- or two-drug regimens (
k4388; W Yao, yaoweimin2014@yeah.net).
>>>PNN NewsWatch
* FDA’s New Inspection Protocol Project uses standardized electronic inspection protocols to collect data in a structured manner for more consistent oversight of aseptic manufacturing facilities, FDA Commissioner Scott Gottlieb says in a statement posted on Friday.
>>>PNN JournalWatch
* Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis, in Chest, 2018; 154: 1108–14. (L. T. Hong, lhong@llu.edu)
*
Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report, in Chest, 2018; 154: 1121–201. (G. Y. H. Lip, gregory.lip@liverpool.ac.uk)
*
Antimicrobial Resistance and Respiratory Infections, in Chest, 2018; 154: 1202–12. (G. D. Wright, wrightge@mcmaster.ca)
*
Evaluation of Community Pharmacy Tech-Check-Tech as a Strategy for Practice Advancement, in Journal of the American Pharmacists Assoc., 2018; 58: 652–8. (R. Fleagle Miller, rachael.fleaglemiller@nm.org)

PNN Pharmacotherapy Line
Nov. 13, 2018 * Vol. 25, No. 219
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Nov. issue of JAMA Internal Medicine (2018; 178).
Low-Dose Amitriptyline for Chronic Low Back Pain: When the only alternative is an opioid, low-dose amitriptyline “may be worth considering” in patients with chronic low back pain, authors conclude based on results of a 146-patient, 6-month trial (pp. 1474–81). Compared with benztropine mesylate 1 mg/d, amitriptyline 25 mg/d reduced disability at 3 months, improved pain intensity nonsignificantly at 6 months, and produced minimal adverse effects. (D. M. Urquhart, donna.urquhart@monash.edu)
NSAIDs & HTN, HF or CKD: Short-term use of prescription NSAIDs was not associated with increased risk of adverse safety outcomes in older adults with hypertension, heart failure, or chronic kidney disease in a retrospective cohort study from Ontario (pp. 1516–25). Administrative claims data analysis showed these results for patients aged 65 years or older and histories of these conditions: “The study identified 2,415,291 musculoskeletal-related primary care visits by 814,049 older adults (mean [SD] age, 75.3 [4.0] years; 61.1% female) with hypertension, heart failure, or CKD, of which 224,825 (9.3%) were followed by prescription NSAID use. The median physician-level prescribing rate was 11.0% (interquartile range, 6.7%–16.7%) among 7,365 primary care physicians. Within a sample of 35,552 matched patient pairs, each consisting of an exposed and nonexposed patient matched on the logit of their propensity score for prescription NSAID use (exposure), the study found similar rates of cardiac complications (288 [0.8%] vs 279 [0.8%]), renal complications (34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]). For cardiovascular and renal-safety related outcomes, there was no difference between exposed patients (308 [0.9%]) and nonexposed patients (300 [0.8%]) (absolute risk reduction, 0.0003; 95% CI, −0.001 to 0.002; P = .74).” (R. S. Bhatia, sacha.bhatia@wchospital.ca)
Commenting on this and another real-world study of allopurinol use in patients with gout (
pp. 1526–33; T. Neogi, tneogi@bu.edu), editorialists point to the importance of adding information available in large databases on patient experiences to findings from randomized controlled trials (RCTs) (pp. 1533–4): “Done well, observational studies can provide valuable information about the real-world safety of drugs. Moving forward, detailed real-world data will be increasingly available in electronic health records and registries. In response to initiatives such as the 21st Century Cures Act, the National Evaluation System for Health Technology, and the US Food and Drug Administration’s Sentinel Initiative, we can expect to see more observational studies testing longstanding assumptions about treatments, along with new uses for old therapies. Yes, the findings will need to be contextualized and viewed with more skepticism than RCTs, but in some instances, they can be thoughtfully integrated into our treatment decisions.” (D. N. Juurlink, dnj@ices.on.ca)
Long-Term Benzodiazepine Use Among Older Adults: Among older adults covered by Pennsylvania’s prescription assistance program, transitions of new prescriptions for benzodiazepines to long-term use were associated with white race, provision of refills, and higher number of days supplied (pp. 1560–2), as shown in these results: “The mean (SD) age of adults newly prescribed a benzodiazepine was 78.4 (7.0) years. One year after the index prescription, 152 (26.4%) met the definition of long-term use; this group was prescribed a mean (SD) of 232.7 (82.6) benzodiazepine days. In adjusted analyses, white race (odds ratio [OR], 4.19; 95% CI, 1.51–11.59), days supplied in the index prescription (OR, 1.94; 95% CI, 1.52–2.47), and poor sleep quality (OR, 4.05; 95% CI, 1.44–11.43) were associated with increased long-term benzodiazepine use. High anxiety and depression did not predict long-term benzodiazepine use in either unadjusted or adjusted analyses.” (L. B. Gerlach, glauren@med.umich.edu)
>>>PNN NewsWatch
* FDA has approved revefenacin (Yupelri, Theravance Biopharma and Mylan) inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease. The drug, a long-acting muscarinic antagonist, is the first and only once-daily, nebulized bronchodilator approved for the treatment of COPD in the U.S.

PNN Pharmacotherapy Line
Nov. 14, 2018 * Vol. 25, No. 220
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 13 issue of JAMA (2018; 320).
Pharmacist Interventions: Three studies and an editorial examine the extent and impact of pharmacists’ interventions. 
In the D-PRESCRIBE (Developing Pharmacist-Led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly) trial, community pharmacists decreased use of inappropriate medications at 6 months through interventions with older adults (
pp. 1889–98). Compared with usual care, education of older adults in Quebec who were on one of four Beers criteria medications produced these results: “Among 489 patients (mean age, 75 years; 66% women), 437 (89%) completed the trial (219 [88%] in the intervention group vs 218 [91%] in the control group). At 6 months, 106 of 248 patients (43%) in the intervention group no longer filled prescriptions for inappropriate medication compared with 29 of 241 (12%) in the control group (risk difference, 31% [95% CI, 23% to 38%]). In the intervention vs control group, discontinuation of inappropriate medication occurred among 63 of 146 sedative–hypnotic drug users (43.2%) vs 14 of 155 (9.0%), respectively (risk difference, 34% [95% CI, 25% to 43%]); 19 of 62 glyburide users (30.6%) vs 8 of 58 (13.8%), respectively (risk difference, 17% [95% CI, 2% to 31%]); and 19 of 33 nonsteroidal anti-inflammatory drug users (57.6%) vs 5 of 23 (21.7%), respectively (risk difference, 35% [95% CI, 10% to 55%]) (P for interaction = .09). Analysis of the antihistamine drug class was not possible because of the small sample size (n = 12). No adverse events requiring hospitalization were reported, although 29 of 77 patients (38%) who attempted to taper sedative–hypnotics reported withdrawal symptoms.” (C. Tannenbaum, cara.tannenbaum@umontreal.ca)
Two years after a state law permitted trained pharmacists to furnish naloxone without a physician’s prescription, only a quarter of California pharmacies were were doing so, a study shows (
pp. 1933–4). An anonymous 20% random sample of community pharmacies in the state showed these results in early 2018: “Pharmacist-furnished naloxone was available at 23.5% (95% CI, 21.0%–26.0%) of pharmacies.… There was a significant difference by pharmacy type, with 31.6% (95% CI, 28.3%–35.1%) of chain pharmacies compared with 7.5% (95% CI, 5.1%–10.6%) of independent pharmacies furnishing naloxone (P < .001).
“Among pharmacies furnishing naloxone (n = 269), 225 (83.6%) offered a nasal formulation. Fourteen (5.2%) offered combination buprenorphine–naloxone tablets used for treatment of opioid use disorder, not opioid overdose. Of pharmacies furnishing naloxone, 50.6% had nasal naloxone in stock. Chain pharmacies were significantly more likely to have nasal naloxone in stock (52.3%; 95% CI, 46.3%–59.4%) compared with independents (31.0%; 95% CI, 15.3%–50.8%) (P = .03). Regarding insurance billing, 59.9% of pharmacies replied correctly that pharmacist-furnished naloxone could be billed, with no significant difference by pharmacy type. The median cash price of nasal naloxone (pack of 2) at chain pharmacies was $136 (IQR, $120–$143.50) compared with $150 (IQR, $138.50–$170) (P = .04) at independents.” (T. Puzantian, 
talia_puzantian@kgi.edu)
In mid-2018, naloxone was generally available at Texas chain pharmacies, researchers report (
pp. 1934–7). Interviews of one pharmacist at each of 2,317 major chain units in the state showed that 83.7% of respondents would dispense naloxone without a prescription, 76.4% currently stocked naloxone, 79.9% would allow naloxone purchase for someone else, and 49.7% would bill the purchaser’s insurance. (K. E. Evoy, evoy@uthscsa.edu)
“Once started, medications can be difficult to stop,” editorialists write in response to the three studies (
pp. 1867–9). “Older adults often take too many medications. More naloxone in the hands of friends and family can save lives. Change, or overcoming inertia in health care, is difficult but essential to deprescribing harmful medications and making effective medications available to individuals who need them. Involving groups that are less often the target of interventions to overcome inertia, such as patients and pharmacists, will likely be necessary for medicine to achieve such changes. These changes are more likely to be achieved if patients, pharmacists, nurses, and organizations all push and pull in the same direction.” (C. S. Landefeld, sethlandefeld@uabmc.edu)

PNN Pharmacotherapy Line
Nov. 15, 2018 * Vol. 25, No. 221
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 15 issue of and early-release articles from New England Journal of Medicine (2018; 379).
Prednisone for Preventing Paradoxical TB-Associated IRIS: For preventing paradoxical tuberculosis (TB)–associated immune reconstitution inflammatory syndrome (IRIS) in patients with HIV and TB, prednisone provides protection during the early initiation of antiretroviral therapy (ART), researchers report (pp. 1915–25). Compared with placebo, prednisone 40 mg/d for 14 days and then 20 mg/d for 14 days yielded these results: “Among the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P = 0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P = 1.00). Severe infections (acquired immunodeficiency syndrome–defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P = 0.23). One case of Kaposi’s sarcoma occurred in the placebo group.” (G. Meintjes, graemein@mweb.co.za)
Palbociclib/Fulvestrant in Advanced Breast Cancer: Among women with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, addition of palbociclib to fulvestrant therapy extended overall survival in a placebo-controlled trial (pp. 1926–36). Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, produced significant changes in this subgroup but no significant benefits in the overall population: “Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P = 0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P <0.001). No new safety signals were observed with 44.8 months of follow-up.” (N. C. Turner, nick.turner@icr.ac.uk)
Disclosing Prescription-Drug Prices in Advertisements: Aspects of a recent CMS rule proposing disclosure of prescription-drug prices in direct-to-consumer advertising “undercut the government’s ability to argue that it will materially improve patient decision making and reduce drug spending,” according to authors of a Perspective article (10.1056/NEJMp1814065). (S. B. Dusetzina)
>>>PNN NewsWatch
FDA yesterday warned of serious complications when medications are delivered into spinal fluid with implanted pumps not approved for that use. Complications may include dosing errors, pump failure, opioid withdrawal, infection, and other complications such as pain, fever, vomiting, muscle spasms, cognitive changes, weakness, and cardiac or respiratory distress. FDA recommends that health professionals review the implanted pump labeling to identify the medicines and medicine concentrations approved for use with that device.

PNN Pharmacotherapy Line
Nov. 16, 2018 * Vol. 25, No. 222
Providing news and information about medications and their proper use

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>>>Infectious Diseases Report
Source:
 Dec. 1 issue of Clinical Infectious Diseases (2018; 67).
Benchmarking Inpatient Antimicrobial Use: In 2.7 million inpatient admissions, a simplified antimicrobial stewardship program (ASP) ratio showed promise for improving the comparison of antibiotic use between health care facilities, researchers report (pp. 1677–85). The model — which included common facility and encounter factors in a single-level parsimonious model — yielded these results in comparison with a complex ratio based on all available factors and a facility ratio using only broad hospital characteristics: “Diagnosis-related groups, infection present on admission, patient class, and unit type were the major predictors of expected antibiotic use. Aside from a history of gram-positive resistance in the prior 12 months for anti–methicillin-resistant Staphylococcus aureus drugs, additional clinical and comorbid history information did not improve the model. The simplified ASP ratio demonstrated higher Pearson correlation (R2 = 0.97–0.99) to the complex ratio than the facility ratio (R2 = 0.57–0.85) and provided clinical explanations when discordant.” (K. C. Yu, kalvin.c.yu@kp.org)
Zoster Vaccine Live in HIV-Infected Adults with High CD4 Counts: In a study of adult patients with HIV on antiretroviral therapy (ART) whose CD4+ counts were 200 cells/µL or more, live attenuated zoster vaccine (ZV) was safe and efficacious (pp. 1712–9). Two vaccine doses were studied, with these results based on a primary endpoint of serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose: “Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%–8.2%] vs 2.1% [95% CI, .3%–7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%–47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%–20.6%) (P < .001). Week 12 median natural log [varicella zoster virus (VZV)] antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4+ stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction–confirmed [herpes zoster] occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related.” (C. A. Benson, cbenson@ucsd.edu)
>>>Vaccine Highlights
Source:
 Nov. 26 issue of Vaccine (2018; 36).
Acute Otitis Media & Antimicrobial Rx’s Declining: During the 2011–16 period, the incidence of acute otitis media (AOM), antimicrobial prescriptions for AOM, and associated medical expenses declined in the U.S., a study shows, with authors concluding that further research is needed to see if the results correlate with the 2007 change in pneumococcal vaccine in the pediatric vaccination schedule (pp. 7479–86). For children 9 years of age or younger, these findings were obtained from national data on AOM cases, medical expenditures, and population: “In 2011, there were an estimated 11.5 million AOM episodes in children aged 0–9 years in the U.S. with AOM incidence rates (IR) of 476, 204, and 284 episodes per 1,000 children aged 0–2, 3–9, and 0–9 years, respectively. All subsequent years had lower IRs, and by 2016, IR was 25.1% lower than in 2011 in children 0–9 years. In addition, there were estimates of 10.8 million and 9.2 million fewer cumulative AOM episodes and antimicrobial prescriptions for AOM nationwide between 2012 and 2016, compared to annual 2011 estimates, representing a ~$5.6 billion decrease in direct medical expenditures. The average number of antibiotic prescriptions per AOM visit remained stable with 0.89 and 0.86 prescriptions per visit in 2011 and 2016, respectively.” (J. A. Suaya, Jose.suaya@pfizer.com)
Pneumococcal Vaccination Among Older Adults: Completion rates of the two-vaccine series for pneumococcal disease is low among adults age 65 years or older, according to data on 224,132 people with records in the Clinformatics DataMart database (pp. 7574–9; X. Yang, xiaoqin.yang@merck.com).
>>>PNN NewsWatch
* In statements released yesterday, FDA detailed its rationale on reducing the use of flavors in e-cigarettes and results of the 2018 National Youth Tobacco Survey showing a “dramatic increase in e-cigarette use among youth over past year.”

PNN Pharmacotherapy Line
Nov. 19, 2018 * Vol. 25, No. 223
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 (2018; 362).
Inappropriate Prescribing in Older People & Hospital Admission: Medications considered potentially inappropriate in older adults were associated with increased risk of hospital admissions in a longitudinal study of 44 general practices in Ireland in 2012–15 (k4524). Using 45 criteria from the Screening Tool for Older Persons’ Prescription (STOPP) version 2, the investigators found these results among 38,229 patients with an average age of 76.8 years in 2012: “Each year, 10.4–15.0% (3,015/29,077 in 2015 to 4,537/30,231 in 2014) of patients had at least one hospital admission. The overall prevalence of potentially inappropriate prescribing ranged from 45.3% (13,940/30,789) of patients in 2012 to 51.0% (14,823/29,077) in 2015. Independently of age, sex, number of prescription items, comorbidity, and health cover, hospital admission was associated with a higher rate of distinct potentially inappropriate prescribing criteria met; the adjusted hazard ratio for hospital admission was 1.24 (95% confidence interval 1.20 to 1.28).” (F. Moriarty, frankmoriarty@rcsi.ie)
SGLT2 Inhibitors & Serious Adverse Events: Lower limb amputation and diabetic ketoacidosis were significantly more common with use of SGLT2 inhibitors than GLP1 agonists, according to an analysis of nationwide registries of Sweden and Denmark (k4365). The frequencies of seven serious adverse events were analyzed: lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis. Comparing use of SGLT2 inhibitors versus GLP1 agonists, significant increases in hazard ratios were found for lower limb amputation (2.7 vs. 1.1 events per 1,000 person–years; hazard ratio 2.32) and diabetic ketoacidosis (1.3 vs. 0.6 events per 1,000 person–years; hazard ratio, 2.14). (P. Ueda, peter.ueda@ki.se)
>>>Lancet Highlights
Source:
 Nov. 17 issue of Lancet (2018; 392).
LY3298176 in Type 2 Diabetes: The novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist LY3298176 showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile, in patients with type 2 diabetes, researchers report (pp. 2180–93). Among 316 participants in the phase 2 trial, comparison of LY3298176 with placebo or selected GLP01 agonists showed significant improvements in the primary outcome, A1C levels, at 26 weeks. Secondary outcomes were also improved significantly, including change in A1C levels from baseline to 12 weeks; change in body weight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the A1C target (≤6.5% and <7.0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% body weight loss from baseline to 26 weeks. (A. Haupt, haupt_axel@lilly.com)
>>>PNN NewsWatch
FDA on Friday approved the antibacterial drug rifamycin (Aemcolo, Cosmo Technologies), with an indication for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli not complicated by fever or blood in the stool.
* “The timely completion of 
postmarketing studies remains a critical part of our regulatory responsibility,” FDA Commissioner Scott Gottlieb, MD, said on Friday in a statement reviewing FDA’s efforts to hold industry accountable for fulfilling such studies on the benefits and safety of new drugs.
>>>PNN JournalWatch
Early Clindamycin for Bacterial Vaginosis in Pregnancy (PREMEVA): A Multicentre, Double-Blind, Randomised Controlled Trial, in Lancet, 2018; 392: 2171–9. (R. Dessein, rodrigue.dessein@chru-lille.fr)
The Effect of Antibiotic Selection Pressure on the Nasopharyngeal Macrolide Resistome: A Cluster-Randomized Trial, in Clinical Infectious Diseases, 2018; 67: 1736–42. (J. D. Keenan, jeremy.keenan@ucsf.edu)
Understanding Barriers and Predictors of Maternal Immunization: Identifying Gaps Through an Exploratory Literature Review, in Vaccine, 2018; 36: 7445–55. (C. S. Lutz, nfi5@cdc.gov)
Personalizing Medicine, in Journal of Clinical Oncology, 2018; 10.1200/JCO.18.01240. (T. Gilligan, Gilligt@ccf.org)

PNN Pharmacotherapy Line
Nov. 20, 2018 * Vol. 25, No. 224
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 (2018; 169).
Diabetes Outcomes With Nonphysician Care: At 568 VA facilities, diabetic outcomes were similar among 368,481 adult patients whose care was managed by physicians, nurse practitioners (NPs), and physician assistants (PAs), a study shows (10.7326/M17-1987). The results suggest that “similar chronic illness outcomes may be achieved by physicians, NPs, and PAs,” the authors conclude based on these findings for primary care provider (PCP) type and disease outcomes (hemoglobin A1c [HbA1c], systolic blood pressure [SBP], and low-density lipoprotein cholesterol [LDL-C]): “The PCPs were physicians (n = 3487), NPs (n = 1445), and PAs (n = 443) for 74.9%, 18.2%, and 6.9% of patients, respectively. The difference in HbA1c values compared with physicians was −0.05% (95% CI, −0.07% to −0.02%) for NPs and 0.01% (CI, −0.02% to 0.04%) for PAs. For SBP, the difference was −0.08 mm Hg (CI, −0.34 to 0.18 mm Hg) for NPs and 0.02 mm Hg (CI, −0.42 to 0.38 mm Hg) for PAs. For LDL-C, the difference was 0.01 mmol/L (CI, 0.00 to 0.03 mmol/L) (0.57 mg/dL [CI, 0.03 to 1.11 mg/dL]) for NPs and 0.03 mmol/L (CI, 0.01 to 0.05 mmol/L) (1.08 mg/dL [CI, 0.25 to 1.91 mg/dL]) for PAs. None of these differences were clinically significant.” (G. L. Jackson, george.l.jackson@duke.edu)
“The time has come to embrace many different approaches to providing primary care, particularly for persons with a chronic disease, such as diabetes,” writes an editorialist (
10.7326/M18-2941). “To this end, we have certified diabetes educators (including providers from registered nurses to physicians), pharmacists, registered dietitians, therapists (of all sorts), physical and occupational therapists, exercise physiologists, and podiatrists, among others, who are part of the diabetes treatment team,” the writer adds. “Given the right system—with resources to provide education and support, along with referral to an endocrinologist or a diabetes team if needed, and including more innovative programs, such as telehealth, online programs, and device-based data transfer and support—persons with diabetes can achieve their goals. Moreover, it is time to stop calling NPs and PAs ‘midlevel’ providers, as is common in certain systems. Nurse practitioners and PAs are competent PCPs in their own right and should be fully accepted as such.” (A. L. Peters)
Delays in Diabetes Care With High-Deductible Plans: Patients with diabetes had delays in care for first symptoms of macrovascular disease, the first diagnostic test, and the first procedure-based treatment following employer-mandated transitions to high-deductible insurance plans, researchers report (10.7326/M17-3365). Compared with control patients in low-deductible plans, 33,957 people with diabetes whose care was transitioned from low- to high-deductible plans had these outcomes: “The delay for the high-deductible group was 1.5 months (95% CI, 0.8 to 2.3 months) for seeking care for the first major symptom, 1.9 months (CI, 1.4 to 2.3 months) for the first diagnostic test, and 3.1 months (CI, 0.5 to 5.8 months) for the first procedure-based treatment.” (J. F. Wharam, jwharam@post.harvard.edu)
“[This] natural experiment provides an important piece (but only 1 piece) of the puzzle of whether or when high-deductible health plans are a good idea for patients,” an editorialist writes (
10.7326/M18-2825). “Confidence that they are not for patients with known diabetes is enhanced by this research. High cost sharing is a powerful tool; the authors prudently recommend caution to employers and policymakers considering high-deductible plans. One thing is certain: The switch is going to be a bumpy ride.” (M. V. Pauly)
>>>PNN NewsWatch
* Manufacturers of edible oils containing high levels of oleic acid can now make qualified health claims for cardiovascular benefits, FDA Commissioner Scott Gottlieb, MD, writes in a statement. Labeling must state that “supportive but not conclusive scientific evidence suggests that daily consumption of about 1.5 tablespoons (20 grams) of oils containing high levels of oleic acid may reduce the risk of coronary heart disease.” The claim will also need to make it clear that to achieve this benefit, these oils “should replace fats and oils higher in saturated fat and not increase the total number of calories you eat in a day.”

PNN Pharmacotherapy Line
Nov. 21, 2018 * Vol. 25, No. 225
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 20 issue of JAMA (2018; 320).
Recombinant Alkaline Phosphatase in Acute Kidney Injury: In a dose-finding adaptive phase 2a/2b trial of 301 critically ill adults with sepsis and associated acute kidney injury (AKI), human recombinant alkaline phosphatase had no significant effect on 7-day creatinine clearances, compared with placebo, researchers report (pp. 1998–2009). Results from the STOP-AKI trial showed “the optimal therapeutic dose of recombinant alkaline phosphatase was 1.6 mg/kg,” the authors write. “Treatment with this dose for 3 days when added to standard care resulted in a median increase in endogenous creatinine clearance of 27.6 mL/min vs 14.7 mL/min for placebo in the first 7 days, a difference that was not statistically significant.” (P. Pickkers, peter.pickkers@radboudumc.nl)
Lanreotide in Autosomal Dominant Polycystic Kidney Disease: The somatostatin analogue lanreotide failed to slow the decline in renal function in 305 adult patients with autosomal dominant polycystic kidney disease (ADPKD) in a study conducted at four Dutch nephrology clinics (pp. 2010–9). Compared with standard care in the open-label trial, lanreotide had these effects on annual rates of change of estimated glomerular filtration rate (eGFR): “Annual rate of eGFR decline for the lanreotide vs the control group was −3.53 vs −3.46 mL/min/1.73 m2 per year (difference, −0.08 [95% CI, −0.71 to 0.56]; P = .81). There were no significant differences for incidence of worsening kidney function (hazard ratio, 0.87 [95% CI, 0.49 to 1.52]; P = .87), change in eGFR (−3.58 vs −3.45; difference, −0.13 mL/min/1.73 m2 per year [95% CI, −1.76 to 1.50]; P = .88), and change in quality of life (0.05 vs 0.07; difference, −0.03 units per year [95% CI, −0.13 to 0.08]; P = .67).…” (R. T. Gansevoort, R.T.Gansevoort@umcg.nl)
Physical Activity Guidelines for Americans: “With so many health benefits, why is it so difficult to get people moving?” ask the HHS Assistant and Deputy Assistant Secretaries for Health in a Viewpoint article (pp. 1971–2). Responding to publication of Physical Activity Guidelines for Americans, 2nd edition (pp. 2020–8; R P. Troiano, troianor@mail.nih.gov) and its information and guidance on the types and amounts of physical activity that provide substantial health benefits, and an accompanying editorial (pp. 1983–4; P. D. Thompson, Paul.Thompson@hhchealth.org), the Viewpoint authors write: “Numerous factors influence physical activity behavior. Although some of the benefits of physical activity begin immediately, benefits related to the reduction of disease risk require regular physical activity over time and thus may not be immediately evident. In addition, making physical activity a habit requires overcoming personal barriers such as lack of time, fatigue, disability, perceived lack of enjoyment, and finding ways to make activity a routine part of the day despite other responsibilities. Family, friends, and peers can significantly influence this lifestyle choice, as do environmental factors such as climate, weather, personal safety, and access to parks, sidewalks, playgrounds, and organized sports.” (B. P. Giroir, Brett.Giroir@hhs.gov)
>>>PNN NewsWatch
FDA yesterday approved emapalumab-lzsg (Gamifant, Novimmune SA) for treatment of pediatric and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy. FDA said this is the first approval of a drug specifically for HLH. Emapalumab-lzsg has been designated an orphan drug, and the application was handled through FDA priority review and breakthrough therapy processes.
FDA has posted warning letters issued to two companies for illegal marketing of products labeled as dietary supplements that contain tianeptine, a chemical compound that FDA says the “companies are illegally claiming treats opioid use disorder, pain, and anxiety, and [making] other unlawful and unproven claims.”
Dayna Less, PharmD, a PGY1 pharmacy resident, was among those killed on Monday in the shootings at Mercy Hospital in Chicago, writes Thomas E. Menighan in an APhA CEO blog
PNN will not be published on Thurs. and Fri., Nov. 22 and 23, Thanksgiving Day.

PNN Pharmacotherapy Line
Nov. 26, 2018 * Vol. 25, No. 226
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Nov. 26 New England Journal of Medicine (2018; 379).
Oral Peanut Desensitization: A clinical trial of 12% defatted peanut flour (AR101) (pp. 1991–2001; PALISADE Group of Clinical Investigators) opens the door for more specific oral immunotherapies for peanut allergy, an editorialist writes (pp. 2074–5): “The clinical value of AR101 will be to allow the initiation of peanut immunotherapy with a product that reliably contains the tiny initial quantities of peanut that are required to safely launch oral desensitization. The lowest-dose capsules of AR101 contain 0.5 mg and 1 mg of peanut protein. In the absence of a product such as AR101, it is extremely difficult to administer such a small amount of allergen to a patient on a consistent basis. The Cambridge group used microscales and issued the doses of peanut flour in vials. However, errors regarding the initial doses during the increasing-dose phase would seem to be a more likely occurrence if allergy treatment centers all measured their own doses of peanut flour rather than using a carefully manufactured product. Furthermore, the issuing of peanut flour to a patient with peanut allergy may result in the peanut being deemed an unlicensed medicinal product by regulatory organizations in some countries. Once a product such as AR101 appears, such regulators will insist that a licensed product be used when it is available, thus preventing the ongoing use of peanut flour itself.” (M. R. Perkin)
Probiotics in Children With Gastroenteritis: Commenting on a negative trial of Lactobacillus rhamnosus GG for acute gastroenteritis in children (pp. 2002–14; D. Schnadower, david.schnadower@cchmc.org) an editorialist concludes (pp. 2076–7). “These negative trial data will be valuable to clinicians and professional bodies in making decisions regarding the use of either of these probiotic formulations in children with diarrhea. However, given the large number of probiotic agents now available and considering their various mechanisms of action, abilities to colonize the bowel, and probably narrow potential efficacy for specific diseases, the possibility remains that probiotics other than L. rhamnosus might be effective in infectious diarrhea in children. For example, a recent large, placebo-controlled trial in rural India showed that prophylaxis with a probiotic formula containing L. plantarum in healthy newborns in the first 5 days of life led to a significant reduction in the rate of sepsis and lower respiratory tract infections in the first 2 months of life. This particular probiotic strain, as compared with other probiotics, including L. rhamnosus, can colonize the intestinal tract for a prolonged period.…” (J. T. LaMont)
>>>Lancet Highlights
Source:
 Nov. 24 issue of Lancet (2018; 392).
Lorcaserin & Type 2 Diabetes in Overweight and Obesity: A selective serotonin 2C receptor agonist, lorcaserin reduces risk of incident diabetes and microvascular complications and induces remission of hyperglycemia in patients with obesity and overweight, researchers report (pp. 2269–79). Results of the CAMELLIA-TIMI 61 trial support use of the agent “as an adjunct to lifestyle modification for chronic management of weight and metabolic health,” the authors conclude based on these placebo-controlled results in 12,000 patients in 8 countries: “At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2.6 kg (95% CI 2.3–2.9) for those with diabetes, 2.8 kg (2.5–3.2) for those with prediabetes, and 3.3 kg (2.6–4.0) for those with normoglycaemia (p <0.0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8.5%] of 2,015 vs 204 [10.3%] of 1,976; hazard ratio 0.81, 95% CI 0.66–0.99; p = 0.038) and by 23% in patients without diabetes (174 [6.7%] of 2,615 vs 215 [8.4%] of 2,569; 0.77, 0.63–0.94; p = 0.012).…” (E. A. Bohula, ebohula11@bwh.harvard.edu)
>>>PNN NewsWatch
Glasdegib (Daurismo, Pfizer) was approved last week by FDA for use with low-dose cytarabine for treatment of newly diagnosed acute myeloid leukemia in adults aged 75 years or older or with comorbidities that may preclude use of intensive chemotherapy.
>>>PNN JournalWatch
Efficacy and Tolerability of Erenumab in Patients With Episodic Migraine in Whom Two-to-Four Previous Preventive Treatments Were Unsuccessful: A Randomised, Double-Blind, Placebo-Controlled, Phase 3b Study, in Lancet, 2018; 392: 2280–7. (U. Reuter, uwe.reuter@charite.de)

PNN Pharmacotherapy Line
Nov. 27, 2018 * Vol. 25, No. 227
Providing news and information about medications and their proper use

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>>>Geriatrics Report
Source:
 Nov. issue of and early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Marijuana Use in Community-Dwelling Older Adults: In one of the states where marijuana has been legalized for medical and recreational use, community-dwelling older adults report use of Cannabis for a variety of common geriatric conditions (pp. 2167–71). In an anonymous survey conducted at two academic geriatric primary care clinics, English-speaking respondents report the following: “Three hundred forty-five individuals completed the survey (55% response rate); 113 (32%) had used marijuana in the past, of whom 55 (16%) had used since legalization. More than half of current users were aged 75 and older, and one-quarter were aged 85 and older. Most current users were white women. Of current users, 44% used marijuana products at least weekly for common conditions including chronic pain, depression, anxiety, and insomnia, and most found marijuana helpful for these conditions. Most respondents reported obtaining marijuana recreationally (67%) without a prescription. Nine respondents reported negative side effects attributable to marijuana use.” (G. Orosz, Gretchen.Orosz@ucdenver.edu)
Trauma with Glucose-Lowering Drugs: Use of hypoglycemic glucose-lowering drugs (GLDs) in adults aged 65 years or older is associated with an increased risk of serious trauma, report authors of an observational, nested case–control study conduced in France (pp. 2086–91). Patients with first hospitalizations for trauma in 2009–15 were assessed based on records in the Echantillon Généraliste de Bénéficiaires claims database, with these results: “Risk of hospitalization for trauma was significantly higher with use of GLDs (HR = 1.15, 95% CI = 1.08–1.22). Greater risk was found only in individuals treated with hypoglycemic GLDs alone (HR = 1.26, 95% CI = 1.15–1.38), particularly insulin (HR = 1.49, 95% CI = 1.32–1.68) and glinides (HR = 1.34, 95% CI = 1.12–1.61).” (F. Salvo, francesco.salvo@u-bordeaux.fr)
Nonspecific Symptoms & Infection in Older Patients: In the emergency department (ED), “altered mental status or malaise/lethargy does not substantially increase the probability of bacterial infection in older adults … and should not be used alone to indicate infection in this population,” authors of a 424-patient study conclude (10.1111/jgs.15679). Fever of 38° C is associated with higher risk of infection, the group adds based on these positive and negative likelihood ratios (PLR and NLR) from a prospective, observational study: “Fever of 38° C or higher either before or during the ED visit had moderate to large increases in probability of infection (PLR, 5.15–18.10), with initial fever in the ED perfectly predictive, but absence of fever did not rule out infection (NLR, 0.79–0.92). Results were similar when analyzing lower respiratory, gastrointestinal, and urinary tract infections (UTIs) individually. Of older adults diagnosed as having UTIs, 47% did not complain of UTI symptoms.” (J. M. Caterino, jeffrey.caterino@osumc.edu)
>>>PNN NewsWatch
* Moving toward “a new paradigm in the development of cancer drugs that are ‘tissue agnostic,’” FDA announced yesterday that it has granted accelerated approval to larotrectinib (Vitrakvi, Loxo Oncology) for treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. NTRK genes, encoding for TRK proteins, can become fused to other genes abnormally, resulting in growth signals that support the growth of tumors. NTRK fusions, while rare, occur in cancers arising in many sites. Before this approval, no treatment had been approved for cancers frequently expressing this mutation, including mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma, and infantile fibrosarcoma. This is the second time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than the anatomic location or source of the tumor. The approval follows policies that FDA developed in a guidance document released earlier this year.

PNN Pharmacotherapy Line
Nov. 28, 2018 * Vol. 25, No. 228
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Nov. 27 issue of JAMA (2018; 320).
Decontamination Strategies in Ventilated Patients: Interventions to reduce the risk of septicemia in ventilated patients were all ineffective in comparison with standard care in a study conducted in 13 European intensive-care units (pp. 2087–98). In a 6-month study, use of chlorhexidine 2% mouthwash, selective oropharyngeal decontamination (SOD) using antibiotic (colistin, tobramycin, and nystatin) toothpaste, and selective digestive tract decontamination (SDD) using the toothpaste and a gastrointestinal suspension with the same antibiotics all yielded similar rates of ICU-acquired bloodstream infections with multidrug-resistant gram-negative bacteria and 28-day mortality in ICUs with moderate-to-high levels of antibiotic resistance as chlorhexidine body washes with a hand-hygiene improvement program. (B. H. Wittekamp, b.h.j.wittekamp@umcutrecht.nl)
Given the challenges of conducting this study in several countries with varying ICU practices, “it is … somewhat unfortunate that the authors used an historical baseline period to compare the outcomes associated with the different regimens,” editorialists write (
pp. 2081–3). “Trials with historical control groups have become less common because of the possible bias and uncertainty about differences in care practices and patient populations between baseline and study periods. Such studies tend to favor the experimental treatment; even so, the decontamination regimens failed to show a positive association with reductions in bloodstream infections or mortality. One possibility is that in this trial, SDD failed because the 4-day course of intravenous third-generation cephalosporins that is always used with SDD in the Netherlands was omitted, but, as stated by the authors, SOD also failed, which worked in the Netherlands, but never includes prophylaxis with intravenous cephalosporins.” (C. M. J. E. Vandenbroucke-Grauls, vandenbrouckegrauls@vumc.nl)
Prevention of Hereditary Angioedema With Lanadelumab: A fully human monoclonal antibody that selectively inhibits active plasma kallikrein, lanadelumab administered subcutaneously to patients with hereditary angioedema type I or II for 26 weeks significantly reduced the attack rate compared with placebo, researchers report (pp. 2108–21). “These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema,” the Hereditary Angioedema Long-term Prophylaxis (HELP) study group concludes. “Further research is needed to determine long-term safety and efficacy.” (A. Banerji, abanerji@mgh.harvard.edu)
Gabapentinoid Prescribing Patterns in the U.K.: Between 2007 and 2017, the rate of prescribing by U.K. primary care physicians of the gabapentinoids gabapentin and pregabalin tripled, according to a research letter (pp. 2149–51). With 50% of the prescriptions for off-label indications and 20% with a coprescription for opioids, “caution is necessary when prescribing gabapentinoids, especially among patients also prescribed opioids,” the investigators conclude. (C. Renoux, christel.renoux@mcgill.ca)
Influenza Vaccine for 2018–19: A summary of the influenza vaccines for the current season is reprinted from a recent issue of the Medical Letter (pp. 2143–4). In addition to information on seasonal trivalent and quadrivalent products presented in tabular form, details are included in a separate table on the vaccines licensed for use in older adults: recombinant vaccine (Flublok Quadrivalent), high-dose vaccine (Fluzone High-Dose), and adjuvanted vaccine (Fluad). “[These] vaccines elicit greater antibody responses than standard-dose unadjuvanted vaccines among persons aged 65 years or older, and the high-dose and recombinant vaccines have been shown in randomized clinical trials to be more effective among older patients in preventing laboratory-confirmed influenza,” the article concludes. (www.medicalletter.org/tmlj)
>>>PNN NewsWatch
Teva Pharmaceuticals has initiated a voluntary recall to the patient level of all lots of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide tablets because of an impurity in a source ingredient.
FDA is warning consumers not to purchase or use Rhino male enhancement products because of recent reports of associated chest pain, severe headaches, and prolonged erections.

PNN Pharmacotherapy Line
Nov. 29, 2018 * Vol. 25, No. 229
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>>>NEJM Report
Source:
 Nov. 29 issue of the New England Journal of Medicine (2018; 379).
Alirocumab & Cardiovascular Outcomes After ACS: In a placebo-controlled trial, fatal and nonfatal ischemic cardiovascular events were significantly reduced in patients with prior acute coronary syndromes during treatment with the PCSK9 inhibitor alirocumab plus high-intensity statin therapy, researchers report (pp. 2097–107). The ODYSSEY OUTCOMES study included 18,924 patients at sites worldwide with high LDL cholesterol, non–HDL cholesterol, or apolipoprotein B levels despite statin therapy at a high-intensity dose or at the maximum tolerated dose. Randomized therapy with added alirocumab or placebo produced these outcomes based on a primary end point of composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization: “The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1,052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P <0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).” (G. G. Schwartz, gregory.schwartz@ucdenver.edu)
These results “will change clinical practice,” editorialists conclude (
pp. 2161–2). “The use of alirocumab to target an LDL cholesterol level of 25 to 50 mg per deciliter after an acute coronary syndrome resulted in a lower risk of major adverse cardiac events than placebo. Patients who had a baseline LDL cholesterol level of 100 mg per deciliter (2.6 mmol per liter) or more seemed to derive more benefit. However, the high cost of monoclonal antibodies to PCSK9 (even after recent substantial price reductions in the United States) obligates careful consideration of the type of high-risk patient who would most benefit from their clinical use.” (J. R. Burnett)
Atezolizumab in Advanced Triple-Negative Breast Cancer: Compared with nanoparticle albumin-bound (nab)–paclitaxel, atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in a phase 3 trial (pp. 2108–21; P. Schmid, p.schmid@qmul.ac.uk).
>>>PNN NewsWatch
* One of three FDA product approvals announced yesterday, the breakthrough therapy and orphan drug amifampridine (Firdapse, Catalyst Pharmaceuticals) tablets became the first marketed U.S. product for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults following a priority review. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles, producing weakness and other symptoms.
* Following a fast-track, priority review, 
FDA approved the orphan drug gilteritinib (Xospata, Astellas) tablets for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation as detected by an FDA-approved test. The FDA also approved an expanded indication for a companion diagnostic to include use with gilteritinib — the LeukoStrat CDx FLT3 Mutation Assay, developed by Invivoscribe Technologies, which is used to detect the FLT3 mutation in patients with AML.
FDA approved its 15th biosimilar productrituximab-abbs (Truxima, Celltrion and Teva) as the first biosimilar to rituximab (Rituxan). The product is approved for the treatment of adult patients with CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL) to be used as a single agent or in combination with chemotherapy. This is the first biosimilar to be approved in the U.S. for the treatment of NHL. In the past month, FDA has also approved adalimumab-adaz (Hyrimoz, Sandoz) as a biosimilar to adalimumab (Humira) and pegfilgrastim-cbqv (Udenyca, Coherus) as a biosimilar to pegfilgrastim (Neulasta).

PNN Pharmacotherapy Line
Nov. 30, 2018 * Vol. 25, No. 230
Providing news and information about medications and their proper use

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>>>Diabetes Report
Source:
 Dec. issue of Diabetes Care (2018; 41).
SGLT Inhibitors in Type 1 Diabetes: Research reports and an editorial examine utility of SGLT-1 inhibitors in type 1 diabetes (T1D).
In the DEPICT-1 trial, dapagliflozin improved glycemic control and weight loss in 708 patients with T1D but also increased the risk of diabetic ketoacidosis (DKA; 
pp. 2552–9). The phase 3 trial used a placebo control and produced these results: “Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA1c (difference vs. placebo [95% CI] −0.33% [−0.49, −0.17] [−3.6 mmol/mol (−5.4, −1.9)] and −0.36% [−0.53, −0.20] [−3.9 mmol/mol (−5.8, −2.2)], respectively) and body weight (difference vs. placebo [95% CI] −2.95% [−3.83, −2.06] and −4.54% [−5.40, −3.66], respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite DKA (4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively).” (P. Dandona, pdandona@kaleidahealth.org)
Ketoacidosis rates were elevated with higher doses of empagliflozin in the EASE trial, which also showed improvements in glycemic control and weight (
pp. 2560–9). In 1,707 patients with T1D, outcomes with empagliflozin or placebo were as follows: “The observed largest mean placebo-subtracted glycated hemoglobin reductions were −0.28% (95% CI −0.42, −0.15) for 2.5 mg, −0.54% (−0.65, −0.42) for 10 mg, and −0.53% (−0.65, −0.42) for 25 mg (all P < 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by −1.8/−3.0/−3.4 kg (all P < 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (P < 0.0001 for 10 and 25 mg); lowered total daily insulin dose by −6.4/−13.3/−12.7% (all P < 0.0001); and decreased systolic blood pressure by −2.1/−3.9/−3.7 mmHg (all P < 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated [DKA] occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
“These observations … have important clinical implications,” editorialists write (
pp. 2444–7). “Balancing benefits versus risks of SGLTi will require thoughtful decisions by regulatory and professional groups, care providers, and also people with diabetes. The most obvious responsibility falls upon regulators and groups creating guidance for clinical care. Does the evidence provided by these short-term studies justify approval of these agents for use in T1D? If so, what tactics for mitigation of risks are needed? Are we at a stage where we can stratify individual patients according to benefits versus risks so as to allow appropriate use of these new drugs by selected cohorts? We can expect a vigorous discussion of these questions. To support such decisions, we need more information. Of particular interest is whether a direct renal effect limiting progression of nephropathy—beyond that provided by improved control of A1C and blood pressure—can be demonstrated in T1D, and the present studies do not address this question. Also, confirmation of the short-term risk of DKA in T1D reminds us that long-term risks also need further evaluation in both T1D and T2D. As suggested in earlier commentaries, drugs in this class should be prescribed cautiously until longer-term, prospectively collected experience with them is available.” (M. C. Riddle, riddlem@ohsu.edu)
>>>PNN NewsWatch
National Influenza Vaccination Week begins Sunday. Resources are available on the CDC website for health professionals, employers and other vaccine advocates. Data in this week’s MMWR show that 46.7% of adult women in the U.S. received an influenza vaccination in the past 12 months, as did 39.9% of men. Figures increase with age, reaching 67.1% of older adults.
World AIDS Day is observed each year on Dec. 1. Worldwide, 36.9 million people are living with HIV/AIDS, CDC says in an MMWR article published this week, and 940,000 people died from AIDS-related illnesses in 2017. Spread of the virus continues; 1.8 million persons were newly infected in 2017.

PNN Pharmacotherapy Line
Dec. 3, 2018 * Vol. 25, No. 231
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>>>Lancet Highlights
Source:
 Dec. 1 issue of Lancet (2018; 392).
Kinase Inhibition in Immune Diseases: In the first of two studies of filgotinib, the selective Janus kinase 1 (JAK1) inhibitor was effective without new safety signals in patients with active psoriatic arthritis (pp. 2367–77). In Europe, the phase 2 EQUATOR trial randomized patients with moderate-to-severe psoriatic arthritis to filgotinib 200 mg or placebo orally once daily for 16 weeks while they continued one or more conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Results based on 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 were as follows: “Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30.2–59.6], p <0.0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group.” (P. Mease, pmease@philipmease.com)
In the TORTUGA trial, adults filgotinib was efficacious and safe for treatment of active ankylosing spondylitis in adult patients from the same seven European countries as in the EQUATOR trial (
pp. 2378–87). Investigators in the phase 2 trial included patients with active disease with inadequate response or intolerance to two or more NSAIDs. Filgotinib 200 mg or placebo once daily was added to current use of csDMARDs and evaluated based on change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12: “Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n = 58) or placebo (n = 58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was −1.47 (SD 1.04) in the filgotinib group and −0.57 (0.82) in the placebo group, with a least squares mean difference between groups of −0.85 (95% CI −1.17 to −0.53; p <0.0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study.” (D. van der Heijde, mail@dvanderheijde.nl)
>>>PNN JournalWatch
Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association, in Diabetes Care, 2018; 41: 2648–687. (S. Arslanian, silva.arslanian@chp.edu)
Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), in Diabetes Care, 2018; 41: 2669–701. (J. B. Buse, jbuse@med.unc.edu)
Clinical Practice Guideline: Maintenance Intravenous Fluids in Children, in Pediatrics, 2018; 142: 10.1542/peds.2018-3083. (L. G. Feld, feldllc@gmail.com)
Pediatric Considerations Before, During, and After Radiological or Nuclear Emergencies, in Pediatrics, 2018; 142: 10.1542/peds.2018-3000. (J. A. Paulson; AAP Council on Environmental Health)
Improving Depression Outcome by Patient-Centered Medical Management, in American Journal of Psychiatry, 2018; 175: 1187–98. (A. J. Rush)
Perspectives on the Management of Vascular Depression, in American Journal of Psychiatry, 2018; 175: 1169–75. (W. D. Taylor)
Stakeholder Perspectives on the Optimizing Patient Transfers, Impacting Medical Quality, and Improving Symptoms: Transforming Institutional Care (OPTIMISTIC) Project, in Gerontologist, 2018; 58: 1177–87. (M. Ersek, ersekm@upenn.edu)

PNN Pharmacotherapy Line
Dec. 4, 2018 * Vol. 25, No. 232
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-release articles from and Dec. 4 issue of Annals of Internal Medicine (2018; 169).
Drug Use–Associated Infective Endocarditis & Valve Surgeries: In North Carolina from 2007 to 2017, drug use–associated infective endocarditis (DUA-IE) and heart valve surgeries increased by 12-fold, according state hospital data, a likely outcome of the opioid epidemic (10.7326/M18-2124). By the end of the study period, more than half of all IE valve surgeries were in those with DUA-IE, as shown in these results: “Of 22,825 IE hospitalizations, 2,602 (11%) were for DUA-IE. Valve surgery was performed in 1,655 IE hospitalizations (7%), including 285 (17%) for DUA-IE. Annual DUA-IE hospitalizations increased from 0.92 to 10.95 and DUA-IE hospitalizations with surgery from 0.10 to 1.38 per 100,000 persons. In the final year, 42% of IE valve surgeries were performed in patients with DUA-IE. Compared with other surgical patients with IE, those with DUA-IE were younger (median age, 33 vs. 56 years), were more commonly female (47% vs. 33%) and white (89% vs. 63%), and were primarily insured by Medicaid (38%) or uninsured (35%). Hospital stays for DUA-IE were longer (median, 27 vs. 17 days), with higher median charges ($250,994 vs. $198,764). Charges for 282 DUA-IE hospitalizations exceeded $78 million.” (A. J. Schranz, aschranz@med.unc.edu)
“In the midst of the 1930s malaria outbreak [in New York City among people injecting heroin], the population at risk started to cut heroin with quinine to prevent malaria infection,” writes an editorialist (
10.7326/M18-3026). “They saw a threat and developed a strategy to effectively reduce it. The field is open for innovative patient-centered research on how to prevent endocarditis and provide equitable, evidence-based treatment focusing not only on the microbe but on the underlying substance use disorder. Action is urgently needed to understand and improve the cascade of care for persons with DUA-IE.” (A. G. Wurcel, awurcel@tuftsmedicalcenter.org)
Managing Gout: In a patient-focused beyond-the-guidelines review article, authors offer this assessment of gout management (pp. 788–95). “Gout is the most common form of inflammatory arthritis. In 2012, the American College of Rheumatology (ACR) issued a guideline, which was followed in 2017 by one from the American College of Physicians (ACP). The guidelines agree on treating acute gout with a corticosteroid, nonsteroidal anti-inflammatory drug, or colchicine and on not initiating long-term urate-lowering therapy (ULT) for most patients after a first gout attack and in those whose attacks are infrequent (<2 per year). However, they differ on treatment of both recurrent gout and problematic gout. The ACR advocates a ‘treat-to-target’ approach, and the ACP did not find enough evidence to support this approach and offered an alternative strategy that bases intensity of ULT on the goal of avoiding recurrent gout attacks (‘treat-to-avoid-symptoms&rsquoWinking with no monitoring of urate levels. They also disagree on the role of a gout-specific diet. [In this aricle], a general internist and a rheumatologist discuss these guidelines; they debate how they would manage an acute attack of gout, if and when to initiate ULT, and the goals for ULT. Lastly, they offer specific advice for a patient who is uncertain about whether to begin this therapy.” (R. B. Burns, rburns@bidmc.harvard.edu)
Fractional-Dose Yellow Fever Vaccination: A study of fractional doses of yellow fever vaccination shows that people receiving one-fifth the usual dose of the vaccine require no booster shots for 10 years (pp. 761–5). Because of vaccine shortages, fractional doses of 17D yellow fever virus (17D-YFV) vaccine have been used as a vaccine-sparing strategy. Among 155 participants in an original trial showing noninferiority of this approach over 1 year after vaccination, 75 patients participated in a 10-year follow-up study, with these results: “Thirty-nine of 40 (98% [95% CI, 89% to 100%]) participants had protective levels of yellow fever–neutralizing antibodies more than 10 years after receiving a fractional dose of 17D-YFV vaccine compared with 34 of 35 (97% [CI, 87% to 100%]) in the standard-dose group.” (A. H. E. Roukens)
>>>PNN NewsWatch
* At ASHP’s 53rd Midyear Clinical Meeting and Exhibition in Anaheim, Abdul Latif Sheikh, BSPharm, MS, FFIP, President and CEO of the Pakistan Society of Health-System Pharmacists, received the 2018 Donald E. Francke Medal.

PNN Pharmacotherapy Line
Dec. 5, 2018 * Vol. 25, No. 233
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>>>JAMA Report
Source:
 Dec. 4 issue of JAMA (2018; 320).
Vaccines as Integral Components of Cancer Immunotherapy: The “renaissance in immuno-oncology came with the use of [checkpoint inhibitor monoclonal antibody (CIMA) therapy],” write authors of a Viewpoint, the first in a series (pp. 2195–6). “Evidence is emerging demonstrating synergy in the use of cancer vaccines plus CIMAs. Advances in basic immunology and translational immunotherapy are rapidly unravelling the complexity of the immune system and, consequently, agents and strategies are being developed that can be and are being used to increase the efficacy of therapeutic cancer vaccines. As such, the use of vaccines could be considered a necessary, albeit insufficient, component of an effective anticancer therapeutic regimen among patients with low T-cell count tumors.” (J. Schlom, js141c@nih.gov)
“With regulatory approval last year of the first tumor site agnostic drug (immunotherapy for tumors with high microsatellite instability expression), the era in which therapies are dictated by the anatomic site of origin is coming to an end,” editorialists write in describing the “changes, challenges, and opportunities” of “oncology in transition” (
pp. 2203–4). “For the next year, a series of commissioned Viewpoints will explore facets of oncology to help readers understand how the field has arrived at this exciting moment, delineate the challenges ahead, and prioritize what needs to happen to continue progress and ensure that recent discoveries achieve their full potential. Some thought leaders argue that medicine is on a path of drug discovery toward cure or prolonged stability of most cancers, emblemized by substantial progress in immunotherapy; others contend that this is exaggerated or that the cost of this development and resulting care delivery will be untenable.” (E. Basch, ebasch@med.unc.edu)
Anticoagulants, PPIs & Upper GI Bleeds: In patients at high risk of hospitalization for upper gastrointestinal bleeds, selection of anticoagulants and use of PPI cotherapy are important factors. (pp. 2221–30). A study of Medicare beneficiaries showed the following: “During 754,389 person-years of anticoagulation treatment with apixaban, dabigatran, rivaroxaban, and warfarin, the risk of hospitalization for upper gastrointestinal tract bleeding was highest for rivaroxaban [and lowest for apixaban]. The use of PPI cotherapy (264,447 person–years) was associated with a significantly lower overall risk of gastrointestinal bleeding for all anticoagulants (incidence rate ratio, 0.66).” (W. A. Ray, wayne.ray@vanderbilt.edu)
>>>PNN NewsWatch
* Patients in Idaho who are long-term users of opioids commonly have concomitant prescriptions for benzodiazepines, often written by the same prescriber, according to a presentation yesterday at the ASHP Midyear Clinical Meeting in Anaheim. Idaho State researchers (Berain et al.) examined all prescriptions of controlled substances for 301,975 patients reported to the Idaho Prescription Drug Monitoring Program in 2017. One-third of the patients receiving a controlled substance were identified as long-term users, meaning they had taken the drugs for more than 90 days without a break of at least 7 days. Nearly one-quarter of those chronic users were also prescribed a benzodiazepine or other CNS depressants, with 56% of the overlapping prescriptions coming from the same prescriber.
Mylan Pharmaceuticals is expanding its consumer-level voluntary nationwide recall to include all lots of valsartan-containing products within expiry. The 104 additional lots include 26 lots of Amlodipine and Valsartan Tablets, USP, 51 lots of Valsartan Tablets, USP, and 27 lots of Valsartan and Hydrochlorothiazide Tablets, USP. These products are being recalled due to detected trace amounts of the N-nitrosodiethylamine carcinogen contained in Mylan’s API Valsartan, USP.
FDA yesterday recognized the genetic variant information in the Clinical Genome Resource (ClinGen) consortium’s ClinGen Expert Curated Human Genetic Data, funded by NIH to support clinical validity in premarket submissions. The information contained in this open database has been collected and studied by researchers across the world. FDA said this is first time the agency has formally recognized a public database that contains information about genes, genetic variants, and their relationship to disease.

PNN Pharmacotherapy Line
Dec. 6, 2018 * Vol. 25, No. 234
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Dec. 6 New England Journal of Medicine (2018; 379).
Pantoprazole for GI Bleeding Prophylaxis in Critical Care: The utility of PPIs in the ICU is questioned in a 3,282-patient study showing no mortality difference between placebo and pantoprazole for prevention of gastrointestinal bleeding (pp. 2199–208). The European study provides these results for I.V. pantoprazole 40 mg daily using a primary outcome of 90-day mortality: “At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P = 0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.” (A. Perner, anders.perner@regionh.dk)
“The take-home message from this trial is that, given the low incidence of clinically important upper gastrointestinal bleeding in the ICU, prophylaxis with a PPI, if initiated, should be reserved for seriously ill patients who are at high risk for this complication,” editorialists conclude (
pp. 2263–4). “Although 90-day mortality was not affected by pantoprazole administration in the current trial, the between-group difference in the rate of important upper gastrointestinal bleeding may still support the recommendation of using a prophylactic PPI, particularly given the absence of a difference in the rate of adverse events between the pantoprazole group and the placebo group. We base this view mainly on the admittedly small (1.7-percentage-point) difference in bleeding rates between the groups. Additional data are needed to determine the clinical effects of prophylaxis for gastrointestinal bleeding in the ICU, especially in groups of patients who are at very high risk for this complication, and to quantify any protective or harmful effects attributable to the coadministration of enteral nutrition.” (A. Barkun)
Interstitial Lung Disease in Rheumatoid Arthritis: Reacting to a study showing a strong genetic association between rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) and a gain-of-function promoter variant seen in patients with idiopathic pulmonary fibrosis (pp. 2209–19; D. A. Schwartz, david.schwartz@ucdenver.edu), editorialists provide these insights (pp. 2265–6). “The strong association of the MUC5B promoter variant with ILD in patients with RA raises the question of whether all patients with RA should be evaluated for MUC5B carrier status. This will be most appropriate when early detection can mandate preventive or effective therapies. On the other hand, once clinical disease is present, MUC5B genotyping might provide information on prognosis and, as understanding of pathogenesis improves, may guide management. Overall, [these results] support the concept that genetics really can add to our understanding of disease heterogeneity, and the results provide hope that this approach will lead to further insights in the future.” (P. K. Gregersen)
Politics & Pandemics: Marking the 100th anniversary of the influenza pandemic of 1918, the Obama administration Ebola czar notes that Spanish flu “killed more Americans than World Wars I and II combined” (pp. 2191–3). Reviewing current trends that pose threats to an effective response to pandemics (isolationism and xenophobia, antiscientific thinking and resistance to evidence-based medicine, disease-related dangers of climate change), the Viewpoint author suggests a health professional response: “Now, we need the medical community to take on the criticism and controversy, the unpleasantness and attacks, and to step into the halls of Congress, the offices of the executive branch, and the public arena in order to win passage of key policies and to confront the social and political trends that are making global health less secure. The men and women of this community are in a position to help make us all safer by wading into difficult and divisive issues that are undermining our global capacity to face down a future pandemic.” (R. Klain)

PNN Pharmacotherapy Line
Dec. 7, 2018 * Vol. 25, No. 235
Providing news and information about medications and their proper use

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>>>Psychiatry Report
Source:
 Dec. issue of the American Journal of Psychiatry (2018; 175).
Opioid Effects in Antidepressant Effects of Ketamine: In a study terminated at the interim analysis, researchers show that the rapid antidepressant effects of ketamine require opioid system activation but that the dissociative effects of the drug are not mediated by the opioid system (pp. 1205–15). The planned study of 30 adults with treatment-resistant depression had treated 12 participants in crossover fashion with both placebo and naltrexone 50 mg preceding an intravenous infusion of ketamine 0.5 mg/kg at termination. Results showed: “In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item [Hamilton Depression Rating Scale] scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.” (N. R. Williams)
“Clearly, more work is needed to understand ketamine’s antidepressant effects and its mechanisms,” writes an editorialist (
pp. 1157–8). Referring to the three current “epidemics” of opioid dependence, depression, and suicide, the author concludes: “In Greek mythology, several monsters had multiple heads. If you cut off one of the Hydra’s heads, it grew back, and sometimes more than one. We would hate to treat the depression and suicide epidemics by overusing ketamine, which might perhaps unintentionally grow the third head of opioid dependence. With these new findings, we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form. If ketamine does indirectly activate opioid receptors, it could even have positive effects in approaching the opioid as well as the other epidemics. In any case, we need to better understand ketamine’s mode of action and how it should best be used and administered.” (M. S. George, georgem@musc.edu)
Prazosin for Alcohol Use Disorder: Seeking to confirm positive results of a preliminary study, investigators show that “prazosin holds promise as a harm-reduction pharmacologic treatment for alcohol use disorder and deserves further evaluation by independent research groups” (pp. 1216–24). Among 80 participants with alcohol use disorder and without posttraumatic stress disorder, titrated doses of prazosin or placebo had these effects in a 12-week trial: “There was a significant interaction between condition and week for both number of drinks and number of heavy drinking days, such that the rate of drinking and the probability of heavy drinking showed a greater decrease over time for participants in the prazosin condition compared with those in the placebo condition. Participants in the prazosin condition were more likely to report drowsiness and edema than participants in the placebo condition.” (T. L. Simpson)
While prior work has shown prazosin and other alpha-1 adrenergic agents to be possibly beneficial in management of alcohol use disoder, the moderate effect size and some mixed findings indicate a need to identify and test “key moderators of the positive effect,” an editorialist writes (
pp. 1159–60): “It appears that individuals with alcohol use disorder who have withdrawal-related alcohol intake may be those likely to benefit the most from prazosin treatment. Further testing and development of this key moderator could enhance personalized-medicine approaches in the treatment of alcohol use disorders.” (R. Sinha)
>>>PNN NewsWatch
* Despite improvements, one in four nonsmokers in the U.S. continues to be exposed to secondhand smoke, an MMWR article reports (pp. 1342–6; J.Tsai, jxt9@cdc.gov). Disparities are also evident, with 14.0 million children aged 3–11 years exposed, including about two-thirds of non-Hispanic black children, 40% of non-Hispanic white kids, and 20% of Hispanic children.

PNN Pharmacotherapy Line
Dec. 10, 2018 * Vol. 25, No. 236
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>>>Lancet Highlights
Source:
 Dec. 8 issue of Lancet (2018; 392).
Ixekizumab in Ankylosing Spondylitis: In 341 patients with ankylosing spondylitis not previously treated with biological disease-modifying anti-rheumatic drugs (bDMARDs), the high-affinity interleukin-17A (IL-17A) monoclonal antibody ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms, researchers report (pp. 2441–51). The phase 3 superiority study of patients with inadequate response to or intolerance of NSAIDs produced these results using every 2- or 4-week doses of ixekizumab, active comparator (adalimumab every 2 weeks), or placebo: “At week 16, compared with placebo (16 [18%] of 87), more patients achieved [40% improvement in Assessment of SpondyloArthritis international Society (ASAS) criteria] with ixekizumab Q2W (43 [52%] of 83; p <0.0001), ixekizumab Q4W (39 [48%] of 81; p <0.0001), and adalimumab (32 [36%] of 90; p = 0.0053). One serious infection occurred in each of the ixekizumab Q2W (1%), ixekizumab Q4W (1%), and adalimumab (1%) groups; none were reported with placebo. One (1%) Candida infection occurred in the adalimumab group and one (1%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn’s disease. No treatment-emergent opportunistic infections, malignancies, or deaths occurred.” (D. van der Heijde, mail@dvanderheijde.nl)
Health & Climate Change: As the United Nations’ Katowice Climate Change Conference opens in Poland, Lancet publishes in print form its 2018 health and climate change countdown report (pp. 2479–514). Assessment of effects of climate change on health-related factors such as extreme weather events and vector- and water-borne diseases led to these key messages (N. Watts, nicholas.watts@ucl.ac.uk):
* “Present day changes in heat waves, labour capacity, vector-borne disease, and food security provide early warning of the compounded and overwhelming impact on public health that are expected if temperatures continue to rise. Trends in climate change impacts, exposures, and vulnerabilities show an unacceptably high level of risk….”
* “A lack of progress in reducing emissions and building adaptive capacity threatens both human lives and the viability of the national health systems they depend on, with the potential to disrupt core public health infrastructure and overwhelm health services.”
* “Despite these delays, a number of sectors have seen the beginning of a low-carbon transition, and it is clear that the nature and scale of the response to climate change will be the determining factor in shaping the health of nations for centuries to come.”
* “Ensuring a widespread understanding of climate change as a central public health issue will be crucial in delivering an accelerated response, with the health profession beginning to rise to this challenge.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 362).
Incretin-Based Drugs & Cholangiocarcinoma: Increased risk of cholangiocarcinoma in adults with type 2 diabetes taking incretin-based drugs is evident in a population-based cohort study from the U.K. (k4880): “During 614,274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100,000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively).” (L. Azoulay, laurent.azoulay@mcgill.ca)
>>>PNN JournalWatch
Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine, in American Journal of Psychiatry, 2018; 175: 1225–31. (L. S. Cohen )
Bacterial Vaginosis and Desquamative Inflammatory Vaginitis, in New England Journal of Medicine, 2018; 379: 2246–54. (J. Paavonen, jorma.paavonen@hus.fi)
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