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

Click here for a PDF of this issue.

>>>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.