Jun 2018

PNN April–June 2018

PNN Pharmacotherapy Line
Apr. 2, 2018 * Vol. 25, No. 63
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Mar. 31 issue of Lancet (2018; 391).
Duration of Dual Antiplatelet Therapy After PCI in ACS: Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor for at least 12 months should remain the standard of care after implantation of drug-eluting stents (DES) in patients with acute coronary syndrome, SMART-DATE investigators conclude based on a comparison with 6-month regimens (pp. 1274–84). “The increased risk of myocardial infarction with 6-month DAPT and the wide non-inferiority margin prevent us from concluding that short-term DAPT is safe in patients with acute coronary syndrome undergoing percutaneous coronary intervention with current-generation DES,” the group concludes. (H-C Gwon, hcgwon@naver.com)
Siponimod in MS: In a phase 3 trial conducted in 31 countries, the selective sphingosine 1-phosphate receptor1,5 modulator siponimod reduced the risk of disability in patients with secondary progressive multiple sclerosis and had a safety profile similar to other agents in this class (pp. 1263–73). Participants assigned to active therapy had significantly fewer events indicating disease progression, compared with placebo, and serious adverse events were reported in 18% of those on siponimod and 15% of patients on placebo. (L. Kappos, ludwig.kappos@usb.ch)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 360).
Antipsychotics & In-Hospital Mortality Risk in AMI: Patients admitted to U.S. hospitals for acute myocardial infarction had a small increased risk of death within 7 days when they were started on oral haloperidol rather than oral second-generation antipsychotics, according to a cohort study (k1218). National data from 700 hospitals for medical adult patients showed these risk patterns: “Among 6,578 patients (mean age 75.2 years) treated with an oral antipsychotic drug, 1,668 (25.4%) initiated haloperidol and 4,910 (74.6%) initiated atypical antipsychotics. The mean time from admission to start of treatment (5.3 v 5.6 days) and length of stay (12.5 v 13.6 days) were similar, but the mean treatment duration was shorter in patients using haloperidol compared with those using atypical antipsychotics (2.4 v 3.9 days). 1:1 propensity score matching was used to adjust for confounding. In intention to treat analyses with the matched cohort, the absolute rate of death per 100 person days was 1.7 for haloperidol (129 deaths) and 1.1 for atypical antipsychotics (92 deaths) during seven days of follow-up from treatment initiation. The survival probability was 0.93 in patients using haloperidol and 0.94 in those using atypical antipsychotics at day 7, accounting for the loss of follow-up due to hospital discharge.” (Y. Park, yypark@mail.harvard.edu)
>>>PNN NewsWatch
* Enhancing “the patient perspective and experience in drug development and review” is the goal of an update to FDA’s benefit–risk framework document, FDA Commissioner Scott Gottlieb, MD, said on Friday. “The goal of the FDA’s Benefit-Risk Framework is to improve the clarity and consistency in communicating the reasoning behind drug regulatory decisions, and ensure that the FDA reviewers’ detailed assessments can be readily understood in the broader context of patient care and public health,” he wrote. “The structured framework also helps drug sponsors and other external stakeholders better understand the factors that contribute to the FDA’s decision-making process when evaluating new drugs, including drugs under development. A standard Benefit-Risk Framework will also better ensure that the patient community can continue to engage effectively with the agency, and help us improve how we evaluate benefits and risks from the patient’s perspective.”
>>>PNN JournalWatch
Estimates of Global Seasonal Influenza-Associated Respiratory Mortality: A Modelling Study, in Lancet, 2018; 391: 1285–300. (A. D. Iuliano, aiuliano@cdc.gov)
Current Challenges and Opportunities in the Prevention and Management of Diabetic Foot Ulcers, in Diabetes Care, 2018; 41: 645–52. (W. J. Jeffcoate, william.jeffcoate@gmail.com)
Treatment for Patients With a Functional Neurological Disorder (Conversion Disorder): An Integrated Approach, in American Journal of Psychiatry, 2018; 175: 307–14. (M A. O’Neal)

PNN Pharmacotherapy Line
Apr. 3, 2018 * Vol. 25, No. 64
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Apr. 3 issue of Annals of Internal Medicine (2018; 168).
Second-Line Nilotinib in Chronic Myeloid Leukemia: Administered to adults with chronic myeloid leukemia (CML) in chronic phase after 3 or more years of tyrosine kinase inhibitor (TKI) therapy, nilotinib produced treatment-free remission (TFR) in substantial proportions of patients (pp. 461–70). Participants had achieved sustained MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]). Results based on loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) were as follows: “163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation.” (T. P. Hughes, tim.hughes@sahmri.com)
Prophylaxis of Postoperative Delirium: A psychiatrist and a geriatrician debate whether a 79-year-old man with a history of delirium after surgery should be given prophylactic antipsychotics before undergoing knee replacement surgery (pp. 498–505). The patient had a history of diabetes, high cholesterol, hypertension, obesity, prostate cancer, renal cell carcinoma, obstructive sleep apnea, atrial fibrillation, and several other chronic conditions. The patient was hesitant to undergo a needed knee replacement surgery because of a frightening episode of delirium that included confusion following a previous surgery. 
The psychiatrist argued that because of the patient’s many risk factors, he was likely to become delirious after another surgery, even with relatively minor stressors. He suggested that the best way to prevent delirium would be to not do the surgery at all. But if that was not an option, the psychiatrist suggested a low-dose antipsychotic before surgery. The geriatrician maintained that nonpharmacologic measures are the most important tools for prevention and treatment. Rather than prescribing medication, she would recommend that a family member or friend stay at the patient’s bedside to offer a reassuring presence. She also suggested a focus on addressing modifiable risk factors that could contribute to delirium before surgery. (A. V. Tess, 
atess@bidmc.harvard.edu)
Hot Tea Interaction With Alcohol, Tobacco: In a prospective cohort study conducted in China, consumption of high-temperature hot tea was associated with increased risk of esophageal cancer when combined with excessive alcohol or tobacco use (pp. 489–97). Data on 456,155 adults aged 30 to 79 years in the China Kadoorie Biobank showed these risks of esophageal cancer through 2015: “During a median follow-up of 9.2 years, 1,731 incident esophageal cancer cases were documented. High-temperature tea drinking combined with either alcohol consumption or smoking was associated with a greater risk for esophageal cancer than hot tea drinking alone. Compared with participants who drank tea less than weekly and consumed fewer than 15 g of alcohol daily, those who drank burning-hot tea and 15 g or more of alcohol daily had the greatest risk for esophageal cancer (hazard ratio [HR], 5.00 [95% CI, 3.64 to 6.88]). Likewise, the HR for current smokers who drank burning-hot tea daily was 2.03 (CI, 1.55 to 2.67).” (J. Lv, lvjun@bjmu.edu.cn)
CEA of PCSK9 Inhibitors: Outcomes-based pricing (such as money-back guarantees) are less relevant for preventive medicines, according to a research brief that assessed PCSK9 inhibitors (10.7326/M17-3367). Low event rates and long duration of treatment, connecting events with drug failure, and changes in insurance make attribution of drug effects difficult. (D. S. Kazi)
>>>PNN NewsWatch
MarcasUSA and Industria Farmacéutica Andromaco, S.A. de C.V. voluntarily recalled four lots of the OTC product Pasta De Lassar Andromaco Skin Protectant, 25% zinc oxide, to the retail level because of contamination with high levels of yeast, mold, and bacteria.

PNN Pharmacotherapy Line
Apr. 4, 2018 * Vol. 25, No. 65
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 3 issue of JAMA (2018; 319).
Atorvastatin Loading Doses Before Planned PCI: In the SECURE-PCI trial of patients with acute coronary syndrome (ACS), the 30-day rate of major adverse cardiovascular events (MACE) was not affected by use of loading doses of atorvastatin before planned interventions, investigators write (pp. 1331–40). The randomized, placebo-controlled trial evaluated 4,191 patients in Brazil who were undergoing planned percutaneous coronary intervention (PCI). Two loading doses of atorvastatin 80 mg administered before and 24 hours after PCI produced these results based on a composite rate of 30-day MACE (all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization): “Among the 4,191 patients (mean age, 61.8 [SD, 11.5] years; 1,085 women [25.9%]) enrolled, 4,163 (99.3%) completed 30-day follow-up. A total of 2,710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1,144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, −0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69–1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group.” (O. Berwanger, tavioberwanger@gmail.com">otavioberwanger@gmail.com)
“Treatment guidelines already suggest that such patients should receive high-intensity statin therapy and that routine in-hospital initiation is likely to be of benefit for both prevention of subsequent cardiovascular events and increased long-term adherence to statin therapy, which is a cornerstone of secondary prevention,” editorialists write (
pp. 1325–6). “Whether such therapy should be administered as soon as possible in the ACS hospitalization remains to be fully elucidated. SECURE-PCI certainly provides reassurance that such early administration is not associated with harm. The subgroup findings suggest potential benefit among patients who are deemed more likely to undergo PCI at the time of angiography. To what degree such findings may be exclusive to intensive statin therapy, or whether similar results would be observed with early initiation of additional lipid-lowering agents, some of which do not appear to have pleiotropic effects in humans, is unknown. While a generation of lipid-lowering studies has supported the concept ‘the lower and longer, the better’ and, in ACS patients, ‘early is good’ it remains to be established whether this concept will evolve to ‘the earlier, the lower, and the longer, the better.’ Only sufficiently large clinical trials may provide such answers.” (S. J. Nicholls, stephen.nicholls@sahmri.com)
Neonatal Abstinence Syndrome: Nonpharmacologic approaches to management of neonatal abstinence syndrome are reducing the need for pharmacotherapy, authors of a review article report (pp. 1362–74): “The most substantial number of studies of neonatal abstinence syndrome management pertain to nonpharmacologic care—specifically, interventions that promote breastfeeding or encourage parents to room-in with their newborns. Although these nonpharmacologic interventions appear to decrease the need for pharmacologic treatment and result in shorter hospitalizations, the interventions are heterogeneous and there are no high-quality clinical trials to support them. Regarding pharmacologic interventions, only 5 randomized clinical trials with prespecified sample size calculations (4 infant, 1 maternal treatment) have been published. Each of these trials was small (from 26 to 131 participants) and tested different therapies, limiting the extent to which results can be aggregated. There is insufficient evidence to support an association between any diagnostic or treatment approach and differential neurodevelopmental outcomes among infants with neonatal abstinence syndrome.” (E. M. Wachman, elisha.wachman@bmc.org)
>>>PNN NewsWatch
FDA yesterday announced it has issued a mandatory recall order for all food products containing powdered kratom manufactured, processed, packed, or held by Triangle Pharmanaturals after several were found to contain Salmonella. The agency said it took this action — the first mandatory recall of a contaminated food product — after the company failed to cooperate with FDA’s request for a voluntary recall.

PNN Pharmacotherapy Line
Apr. 5, 2018 * Vol. 25, No. 66
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 5 issue of the New England Journal of Medicine (2018; 378).
Pharmacist Care of Hypertension in Black Barbershops: Combining the health-promotion skills of barbers with the clinical acumen of pharmacists proved an effective formula for reducing elevated blood pressures in a population of patrons of black-owned barbershops (pp. 1291–301). Using a cluster-randomized design at 52 barbershops, non-Hispanic black men with systolic blood pressures of 140 mm Hg or more were assigned to a pharmacist-led intervention (in which barbers encouraged meetings in barbershops with specialty-trained pharmacists who prescribed drug therapy under a collaborative practice agreement with the participants’ doctors) or to an active control approach (in which barbers encouraged lifestyle modification and doctor appointments). Results based on a primary outcome of reduction in systolic blood pressure at 6 months showed the following: “At baseline, the mean systolic blood pressure was 152.8 mm Hg in the intervention group and 154.6 mm Hg in the control group. At 6 months, the mean systolic blood pressure fell by 27.0 mm Hg (to 125.8 mm Hg) in the intervention group and by 9.3 mm Hg (to 145.4 mm Hg) in the control group; the mean reduction was 21.6 mm Hg greater with the intervention (95% confidence interval, 14.7 to 28.4; P <0.001). A blood-pressure level of less than 130/80 mm Hg was achieved among 63.6% of the participants in the intervention group versus 11.7% of the participants in the control group (P <0.001). In the intervention group, the rate of cohort retention was 95%, and there were few adverse events (three cases of acute kidney injury).” (R. G. Victor, ronald.victor@cshs.org)
Essential elements in the pharmacist intervention factored into the “substantial blood-pressure improvement [observed] in this challenging population,” an editorialist writes (
pp. 1345–7): “First, the pharmacists had direct prescribing authority and used a highly effective antihypertensive protocol that started with evidence-based dual therapy. Most men were treated initially with a dihydropyridine calcium-channel blocker combined with either an angiotensin-converting–enzyme inhibitor or angiotensin-receptor blocker. The next treatment step added a thiazide diuretic, followed by an aldosterone antagonist if a fourth drug was needed. Second, pharmacists had frequent contact with the participants during the 6-month trial period — face-to-face visits occurred about once per month, plus four outbound telephone calls from pharmacists were made and six additional inbound messages or calls from participants were received. Third, treatment was intensified until a target 5 mm Hg lower than the usual goal for out-of-office blood pressure was attained (130/80 mm Hg, as compared with 135/85 mm Hg). At the end of the 6-month trial period, participants in the intervention group were receiving a mean of 2.6 medications, as compared with 1.4 in the control group.” (K. L. Margolis)
Checkpoint Inhibition in Renal-Cell Cancer: “Although the precise mechanics of tumor regression or control with T-cell checkpoint antibodies is not fully understood, there is a consensus that antitumor effects are mediated through enhanced survival and cytotoxic activity of CD8 T cells that have already recognized tumor-associated antigens before checkpoint immunotherapy,” an editorialist writes (pp. 1344–5) in response to a phase 3 trial showing significantly higher overall survival and objective response rates with nivolumab plus ipilimumab for previously untreated clear-cell advanced renal-cell carcinoma, compared with sunitinib (pp. 1277–90; R. J. Motzer, motzerr@mskcc.org). “Decreasing the activity of regulatory T cells with the use of anti–CTLA-4 may also account for the difference in activity between ipilimumab and nivolumab in combination and nivolumab monotherapy in some patients. It is notable that tumors with a greater number of mutations appear more likely to have a response to checkpoint immunotherapy. This suggests that there may be a higher tumor mutational load and a broad, though ineffective, extant adaptive immune response in patients with intermediate- and poor-risk renal-cell carcinoma as compared with patients with favorable-risk disease.” (B. D. Curti)

PNN Pharmacotherapy Line
Apr. 6, 2018 * Vol. 25, No. 67
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
 Apr. issue of the American Journal of Psychiatry (2018; 175).
Ketamine for Suicidal Ideation in Major Depression: Compared with midazolam infusion, adjunctive subanesthetic intravenous ketamine produced significant reductions in clinically significant suicidal ideation in depressed patients within 24 hours (pp. 327–35). Study participants were 80 adults with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI); 54% of patients were taking antidepressant medication. Results in the 24 hours after infusion showed the following: “The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI = 2.33, 7.59; Cohen’s d = 0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio = 2.85, 95% CI = 1.14, 7.15; number needed to treat = 4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate = 7.65, 95% CI = 1.36, 13.94), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.” (M. F. Grunebaum)
Hormonal Contraception & Suicide Attempts/Suicides: A nationwide prospective cohort study of all women in Denmark shows an association between use of hormonal contraception and suicide attempt and suicide, particularly in adolescents, researchers report (pp. 336–42). The study began in 1996 and included women who turned 15 during the study period, which ended in 2013. Those included in the analysis had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15. Results showed: “Among nearly half a million women followed on average for 8.3 years (3.9 million person–years) with a mean age of 21 years, 6,999 first suicide attempts and 71 suicides were identified. Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI = 1.85–2.10) for suicide attempt and 3.08 (95% CI = 1.34–7.08) for suicide. Risk estimates for suicide attempt were 1.91 (95% CI = 1.79–2.03) for oral combined products, 2.29 (95% CI = 1.77–2.95) for oral progestin-only products, 2.58 (95% CI = 2.06–3.22) for vaginal ring, and 3.28 (95% CI = 2.08–5.16) for patch. The association between hormonal contraceptive use and a first suicide attempt peaked after 2 months of use.” (C. W. Skovlund)
>>>Pediatrics Highlights
Source:
 Apr. issue of Pediatrics (2018; 141).
Influenza-Associated Pediatric Deaths: Half of American children who die from influenza have no pre-existing medical conditions, an analysis shows (10.1542/peds.2017-2918). In the 2010–11 through 2015–16 influenza seasons, the 675 children younger than 18 years whose deaths were associated with influenza showed these demographic and clinical patterns: “The median age was 6 years (interquartile range: 2–12). The average annual incidence was 0.15 per 100,000 children (95% confidence interval: 0.14–0.16) and was highest among children aged <6 months (incidence: 0.66; 95% confidence interval: 0.53–0.82), followed by children aged 6–23 months (incidence: 0.33; 95% confidence interval: 0.27–0.39). Only 31% (n = 149 of 477) of children aged ≥6 months had received any influenza vaccination. Overall, 65% (n = 410 of 628) of children died within 7 days after symptom onset. Half of the children (n = 327 of 654) had no preexisting medical conditions. Compared with children with preexisting medical conditions, children with none were younger (median: 5 vs 8 years old), less vaccinated (27% vs 36%), more likely to die before hospital admission (77% vs 48%), and had a shorter illness duration (4 vs 7 days; P < .05 for all).” (A. M. Fry, afry@cdc.gov)
Opioid-Related Pediatric ICU Admissions: Critical care admissions for opioid ingestions increased during 2004 to 2015 in U.S. children’s hospitals, a study shows (10.1542/peds.2017-3335): “Current efforts to reduce adult opioid use have not curtailed the incidence of pediatric opioid ingestions, and additional efforts are needed to reduce preventable opioid exposure in children.”(J. M. Kane, jasonk@uchicago.edu)

PNN Pharmacotherapy Line
Apr. 9, 2018 * Vol. 25, No. 68
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 360).
Switchbacks With Authorized v. Other Generic Drugs: An observational cohort analysis of private and public health plans in the U.S. shows that rates of switchbacks were lower among those switched from branded to authorized generic products rather than to other generic drug products (k1180). The study included a primary cohort of beneficiaries of a large commercial insurer from 2004 to 2013 and a replication cohort of Medicaid beneficiaries for 2000–10. Those taking branded alendronate tablets, amlodipine tablets, amlodipine–benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets had these switchback rates following substitution using authorized generics or generic drug products: “A total of 94,909 patients switched from branded to authorized generic drug products and 116,017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine–benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort.” (R. Desai, rdesai@bwh.harvard.edu)
>>>Lancet Highlights
Source:
 Apr. 7 issue of Lancet (2018; 391).
Antidepressants in Acute Treatment of Major Depression: Based on a systematic review and network meta-analysis of 21 antidepressants in acute treatment of adult patients with major depressive disorder, investigators conclude that all are more effective than placebo (pp. 1357–66). “Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials,” the group writes of the 522 trials with 116,477 participants. “These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.” (A. Cipriani, andrea.cipriani@psych.ox.ac.uk)
Initial & Repeated Treatment of Uncomplicated Malaria: In a phase 3b/4 trial of adults and children aged 6 months or older in Guinea and Mali being treated or retreated for malaria, pyronaridine–artesunate and dihydroartemisinin–piperaquine were well tolerated and exhibited efficacy noninferior to that of first-line artemisinin-based combination therapies, researchers report (pp. 1378–90). “Greater access to these efficacious treatments in west Africa is justified,” the authors conclude. (A. A. Djimde, adjimde@icermali.org)
>>>PNN JournalWatch
Reduced Mortality With Sodium-Glucose Cotransporter–2 Inhibitors in Observational Studies: Avoiding Immortal Time Bias, in Circulation, 2018: 137: 1432–4. (S. Suissa)
The Therapeutic Potential of Hyaluronan in COPD, in Chest, 2018: 153: 792–8. (G. M. Turino, gmt1@columbia.edu)
* Should an Attempt Be Made to Withdraw Inhaled Corticosteroids in All Patients With Stable GOLD 3 (30% ≤ FEV1 < 50% Predicted) COPD? — 
Yes (J. D. Chalmers, jchalmers@dundee.ac.uk); No (I. D. Pavord, ian.pavord@ndm.ox.ac.uk), in Chest, 2018: 153: 778–82 and 782–4.
Respiratory Syncytial Virus and Associations With Cardiovascular Disease in Adults, in Journal of the American College of Cardiology, 2018: 71: 1574–83. (K. S. Ivey)
A Changing Landscape in Cardiovascular Research Publication Output: Bridging the Translational Gap, in Journal of the American College of Cardiology, 2018: 71: 1584–9. (K. R. Sipido, karin.sipido@kuleuven.be)
Squaring the Curve of Cardiovascular Health From the Beginning of Life, in Pediatrics, 2018: 141:10.1542/peds.2017-2075. (A. M. Perak)
Hormonal Treatment in Young People With Gender Dysphoria: A Systematic Review, in Pediatrics, 2018: 141: 10.1542/peds.2017-3742. (D. Chew)
The Role of the Microbiome in the Developmental Origins of Health and Disease, in Pediatrics, 2018: 141: 10.1542/peds.2017-2437. (L. T. Stiemsma)

PNN Pharmacotherapy Line
Apr. 10, 2018 * Vol. 25, No. 69
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online articles from and Apr. issue of JAMA Internal Medicine (2018; 178).
Cardiovascular Safety of Smoking Cessation Medications: In the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) and an extension trial, pharmacotherapies for smoking cessation were not associated with increased risk of major adverse cardiovascular events (MACE, cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) (10.1001/jamainternmed.2018.0397). The study assessed effects of varenicline 1 mg twice daily; bupropion hydrochloride 150 mg twice daily; and nicotine replacement therapy 21-mg/d patch with tapering. Among participants at 140 multinational centers, the agents produced these outcomes based on time to development of MACE: “Of the 8,058 participants, 3,553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05–1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10–2.50).” (N. L. Benowitz, neal.benowitz@ucsf.edu)
Industry Payments & Oncologists’ Drug Choices: Oncologists who received industry payments were more likely to prescribe the company’s products for targeted cancer care in an analysis that links Medicare Part D prescriptions for Medicare beneficiaries with CMS Open Payments data (10.1001/jamainternmed.2018.0776). Open Payments include both general payments such as gifts and consultancy/speaker fees and research monies. Agents for metastatic renal cell cancer (mRCC) and chronic myeloid leukemia (CML) were examined, with these results: “Among 354 physicians who prescribed mRCC drugs and 2,225 physicians who prescribed CML drugs, we found increased odds of prescribing a manufacturer’s drug among physicians receiving general payments only or either payment type. Of physicians prescribing the drugs, 9.0% (32 of 354) of those prescribing for mRCC and 3.8% (38 of 2,225) of those prescribing for CML received research payments in both 2013 and 2014, compared with 25.1% (89 of 354) and 39.5% (879 of 2,225) for general payments, respectively. Receipt of research payments was associated with increased prescribing for mRCC but not CML. Similarly, when treating payments as a continuous variable, increasing amounts of general payments were associated with increased prescribing.” (S. B. Dusetzina, s.dusetzina@vanderbilt.edu)
Antituberculosis Therapy Dosing in Patients With HIV: A daily antitubercular drug dosing regimen produced results superior to those with thrice-weekly dosing among a group of patients with HIV infections who were being treated for pulmonary tuberculosis (TB) (pp. 485–93). Using direct observed therapy on weekdays, investigators found these results for daily, part daily (daily during initiation and intermittent during continuation), and intermittent (three times weekly throughout) dosing: “Favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O’Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. Six, 4, and 6 patients in the daily, part-daily, and intermittent regimens, respectively, had TB recurrence.” (S. Swaminathan, doctorsoumya@yahoo.com)
>>>PNN NewsWatch
FDA yesterday restricted sales of the Essure contraceptive implant to physicians and health facilities that use the FDA-approved “Patient-Doctor Discussion Checklist – Acceptance of Risk and Informed Decision Acknowledgment.” Sale and distribution of Bayer product is limited to health providers who agree to review this checklist with patients and give them the opportunity to sign it before Essure implantation. FDA said it has approved this new safety measure to ensure that the device meets standards for a reasonable assurance of safety and effectiveness.

PNN Pharmacotherapy Line
Apr. 11, 2018 * Vol. 25, No. 70
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 10 issue of JAMA (2018; 319).
Pharmacotherapy of Persistent Asthma: In systematic reviews and meta-analyses prepared by PharmD-heavy author teams, efficacy and safety of combinations of antiasthmatic drugs are examined in patients with persistent asthma.
In 15 trials of 7,122 patients with uncontrolled, persistent asthma, long-acting muscarinic antagonists (LAMAs) were more effective than placebo as add-on therapy to inhaled corticosteroids, but benefits with LAMAs was similar to those of long-acting beta-agonists (LABAs) (
pp. 1473–84): “Adding LAMA vs placebo to inhaled corticosteroids was associated with a significantly reduced risk of exacerbation requiring systemic corticosteroids (RR, 0.67 [95% CI, 0.48 to 0.92]; [risk differences (RD)], −0.02 [95% CI, −0.04 to 0.00]). Compared with adding LABA, adding LAMA to inhaled corticosteroids was not associated with significant improvements in exacerbation risk (RR, 0.87 [95% CI, 0.53 to 1.42]; RD, 0.00 [95% CI, −0.02 to 0.02]), or any other outcomes of interest. Triple therapy was not significantly associated with improved exacerbation risk vs inhaled corticosteroids and LABA (RR, 0.84 [95% CI, 0.57 to 1.22]; RD, −0.01 [95% CI, −0.08 to 0.07]).” (D. M. Sobieraj, diana.sobieraj@uconn.edu)
Single maintenance and reliever therapy (SMART) using inhaled corticosteroids plus LABAs was associated with a lower risk of asthma exacerbations in patients with persistent asthma, according to results of the second systematic review and meta-analysis (
pp. 1485–96): “The analyses included 16 randomized clinical trials (N = 22,748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22,524; mean age, 42 years; 14,634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, −6.4% [95% CI, −10.2% to −2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, −2.8% [95% CI, −5.2% to −0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4–11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, −12.0% [95% CI, −22.5% to −1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, −23.2% [95% CI, −33.6% to −12.1%]).” (W. L. Baker, william.baker_jr@uconn.edu)
The results of both of these analyses highlight the pressing need for an update to the 2007 Expert Panel Report 3 (EPR-3), editorialists write (
pp. 1441–3). “More challenging are the next steps given the evidence about SMART presented in the second meta-analysis…. Although the EPR-3 guidelines should also be updated to reflect the evidence supporting the use of SMART, the dry-powder inhaler device for combination formoterol and budesonide is not currently approved by the FDA. It is possible that SMART was more effective than scheduled doses of inhaled corticosteroids and LABA because of a faster onset of action from formoterol; however, the beneficial effects could also be specific to the inhaler device. Dry-powder and metered-dose inhaler devices require different techniques that could contribute to different types of errors in inhaler use, differences in drug deposition in the airways, and different clinical outcomes. Thus, the efficacy and safety of medications using one type of inhaler device should not be presumed to be equally efficacious using another device. Studies assessing the efficacy of SMART using combination formoterol and budesonide via a metered-dose inhaler are needed.” (J. A. Krishnan, jakris@uic.edu)
>>>PNN NewsWatch
* Club 13 is recalling several kratom formulations marketed as Maeng Da Red Powder and Capsules. The products were distributed to retail stores and through mail orders nationwide and are recalled because of possible contamination with Salmonella.

PNN Pharmacotherapy Line
Apr. 12, 2018 * Vol. 25, No. 71
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 12 New England Journal of Medicine (2018; 378).
Genetics & Pathogenesis of Diffuse Large B-Cell Lymphoma: Precision-medicine strategies for diffuse large B-cell lymphomas (DLBCLs) are conceivable based on genetic subtypes identified in an analysis of 574 biopsy samples (pp. 1396–407). Investigators conclude the findings could provide “a potential nosology for precision-medicine strategies in DLBCL.” Exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes found these genes with recurrent aberrations: “We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on ‘chronic active’ B-cell receptor signaling that is amenable to therapeutic inhibition.” (L. M. Staudt, lstaudt@mail.nih.gov)
Apalutamide in Prostate Cancer: An androgen inhibitor, apalutamide extended metastasis-free survival and time to symptomatic progression among men with nonmetastatic castration-resistant prostate cancer, researchers report (pp. 1408–18). Phase 3 trial participants were randomized to apalutamide 240 mg/d or placebo; all continued androgen-deprivation therapy. Results based on a primary end point of metastasis-free survival showed the following: “A total of 1,207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P <0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P <0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).” (M. R. Smith, smith.matthew@mgh.harvard.edu)
FDA Breakthrough-Drug Designations: The rising number of investigational drugs assigned the “breakthrough” designation by FDA is reviewed in a Health Policy Report (pp. 1444–53): “The percentage of drugs that were approved with breakthrough designations was 22% in 2014 and 2015, 32% in 2016, and 37% in 2017. Ideally, the FDA would have sufficient resources to offer the efficiency benefits of the breakthrough designation, such as early consultation, to the sponsors of all experimental drugs. In a resource-constrained environment, tethering benefits to only the most promising drugs is sensible, but it also creates incentives for industry to seek breakthrough designation even for drugs that do not offer large benefits. Because the designation is made so early in development, the attachment of the designation to approved drugs can also promote the use of drugs that do not live up to expectations, even if less expensive or equally effective alternatives are available. With numerous studies showing a higher incidence of safety-related label changes and other risks associated with expedited premarket testing of new drugs, close postmarket follow-up of breakthrough-designated drugs should also be undertaken.” (J. J. Darrow)
>>>PNN NewsWatch
* Citing lack of sterility assurance, Premier Pharmacy Labs is recalling several lots of four injectable products. Hospital pharmacy, clinic, and other facilities with recalled lots should stop using and return products to Premier Pharmacy Labs as described in a reply form included in a certified letter sent to all affected clients.

PNN Pharmacotherapy Line
Apr. 13, 2018 * Vol. 25, No. 72
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Cardiology Report
Source:
 Apr. 17 issue of the Journal of the American College of Cardiology (2018; 71).
Genetics, Drugs & Long QT Syndrome: Nadolol is superior to other agents for prevention of life-threatening arrhythmic events (LAEs) in patients with long QT syndrome (LQTS), researchers report (10.1016/j.jacc.2018.01.078). Among 1,710 patients who were followed for a median of 7.1 years, these relationships were identified among QTc duration, genotype, the antiarrhythmic efficacy of beta-blockers, and the 5-year risk of LAEs: “The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03).” (A. Mazzanti)
Stent Thrombosis, Restenosis & Bleeding: Commenting on the roles of antithrombotic therapy and drug-eluting stents in interventional cardiology, authors provide this review of developments in the field over the past 40 years (10.1016/j.jacc.2018.02.023): “The introduction of first-generation drug-eluting stents significantly reduced the rates of restenosis, but at the expense of an increase of late stent thrombosis. Prolonged antithrombotic therapy reduced rates of stent thrombosis, but at the cost of increased bleeding. Although the advent of second-generation drug-eluting stents subsequently reduced the incidence of late stent thrombosis, its permanent nature prevents full recovery of vascular structure and function with accordant risk of very late stent failure. In the present era of interventional cardiology, the tradeoff between stent thrombosis, restenosis, and bleeding presents as a particularly complex challenge. In this review, the authors highlight major contributors of late/very late stent thrombosis while targeting stent restenosis, and they discuss evolutionary advances in stent technology and antiplatelet therapy, to further improve upon the care of patients with coronary artery disease.” (J. Torrado)
>>>Chest Highlights
Source:
 Apr. issue of Chest (2018; 153).
Statins & Sepsis Outcomes: Confirming in vitro findings, a clinical study shows that statins act to lower mortality in patients with sepsis through a mechanism other than lipid lowering (pp. 805–15). Cumulative use of statins for more than 30 days among patients in the National Health Insurance Research Database showed these outcomes during index sepsis admissions: “A total of 52,737 patients with sepsis fulfilled the inclusion criteria, of which 1,855 were prescribed atorvastatin, 916 were prescribed simvastatin, and 732 were prescribed rosuvastatin. Compared with nonusers, simvastatin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68–0.90) were associated with an improved 30-day survival, whereas rosuvastatin was not (HR, 0.87; 95% CI, 0.73–1.04). Using rosuvastatin as the reference, atorvastatin (HR, 0.79; 95% CI, 0.64–0.99) and simvastatin (HR, 0.77; 95% CI, 0.59–0.99) had superior effectiveness in preventing mortality.” (C-C Lee, cclee100@gmail.com)
>>>Circulation Report
Source:
 Apr. 10 issue of Circulation (2018; 137).
Adding Ezetimibe to Statin Therapy: Patients with diabetes or at high risk of cardiovascular events had reduced chances of a composite of cardiovascular death, major coronary events, or stroke when ezetimibe was added to their statin therapy, according to results of the IMPROVE-IT trial (pp. 1571–82). The trial included 18,144 patients with acute coronary syndrome whose baseline LDL cholesterol level was 50–125 mg/dL. In those with diabetes, the largest risk reductions were for myocardial infarction (24%) and ischemic stroke (39%). (R. P. Giugliano, rgiugliano@partners.org)

PNN Pharmacotherapy Line
Apr. 16, 2018 * Vol. 25, No. 73
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 Apr. 14 issue of Lancet (2018; 391).
Risk Thresholds for Alcohol Consumption: Based on data for nearly 600,000 participants in 83 prospective studies, alcohol intake at or below about 100 g/wk is associated with the lowest risk of all-cause mortality —about half of current recommendations for men — and those with cardiovascular disease other than myocardial infarction should reconsider any intake of alcohol (pp. 1513–23). The analysis was based on current drinkers in 19 high-income countries with data in the Emerging Risk Factors Collaboration, EPIC-CVD, and the U.K. Biobank. Investigators report these results: “In the 599,912 current drinkers included in the analysis, we recorded 40,310 deaths and 39,018 incident cardiovascular disease events during 5.4 million person–years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1.14, 95% CI, 1.10–1.17), coronary disease excluding myocardial infarction (1.06, 1.00–1.11), heart failure (1.09, 1.03–1.15), fatal hypertensive disease (1.24, 1.15–1.33); and fatal aortic aneurysm (1.15, 1.03–1.28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0.94, 0.91–0.97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.” (A. M. Wood, amw79@medschl.cam.ac.uk)
NaV1.4 Dysfunction in Sudden Infant Death Syndrome: A potentially modifiable variation in muscle sodium channels could contribute to sudden infant death syndrome (SIDS) in a subset of patients, researchers report (pp. 1483–92). The sodium channel NaV1.4, encoded by the gene SCN4A, is involved in excitation and contraction of skeletal respiratory muscles. “Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome,” the authors report. In a case–control study of two consecutive cohorts of 278 SIDS cases of European ancestry and 729 ethnically matched controls, the investigators found: “Four (1.4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p = 0.0057).” (M. G. Hanna, m.hanna@ucl.ac.uk)
>>>PNN NewsWatch
* FDA on Friday issued a new guidance to clarify that dietary supplements containing pure or highly concentrated caffeine in powder or liquid forms are considered unlawful when sold in bulk quantities directly to consumers. Because of these products represent a significant public health concern, FDA said this guidance is in effect immediately and that the agency is prepared to take steps right away to begin removing illegal products from the market.
* FDA is alerting health care professionals to an Apr. 5 voluntary recall of all nonexpired products marketed as sterile made by 
Coastal Meds because of observed particles in some products. During FDA’s recent inspection of Coastal Meds, investigators observed visible particulates and poor sterile production practices that “further raise concerns about particulates in Coastal Meds’ drug products intended for injection.” FDA said.
>>>PNN JournalWatch
Use of Intensive Glycemic Management in Older Adults with Diabetes Mellitus, in Journal of the American Geriatrics Society, 2018: 66: 10.1111/jgs.15335. (S. V. Arnold, suz.v.arnold@gmail.com)
A Roadmap to Implementing Antimicrobial Stewardship Principles in Long-term Care Facilities (LTCFs): Collaboration Between an Acute-Care Hospital and LTCFs, in Clinical Infectious Diseases, 2018: 66: 1304–12. (R. Kullar, Ravina.kullar@gmail.com)
Carbapenemase-Producing Organisms: A Global Scourge, in Clinical Infectious Diseases, 2018: 66: 1290–7. (E. M. Burd, eburd@emory.edu)
Current Epidemiology and Trends in Meningococcal Disease—United States, 1996–2015, in Clinical Infectious Diseases, 2018: 66: 1276–81. (J. R. MacNeil, jmacneil@cdc.gov)

PNN Pharmacotherapy Line
Apr. 17, 2018 * Vol. 25, No. 74
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-release articles from and the Apr. 17 issue of Annals of Internal Medicine (2018; 168).
Drug Overdoses & Organ Donations: Concerns over poor outcomes and transmission of infectious agents via transplants of organs from those dying of drug overdoses in the U.S. are not accurate, researchers report (10.7326/M17-2451). The drug-overdose epidemic has increased the number of available organs. Using 2000–17 data from the Scientific Registry of Transplant Recipients, investigators report the following for overdose-death donors (ODDs), trauma-death donors (TDDs), or medical-death donors (MDDs): “A total of 7,313 ODDs and 19,897 ODD transplants (10,347 kidneys, 5,707 livers, 2,471 hearts, and 1,372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased–infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (minimal difference for kidneys and lungs, marginally lower [standardized risk difference (sRD), −3.2%] for livers, and marginally higher [sRD, 1.9%] for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference.” (C. M. Durand, cdurand2@jhmi.edu)
Direct-Acting Antivirals in Kidney Transplantation: Used as prophylaxis before and after kidney transplantation from donors infected with hepatitis C virus (HCV) to noninfected recipients, direct-acting antivirals (DAAs) were safe and effective in a small study (pp. 533–40). As reported previously in the Mar. 6 PNN, the transplant kidneys came from deceased donors aged 13 to 50 years with confirmed HCV infection. All recipients received grazoprevir 100 mg and elbasvir 50 mg immediately before transplant and continued receiving this combination for 12 weeks after transplant. Recipients who received organs from donors with HCV genotype 2 or 3 infection had sofosbuvir 400 mg added to their regimen. Among the 10 organ recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. “If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection,” the authors conclude. (C. M. Durand, christinedurand@jhmi.edu)
Cardiovascular Disparities Among Adults Without CVD: Declines in the cardiovascular health gap in the U.S. are the result of worsened health among whites rather than gains by blacks or Hispanics, according to data for adults in the National Health and Nutrition Examination Survey (NHANES) for 1988 through 2014 (pp. 541–9): “Rates of optimal cardiovascular health remain below 40% among whites, 25% among Mexican Americans, and 15% among African Americans. Disparities in optimal cardiovascular health between whites and African Americans persisted but decreased over time. In 1988 to 1994, the percentage of African Americans with optimal [Life’s Simple 7 (LS7)] scores was 22.8 percentage points (95% CI, 19.3 to 26.4 percentage points) lower than that of whites in persons aged 25 to 44 years and 8.0 percentage points (CI, 6.4 to 9.7 percentage points) lower in those aged 65 years or older. By 2011 to 2014, differences decreased to 10.6 percentage points (CI, 7.4 to 13.9 percentage points) and 3.8 percentage points (CI, 2.5 to 5.0 percentage points), respectively.… Between 1988 to 1994 and 2011 to 2014, the percentage of whites with optimal cardiovascular health decreased 15.3 percentage points (CI, 11.1 to 19.4 percentage points) for those aged 25 to 44 years and 4.6 percentage points (CI, 2.7 to 6.5 percentage points) for those aged 65 years or older.” (A. F. Brown, ABrown@mednet.ucla.edu)
>>>PNN NewsWatch
* Epic Products, LLC is voluntarily recalling all lots of Euphoric capsules, packaged in 1-count blister cards, 3-count bottles, and 12-count bottles to the consumer level. FDA analysis found Euphoric samples tainted with undeclared sildenafil and tadalafil, the agency said.

PNN Pharmacotherapy Line
Apr. 18, 2018 * Vol. 25, No. 75
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 17 issue of JAMA (2018; 319).
Comparative Mortality & CV Event Reductions With Newer Antidiabetics: Used for treating patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors have different effects on all-cause mortality and cardiovascular (CV) measures such as CV mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke, and on adverse events or hypoglycemia (pp. 1580–91). In a network meta-analysis, “The use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment,” the authors conclude. “Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.” In the safety analysis, GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors or DPP-4 inhibitors. (S. L. Zheng, sean.zheng@nhs.net)
Vitamin D and/or Calcium for Primary Fracture Prevention: In a recommendation statement, the U.S. Preventive Services Task Force concludes, “The current evidence is insufficient to assess the balance of the benefits and harms of vitamin D and calcium supplementation, alone or combined, for the primary prevention of fractures in community-dwelling, asymptomatic men and premenopausal women” (pp. 1592–9). “The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with doses greater than 400 IU of vitamin D and greater than 1000 mg of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D and 1000 mg or less of calcium for the primary prevention of fractures in community-dwelling, postmenopausal women. (D recommendation — [indicating moderate to high certainty that the service has no net benefit or that harms outweigh benefits]) These recommendations do not apply to persons with a history of osteoporotic fractures, increased risk for falls, or a diagnosis of osteoporosis or vitamin D deficiency.” (D. C. Grossman, chair@uspstf.net)
The USPSTF recommendations are based on these findings from a systematic review of 11 randomized controlled trials (RCTs) conducted over 2–7 years in people aged 50 years or older (
pp. 1600–12): “Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2,686]; absolute risk difference [ARD], −2.26% [95% CI, −4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5,496]; pooled ARD, −0.01% [95% CI, −0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36,282]; ARD, −0.35% [95% CI, −1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36,727]; ARD from the larger trial, −0.14% [95% CI, −0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from −1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39,213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1,259]; pooled ARD, 0.00% [95% CI, −0.87% to 0.87%]).” (L. C. Kahwati, lkahwati@rti.org)
>>>PNN NewsWatch
* FDA yesterday approved burosumab (Crysvita, Ultragenyx), the first drug approved to treat adults and children 1 year or older with X-linked hypophosphatemia (XLH), a rare, inherited form of rickets. XLH causes low serum phosphate levels, leading to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a patient’s life. The condition affects approximately 3,000 children and 12,000 adults in the U.S. Symptoms include bowed/bent legs, short stature, bone pain, and severe dental pain in children and persistent discomfort or complications — joint pain, impaired mobility, tooth abscesses, and hearing loss — in adults.

PNN Pharmacotherapy Line
Apr. 19, 2018 * Vol. 25, No. 76
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 19 issue of the New England Journal of Medicine (2018; 378).
Saline Shortages: In the first of two Perspective articles on the current shortage of saline solutions in the U.S., two pharmacists write that “a multifaceted approach will be needed to ensure that patients safely get the medications they need” (pp. 1472–4). “The saline shortage has required clinicians to use a number of work-arounds that consume valuable resources and increase health care costs. Supplies may need to be reserved for the sickest patients, and providers require an ethical framework for rationing products, while pharmacy staff closely monitor inventory. Some medications now have to be administered as direct injections over several minutes, which increases the time nurses must spend with each patient. Some institutions have switched to syringe pumps or use Buretrol (Baxter) infusion devices (which hold small quantities of fluids) to deliver medications. Hospitals are also using more expensive premixed products and are changing the concentration of some medications so they can be mixed in larger volumes, when small-volume bags are unavailable. Making such changes requires substantial informatics resources, because the ordering platform in the electronic health record must be altered. To conserve large-volume saline bags, oral hydration is recommended when possible [see second article]. For patients who cannot take oral fluids or who require aggressive resuscitation, alternative crystalloid solutions may be considered. During shortages of large-volume saline irrigation solution, sterile water or even tap water may be substituted when appropriate.” (M. Mazer-Amirshahi)
An oral rehydration strategy for emergency departments (EDs) is described in the second article (
pp. 1475–7): “Under our protocol, we aim to have patients take 500 to 1000 ml of oral fluids while in the ED, since patients who drink this volume successfully can most likely continue oral rehydration at home. Providers are encouraged to offer analgesics, antipyretics, and antiemetics as needed to improve the tolerance of oral hydration. Patients may start drinking immediately if they are able, or they may wait 20 minutes for symptom improvement after administration of these comfort medications. Patients are offered their choice of drinks, including artificially flavored oral electrolyte solution, water, dilute juice, or dilute sports drinks.…
“Each patient is provided a straw, a 30-ml medicine cup, and 1000 ml of the patient’s preferred fluid. Patients are instructed to drink 30 ml (two large sips) every 3 to 5 minutes and may ask family members or use a cellphone to time the sips. Providers explain the drinking goals … and draw lines on the pitchers to delineate target volumes (e.g., “250 ml left&rdquoWinking.” (A. M. Patiño)
Intussusception After Monovalent Rotavirus Vaccination: In seven lower-income sub-Saharan African countries, infants who received rotavirus vaccine were at no higher risk of risk of intussusception than other infants, a study shows (pp. 1521–8). A self-controlled case-series analysis showed these risks of risk of intussusception on days 1–7 and 8–21 following receipt of the vaccine at ages 28 through 245 days: “Data on 717 infants who had intussusception and confirmed vaccination status were analyzed. One case occurred in the 1 to 7 days after dose 1, and 6 cases occurred in the 8 to 21 days after dose 1. Five cases and 16 cases occurred in the 1 to 7 days and 8 to 21 days, respectively, after dose 2. The risk of intussusception in the 1 to 7 days after dose 1 was not higher than the background risk of intussusception (relative incidence [i.e., the incidence during the risk window vs. all other times], 0.25; 95% confidence interval [CI], <0.001 to 1.16); findings were similar for the 1 to 7 days after dose 2 (relative incidence, 0.76; 95% CI, 0.16 to 1.87). In addition, the risk of intussusception in the 8 to 21 days or 1 to 21 days after either dose was not found to be higher than the background risk.” (J. E. Tate, jqt8@cdc.gov)
>>>PNN NewsWatch
* AMA Wholesale Inc. (distributor/reseller), is voluntarily recalling Rhino 69 Extreme 50000 capsules to the consumer level. FDA analysis found the product to be tainted with undeclared tadalafil, the agency said. Consumers/distributors/retailers that have purchased Rhino 69 Extreme 50000 should immediately stop consumption and resale of the product and return it to the place of purchase for a refund.

PNN Pharmacotherapy Line
Apr. 20, 2018 * Vol. 25, No. 77
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Oncology Highlights
Source:
 Apr. 20 issue of the Journal of Clinical Oncology (2018; 36).
Biosimilars in Oncology: A statement from the American Society of Clinical Oncology offers guidance regarding the use of biosimilars in the oncology setting with regard to (1) naming, labeling, and other regulatory considerations, (2) safety and efficacy of biosimilars, (3) interchangeability, switching, and substitution, (4) value of biosimilars, and (5) prescriber and patient education (pp. 1260–5). “Biosimilars will play an important role in the future care of patients with cancer and will improve access to valuable medicines,” the authors conclude. “Whereas many biosimilars in oncology will be available in the next several years, their use and effect on patient care and health care costs will largely depend on patient and provider acceptance on the basis of an adequate understanding of the safety and efficacy of these agents in cancer care. This statement affirms ASCO’s commitment to ensure the availability of biologics that are necessary in the delivery of high-quality, high-value care. To enhance patient and provider confidence in biosimilars, it is necessary to educate oncology providers and continue to advocate for federal and state policies that ensure the efficient approval, unrestricted access, and appropriate use of biosimilars.” (G. H. Lyman, glyman@fredhutch.org)
>>>Infectious Diseases Report
Source:
 May 1 issue of Clinical Infectious Diseases (2018; 66).
Unrestricted Access to HCV Agents in Patients With HIV: Unrestricted access to direct-acting antivirals (DAAs) in the Netherlands since Nov. 2015 has the country on a course to eliminate hepatitis C virus (HCV) from the population of people coinfected with HIV, researchers report (pp. 1352–9). Those included in the ATHENA HIV observational cohort had these outcomes 15 months after unrestricted access to DAAs: “Of 23,574 HIV-infected patients ever linked to care, 1,471 HCV-coinfected patients (69% men who have sex with men, 15% persons who [formerly] injected drugs, and 15% with another HIV transmission route) fulfilled the inclusion criteria. Of these, 87% (1,284 of 1471) had ever initiated HCV treatment between 2000 and 2017, 76% (1,124 of 1,471) had their HCV infection cured; DAA treatment results were pending in 6% (92 of 1,471). Among men who have sex with men, 83% (844 of 1,022) had their HCV infection cured, and DAA treatment results were pending in 6% (66 of 1,022). Overall, 187 patients had never initiated treatment, DAAs had failed in 14, and a pegylated interferon-alfa–based regimen had failed in 54.” (A. Boerekamps, a.boerekamps@erasmusmc.nl)
Similarly, acute HCV infections among HIV-positive men who have sex with men (MSM) in the Netherlands have decreased by 51% since DAAs became available on an unrestricted basis (pp. 1360–5). At 17 Dutch HIV centers that provide care to 76% of the HIV-positive MSM in the country, two studies show these outcomes for the years before and after unrestricted DAA availability: “The incidence of acute HCV infection decreased from 93 infections during 8,290 person–years of follow-up (PYFU) in 2014 (11.2/1,000 PYFU; 95% confidence interval [CI], 9.1–13.7) to 49 during 8,961 PYFU in 2016 (5.5/1000 PYFU; 4.1–7.2). The incidence rate ratio of 2016 compared with 2014 was 0.49 (95% CI, .35–.69). Simultaneously, a significant increase in the percentage positive syphilis (+2.2%) and gonorrhea (+2.8%) tests in HIV-positive MSM was observed at sexual health clinics across the Netherlands and contradicts a decrease in risk behavior as an alternative explanation.” (A. Boerekamps, 
a.boerekamps@erasmusmc.nl)
>>>PNN NewsWatch
* Two additional kratom-containing products are being recalled because of possible Salmonella contamination: NxtGen Botanicals Maeng Da Kratom (NGB Corp.) and powder products marketed by Viable Solutions.
* A federal judge yesterday entered a consent decree of permanent injunction between the U.S. and 
Cantrell Drug Company of Little Rock, AR, and the company’s CEO and co-owner. The agreement prohibits the company and officer from manufacturing, processing, packing, holding, or distributing drugs until they comply with the Federal Food, Drug, and Cosmetic Act and FDA regulations, in addition to other requirements, FDA said.

PNN Pharmacotherapy Line
Apr. 23, 2018 * Vol. 25, No. 78
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 360).
Artificial Pancreas Treatment of Type 1 Diabetes: In ambulatory patients with type 1 diabetes, artificial pancreas systems are safe and efficacious, researchers report based on a systematic review and meta-analysis (k1310). Artificial pancreas systems are a type of closed-loop glucose control in which insulin pumps are used in conjunction with sensor-augmented pump technology combined with a low-glucose suspend feature. Based on the following findings, the authors conclude that “the main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials”: “40 studies (1,027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system. Only nine studies were at low risk of bias. Proportion of time in the near normoglycaemic range (3.9–10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%). Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (−8.52%, −11.14% to −5.9%) or below 3.9 mmol/L (−1.49%, −1.86% to −1.11%) over 24 hours, compared with control treatment. Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%). Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems.” (A. Tsapas, atsapas@auth.gr)
>>>Lancet Highlights
Source:
 Apr. 21 issue of Lancet (2018; 391).
Re-emergence of Yaws After Mass Azithromycin Treatment: In a longitudinal study conducted in Papua New Guinea, investigators find that the World Health Organization’s newly adopted strategy for eradication of yaws likely needs to be modified (pp. 1599–60). WHO is advocating an approach of a single mass azithromycin treatment in high-endemic communities followed by targeted treatment programs. Because of people absent from the community at the time of mass treatment in whom yaws reactivated, the strategy failed, as the authors report in these results: “Mass azithromycin treatment (coverage rate of 84%) followed by targeted treatment programmes reduced the prevalence of active yaws from 1.8% to a minimum of 0.1% at 18 months (difference from baseline −1.7%, 95% CI, −1.9 to −1.4; p<0.0001), but the infection began to re-emerge after 24 months with a significant increase to 0.4% at 42 months (difference from 18 months 0.3%, 95% CI 0.1 to 0.4; p <0.0001). At each timepoint after baseline, more than 70% of the total community burden of yaws was found in individuals who had not had the mass treatment or as new infections in non-travelling residents. At months 36 and 42, five cases of active yaws, all from the same village, showed clinical failure following azithromycin treatment, with PCR-detected mutations in the 23S ribosomal RNA genes conferring resistance to azithromycin. A sustained decrease in the prevalence of high-titre latent yaws from 13.7% to <1.5% in asymptomatic children aged 1–5 years old and of genetic diversity of yaws strains from 0.139 to less than 0.046 between months 24 and 42 indicated a reduction in transmission of infection.” (O. Mitjà, riol.mitja@isglobal.org">oriol.mitja@isglobal.org)
>>>PNN NewsWatch
FDA on Friday released the first of two new draft guidances intended to aid industry in developing new agents for use in medication-assisted treatment for opioid dependence. The guidance explains FDA’s current thinking about drug development and clinical trial design issues relevant to the study of sustained-release “depot” buprenorphine products (i.e., modified-release products for injection or implantation). The Commissioner comments on the policy in a separate statement.
>>>PNN JournalWatch
Chronic Myelogenous Leukemia: Pregnancy in the Era of Stopping Tyrosine Kinase Inhibitor TherapyJournal of Clinical Oncology, 2018; 36: 1250–6. (E. Berman, bermane@mskcc.org)

PNN Pharmacotherapy Line
Apr. 24, 2018 * Vol. 25, No. 79
Providing news and information about medications and their proper use

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>>>Geriatrics Highlights
Source:
 Online content from the Journal of the American Geriatrics Society (2018; 66).
Electronic Medication Administration Records in LTCFs: Research into the effects of standalone electronic medication administration record (eMAR) systems in long-term care facilities (LTCFs) is weak, according to a systematic review of 34 articles (10.1111/jgs.15384). “Further investigation is required to rigorously evaluate the effect of standalone eMAR systems on medication administration errors and patient safety, the extent of eMAR implementation, pharmacists’ perceptions, and cost effectiveness of eMAR systems in LTCF,” the authors conclude based on these findings: “Studies were published between 2006 and 2016 and were mostly from the United States (n = 25). Twenty studies (59%) used quantitative methods, including surveys and analysis of eMAR data; 7 (21%) used qualitative methods, including interviews, focus groups, document review, and observation; and 7 (21%) used mixed methods. Three major research areas were explored: medication and medication administration error rates (n = 11), eMAR benefits and challenges (n = 19), and eMAR prevalence and uptake (n = 15). Evidence linking eMAR use and reductions in medication errors is weak because of suboptimal study design and reporting. The majority of studies were descriptive and documented inconsistent benefits and challenges and low levels of eMAR implementation.” (M. J. Makowsky, makowsky@ualberta.ca)
Age-Related Differences in Care Following STEMI: In a study of 23 hospitals in the northern French Alps, age-related differences in care show that adults with advanced age (≥75 years) who met the criteria for reperfusion therapy following ST-segment myocardial infarction (STEMI) were more likely to have treatment delays and to die than younger patients (10.1111/jgs.15383). Among 4,813 patients presenting with STEMI less than 12 hours after symptom onset, reperfusion rates were “92.9% for those younger than 75, 89.0% for those aged 75 to 84, and 78.7% for those aged 85 and older (P < .001). The percentages of patients undergoing primary percutaneous coronary intervention were 63.7%, 70.3%, 72.4% (P < .001); and the percentages of patients receiving timely delivery of reperfusion therapy were 44.6%, 36.8%, 29.9% (P < .001). In-hospital all-cause mortality was 3.4% for those younger than 75, 10.2% for those aged 75 to 84, and 19.8% for those aged 85 and older (P <.001). In multivariable analysis adjusting for baseline characteristics, timely delivery of reperfusion therapy was associated with lower in-hospital mortality (adjusted odds ratio=0.63, 95% confidence interval=0.46–0.85) with no significant heterogeneity between age groups (P-value for interaction = .45).” (J. Labarère, JLabarere@chu-grenoble.fr)
>>>Allergy/Immunology Report
Source:
 Apr. issue of the Journal of Allergy and Clinical Immunology (2018; 141).
Obese-Asthma Phenotype in Children: Children with asthma may have differing risks for exacerbations based on obesity status, a study shows, but lack of precision in a retrospective cohort study prevents determination of whether those with obesity had a differential response to step 3 interventions (pp. 1239–49.e4). In children ages 2 to 18 years seen at the Montreal Children’s Hospital Asthma Center in 2000–07, investigators sought to determine whether obesity was associated with time to first exacerbation among children exposed to step 3 maintenance therapies and whether it modifies the effectiveness of step 3 therapies. Results for those started on medium/high-dose inhaled corticosteroids (ICSs) monotherapy or low/medium-dose ICS with leukotriene receptor antagonist/long-acting beta-agonist (combination therapy) were as follows: “Of the 4,621 cohort patients, 231 initiated ICS monotherapy, and 97 initiated combination therapy. The hazard ratio (HR) for obesity was 1.67 (95% CI, 1.41–1.98). Compared with nonobese nonadherers, the HR for obese nonadherers was 1.54 (95% CI, 0.97–2.45); the HR for ICS monotherapy in obese and nonobese children was 0.85 (95% CI, 0.47–1.52) and 0.58 (95% CI, 0.37–0.91), respectively; and the HR for combination therapy in obese and nonobese children was 0.50 (95% CI, 0.13–1.89) and 0.46 (95% CI, 0.23–0.92), respectively.” (T. A. Barnett, tracie.barnett@iaf.inrs.ca)
Obesity and asthma is reviewed in a second article (
pp. 1169–79; E. Forno, erick.forno@chp.edu).

PNN Pharmacotherapy Line
Apr. 25, 2018 * Vol. 25, No. 80
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 Apr. 24 issue of JAMA (2018; 319).
Antiplatelet Therapy After CABG: In 461 patients undergoing elective coronary artery bypass grafting (CABG), saphenous vein graft patency was significantly better at 1 year with ticagrelor + aspirin than aspirin alone (pp. 1677–86). The Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery (DACAB) trial reports these results from six Chinese centers: “Saphenous vein graft patency rates 1 year post-CABG were 88.7% (432 of 487 vein grafts) with ticagrelor + aspirin; 82.8% (404 of 488 vein grafts) with ticagrelor alone; and 76.5% (371 of 485 vein grafts) with aspirin alone. The difference between ticagrelor + aspirin vs aspirin alone was statistically significant (12.2% [95% CI, 5.2% to 19.2%]; P < .001), whereas the difference between ticagrelor alone vs aspirin alone was not statistically significant (6.3% [95% CI, –1.1% to 13.7%]; P = .10). Five major bleeding episodes occurred during 1 year of follow-up (3 with ticagrelor + aspirin; 2 with ticagrelor alone).” (Q. Zhao, zq11607@rjh.com.cn)
“The combination of ticagrelor + aspirin increased vein graft patency; however, this mechanistically important observation is not sufficient to change practice,” an editorialist writes (
pp. 1661–2). “Fundamentally, angiographic vein graft patency is an imaging outcome and not a direct measure of how a patient feels, functions, or survives. For these reasons, it is premature to endorse the routine addition of ticagrelor to aspirin after CABG surgery. Data from randomized trials evaluating clinical outcomes are needed to understand the effects of ticagrelor on ischemic events and bleeding. Such a trial would be large, on the order of several thousand patients. Fortunately, adequately powered clinical trials with ticagrelor following CABG surgery are under way, and will inform patient outcomes associated with improved vein graft patency.” (J. H. Alexander, john.h.alexander@duke.edu)
Lonafarnib in Hutchinson-Gilford Progeria Syndrome: During a median of 2.2 years of treatment, lonafarnib improved mortality rates in an observational cohort study of patients with the rare disease Hutchinson–Gilford progeria syndrome (HGPS) (pp. 1687–95). Compared with matched untreated patients in a separate natural history study, the new drug produced these outcomes: “Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01–0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06–0.90; P = .04).” (L. B. Gordon, leslie_gordon@brown.edu)
“Precision medicine, by leveraging rational pathway-based repurposing of drugs based on genetic variation, is becoming increasingly common in diseases from cancer to epilepsy,” editorialists write (
pp. 1663–4). “Poly(adenosine diphosphate-ribose) polymerase inhibitors were first used in the treatment of ovarian adenocarcinoma but recently have been shown to be effective in metastatic prostate cancer. Some children with epileptic encephalopathies refractory to conventional treatments are found to have disease-causing gain-of-function variants in GRIN2A or GRIN2D, which encode subunits of the N-methyl-d-aspartate (NMDA) receptor; early case reports suggest that improvements in seizure control and development are possible with drugs that block the NMDA receptor channel, including memantine.” (F. M. Hisama, fmh2@uw.edu)
>>>PNN NewsWatch
* FDA yesterday posted remarks the FDA Commissioner gave to the Senate Committee on Appropriations regarding the agency’s fiscal year 2019 budget and a statement on youth use of and access to JUUL and other e-cigarettes.

PNN Pharmacotherapy Line
Apr. 26, 2018 * Vol. 25, No. 81
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 Apr. 26 issue of the New England Journal of Medicine (2018; 378).
Tenecteplase Before Thrombectomy in Ischemic Stroke: Among patients with ischemic stroke, the more fibrin-specific tenecteplase produced better outcomes than alteplase when used before thrombectomy in eligible patients, report investigators in the Tenecteplase versus Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial (pp. 1573–82). Reperfusion and functional outcomes were better with tenectplase administered within 4.5 hours of symptom onset, as shown by a primary outcome of reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment: “Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P = 0.002 for noninferiority; P = 0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group.” (B. C. V. Campbell, bruce.campbell@mh.org.au)
An editorialist concludes that “the trial conducted by Campbell et al. has paved the way for tenecteplase to provide an alternative or replacement for alteplase in patients undergoing bridging therapy for acute stroke and to avoid thrombectomy procedures in some patients” (
pp. 1635–6). “Changes to practice would require not only further demonstration that tenecteplase is noninferior or superior in clinical efficacy to alteplase but also evidence of convenience, accessibility, affordability, and practicality. Tenecteplase could tick all these boxes.” (A. E. Baird)
Birth Outcomes With Tenofovir–Emtricitabine: Data from two U.S.-based cohort studies of pregnant women with HIV infections contradict previous research showing an elevated risk of adverse birth outcomes when certain agents were used in antiretroviral therapy (pp. 1593–603): “There were 4,646 birth outcomes. Few infants or fetuses were exposed to [tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF–FTC–LPV/r)] (128 [2.8%]) as the initial ART regimen during gestation, in contrast with [TDF–FTC with ritonavir-boosted atazanavir (ATV/r)](539 [11.6%]) and [zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV–3TC–LPV/r)] (954 [20.5%]). As compared with women receiving ZDV–3TC–LPV/r, women receiving TDF–FTC–LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF–FTC–ATV/r, women receiving TDF–FTC–LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight.” (K. Rough, ker704@mail.harvard.edu)
Mass Administration of Azithromycin in Sub-Saharan Africa: Childhood mortality was reduced by mass distribution of azithromycin to communities in Malawi, Niger, and Tanzania with the goal of controlling ocular chlamydia, which produces trachoma (pp. 1583–92). “Childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger,” the authors conclude. “Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance.” (T. M. Lietman, tom.lietman@ucsf.edu)
>>>PNN NewsWatch
* FDA is changing the product labeling of lamotrigine (Lamictal) to warn of hemophagocytic lymphohistiocytosis, which can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly.

PNN Pharmacotherapy Line
Apr. 27, 2018 * Vol. 25, No. 82
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>>>Diabetes Report
Source:
 May issue of Diabetes Care, with a special section on the Costs of Diabetes (2018; 41).
Growing Cost of Diabetes in U.S.: The Medicare program is taking a large and growing financial hit from increasing cost of diabetes care in the U.S., a study shows (pp. 917–28). In 2017, the estimated cost of care for diagnosed diabetes was $327 billion; this includes $90 billion in reduced productivity. “After adjusting for inflation, economic costs of diabetes increased by 26% from 2012 to 2017 due to the increased prevalence of diabetes and the increased cost per person with diabetes,” the American Diabetes Association report concludes. “The growth in diabetes prevalence and medical costs is primarily among the population aged 65 years and older, contributing to a growing economic cost to the Medicare program. The estimates in this article highlight the substantial financial burden that diabetes imposes on society, in addition to intangible costs from pain and suffering, resources from care provided by nonpaid caregivers, and costs associated with undiagnosed diabetes.” (M. P. Petersen, mpetersen@diabetes.org)
“The increased per capita cost of care for diabetes [demonstrated in the above article] poses an equally urgent challenge and potential opportunity to control costs,” authors of an accompanying article write (
pp. 929–32). “Between 2012 and 2017, the fraction of annual per capita health care expenditures for a person with diabetes that were attributed to institutional care has decreased from 50% to 36%. Over the same interval, the percentage attributed to outpatient services other than medications and supplies increased slightly (from 23% to 26%) and that attributed to outpatient medications and supplies increased dramatically (from 27% to 38%). The largest increase occurred in expenditures for insulin. This shift of expenditures from inpatient settings to ambulatory care suggests progress in controlling chronic complications related to diabetes and points to potential targets for intervention to reduce ambulatory costs.” (M. C. Riddle, riddlem@ohsu.edu)
Unstable Housing and Diabetes-Related Hospital/ED Use: Data from the 2014 Health Center Patient Survey (HCPS) show that people with unstable housing have significantly higher risk of use of emergency department (ED) and inpatient visits for diabetes-related problems (pp. 933–9). Unstable housing — defined in the study as “not having enough money to pay rent or mortgage, moving two or more times in the past 12 months, or staying at a place one does not own or rent” — was associated with a 5-fold increase in ED use or hospitalization, yet only 0.9% of those with unstable housing received help through their clinic. (S. A. Berkowitz, seth_berkowitz@med.unc.edu)
High-Deductible Insurance & High-Acuity Diabetes Outcomes: Implementation of high-deductible health plans (HDHPs) was associated with a decline of 11.1% in direct hospitalization costs among people with diabetes, but “members from low-income neighborhoods experienced large, concerning increases in high-severity emergency department visit expenditures and hospitalization days,” researchers report (pp. 940–8). In the Natural Experiment for Translation in Diabetes (NEXT-D) study, 23,493 HDHP adolescents and adults through age 64 with diabetes had these outcomes following an employer-mandated switch from a low-deductible (≤$500) plan to HDHP (≥$1,000): “After the HDHP transition, emergency department visits declined by 4.0% (95% CI −7.8, −0.1), hospitalizations fell by 5.6% (−10.8, −0.5), direct (nonemergency department–based) hospitalizations declined by 11.1% (−16.6, −5.6), and total health care expenditures dropped by 3.8% (−4.3, −3.4). Adverse outcomes did not change in the overall HDHP cohort, but members from low-income neighborhoods experienced 23.5% higher (18.3, 28.7) high-severity emergency department visit expenditures and 27.4% higher (15.5, 39.2) high-severity hospitalization days.” (J. F. Wharam, jwharam@post.harvard.edu)
Placebo Response in Oral Antihyperglycemic Trials: In clinical trials of oral hypoglycemic agents, placebo-treated participants have significant declines in A1C levels, according to FDA data from drugs reviewed in 1999–2015 (pp. 994–1000). The effect is stronger with augmented placebo controls, and placebo response increases over time without affecting efficacy outcomes, the investigators report. (A. Khan, akhan@nwcrc.net)

PNN Pharmacotherapy Line
Apr. 30, 2018 * Vol. 25, No. 83
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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 360).
Risk Factor Burdens & Lifetime Atrial Fibrillation Risk: Risk factors that increase patients’ chances of developing atrial fibrillation are similar at baseline ages of 55, 65, and 75 years, analysis of longitudinal data from the Framingham study shows (k1453). People with optimal values for several risk factors — smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction — had about a 1 in 5 lifetime risk of developing atrial fibrillation, while those with elevated risk of one or more of these risk factors had a 1 in 3 chance of atrial fibrillation. Results considered index ages up to 95 and accounted for competing risks of death. Results showed: “At index age 55 years, the study sample comprised 5,338 participants (2,531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1,415 (26.5%) had a borderline risk profile, and 3,676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years.” (L. Trinquart, ludovic@bu.edu)
Anticholinergic Drugs & Dementia Risk: In a case–control study conducted at U.K. primary practices, researchers report that “a robust association between some classes of anticholinergic drugs and future dementia incidence was observed” (k1315). Confounding factors could contribute to the significant relationship — including properties of agents used in treating early symptoms of dementia — and the investigators conclude that more research is needed into the effects of anticholinergic drug classes versus intrinsic or exposure anticholinergic effects. Specific results of examination of daily defined doses using the Anticholinergic Cognitive Burden (ACB) scale for time periods 4 to 20 years before a dementia diagnosis showed the following: “14,453 (35%) cases and 86,403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15–20 years before a diagnosis.” (K. Richardson, k.richardson@uea.ac.uk)
>>>Lancet Highlights
Source:
 Apr. 28 issue of Lancet (2018; 391).
COPD in China: With a previously unknown prevalence in the world’s most populous country, chronic obstructive pulmonary disease (COPD) is shown to be highly prevalent in China in a cross-sectional, nationally representative study (pp. 1706–17). “Cigarette smoking, ambient air pollution, underweight, childhood chronic cough, parental history of respiratory diseases, and low education are major risk factors for COPD,” China Pulmonary Health study investigators report. “Prevention and early detection of COPD using spirometry should be a public health priority in China to reduce COPD-related morbidity and mortality.” (C. Wang, cyh-birm@263.net)
>>>PNN JournalWatch
Toxidrome Recognition in Chemical-Weapons Attacks, in New England Journal of Medicine, 2018: 378: 1611–20. (G. R. Ciottone, gciotton@bidmc.harvard.edu)
Effect of the Duodenal-Jejunal Bypass Liner on Glycemic Control in Patients With Type 2 Diabetes With Obesity: A Meta-analysis With Secondary Analysis on Weight Loss and Hormonal Changes, in Diabetes Care, 2018: 41: 1106–15. (C. C. Thompson, cthompson@hms.harvard.edu)
Gaps in Guidelines for the Management of Diabetes in Low- and Middle-Income Versus High-Income Countries—A Systematic Review, in Diabetes Care, 2018: 41: 1097–105. (M. O. Owolabi, mayowaowolabi@yahoo.com)

PNN Pharmacotherapy Line
May 1, 2018 * Vol. 25, No. 84
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>>>Internal Medicine Report
Source:
 May 1 issue of Annals of Internal Medicine (2018; 168).
E-Cigarette Use With Smoking Cessation: Patients trying to stop smoking after hospitalizations had worse 6-month results when they included e-cigarettes in the cessation effort than those who did not, researchers report (pp. 613–20). At three hospitals, 1,357 inpatient adult cigarette smokers who planned to quit smoking received cessation counseling and were randomly assigned to a tobacco treatment recommendation (control) or free tobacco treatment (intervention). Results based on self-reported use of e-cigarettes at 1 and 3 month after discharge produced these results: “Twenty-eight percent of participants used an e-cigarette within 3 months after discharge. In an analysis of 237 propensity score–matched pairs, e-cigarette users were less likely than nonusers to abstain from tobacco use at 6 months (10.1% vs. 26.6%; risk difference, −16.5% [95% CI, −23.3% to −9.6%]). The association between e-cigarette use and quitting varied between intervention patients, who were given easy access to conventional treatment (7.7% vs. 29.8%; risk difference, −22.1% [CI, −32.3% to −11.9%]), and control patients, who received only treatment recommendations (12.0% vs. 24.1%; risk difference, −12.0% [CI, −21.2% to 2.9%]) (P for interaction = 0.143).” (N. A. Rigotti, nrigotti@partners.org)
Reflecting on a Jan. 2018 National Academies of Sciences, Engineering, and Medicine report, “Public Health Consequences of E-Cigarettes,” the corresponding author of the above research article provides this practical interpretation of available data on use of e-cigarettes in cessation attempts (
pp. 666–7): “The report offers no explicit clinical guidance to physicians, but its findings provide an evidence base that clinicians can interpret when answering patients’ questions. My approach is as follows: I tell patients that using e-cigarettes is less harmful than continuing to smoke cigarettes, but because e-cigarettes are so new, I caution them that many questions about their long-term safety remain unanswered. I recommend FDA-approved smoking cessation aids with established safety and efficacy as first-line treatment. If smokers want to try e-cigarettes, I recommend switching completely and avoiding flavored e-cigarettes. I encourage smokers who switch to e-cigarettes to eventually quit using e-cigarettes too because of uncertainty regarding their long-term safety. To avoid exposing others to chemicals in the e-cigarette aerosol, I advise users not to vape indoors or around children. Overall, the message I aim to convey is that I will continue to support and assist patients on their journey to becoming nonsmokers.” (N. A. Rigotti, nrigotti@partners.org)
Cardiovascular Disease & Risk Management in Diabetes: Authors review 2018 standards from the American Diabetes Association relevant to diagnosis and treatment of cardiovascular risk factors (hypertension and dyslipidemia), aspirin use, screening for and treatment of coronary heart disease, and lifestyle interventions (pp. 640–50). Addressing recommendations against using combinations of statins with fibrates or niacin in management of hypertriglyceridemia, the authors write: “Combination therapy with a statin and a fibrate is associated with increased risk for abnormal aminotransferase levels, myositis, and rhabdomyolysis. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke compared with simvastatin alone. Combination therapy with a statin and extended-release niacin was evaluated in a trial that was halted early due to lack of efficacy on the primary composite outcome (cardiac death, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization) and a possible increase in ischemic stroke in patients receiving combination therapy.” (J J. Chamberlain, jimchammd@yahoo.com)
Ethical Obligations in Short-Term Medical Missions: An American College of Physicians position paper provides five core principles that should be applied in short-term global health clinical experiences (pp. 651–7). “Addressing these challenges is critical to protecting patient welfare in all geographic locales, promoting fair and equitable care globally, and maintaining trust in the profession,” the authors write. (L. Snyder Sulmasy, lsnyder@acponline.org)

PNN Pharmacotherapy Line
May 2, 2018 * Vol. 25, No. 85
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 1 issue of JAMA (2018; 319).
Synthetic Opioids in Drug Overdose Deaths: “Synthetic opioids eclipsed prescription opioids as the most common drug involved in overdose deaths” in the U.S. during 2016, researchers report (pp. 1819–21). Data from the National Vital Statistics System show these causes of death and trends for 2010–16: “Among the 42,249 opioid-related overdose deaths in 2016, 19,413 involved synthetic opioids, 17,087 involved prescription opioids, and 15,469 involved heroin. Synthetic opioid involvement in these deaths increased significantly from 3,007 (14.3% of opioid-related deaths) in 2010 to 19,413 (45.9%) in 2016 (P for trend <.01). Significant increases in synthetic opioid involvement in overdose deaths involving prescription opioids, heroin, and all other illicit or psychotherapeutic drugs were found from 2010 through 2016.
“Among synthetic opioid–related overdose deaths in 2016, 79.7% involved another drug or alcohol. The most common co-involved substances were another opioid (47.9%), heroin (29.8%), cocaine (21.6%), prescription opioids (20.9%), benzodiazepines (17.0%), alcohol (11.1%), psychostimulants (5.4%), and antidepressants (5.2%).” (C. M. Jones, 
christopher.jones@samhsa.hhs.gov)
Gestational Diabetes Complications With Glyburide, Insulin: The common practice of using oral glyburide rather than the recommended subcutaneous insulin in women with gestational diabetes is not supported by results of a noninferiority trial at 13 French academic medical centers (pp. 1773–80). Women failing a 10-day dietary intervention received glyburide or insulin, with these results based on a a composite criterion including macrosomia, neonatal hypoglycemia, and hyperbilirubinemia: “Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, −∞ to 10.5%; P=.19).” (M-V Sénat, marie-victoire.senat@aphp.fr)
“The advantages of oral dosing of glyburide compared with insulin injections in terms of cost and patient satisfaction should be weighed against a possible risk of perinatal complications as high as 10.5% as reported in this study and the lack of information about possible long-term effects on offspring,” editorialists conclude (
pp. 1769–70). “Use of glyburide may be most appropriate when insulin injections are not acceptable or practical. When glyburide or other oral agents that cross the placenta are prescribed for pregnant women, concerns about the equivalence in perinatal outcomes and unanswered questions regarding long-term effects on offspring should be discussed frankly.” (D. R. Coustan, dcoustan@wihri.org)
Antibiotic Regimens for Uncomplicated UTI in Women: A 5-day course of nitrofurantoin produced a significantly greater likelihood of clinical and microbiologic resolution at 28 days after completion of therapy than did a single dose of fosfomycin, a 513-patient study shows (pp. 1781–9): “Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%–21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively).” (S. Harbarth, stephan.harbarth@hcuge.ch)
Concluding that “nitrofurantoin can be the agent of choice” in “regions of the world where nitrofurantoin susceptibility is preserved, particularly for 
[Escherichia] coli,” editorialists conclude “the verdict is in” and that future trials should focus on treatment of multidrug-resistant pathogens (pp. 1771–2; M. Juthani-Mehta, manisha.juthani@yale.edu).
>>>PNN NewsWatch
* Now in its 25th year, PNN has been published for nearly 6,000 business mornings since this date in 1994.

PNN Pharmacotherapy Line
May 3, 2018 * Vol. 25, No. 86
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 3 New England Journal of Medicine (2018; 378).
Triple Inhaled Therapy for COPD: In a trial of 10,355 patients with chronic obstructive pulmonary disease (COPD), exacerbations and hospitalizations were lower with use of a once-daily, single Ellipta inhaler containing three drugs than with some dual-drug combinations (pp. 1671–80). The IMPACT study compared an inhaled glucocorticoid (fluticasone furoate), a long-acting muscarinic antagonist (LAMA; umeclidinium), and a long-acting beta-2-agonist (LABA; vilanterol), and the glucocorticoid–LABA or LAMA–LABA combinations, with these results: “The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P <0.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P <0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P <0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P <0.001).” (D. A. Lipson, david.a.lipson@gsk.com)
“Until further evidence is available, we think that clinicians should rely on the updated GOLD 2017 guidelines recommending that escalation to triple therapy occur only after maximized bronchodilator treatment with LAMA–LABA regimens and be limited to patients with more symptomatic GOLD group D COPD with frequent exacerbations,” editorialists conclude (
pp. 1723–4). “Although single-inhaler triple therapy offers simplicity in treating COPD, any potential benefit could be lost and potential undue harm induced if triple therapy is expanded to patients with GOLD groups A, B, and C COPD.” (S. Suissa)
Omega-3 Fatty Acids for Dry Eye Disease: Outcomes at 6 and 12 months were not significantly improved in 349 patients with moderate-to-severe dry eye disease treated with fish-derived n−3 eicosapentaenoic and docosahexaenoic acids 3,000 mg daily or an olive oil placebo (pp. 1681–90). The primary outcome relied on scores on the Ocular Surface Disease Index (OSDI), which uses scores ranging from 0 (least severe) to 100 (most severe). Results showed: “The mean change in the OSDI score was not significantly different between the active supplement group and the placebo group (−13.9 points and −12.5 points, respectively; mean difference in change after imputation of missing data, −1.9 points; 95% confidence interval [CI], −5.0 to 1.1; P = 0.21). This result was consistent across prespecified subgroups. There were no significant differences between the active supplement group and the placebo group in mean changes from baseline in the conjunctival staining score (mean difference in change, 0.0 points; 95% CI, −0.2 to 0.1), corneal staining score (0.1 point; 95% CI, −0.2 to 0.4), tear break-up time (0.2 seconds; 95% CI, −0.1 to 0.5), and result on Schirmer’s test (0.0 mm; 95% CI, −0.8 to 0.9). At 12 months, the rate of adherence to treatment in the active supplement group was 85.2%, according to the level of n−3 fatty acids in red cells. Rates of adverse events were similar in the two trial groups.” (M. G. Maguire, maguirem@pennmedicine.upenn.edu)
Verubecestat for Mild-to-Moderate Alzheimer’s Disease: In patients with mild-to-moderate Alzheimer’s disease, authors report that the orally active beta-site amyloid precursor protein–cleaving enzyme 1 inhibitor “verubecestat did not reduce cognitive or functional decline … and was associated with treatment-related adverse events,” (pp. 1691–703). “The estimated mean change from baseline to week 78 in the [cognitive subscale of the Alzheimer’s Disease Assessment Scale] score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P = 0.63 for the comparison between the 12-mg group and the placebo group and P = 0.46 for the comparison between the 40-mg group and the placebo group).” (M. F. Egan, michael.egan@merck.com)

PNN Pharmacotherapy Line
May 4, 2018 * Vol. 25, No. 87
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Pediatrics Report
Source:
 May issue of Pediatrics (2018; 141).
Inpatient Quality Improvement Interventions for Asthma: Health care reutilization within 30 days of an index hospitalization has not been reduced by inpatient interventions, according to a meta-analysis (e20173334): “Thirty articles met inclusion criteria and 12 provided data on health care reutilization outcomes. Risk ratios for emergency department revisits were: 0.97 (95% confidence interval [CI]: 0.06–14.47) <30 days, 1.70 (95% CI: 0.67–4.29) for 30 days to 6 months, and 1.22 (95% CI: 0.52–2.85) for 6 months to 1 year. Risk ratios for readmissions were: 2.02 (95% CI: 0.73–5.61) for <30 days, 1.68 (95% CI: 0.88–3.19) for 30 days to 6 months, and 1.27 (95% CI 0.85–1.90) for 6 months to 1 year. Subanalysis of multimodal interventions suggested lower readmission rates (risk ratio: 1.49 [95% CI: 1.17–1.89] over a period of 30 days to 1 year after the index admission). Subanalysis of education and discharge planning interventions did not show effect.” (K. Parikh)
Antibiotic Allergy in Pediatrics: Better recognition and management of adverse drug reactions is needed to avoid inaccurate labeling of pediatric patients as allergic to antibiotics, authors of a review article conclude (e20172497). Noting that up to 5 million American pediatric patients are likely labeled as allergic to penicillin, authors write: “We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug–virus interaction, and they usually do not represent a long-lasting, drug-specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins.” (A. E. Norton)
>>>Psychiatry Highlights
Source:
 May issue of the American Journal of Psychiatry (2018; 175).
Genotypes & Escitalopram: Individualization of escitalopram therapy using CYP2C19 genotyping could be clinically useful, researchers report based on patterns of exposure and therapeutic failure as indicated by switching of antidepressant therapy (pp. 463–70). In Norway, 4,228 serum escitalopram concentration measurements in 2,087 CYP2C19-genotyped patients and prescription use showed the following: “Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively.” (M. M. Jukić)
Early Intervention in Bipolar Disorder: Early phases of bipolar disorder might be identifiable, authors conclude, but “further studies will provide the evidence needed to finish shaping the concept of early intervention” (pp. 411–26): “Longitudinal studies … indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable.” (E. Vieta)

PNN Pharmacotherapy Line
May 7, 2018 * Vol. 25, No. 88
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 360).
Education, Exercise & Steroids in Gluteal Tendinopathy: In a study of patients with gluteal tendinopathy, two interventions — education plus exercise (EDX) or a single corticosteroid injection (CSI) — were superior for symptom relief compared with a “wait-and-see” approach, researchers report, and EDX yielded greater relief than CSI (k1662). The condition, also called greater trochanteric bursitis or greater trochanteric pain syndrome, showed these responses at 8 or 52 weeks: “Of 204 randomised participants (including 167 women; mean age 54.8 years (standard deviation 8.8)), 189 (92.6%) completed 52 week follow-up. Success on the global rating of change was reported at eight weeks by 51/66 EDX, 38/65 CSI, and 20/68 WS participants. EDX and CSI had better global improvement scores than WS (risk difference 49.1% (95% confidence interval 34.6% to 63.5%), number needed to treat 2.0 (95% confidence interval 1.6 to 2.9); 29.2% (13.2% to 45.2%), 3.4 (2.2 to 7.6); respectively). EDX had better global improvement scores than CSI (19.9% (4.7% to 35.0%); 5.0 (2.9 to 21.1)). At eight weeks, reported pain on the numerical rating scale was mean score 1.5 (standard deviation 1.5) for EDX, 2.7 (2.4) for CSI, and 3.8 (2.0) for WS. EDX and CSI participants reported less pain than WS (mean difference −2.2 (95% confidence interval −2.89 to −1.54); −1.2 (−1.85 to −0.50); respectively), and EDX participants reported less pain than CSI (−1.04 (−1.72 to −0.37)).… At 52 week follow-up, education plus exercise led to better global improvement than corticosteroid injection use, but no difference in pain intensity.” (B. Vicenzino, b.vicenzino@uq.edu.au)
Emollient Bath Additives for Childhood Eczema: The practice of adding emollients to baths of children with eczema is not supported in a study of 96 general practices in Wales and England (k1332). During 12 months of random assignment to emollients or no bath additives, 482 study participants had these scores on a patient-oriented eczema measure (POEM): “The mean baseline POEM score was 9.5 (SD 5.7) in the bath additives group and 10.1 (SD 5.8) in the no bath additives group. The mean POEM score over the 16 week period was 7.5 (SD. 6.0) in the bath additives group and 8.4 (SD 6.0) in the no bath additives group. No statistically significant difference was found in weekly POEM scores between groups over 16 weeks. After controlling for baseline severity and confounders (ethnicity, topical corticosteroid use, soap substitute use) and allowing for clustering of participants within centres and responses within participants over time, POEM scores in the no bath additives group were 0.41 points higher than in the bath additives group (95% confidence interval −0.27 to 1.10), below the published minimal clinically important difference for POEM of 3 points. The groups did not differ in secondary outcomes, economic outcomes, or adverse effects.” (M. Santer, m.santer@soton.ac.uk)
>>>PNN NewsWatch
FDA has approved two Novartis products, dabrafenib (Tafinlar) and trametinib (Mekinist), administered together, for treatment of BRAF V600E mutation–positive anaplastic thyroid cancer (ATC) that is nonresectable or metastatic. Both agents were previously approved for use, alone or in combination, to treat BRAF V600 mutation–positive metastatic melanoma and in combination to treat BRAF V600E mutation–positive, metastatic nonsmall cell lung cancer.
>>>PNN JournalWatch
Coronary Artery Disease in Patients ≥80 Years of Age, in Journal of the American College of Cardiology, 2018: 71: 10.1016/j.jacc.2017.12.068. (M. V. Madhavan)
Arrhythmias in Patients ≥80 Years of Age: Pathophysiology, Management, and Outcomes, in Journal of the American College of Cardiology, 2018: 71: 10.1016/j.jacc.2018.03.019. (A. B. Curtis)
Valvular Heart Disease in Patients ≥80 Years of Age, in Journal of the American College of Cardiology, 2018: 71: 10.1016/j.jacc.2018.03.459. (S. K. Kodali)
Cardiovascular Magnetic Resonance in Acute ST-Segment–Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions, in Circulation, 2018: 137: 1949–64. (H. Bulluck)
Severely Impaired Control of Bacterial Infections in a Patient With Cystic Fibrosis Defective in Mucosal-Associated Invariant T Cells, in Chest, 2018: 153: e93–6. (J. K. Sandberg, johan.sandberg@ki.se)
Allergen-Specific Immunotherapy in the Treatment of Pediatric Asthma: A Systematic Review, in Pediatrics, 2018: 141: 10.1542/peds.2017-3833. (J. L. Rice)

PNN Pharmacotherapy Line
May 8, 2018 * Vol. 25, No. 89
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 May issue of JAMA Internal Medicine (2018; 178).
CMS Dementia Care Initiative & Drug Prescribing: While the Centers for Medicare & Medicaid Services’ National Partnership to Improve Dementia Care in Nursing Homes appears to have had little impact on use of nonpharmacologic treatments, a prior trend toward use of mood stabilizers rather than antipsychotics continued and accelerated during the 2009–14 intervention period (pp. 640–7). Reporting the results of an interrupted time-series analysis based on a 20% sample of Medicare claims, investigators conclude, “Rather than increasing the use of nonpharmacologic treatments, prescribers may have shifted prescribing from antipsychotics to mood stabilizers even though mood stabilizers have less evidence of benefit for the behavioral and psychological symptoms of dementia.… Measuring use of antipsychotics alone may be an inadequate proxy for quality of care and may have contributed to a shift in prescribing to alternative medications with a poorer risk-benefit balance.” (D. T. Maust, maustd@umich.edu)
Cannabis Laws & Opioid Prescribing: Research studies and an editorial examine the possibility of using greater availability of medical cannabis to reduce opioid prescribing.
Among Medicare Part D beneficiaries, those living in states with medical cannabis laws (MCLs) used significantly less opioid products, a study shows (
pp. 667–72). The relationship is particularly strong in those states with medical dispensaries and for reductions in prescriptions for hydrocodone and morphine, as shown in these longitudinal data on daily doses of opioids: “From 2010 to 2015 there were 23.08 million daily doses of any opioid dispensed per year in the average state under Medicare Part D. Multiple regression analysis results found that patients filled fewer daily doses of any opioid in states with an MCL. The associations between MCLs and any opioid prescribing were statistically significant when we took the type of MCL into account: states with active dispensaries saw 3.742 million fewer daily doses filled (95% CI, −6.289 to −1.194); states with home cultivation only MCLs saw 1.792 million fewer filled daily doses (95% CI, −3.532 to −0.052). Results varied by type of opioid, with statistically significant estimated negative associations observed for hydrocodone and morphine. Hydrocodone use decreased by 2.320 million daily doses (or 17.4%) filled with dispensary-based MCLs (95% CI, −3.782 to −0.859; P = .002) and decreased by 1.256 million daily doses (or 9.4%) filled with home-cultivation–only-based MCLs (95% CI, −2.319 to −0.193; P = .02). Morphine use decreased by 0.361 million daily doses (or 20.7%) filled with dispensary-based MCLs (95% CI, −0.718 to −0.005; P = .047).” (W. D. Bradford, bradfowd@uga.edu)
Similar results were found in an analysis of Medicaid prescribing patterns in relation to state marijuana laws, with authors concluding, “The potential of marijuana liberalization to reduce the use and consequences of prescription opioids among Medicaid enrollees deserves consideration during the policy discussions about marijuana reform and the opioid epidemic” (
pp. 673–9). Cross-sectional analysis of opioid prescribing from 2011 to 2016 showed these relationships with state marijuana status: “State implementation of medical marijuana laws was associated with a 5.88% lower rate of opioid prescribing (95% CI, −11.55% to approximately −0.21%). Moreover, the implementation of adult-use marijuana laws, which all occurred in states with existing medical marijuana laws, was associated with a 6.38% lower rate of opioid prescribing (95% CI, −12.20% to approximately −0.56%).” (H. Wen, hefei.wen@uky.edu)
“For many reasons, ranging from significant barriers to research on cannabis and cannabinoids to impatience, cannabis policy has raced ahead of cannabis science in the United States,” editorialists write (
pp. 679–80). “For science to guide policy, funding the [studies discussed in this editorial] must be a priority at the federal and state level. Many companies and states (via taxes) are profiting from the cannabis industry while failing to support research at the level necessary to advance the science. This situation has to change to get definitive answers on the possible role for cannabis in the opioid crisis, as well as the other potential harms and benefits of legalizing cannabis.” (K. P. Hill, khill1@bidmc.harvard.edu)

PNN Pharmacotherapy Line
May 9, 2018 * Vol. 25, No. 90
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 8 issue of JAMA (2018; 319).
Intravesical Gemcitabine in Bladder Cancer: Intravesical instillation of gemcitabine immediately after transurethral resection of bladder tumor (TURBT) reduced the risk of recurrence compared with saline in patients with suspected low-grade non–muscle-invasive urothelial cancer, researchers report (pp. 1880–8). Over a median of 4 years, patients at 23 U.S. centers had these outcomes with post-TURBT therapy: “Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48–0.90; P <.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non–muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35–0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower.” (E. M. Messing, edward_messing@urmc.rochester.edu)
“The thoughtfully designed, executed, and interpreted study by Messing et al. provides important results for patients and physicians alike, to the extent that the investigators focused on a problem with meaningful implications for individual patients, population health, and the value of care,” write editorialists (
pp. 1864–5). “Given the potential benefits of these findings, it will be important to educate and mobilize patients with bladder cancer, physicians, advocacy organizations, and health system leaders to facilitate diffusion of this simple, safe, effective, and affordable innovation in the treatment of bladder cancer.” (M. E. Nielsen, mnielsen@med.unc.edu)
Atrial Fibrillation in Patients With Distributive Shock: In patients with distributive shock, addition of vasopressin to catecholamine vasopressors lowers the risk of atrial fibrillation, according to results of a systematic review and meta-analysis (pp. 1889–900). “Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand,” the authors write. “Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS).” Using a primary outcome of atrial fibrillation and several secondary measures (including mortality, requirement for renal replacement therapy [RRT], myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital), the investigators report: “Twenty-three randomized clinical trials were identified (3,088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], −0.06 [95% CI, −0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, −0.04 [95% CI, −0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, −0.07 [95% CI, −0.12 to −0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes.” (E. P. Belley-Côté, emilie.belley-cote@phri.ca)
>>>PNN NewsWatch
AuroMedics Pharma is recalling specific lots of these antibiotic products because of presence of particulate matter: Piperacillin and Tazobactam for Injection, USP, 3.375 g/single-dose vials, and Ampicillin and Sulbactam for Injection, USP, 3 g/single-dose vials.

PNN Pharmacotherapy Line
May 10, 2018 * Vol. 25, No. 91
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 May 10 issue of the New England Journal of Medicine (2018; 378).
Adjuvant Pembrolizumab in Resected Stage III Melanoma: Among 1,019 patients with completely resected stage III melanoma, adjuvant pembrolizumab 200 mg every 3 weeks for up to 1 year produced significantly longer recurrence-free survival, compared with placebo, according to results of the European Organization for Research and Treatment of Cancer 1325 (KEYNOTE-054) trial (pp. 1789–901). Looking for changes in the overall intention-to-treat population and in the subgroup of patients with cancer positive for the PD-1 ligand (PD-L1), investigators found: “At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P <0.001) and in the subgroup of 853 patients with PD-L1–positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P <0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.” (A. M. M. Eggermont, alexander.eggermont@gustaveroussy.fr)
Essential Tremor: After presenting the case of a 62-year-old woman with bilateral hand tremors with onset a decade earlier, authors make these first-line treatment recommendations (pp. 1802–10): “Because the patient has not yet received any therapy for essential tremor and reports that tremor interferes with daily life tasks, we would recommend treatment initiation with either propranolol or primidone, with a gradual dose adjustment to target doses (propranolol, 120 to 240 mg per day; primidone, 250 to 750 mg per day). The choice of first-line therapy should be made after assessment for any contraindications (e.g., symptomatic bradycardia or hypotension when beta-blocker therapy is considered) and may also take the patient’s preference into account after education regarding short-term and long-term effects of these drugs, such as dizziness, hypotension, and sedation. After the patient is taking a dose of either drug that provides sufficient benefit without unacceptable side effects, we recommend annual assessments of tremor severity with the use of rating scales such as [the Essential Tremor Rating Assessment Scale].” (M. Hallett, hallettm@ninds.nih.gov)
Idiopathic Pulmonary Fibrosis: Primarily found in older adults, idiopathic pulmonary fibrosis (IPF) is a “chronic, progressive, fibrotic interstitial lung disease of unknown cause, often with characteristic imaging and histologic appearances,” authors of a review article write (pp. 1811–23): “In light of the rising prevalence of IPF and the increase in associated mortality, we hope that the next 5 years will be marked by greater recognition of the disease on the part of primary care providers, leading to earlier involvement of a multidisciplinary team to aid in diagnosis and management. Novel preventive interventions, evolving use of screening biomarkers, and the eventual ability to target newly discovered risk factors for IPF could lead to a decline in the incidence of this disease as well as other fibrotic interstitial lung diseases in coming years. Advances in therapeutics, including individualized approaches and interventions to halt collagen deposition, may one day eliminate the need for lung transplantation and turn IPF into a lifelong chronic disease.” (F. J. Martinez, fjm2003@med.cornell.edu)
IVIG Prevention of Heparin-Induced Thrombocytopenia: In a letter, authors descrribe use of prophylactic intravenous immune globulin in a 59-year-old man at risk for heparin-induced thrombocytopenia (pp. 1845–8; T. E. Warkentin, twarken@mcmaster.ca).
>>>PNN NewsWatch
* In federal court, FDA is seeking permanent injunctions to stop two stem cell clinics from marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements.

PNN Pharmacotherapy Line
May 11, 2018 * Vol. 25, No. 92
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 May 15 issue of Clinical Infectious Diseases (2016; 66).
Oseltamivir in Children: In children with influenza, oseltamivir reduces the duration of illness and lowers the risk of otitis media, authors of a systematic review and two-stage meta-analysis report (pp. 1492–500): “We identified 5 trials that included 2,561 patients in the intention-to-treat (ITT) and 1,598 in the intention-to-treat infected (ITTI) populations. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population ([restricted mean survival time] difference, −17.6 hours; 95% confidence interval [CI], −34.7 to −0.62 hours). In trials that enrolled patients without asthma, the difference was larger (−29.9 hours; 95% CI, −53.9 to −5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group.” (R. E. Malosh, rmalosh@umich.edu)
U.S. Incidence of Seasonal Symptomatic Influenza: Two different approaches to estimating the incidence of seasonal symptomatic influenza in the U.S. yield figures of about 8% and vary from 3% to 11% based on severity of the season (pp. 1511–8). The conventional wisdom had been that influenza incidence is 5% to 20%, figures based on serologic data from 40 years ago that would include asymptomatic individuals. Using national surveillance data and a literature review and meta-analysis, the current authors found: “The statistical estimate of influenza incidence among all ages ranged from 3.0%–11.3% among seasons, with median values of 8.3% (95% confidence interval [CI], 7.3%–9.7%) for all ages, 9.3% (95% CI, 8.2%–11.1%) for children <18 years, and 8.9% (95% CI, 8.2%–9.9%) for adults 18–64 years. Corresponding values for the meta-analysis were 7.1% (95% CI, 6.1%–8.1%) for all ages, 8.7% (95% CI, 6.6%–10.5%) for children, and 5.1% (95% CI, 3.6%–6.6%) for adults.” (J. I. Tokars, jit1@cdc.gov)
>>>Chest Highlights
Source:
 May issue of Chest (2016; 153).
Preemptive Anticoagulation in Patients at High Risk of Pulmonary Embolism: Among 3,497 patients undergoing CT pulmonary angiography at two emergency departments (EDs), preemptive anticoagulation was rarely instituted for those with a high pretest probability of pulmonary embolism (PE), researchers report (pp. 1153–9). The pretest probability for PE using the revised Geneva Score (RGS) was categorized as low (RGS 0–3), intermediate (RGS 4–10), or high (RGS 11–18). Preemptive anticoagulation was defined as therapeutic anticoagulation given before CTPA completion, yielding these results: “167 [patients] (4.8%) had a high pretest probability for PE. After excluding 29 patients for high bleeding risk and 21 patients who were treated for [deep vein thrombosis] prior to CTPA, only two of 117 patients (1.7%) with a high pretest probability for PE received preemptive anticoagulation. Furthermore, 37 of the remaining 115 patients (32%) with a high pretest probability for PE had a preexisting indication for anticoagulation but did not receive preemptive anticoagulation. The time from ED registration to CTPA completion did not differ based on the pretest probability of PE.” (C. G. Elliott, greg.elliott@imail.org)
Long-Term Azithromycin in Severe COPD: While macrolide resistance was increased in patients with severe chronic obstructive pulmonary disorder (COPD), long-term azithromycin therapy beyond the first year produced reductions in exacerbations of COPD (ECOPD) and hospitalizations, a study shows (pp. 1125–33). In the 109-patient trial, continuous cyclic azithromycin for up to 3 years reduced ECOPD by an average of 56% at 12 months, 70% at 24 months, and 41% at 36 months, compared with the prior 12 months, with parallel reductions in hospitalizations of 62.6%, 75.8%, and 39.8%. (X. Pomares, jpomares@tauli.cat)
>>>PNN NewsWatch
FDA is advising health professionals and consumers to avoid using all lots of Medline Remedy Essentials No-Rinse Cleansing Foam because of 10 confirmed infections of Burkholderia cepacia in California, Pennsylvania, and New Jersey.
FDA yesterday issued four new warning letters to manufacturers and retailers for selling e-liquids used in e-cigarettes with labeling and/or advertising that cause them to resemble kid-friendly food products, such as cereal, soda, and pancakes.

PNN Pharmacotherapy Line
May 14, 2018 * Vol. 25, No. 93
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 May 12 issue of Lancet (2018; 391).
Cardiovascular Disease Risk Prediction Equations: Equations recommended for use in the U.S. fail to address the risks of patients seen in primary care practices in New Zealand, a study concludes (pp. 1897–907). In a data analysis that used PREDICT software to construct and analyze a large prospective cohort “representing typical patients in primary care in New Zealand who were recommended for cardiovascular disease risk assessment,” the investigators found, “Most patients are now at low risk of cardiovascular disease, which explains why the [2013 American College of Cardiology/American Heart Association Pooled Cohort Equations (PCEs)] based mainly on old cohorts substantially overestimate risk. Although the PCEs and many other equations will need to be recalibrated to mitigate overtreatment of the healthy majority, they also need new predictors that include measures of socioeconomic deprivation and multiple ethnicities to identify vulnerable high-risk subpopulations that might otherwise be undertreated.” (R. Jackson, rt.jackson@auckland.ac.nz)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 360).
Stroke, TIA Risk in Resolved Atrial Fibrillation: Guidelines for anticoagulation management in patients with resolved atrial fibrillation need to be updated to address continued higher risk of stroke and transient ischemic attacks (TIAs), according to investigators who conducted two retrospective cohort studies (k1717). Among general practices contributing to The Health Improvement Network in 2000–16, risks were as follows for 11,159 patients with resolved atrial fibrillation, 15,059 controls with atrial fibrillation, and 22,266 controls without atrial fibrillation: “Adjusted incidence rate ratios for stroke or TIA in patients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P <0.001) versus controls with atrial fibrillation and 1.63 (1.46 to 1.83, P <0.001) versus controls without atrial fibrillation. Adjusted incidence rate ratios for mortality in patients with resolved atrial fibrillation were 0.60 (0.56 to 0.65, P <0.001) versus controls with atrial fibrillation and 1.13 (1.06 to 1.21, P <0.001) versus controls without atrial fibrillation. When patients with resolved atrial fibrillation and documented recurrent atrial fibrillation were excluded the adjusted incidence rate ratio for stroke or TIA was 1.45 (1.26 to 1.67, P <0.001) versus controls without atrial fibrillation.” (K. Nirantharakumar, K.Nirantharan@bham.ac.uk)
>>>PNN NewsWatch
* Approving a drug for treatment of multiple sclerosis in children for the first time, FDA on Friday expanded the indications of fingolimod (Gilenya, Novartis) to include treatment of relapsing multiple sclerosis in those aged 10 years or older.
* Organized pharmacy reacted cautiously to the President’s Friday announcements on efforts to rein in 
drug pricing. Recently installed ASCP exec Chad Worz, PharmD, BCGP, blogged positively that pharmacists were not mentioned as contributing to the damage in a “broken system” and that the plan does refer to “banning the gag order on pharmacists.” ASHP said in a news release that it “currently reviewing the full drug-pricing blueprint and will be providing a full analysis … of what its proposals mean for our members and their patients. The Administration will also be releasing a Request for Information soliciting ideas for reducing drug costs. ASHP plans to submit comments on the various proposals to decrease drug prices and will reinforce the necessity of engaging pharmacists in these efforts and offering suggestions on how best to accomplish those aims.”
>>>PNN JournalWatch
State Medicaid Hepatitis C Treatment Eligibility Criteria and Use of Direct-Acting Antivirals, in Clinical Infectious Diseases, 2018: 66: 1618–20. (S. N. Kapadia, shk9078@med.cornell.edu)
Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update, in Journal of Clinical Oncology, 2018: 36: 1443–53. (ASCO, guidelines@asco.org)
Oncolytic Virotherapy for Malignant Gliomas, in Journal of Clinical Oncology, 2018: 36: 1440–2. (D. Abate-Daga, daniel.abatedaga@moffitt.org)
The Alchemist’s Nightmare: Might Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?, in Circulation, 2018: 137: 2068–73. (M. Packer)

PNN Pharmacotherapy Line
May 15, 2018 * Vol. 25, No. 94
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Online-first articles and May 15 issue of Annals of Internal Medicine (2018; 168).
Drug Overdoses & Organ Donation: Transplantations of organs from overdose-death donors (ODDs) are increasing in the U.S., with results similar to organs from other types of donors, researchers report (pp. 702–11). Given these results, concerns about risky behaviors of ODDs and higher rates of hepatitis C virus infection “should be minimized given the current organ shortage,” the authors conclude. A prospective observational cohort study based on the Scientific Registry of Transplant Recipients shows these results for ODDs, trauma-death donor (TDDs), or medical-death donor (MDDs) for 2000–17: “A total of 7,313 ODDs and 19,897 ODD transplants (10,347 kidneys, 5,707 livers, 2,471 hearts, and 1,372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased–infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (minimal difference for kidneys and lungs, marginally lower [sRD, −3.2%] for livers, and marginally higher [sRD, 1.9%] for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference.” (C. M. Durand, cdurand2@jhmi.edu)
“Durand and colleagues demonstrate noninferior (and sometimes even superior) outcomes with ODD organs,” concludes an editorialist (
pp. 739–40). Adding “we need to save more lives of persons awaiting organ transplant,” the writer provides this perspective on organs from donors at greater risk of infectious disease: “The use of IRD organs results in substantial long-term survival benefit, and the rate at which they are discarded (20% for kidneys in 2016) must be reduced. Early discussions with recipients and families that include data such as those in this article, with significant weight given to the risk associated with declining organs from IRDs and ODDs, can better frame future organ offers. The transplant community should understand these new data and forge ahead toward better transplant outcomes for more recipients.” (C. N. Kotton, ckotton@partners.org)
Hospitalists Improving Postacute Care Transitions: A discussion of ways of helping hospitalists get past the “black box” of postacute care (PAC) focuses on these three problems (H02–H03): (1) hospitalists often lack understanding of PAC settings and outcomes to effectively coordinate care during the transition, (2) PAC clinicians often do not receive all of the information they need to provide optimal care, and (3) hospitalists receive little feedback about outcomes of patients discharged to PAC, which limits their ability to improve the care transition. (C. D. Jones, christine.jones@ucdenver.edu)
HIV in U.S. Men Who Have Sex With Men: Men who have sex with men (MSM) continue to be the population most affected by new HIV infections in the U.S., a study shows, leading to recommendations for greater detection and preventive efforts (pp. 685–94). Investigators conducting a cross-sectional analysis of information in the National HIV Surveillance System concluded: “Expansion of HIV screening to reduce undiagnosed infections and increased access to care and treatment to achieve viral suppression are critical to reduce HIV transmission. Access to prevention methods, such as condoms and preexposure prophylaxis, also is needed, particularly among MSM of color and young MSM.” (S. Singh, ssingh3@cdc.gov)
>>>PNN NewsWatch
* Two product recalls involve Piperacillin and Tazobactam for Injection, USP 3.375 g/vial and 4.5 g/vial strengths. AuroMedics Pharma LLC is voluntarily recalling two lots of its single-dose vials to the hospital level because of glass particulate matter that is visible only after reconstitution. Apotex Corp. is voluntarily recalling 36 lots of its product to the consumer/user level because of elevated levels of impurities that may result in decreased potency.

PNN Pharmacotherapy Line
May 16, 2018 * Vol. 25, No. 95
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 15 issue of JAMA (2018; 319).
Pediatric Prescription Medication Use: Pediatric patients in the U.S. received fewer prescription medications in the 2011–14 time period than during 1999–2002, researchers report (pp. 2009–20). Antibiotic, antihistamine, and upper respiratory combination medication usage was lower, as shown in the following results from the 1999–2014 National Health and Nutrition Examination Survey (NHANES): “Data on prescription medication use were available for 38,277 children and adolescents (mean age, 10 years; 49% girls). Overall, use of any prescription medication in the past 30 days decreased from 24.6% (95% CI, 22.6% to 26.6%) in 1999–2002 to 21.9% (95% CI, 20.3% to 23.6%) in 2011–2014 (beta = −0.41 percentage points every 2 years [95% CI, −0.79 to −0.03]; P = .04), but there was no linear trend in the use of 2 or more prescription medications (8.5% [95% CI, 7.6% to 9.4%] in 2011–2014). In 2011–2014, the most commonly used medication classes were asthma medications (6.1% [95% CI, 5.4% to 6.8%]), antibiotics (4.5% [95% CI, 3.7% to 5.5%]), attention-deficit/hyperactivity disorder (ADHD) medications (3.5% [95% CI, 2.9% to 4.2%]), topical agents (eg, dermatologic agents, nasal steroids) (3.5% [95% CI, 3.0% to 4.1%]), and antihistamines (2.0% [95% CI, 1.7% to 2.5%]). There were significant linear trends in 14 of 39 therapeutic classes or subclasses, or in individual medications, with 8 showing increases, including asthma and ADHD medications and contraceptives, and 6 showing decreases, including antibiotics, antihistamines, and upper respiratory combination medications.” (C. M. Hales, chales@cdc.gov)
“Ultimately, the analyses conducted by Hales et al. are interesting in the issues they raise but also frustrating in that the study limitations may not enable definitive conclusions to be drawn regarding those same issues,” editorialists write (
pp. 1988–9). “The findings reported by Hales et al. will require additional studies, using different data sources, to provide clarity in the clinical and policy implications of recent trends in medication use among children.” (G. L. Freed, gfreed@med.umich.edu)
Fremanezumab for Prevention of Episodic Migraine: A fully humanized monoclonal antibody that targets calcitonin gene-related peptide, fremanezumab proved more effective than placebo in preventing episodic migraine in an 875-participant study (pp. 1999–2008). “Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period,” investigators conclude. “Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.” (D. W. Dodick, dodick.david@mayo.edu)
“For patients with recurrent migraine, an unresolved issue is whether a 50% reduction in headache days in less than half of patients, as reported in the trial by Dodick et al., is as good as it gets,” editorialists write (
pp. 1985–7). “The simplest response to this modest level of benefit is to blame the treatments, but it is more likely that migraine is a heterogeneous disorder, with causal factors that vary from person to person. The modest efficacy benefits in trials are population effects; the eFigure in the article’s Supplement 3 suggests that there was a small subpopulation of more robust responders as well as a group of participants with no benefit or worsening while receiving treatment, which is similar to the distribution of benefit seen with other preventive treatments. It will be important to identify factors that predict treatment response and to evaluate the durability of responses.” (E. W. Loder, eloder@bwh.harvard.edu)
>>>PNN NewsWatch
FDA yesterday approved epoetin alfa-epbx (Retacrit, Hospira/Pfizer) as a biosimilar to epoetin alfa (Epogen/Procrit) for the treatment of anemia caused by chronic kidney disease, chemotherapy, or use of zidovudine in patients with HIV infection. The biosimilar is also approved for reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery.

PNN Pharmacotherapy Line
May 17, 2018 * Vol. 25, No. 96
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 17 issue of the New England Journal of Medicine (2018; 378).
As-Needed Budesonide–Formoterol in Mild Asthma: Responding to positive results with as-needed budesonide–formoterol in the Symbicort Given as Needed in Mild Asthma (SYGMA) 1 (pp. 1865–76; P. M. O’Byrne, byrnep@mcmaster.ca">obyrnep@mcmaster.ca) and SYGMA 2 trials (pp. 1877–87; E. D. Bateman, eric.bateman@uct.ac.za), an editorialist provides this advice on applicability to clinical practice (pp. 1940–2): “These two trials show persuasively that treatment with budesonide–formoterol on an as-needed basis prevented the most serious outcomes of poorly controlled asthma — exacerbations and loss of lung function — but was less effective at mitigating symptoms. The effects observed with budesonide–formoterol used as needed occurred at a median daily dose of inhaled glucocorticoid that was only 17% to 25% of that in the regular maintenance group. Not only does this reduce the potential for glucocorticoid side effects and improve the acceptability of the treatment regimen to glucocorticoid-averse patients, but it also has the potential to reduce costs dramatically. Assuming that approximately 18.4 million adults in the United States have asthma, that 65% of these have persistent asthma and 50% to 75% of those cases are mild, and that the average cost of a glucocorticoid inhaler is $218 per month, the savings in drug costs in the United States alone would be close to $1 billion per year.” (S. C. Lazarus)
Cannabidiol in Lennox–Gastaut Syndrome: Cannabidiol 10 or 20 mg/kg/d added to a conventional antiepileptic regimen reduced the frequency of drop seizures more than placebo in children and adults with Lennox–Gastaut syndrome, researchers report (pp. 1888–97). The regimen produced elevated liver enzymes, the group notes, as reported in the results based on a primary outcome of percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period: “A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P = 0.005 for the 20-mg cannabidiol group vs. placebo group, and P = 0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.” (O. Devinsky, d4@nyu.edu">od4@nyu.edu)
Generic-Drug Market Failures: With the goal of providing “a stable supply of generic drugs at an affordable price,” several major drug purchasers are establishing a nonprofit generic-drug manufacturer code-named Project Rx, authors of a Perspective article report (pp. 1857–9). The consortium of hospitals and health plans — including Intermountain Healthcare, Trinity Health, SSM Health, and Ascension, in collaboration with the Department of Veterans Affairs and philanthropists — believes that “Project Rx may drive other nonprofit and for-profit manufacturers to enter generic-drug markets, compete among themselves, and collectively improve market efficiency and broaden access to generic drugs.” (D. Liljenquist)
>>>PNN NewsWatch
FDA yesterday approved lofexidine hydrochloride (Lucemyra, U.S. WorldMeds) for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Useful as part of a broader, long-term treatment plan for managing opioid-use disorder, this nonopioid product suppresses the neurochemical surge that produces the acute and painful symptoms of opioid withdrawal, including aches/pains, muscle spasms/twitching, stomach cramps, muscular tension, heart pounding, insomnia/problems sleeping, feelings of coldness, runny eyes, yawning, and feeling sick.

PNN Pharmacotherapy Line
May 18, 2018 * Vol. 25, No. 97
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Highlights
Source:
 May issue of the Journal of the American Geriatrics Society (2018; 66).
Polypharmacy & Cognitive/Physical Capability: Defined as use of 5 to 8 prescribed medications, polypharmacy at ages 60–64 and age 69 is associated with poorer physical and cognitive capability, researchers report (pp. 916–23). In a longitudinal, birth-cohort study from England, Scotland, and Wales, the relationship also held for those on excessive polypharmacy (9 or more prescribed medications). “Stronger negative associations were seen in participants with long-standing polypharmacy, suggesting a cumulative, dose-dependent relationship (where dose is the number of prescribed medications),” the authors conclude. “Future research aiming to improve cognitive and physical capability should consider interventions to reduce the duration and level of polypharmacy at younger ages, in addition to optimizing disease control with appropriate medications.” (M. J. Rawle, m.rawle@ucl.ac.uk)
Medicare Part D Use by Older Medicare Hospice Patients: Medicare beneficiaries aged 66 years or older commonly receive medications through Part D after hospice admission, a study shows (pp. 937–44). Concluding that “further research aimed at better understanding individual-, provider-, and healthcare system–level contributors to nonpalliative medication use in the hospice population is warranted,” investigators find these patterns in a descriptive cohort analysis using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database for 2008–13: “More than half of individuals admitted to hospice for cancer (53.5%) and noncancer causes (52.9%) received at least 1 medication through Part D after hospice admission. The prevalence of receiving at least 1 Part D medication after admission was greatest in individuals admitted for debility or failure to thrive (63.5%) and dementia (61.5%) and lowest in those admitted for ischemic stroke (35.4%) and renal disease (36.0%). Beta-blockers, angiotensin-converting enzyme inhibitors, proton pump inhibitors, and statins were among the most common preventative drug classes received overall, although prevalence differed according to admission diagnosis. Nearly 1 in 6 individuals received opioids through Part D after admission, with prevalence steadily decreasing over the study period.” (T. A. Lee, toddlee@uic.edu)
Opioid Prescribing After Hydrocodone Rescheduling: In 2013 through 2015, Medicare Part D beneficiaries aged 65 or older received slightly fewer prescriptions for hydrocodone after it was reclassified from Schedule III to Schedule II, according to a retrospective cohort study (pp. 945–53). A 20% sample containing records for more than 2.5 million beneficiaries in each year showed the following: “From 2013 to 2015, the proportion of Medicare Part D enrollees who received a hydrocodone prescription in a year decreased from 21.9% to 18.3%. Monthly rates for hydrocodone prescriptions declined significantly in 2014. The risk of receiving prolonged opioid prescriptions decreased by approximately 7% in the multivariable analyses comparing 2015 to 2013 (prevalence ratio = 0.93, 95% confidence interval (CI) = 0.93–0.94). Medicare enrollees with an original entitlement because of disability or with Medicaid eligibility had smaller decreases in prolonged prescriptions and, unexpectedly, small increases in high-dose prescriptions. Opioid-related hospitalizations did not change significantly, but opioid-related hospitalizations without a documented opioid prescription increased (odds ratio = 1.24, 95% CI = 1.03–1.50).” (Y-F Kuo, yokuo@utmb.edu)
>>>PNN NewsWatch
* First-in-class erenumab-aooe (Aimovig, Amgen) was approved yesterday by FDA for the preventive treatment of migraine in adults. It blocks the calcitonin gene-related peptide receptor, which is believed to play a critical role in migraine. Erenumab-aooe 70 mg is self-administered once monthly via Amgen’s device, the SureClick autoinjector, and does not require a loading dose. Some patients may benefit from a dosage of 140 mg once monthly.
FDA Commissioner Scott Gottlieb, MD, is stressing agency efforts to support the Administration’s push to reduce drug prices through increased competition. A simple action is to draw attention to brand manufacturers who block access to the drugs generic companies need to demonstrate equivalency.

PNN Pharmacotherapy Line
May 21, 2018 * Vol. 25, No. 98
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 (2018; 360).
Text Messages for Diabetes Management Support: Among 366 adults with poorly controlled diabetes, glycemic control was modestly improved through use of tailored text message to support a self-management program, New Zealand researchers report (k1959). Added to usual care over a 9-month period, the text messages produced these changes in a primary outcome of change in glycemic control between baseline and 9 months, and in secondary outcome measures: ‘The reduction in HbA1c at nine months was significantly greater in the intervention group (mean −8.85 mmol/mol (standard deviation 14.84)) than in the control group (−3.96 mmol/mol (17.02); adjusted mean difference −4.23 (95% confidence interval −7.30 to −1.15), P = 0.007). Of 21 secondary outcomes, only four showed statistically significant improvements in favour of the intervention group at nine months. Significant improvements were seen for foot care behaviour (adjusted mean difference 0.85 (95% confidence interval 0.40 to 1.29), P <0.001), overall diabetes support (0.26 (0.03 to 0.50), P = 0.03), health status on the EQ-5D visual analogue scale (4.38 (0.44 to 8.33), P = 0.03), and perceptions of illness identity (−0.54 (−1.04 to −0.03), P = 0.04). High levels of satisfaction with [the text message–based diabetes self management support intervention] were found, with 161 (95%) of 169 participants reporting it to be useful, and 164 (97%) willing to recommend the programme to other people with diabetes.” (R. Dobson, r.dobson@auckland.ac.nz)
>>>Lancet Highlights
Source:
 May 19 issue of Lancet (2018; 391).
Stroke Care in Countries at Different Economic Levels: Better care and facilities are needed in low- and middle-income countries to improve care of patients with stroke, according to the INTERSTROKE study (pp. 2019–27). The international observational study enrolled 13,447 patients in 32 countries. Analysis of data by economic status of countries showed the following: “Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p <0.0001) than those in high-income countries, although only differences in patient characteristics explained the poorer clinical outcomes in low and middle-income countries. However, across all countries, irrespective of economic level, access to a stroke unit was associated with improved use of investigations and treatments, access to other rehabilitation services, and improved survival without severe dependency (odds ratio [OR] 1.29; 95% CI 1.14–1.44; all p <0.0001), which was independent of patient casemix characteristics and other measures of care. Use of acute antiplatelet treatment was associated with improved survival (1.39; 1.12–1.72) irrespective of other patient and service characteristics.” (P. Langhorne, peter.langhorne@glasgow.ac.uk)
>>>PNN NewsWatch
* FDA issued several alerts on Friday: decreased survival associated with the use of pembrolizumab (Keytruda) or atezolizumab (Tecentriq) as monotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the programmed death ligand 1 protein; presence of undeclared sildenafil and/or tadalafil in 7K and Poseidon 4500 (Shoreside Enterprises); and serious cases of neural tube birth defects involving the brain, spine, and spinal cord in babies born to women with HIV treated with dolutegravir.
>>>PNN JournalWatch
Medical Marijuana Use in Older Adults, in Journal of the American Geriatrics Society, 2018: 66: 859–63. (J. Briscoe, Joshua.briscoe@duke.edu)
Endotype-Driven Care Pathways in Patients With Chronic Rhinosinusitis, in Journal of Allergy and Clinical Immunology, 2018: 141: 1543–51. (C. Bachert, Claus.Bachert@ugent.be)
Chronic Inducible Urticaria: A Systematic Review of Treatment Options, in Journal of Allergy and Clinical Immunology, 2018: 141: 1726–34. (M. Maurer, marcus.maurer@charite.de)
Patient-Centered Care in Renal Medicine: Five Strategies to Meet the Challenge, in American Journal of Kidney Diseases, 2018: 71: 732–6. (A. M. O’Hare, ann.ohare@va.gov)

PNN Pharmacotherapy Line
May 22, 2018 * Vol. 25, No. 99
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online articles from Annals of Internal Medicine (2018; 168).
Potential Opioid Misuse & Adverse Outcomes in Medicare: “Clinicians should examine a wide range of misuse patterns” among Medicare beneficiaries taking opioids, conclude authors of an observational study of the years 2008 through 2012 (10.7326/M17-3065). In a 5% sample of patients who had an opioid prescription without a cancer diagnosis, a primary outcome of a diagnosis of opioid overdose in the year after a 6-month index period showed the following: “Overall, 0.6% to 8.5% of beneficiaries fulfilled a misuse measure. Subsequent opioid overdose was positively associated with successively greater numbers of prescribers or pharmacies or higher opioid quantities during the index period. For example, patients who obtained opioids from 2, 3, or 4 prescribers were increasingly more likely to have an opioid overdose (adjusted absolute risk per 1,000 beneficiary–years [aAR], 3.5 [95% CI, 3.3 to 3.7]; 4.8 [CI, 4.5 to 5.2]; or 6.4 [CI, 5.8 to 6.9], respectively) than those with a single prescriber (aAR, 1.9 [CI, 1.8 to 2.0]). Subsequent overdose risk increased meaningfully with any deviation in the single prescriber–single pharmacy opioid use pattern. All misuse measures examined had a positive association with subsequent opioid overdose and death.” (M. L. Barnett, mbarnett@hsph.harvard.edu)
“As prescribers, we are privileged to control access to controlled substances,” editorialists write (
10.7326/M18-1146). “With that privilege comes the responsibility of stewardship. Stewardship programs provide coordinated efforts to promote the appropriate use of medications, improve patient outcomes, and reduce adverse public health effects. The most common and successful stewardship programs have been established in the infectious disease field, where they have increased guideline-concordant provision of antibiotics, decreased microbial resistance, and reduced the spread of multidrug-resistant organisms. Given the risks for overdose and death associated with opioid prescribing and the widespread diversion and nonmedical use of controlled substances in the United States, the current findings should spark processes designed to strengthen our stewardship of controlled substances. As a start, an acute need exists to improve and customize [prescription drug monitoring programs] to better serve the needs of prescribers and, in turn, the patients to whom they provide care.” (L. E. Fiellin, lynn.sullivan@yale.edu)
Amyloid-Beta (1–40) & NSTE-ACS: The role of amyloid-beta (1–40) in cardiovascular disease is advanced in a study that shows a correlation between its serum levels and greater risk of non–ST-segment elevation acute coronary syndrome (NSTE-ACS) (10.7326/M17-1540). In a retrospective cohort study using data from 2 independent prospective cohorts, investigators conclude, “Circulating Aß40 is a predictor of mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of Aß40 as a novel biomarker in NSTE-ACS should be further explored and validated.” (K. Stellos, konstantinos.stellos@ncl.ac.uk)
>>>PNN NewsWatch
FDA yesterday approved avatrombopag (Doptelet, AkaRx) tablets to treat thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by FDA for this indication.
* The American Academy of Pediatrics is advising pediatricians give children 
inactivated influenza vaccine during the upcoming season and use live attenuated influenza vaccine (LAIV) only as a last resort, according to a news article posted on the organization’s website. Because of “unknowns” about vaccine effectiveness of the H1N1 component of LAIV, the Academy expressed concern about “putting some children at risk of getting H1N1 disease and not being protected at all” if 2018–19 is an H1N1-predominant year.
* MBI Distributing, Inc., is voluntarily recalling all lots of 
homeopathic Teething Drops, Nausea Drops, Intestinal Colic Drops, Stomach Calm, Expectorant Cough Syrup, Silver-Zinc Throat Spray, and Argentum Elixir, within expiry, to the consumer level, according to an announcement on the FDA website. The drug products have been found to be manufactured with a lack of adequate controls.

PNN Pharmacotherapy Line
May 23, 2018 * Vol. 25, No. 100
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 22/29 issue of JAMA (2018; 319).
Vitamin D Supplementation & Recurrent Wheezing in Preterm Black Infants: In the D-Wheeze randomized clinical trial, black infants born preterm had lower risk of recurrent wheezing by 12 months of age when they received sustained vitamin D supplementation rather than diet-limited amounts of the nutrient, researchers report (pp. 2086–94). “Future research is needed to better understand the mechanisms and longer-term effects of vitamin D supplementation on wheezing in children born preterm,” the authors conclude, citing their comparison of cholecalciferol 200 IU/d in all participants through age 6 months followed by randomization to 400 IU/d or placebo: “Among 300 patients who were randomized (mean gestational age, 33 weeks; median birth weight, 1.9 kg), 277 (92.3%) completed the trial. Recurrent wheezing was experienced by 31.1% of infants in the sustained supplementation group and 41.8% of infants in the diet-limited supplementation group (difference, −10.7% [95% CI, −27.4% to −2.9%]; relative risk, 0.66 [95% CI, 0.47 to 0.94]). Upper and lower respiratory tract infections were among the most commonly reported adverse events. Upper respiratory infections were experienced by 84 of 153 infants (54.9%) in the sustained group and 83 of 147 infants (56.5%) in the diet-limited group (difference, −1.6% [95% CI, −17.1% to 7.0%]). Lower respiratory infections were experienced by 33 of 153 infants (21.6%) in the sustained group and 37 of 147 infants (25.2%) in the diet-limited group (difference, −3.6% [95% CI, −16.4% to 4.4%]).” (A. M. Hibbs, annamaria.hibbs@cwru.edu)
“In the laboratory, the biological actions of 1,25(OH)
2D3 include inhibiting cellular proliferation and differentiation, inhibiting angiogenesis, and inducing apoptosis,” writes an editorialist (pp. 2081–2). “This metabolite also upregulates anti-inflammatory pathways and downregulates molecules that activate immune and inflammatory cells. Although these known actions suggest potential pathways for the interaction of vitamin D and respiratory disease, a recent review concluded that there are few suitable clinical trials to support the beneficial effect of vitamin D supplementation on respiratory disease.…
“Further follow-up studies of the infants … will be needed to determine whether the effects of prenatal or postnatal supplements of vitamin D on respiratory disease in infants are sustained and to inform practice guidelines.” (F. R. Greer, 
frgreer@pediatrics.wisc.edu)
Health Professionals Increasing Naloxone Awareness & Use: The public health advisory released last month by the U.S. Surgeon General addresses the 115 deaths each day in America from opioid overdoses, according to a Viewpoint article (pp. 2073–4): “An important message for health care practitioners, including prescribers, substance use disorder treatment practitioners, and pharmacists, is to amplify this information. Together, clinicians must increase the awareness, possession, and use of naloxone among at-risk populations and broader communities.” (J. M. Adams, Jerome.Adams@hhs.gov)
Preventing Opioid Addiction Through Neurobiology: Rather than focusing on later stages of drug addiction, research efforts would be more effective if prevention strategies were developed, according to Viewpoint authors (pp. 2071–2). For example, ondansetron was recently found to have “an unexpectedly profound effect on early-stage opioid responses” by “substantially reduc[ing] the symptoms of experimentally induced opioid withdrawal in opioid-naive mice and humans,” the authors write. “[Such] early results provide an indication that an improved research agenda that focuses resources on deeper understanding of opioid neurobiology and on prevention of opioid exposure among high-risk individuals will make it more likely that the clinical and public health response to the opioid epidemic could be effective.” (G. Peltz, gpeltz@stanford.edu)
>>>PNN NewsWatch
FDA yesterday issued yet another statement warning consumers not to use kratom products. “The FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse, and dependence,” the agency said. “There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom.”

PNN Pharmacotherapy Line
May 24, 2018 * Vol. 25, No. 101
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 24 issue of the New England Journal of Medicine (2018; 378).
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer: A pilot study of neoadjuvant nivolumab in adults with untreated, surgically resectable early non–small-cell lung cancer (NSCLC) “was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors,” researchers report (pp. 1976–86): “Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both [programmed death ligand 1 (PD-L1)]–positive and PD-L1–negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.” (D. M. Pardoll, dpardol1@jhmi.edu)
“Although this pilot study revealed important pharmacodynamic information, the sample size was small, and the rate of clinical benefit needs to be confirmed in a larger cohort,” writes an editorialist (
pp. 2034–5). “It is not yet known whether cancer recurrence will be prevented, whether recurrent tumors will retain responsiveness to PD-1 blockade, whether challenging molecular resistance pathways will emerge among recurrent tumors, and whether overall patient survival will be improved. Nonetheless, the observation that two doses of nivolumab could be administered without logistical delay of planned surgical resection will undoubtedly encourage additional studies of neoadjuvant immunotherapy in a range of tumor types. Planned phase 3 trials involving patients with NSCLC will ultimately determine whether recurrence-free and overall survival are improved, thus placing immunotherapy on the front line of cancer treatment.” (T. F. Gajewski)
Burosumab in X-Linked Hypophosphatemia: Burosumab, a recently approved inhibitor of fibroblast growth factor 23, was effective in 52 children with X-linked hypophosphatemia in a phase 2 trial (pp. 1987–98). Open-label subcutaneous doses of the drug every 2 or 4 weeks showed these effects: “The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P <0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity.” (T. O. Carpenter, thomas.carpenter@yale.edu)
>>>PNN NewsWatch
FDA yesterday warned consumers that OTC teething products containing benzocaine pose a serious risk of methemoglobinemia in infants and children. The agency also called on companies to voluntarily stop selling these products for this use and add new warnings to all other benzocaine oral health products to describe the serious risks.

PNN Pharmacotherapy Line
May 25, 2018 * Vol. 25, No. 102
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Medical Care Highlights
Source:
 June issue of Medical Care (2018; 56).
Opioids in Marketplace Plans: In plans offered on the 2017 Health Insurance Marketplace exchanges, medications used in treatment of opioid use disorder (OUD) were often not covered or available only with prior authorization, a study shows (pp. 505–9). A sample of 100 plans available in urban and rural counties and weighted by population showed these results: “About 14% of plans do not cover any formulations of buprenorphine/naloxone. Plans were more likely to require prior authorization for any of the covered office-based buprenorphine or naltrexone formulations preferred for maintenance OUD treatment (ie, buprenorphine/naloxone, buprenorphine implants, injectable long-acting naltrexone) than of short-acting opioid pain medications (63.6% vs. 19.4%; P <0.0001). Only 10.6% of plans cover implantable buprenorphine, 26.1% cover injectable naltrexone, and 73.4% cover at least 1 abuse-deterrent opioid pain medication.” (H. A. Huskamp)
Adherence of Parents & Their Children: Among children starting SSRI therapy for pediatric anxiety disorders, parental medication adherence was linked to whether their children received the medication, researchers report (pp. 510–9). Claims from a commercial database showed these patterns of adherence based on proportion of days covered (PDC) for parental SSRIs, statins, and antihypertensives, and for their children’s SSRI medications: “In 70,979 children with an anxiety disorder (59% = female, 14 = median age), the mean 6-month SSRI PDC was 0.72, with variation by anxiety disorder. Overall 64% of children had high adherence if their parent had high SSRI adherence versus 53% of children with parents with low SSRI adherence (RD, 12%; multivariable risk ratios, 1.17; 95% confidence interval, 1.14–1.20). Findings were similar for parent statin (RD = 10%) and antihypertensive adherence (RD = 8%) and when stratified by child age and parent sex. There was minor improvement in risk reclassification and the c-statistic after adding parent adherence and parent-level covariates.” (G. A. Bushnell)
>>>Health Affairs Report
Source:
 May issue of Health Affairs, a theme issue on Precision Medicine (2018; 37).
Approval Rates of Precision Medicines: Precision medicines — those that have a greater probability of success because of prior patient selection — are developed and approved by FDA more quickly and with less supporting evidence than other drugs, according to this analysis of agency data (pp. 724–31):“In the period January 2013–June 2017, precision medicines were developed and reviewed almost two years faster than nonprecision medicines. In addition, approximately 48 percent of the precision medicines in our study qualified for the FDA’s breakthrough therapy designation. Precision medicines were also approved based on fewer pivotal trials with fewer patients, and the trials were less likely to be randomized, blinded, or controlled with either an active or placebo comparator.” (D. C. Hine, d.hine@uq.edu.au)
Clinical Laboratories & Pharmacogenetic Testing: Pharmacogenetic (PGx) testing available in clinical laboratories offers a broad range of assays and methods, as shown in this survey from late 2017 and early 2018 (pp. 717–23): “76 [laboratories] offered PGx testing services. Of these, 31 offered only tests for single genes; 30 offered only tests for multiple genes; and 15 offered both types of tests. Collectively, 45 laboratories offered 114 multigene panel tests covering 295 genes. The majority of these tests did not have any clinical guidelines. PGx tests vary in type and makeup, which presents challenges in appropriate test evaluation and selection for providers, insurers, health systems, and patients alike.” (S. B. Haga, susanne.haga@duke.edu)
>>>PNN NewsWatch
FDA yesterday approved pegvaliase-pqpz (Palynziq, BioMarin Pharmaceutical) for adults with the rare and serious genetic disease phenylketonuria (PKU). The agent is a novel enzyme therapy indicated for PKU patients who have uncontrolled blood phenylalanine concentrations on current treatment.
Lake Michigan Distilling Company, doing business as Ethanol Extraction, is recalling its 95% Ethyl Alcohol product because of possible contamination with methanol.
PNN will not be published on Mon., May 28, Memorial Day.

PNN Pharmacotherapy Line
May 29, 2018 * Vol. 25, No. 103
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Highlights
Source:
 May 26 issue of Lancet (2018; 391).
Inactivated Zoster Vaccine in HSCT Recipients: In a Merck-sponsored phase 3 trial of an inactivated varicella zoster vaccine, autologous hemopoietic stem-cell transplant (auto-HSCT) recipients benefited from early vaccine administration in the peritransplant period with few adverse effects (pp. 2116–27). At 135 medical centers on four continents, 1,230 adult patients had these outcomes when they received vaccine from one of three consistency lots, a high-antigen lot, or placebo: “249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2.4 years (SD 1.3) in the vaccine consistency lot group and 2.3 years (SD 1.3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32.9 per 1000 person–years) and 113 (21%) of 535 in the placebo group (91.9 per 1000 person–years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63.8% (95% CI 48.4–74.6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0.2%, 95% CI −5.1 to 5.5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0.1%, −1.4 to 1.1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22.6%, 95% CI 18.5–26.6; p <0.0001).” (D. J. Winston, dwinston@mednet.ucla.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 361).
Antidepressants & Weight Gain: U.K. data indicate that widespread use of antidepressants could be contributing to weight gain being observed at the population level (k1951). In a cohort study, patients seen at general practices in 2004–14 showed these weight patterns as related to use of antidepressants: “In the year of study entry, 17,803 (13.0%) men and 35,307 (22.4%) women with a mean age of 51.5 years (SD 16.6 years) were prescribed antidepressants. During 1,836,452 person years of follow-up, the incidence of new episodes of ≥5% weight gain in participants not prescribed antidepressants was 8.1 per 100 person years and in participants prescribed antidepressants was 11.2 per 100 person years (adjusted rate ratio 1.21, 95% confidence interval 1.19 to 1.22, P <0.001). The risk of weight gain remained increased during at least six years of follow-up. In the second year of treatment the number of participants treated with antidepressants for one year for one additional episode of ≥5% weight gain was 27 (95% confidence interval 25 to 29). In people who were initially of normal weight, the adjusted rate ratio for transition to overweight or obesity was 1.29 (1.25 to 1.34); in people who were initially overweight, the adjusted rate ratio for transition to obesity was 1.29 (1.25 to 1.33). Associations may not be causal, and residual confounding might contribute to overestimation of associations.” (R. Gafoor, Rafael.gafoor@kcl.ac.uk)
>>>PNN JournalWatch
Tranexamic Acid for Hyperacute Primary IntraCerebral Haemorrhage (TICH-2): An International Randomised, Placebo-Controlled, Phase 3 Superiority Trial, in Lancet, 2018: 391: 2107–15. (N. Sprigg, nikola.sprigg@nottingham.ac.uk)
Postmarket Studies Required by the US Food and Drug Administration for New Drugs and Biologics Approved Between 2009 and 2012: Cross Sectional Analysis, in BMJ, 2018: 361: k2031. (J. D. Wallach, joshua.wallach@yale.edu)
Women’s Health Policy in the United States: An American College of Physicians Position Paper, in Annals of Internal Medicine, 2018: 10.7326/M17-3344. (H. Daniel, hdaniel@acponline.org)
Switching From Reference Adalimumab to SB5 (Adalimumab Biosimilar) in Patients With Rheumatoid Arthritis—Fifty-Two–Week Phase III Randomized Study Results, in Arthritis & Rheumatology, 2018: 70: 832–40. (M. E. Weinblatt, mweinblatt@partners.org)
Generic Price Competition For Specialty Drugs: Too Little, Too Late?, in Health Affairs, 2018: 37: 10.1377/hlthaff.2017.1684. (A. L. Cole)

PNN Pharmacotherapy Line
May 30, 2018 * Vol. 25, No. 104
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Nephrology Report
Source:
 June issue of the American Journal of Kidney Diseases (2018; 71).
Sodium Overcorrection by Tolvaptan in SIADH: To avoid brain dehydration and irreversible neurologic damage, changes in pretherapy parameters should be monitored while correcting chronic hyponatremia with tolvaptan, researchers report, particularly in those with low serum levels of sodium and urea nitrogen (pp. 772–82). Among adults with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or congestive heart failure (CHF) treated with tolvaptan for a serum sodium concentration ≤130 mEq/L at five U.S. hospitals, these results were noted: “28 patients with SIADH and 39 patients with CHF treated with tolvaptan (mean baseline serum sodium, 120.6 and 122.4 mEq/L, respectively) were studied. Correction of serum sodium concentration > 12 mEq/L/d occurred in 25% of patients with SIADH compared to 3% of those with CHF (P <0.001). Among patients with SIADH, the increase in serum sodium over 24 hours was correlated with baseline serum sodium concentration (r = −0.78; P <0.001), serum urea nitrogen concentration (SUN; r = −0.76; P <0.001), and estimated glomerular filtration rate (r = 0.58; P = 0.01). Baseline serum sodium and SUN concentrations were identified as independent predictors of change in serum sodium concentration in multivariable analyses. When patients were grouped into 4 categories according to baseline serum sodium and SUN median values, those with both low baseline serum sodium (≤121 mEq/L) and low baseline SUN concentrations (≤10 mg/dL) exhibited a significantly greater rate of increase in serum sodium concentration (mean 24-hour increase of 15.4 mEq/L) than the other 3 categories (P <0.05). Among patients with CHF, only baseline SUN concentration was identified as an independent predictor of change in serum sodium concentration over time.” (J. C. Q. Velez, juancarlos.velez@ochsner.org)
“Vaptans could still be the magic bullet for SIADH as was promised when they were first released, but what we have now is a cannon,” an editorialist writes (
pp. 763–5). “More research on dosing strategies is needed to give nephrologists the precision low-caliber weapon needed to attack severe hyponatremia.” (R. H. Sterns, richard.sterns@rochesterregional.org)
ESRD Timeline in Children With CKD: The progression of chronic kidney disease (CKD) in children can be staged using estimated glomerular filtration rate (eGFR) and proteinuria (urine protein–creatinine ratio [UPCR]), a study shows (pp. 783–92). Using a prediction equation derived in the North American Chronic Kidney Disease in Children (CKiD) cohort study, a composite event of renal replacement therapy, 50% reduction in estimated glomerular filtration rate (eGFR), or eGFR <15 mL/min/1.73 m2 showed the following: “Among 1,232 children, median age was 12 (IQR, 8–15) years, median eGFR was 47 (IQR, 33–62) mL/min/1.73 m2, 60% were males, and 13% had UPCRs > 2.0 mg/mg at study entry. 6 ordered stages with varying combinations of eGFR categories (60–89, 45–59, 30–44, and 15–29 mL/min/1.73 m2) and UPCR categories (<0.5, 0.5–2.0, and >2.0 mg/mg) described the risk continuum. Median times to event ranged from longer than 10 years for eGFRs of 45 to 90 mL/min/1.73 m2 and UPCRs < 0.5 mg/mg to 0.8 years for eGFRs of 15 to 30 mL/min/1.73 m2 and UPCRs > 2 mg/mg. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the 10 subsample validation models.” (S. Furth, furths@email.chop.edu)
Clinical Disease From Elevated Urate: “Whether uric acid has a causal role in kidney and cardiovascular diseases requires further study,” concludes a National Kidney Foundation report of a scientific workshop (pp. 851–65; G. M. Chertow, gchertow@stanford.edu).
>>>PNN NewsWatch
* Out-of-sequence placebo capsules in a sample pack of Taytulla (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules, Allergan) has prompted recall of one lot of the oral contraceptive product.
X-Jow and Acne Shave Products (Shadow Holdings) are being recalled because of possible bacterial contamination.

PNN Pharmacotherapy Line
May 31, 2018 * Vol. 25, No. 105
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 31 New England Journal of Medicine (2018; 378).
Immune Checkpoint Inhibitors in NSCLC: Added to standard chemotherapy of pemetrexed and a platinum-based drug, pembrolizumab increased overall survival and progression-free survival in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR or ALK mutations, compared with chemotherapy alone, the KEYNOTE-189 study shows (pp. 2078–92). The phase 3 trial assigned 616 patients to pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy, with these results: “After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P <0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P <0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.” (L. Gandhi, leena.gandhi@nyumc.org)
First-line nivolumab plus ipilimumab also improved responses of patients with NSCLC (
pp. 2093–104). A phase 1 trial showed these results in stage IV or recurrent NSCLC: “Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P <0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy.” (M. D. Hellmann, hellmanm@mskcc.org)
“NSCLC has been a victim of therapeutic nihilism since the meta-analysis reported by the Non-small Cell Lung Cancer Collaborative Group more than two decades ago,” an editorialist writes (
pp. 2135–7). “Have we made clinically significant progress since? Absolutely. Just ask any patient with NSCLC who has benefited from these drugs.” (J. H. Schiller)
>>>PNN NewsWatch
* Based on 155 reports to the Vaccine Adverse Event Reporting System in involving the new shingles vaccine, CDC authors advise, “Vaccine providers should be aware of prescribing information, storage requirements, preparation guidelines, and [Advisory Committee on Immunization Practice] recommendations for herpes zoster vaccines.” In an MMWR article, reports of errors involving subcutaneous administration (5 reports), reconstitution (5), incorrect interval or schedule (2), and administration of previously frozen vaccine (1) are discussed.
* Responding to signing of the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina 
Right to Try Act of 2017FDA Commissioner Scott Gottlieb, MD, writes, “This new law amends the Federal Food, Drug, and Cosmetic Act to establish a new pathway aimed at increasing access to unapproved, investigational treatments for patients diagnosed with life-threatening diseases or conditions who have exhausted approved treatment options and who are unable to participate in a clinical trial. Our implementation of the Right to Try Act will build on our long-standing efforts to help patients and families who are facing life-threatening diseases or conditions, in a way that seeks to protect their autonomy, their safety, and the safety of others following in their paths.”


PNN Pharmacotherapy Line
June 1, 2018 * Vol. 25, No. 106
Providing news and information about medications and their proper use

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>>>Diabetes Care Report
Source:
 June issue of Diabetes Care (2018; 41).
CAM Use in Older Adults With Diabetes: Large numbers of older Americans with diabetes used some type of complementary and alternative medicine (CAM) in the year preceding their completion of the 2012 National Health Interview Survey (NHIS), a study shows (pp. e95–6). A sample of 1,475 respondents aged 65 years or older with any type of diabetes, extrapolated nationally, reported the following: “In 2012, more than 2 million older adults with diabetes (25.0%) used some form of CAM in the past year. Among older CAM users with diabetes, the mean age was 72.4 years and 54.3% were female. Race/ethnicity consisted primarily of non-Hispanic whites (73.4%), non-Hispanic blacks (8.8%), and Hispanics (10.6%). Of this sample, over half (56.2%) had some college or higher education.
“The most commonly used classes of CAM were biologically based therapies (62.8%) and manipulative body therapies (36.8%). The most commonly used individual therapies were herbal therapies (62.8%), chiropractic (23.9%), massage (14.7%), acupuncture (10.2%), and yoga (5.2%). Significant prevalence differences by reason for use (for treatment, wellness, or both) were found for herbal therapies, chiropractic, and meditation.” (T. G. Rhee, 
taeho.rhee@yale.edu)
Insulin Access and Affordability: After analyzing the complex insulin supply chain and evaluating drug pricing in the Medicare, Medicaid, and other health insurance systems in the U.S., an American Diabetes Association working group reaches several conclusions and makes numerous recommendations to address access and affordability issues (pp. 1299–311). “After discussions with more than 20 stakeholders in the insulin supply chain, the Working Group remains concerned by the complexity of the system,” members write. “There are numerous stakeholders involved in the delivery of insulin, with multiple opaque transactions between and among these stakeholders. It was also the consensus of the Working Group that incentives throughout the insulin supply chain facilitate and may even promote high list prices.” (W. T. Cefalu, wcefalu@diabetes.org)
In a Perspectives in Care article, authors expand the discussion to include a global perspective (pp. 1125–31): “In the U.S., the rate of diabetic ketoacidosis remains high in certain subpopulations, the cost of insulin being the main precipitating factor. On a global level the main cause of mortality for a child with type 1 diabetes is a lack of access to insulin, and in sub-Saharan Africa the life expectancy of a child with type 1 diabetes can be as low as 1 year. One lens for considering the issue of access to health and medicines is to consider society as a three-legged stool. In this paradigm, the role of the public sector is to provide ‘protections’ to the population it serves; the private sector is made up of ‘responsible businesses’ that supply many of the goods and services people need; and the plural sector comprises communities and not-for-profits providing the ‘social affiliations’ that are needed. For HIV/AIDS, each of these ‘legs’ played a role in improving access. Civil society raised awareness of the issue and advocated for access to treatment. Governments provided funding and responses both nationally and globally. Finally, the private sector played its role, under pressure from civil society and governments, in lowering the price of medicines and developing programs to expand access. Here, we use this framework to describe the shortcomings in access to insulin from a U.S. and global perspective.” (D. Beran, 
david.beran@unige.ch)
>>>PNN NewsWatch
Apotex is recalling a single lot of Fluticasone Propionate Nasal Spray 50 mcg per spray 120 Metered Sprays because small glass particles may be present and occlude the drug-delivery pump or be delivered to the nasal mucosa.
* In statements issued yesterday, the 
FDA Commissioner addresses agency efforts to mitigate shortages of intravenous drug products and create new policies to block brand drug makers from using REMS programs to prevent market entry of generic alternatives.
FDA on Wednesday approved the first stand-alone prosthetic iris in the U.S. It is surgically implanted to treat adults and children whose iris is completely missing or damaged because of congenital aniridia or other damage to the eye.

PNN Pharmacotherapy Line
June 4, 2018 * Vol. 25, No. 107
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 June 2 issue of Lancet (2018; 391).
Guselkumab in Psoriatic Arthritis: During a 44-week trial, signs and symptoms of active psoriatric arthritis were reduced among patients receiving the novel anti-interleukin 23p19 antibody guselkumab, researchers report (pp. 2213–24). Investigators in the phase 2a study report these outcomes from 34 specialty clinics in North America, Europe, and Russia: “Between March 27, 2015, and Jan 17, 2017, we randomly assigned 149 patients to treatment: 100 to guselkumab and 49 to placebo. 17 (35%) of 49 patients in the placebo group and ten (10%) of 100 patients in the guselkumab group were eligible for early escape to ustekinumab at week 16. 29 (59%) of 49 patients in the placebo group crossed over and received guselkumab at week 24. Three (6%) of 49 patients in the placebo group, one (3%) of 29 patients who crossed over from placebo to guselkumab, and six (6%) of 100 patients in the guselkumab group discontinued study treatment before week 44. 58 (58%) of 100 patients in the guselkumab group and nine (18%) of 49 patients in the placebo group achieved an ACR20 response at week 24 (percentage difference 39.7% [95% CI 25.3–54.1]; p <0.0001). Between week 0 and week 24, 36 (36%) of 100 guselkumab-treated patients and 16 (33%) of 49 placebo-treated patients had at least one adverse event. The most frequent adverse event was infection in both groups (16 [16%] of 100 patients in the guselkumab group vs ten [20%] of 49 patients in the placebo group). The prevalence of adverse events between week 0 and week 56 in guselkumab-treated patients (51 [40%] of 129) indicated no disproportional increase with longer guselkumab exposure. No deaths occurred.” (A. Deodhar, deodhara@ohsu.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 361).
Alcohol Intake, CHD & Stroke: Recommendations to reduce alcohol consumption are supported by results of a multicenter case–cohort study of 32,549 participants without baseline cardiovascular disease (CVD) (k934). Opposing effects of alcohol were evident, with higher intake associated with lower nonfatal coronary heart disease (CHD) but increased rates of stroke, as shown in these results: “There were 9,307 non-fatal CHD events, 1,699 fatal CHD, 5,855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0–14.9 g/day, 15.0–29.9 g/day, and 30.0–59.9 g/day of total alcohol intake, respectively, compared with 0.1–4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events.” (P. Ferrari, ferrarip@iarc.fr)
>>>PNN JournalWatch
Clinical Management of Psoriatic Arthritis, in Lancet, 2018: 391: 2285–94. (F. Van den Bosch, filip.vandenbosch@ugent.be)
Aspects of Multicomponent Integrated Care Promote Sustained Improvement in Surrogate Clinical Outcomes: A Systematic Review and Meta-analysis, in Diabetes Care, 2018: 41: 1312–20. (J. C. N. Chan, jchan@cuhk.edu.hk)
Outpatient Antibiotic Use and the Need for Increased Antibiotic Stewardship Efforts, in Pediatrics, 2018: 141: e20174124. (R. M. Zetts)
Nonpharmacologic Treatments for Attention-Deficit/Hyperactivity Disorder: A Systematic Review, in Pediatrics, 2018: 141: e20180094. (A. P. Goode)
Cardiovascular Outcomes of Cholinesterase Inhibitors in Individuals with Dementia: A Meta-Analysis and Systematic Review, in Journal of the American Geriatrics Society, 2018: 10.1111/jgs.15415.  (A. T. Isik, atisik@yahoo.com)
Anxiety About Antidepressants, in American Journal of Psychiatry, 2018: 10.1176/appi.ajp.2018.18040399. (R. H. Perlis, rperlis@mgh.harvard.edu)

PNN Pharmacotherapy Line
June 5, 2018 * Vol. 25, No. 108
Providing news and information about medications and their proper use

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>>>Internal Medicine Report
Source:
 Early-online articles from and June 5 issue of Annals of Internal Medicine (2018; 168).
PDMPs & Drug Overdoses: An increase in heroin overdoses was one of the unintended consequences that occurred in some studies of prescription drug monitoring programs (PDMPs), researchers report (pp. 783–90). Concluding that “evidence that PDMP implementation either increases or decreases nonfatal or fatal overdoses is largely insufficient,” the authors found these patterns in a systematic review of 17 articles: “These articles examined PDMP implementation only (n = 8), program features only (n = 2), PDMP implementation and program features (n = 5), PDMP implementation with mandated provider review combined with pain clinic laws (n = 1), and PDMP robustness (n = 1). Evidence from 3 studies was insufficient to draw conclusions regarding an association between PDMP implementation and nonfatal overdoses. Low-strength evidence from 10 studies suggested a reduction in fatal overdoses with PDMP implementation. Program features associated with a decrease in overdose deaths included mandatory provider review, provider authorization to access PDMP data, frequency of reports, and monitoring of nonscheduled drugs. Three of 6 studies found an increase in heroin overdoses after PDMP implementation.” (D. S. Fink, dsf2130@columbia.edu)
Revised Estimates of Atherosclerotic CVD Risk: The accuracy of 2013 pooled cohort equations (PCEs) at the heart of prevention guidelines for cardiovascular disease (CVD) can be improved through analysis of large databanks, particularly for blacks, according to investigators who used population data to derive and validate new risk equations (10.7326/M17-3011). Data from six U.S. cohorts with a total of 26,689 adults aged 40–79 years yielded these results: “The 2013 PCEs overestimated 10-year risk for atherosclerotic CVD by an average of 20% across risk groups. Misestimation of risk was particularly prominent among black adults, of whom 3.9 million (33% of eligible black persons) had extreme risk estimates (<70% or >250% those of white adults with otherwise-identical risk factor values). Updating these equations improved accuracy among all race and sex subgroups. Approximately 11.8 million U.S. adults previously labeled high-risk (10-year risk ≥7.5%) by the 2013 PCEs would be relabeled lower-risk by the updated equations.” (S. Basu, basus@stanford.edu)
“Risk prediction is an evolving science and will require continual updating through the study of contemporary data from various sources, including consortia of traditional cohorts and ‘big data’ from electronic medical records,” editorialists write (
10.7326/M18-1175). “Risk prediction models that rely solely on risk factors are ultimately limited by how these factors are measured, factors not accounted for in the model, and how the included factors affect individual patients with differing susceptibility to cardiovascular injury. Measures of subclinical vascular disease (such as coronary artery calcium) can assess the cumulative effect of risk factors on a person and improve risk prediction beyond models that use [atherosclerotic cardiovascular disease (ASCVD)] risk factors alone. However, even accurate measures of atherosclerotic burden have limitations. Although atherosclerosis is a requisite substrate for ASCVD events, not all atherosclerotic plaques result in ASCVD events. Factors beyond atherosclerotic burden must be identified to predict susceptibility to the transition from stable atherosclerosis to an ASCVD event.” (A. P. DeFilippis, APDeFi01@louisville.edu)
>>>PNN NewsWatch
FDA yesterday approved pegfilgrastim-jmdb (Fulphila, Mylan) as the first biosimilar to pegfilgrastim (Neulasta). It is indicated for reduction the duration of febrile neutropenia in patients with nonmyeloid cancer who are receiving myelosuppressive chemotherapy.
Hospira is voluntarily recalling lots 72680LL and 76510LL of Naloxone Hydrochloride Injection, USP, 0.4 mg/mL, 1 mL in 2.5 mL, Carpuject Single-use cartridge syringe system to the hospital/institution level because of potential presence of embedded and loose particulate matter on the syringe plunger.
* Numerous 
studies have been published early on the New England Journal of Medicine website in conjunction with the recent meeting of the American Society of Clinical Oncology.

PNN Pharmacotherapy Line
June 6, 2018 * Vol. 25, No. 109
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 June 5 issue of JAMA (2018; 319).
Value-Based Drug Pricing: Three Viewpoint articles examine aspects of value-based drug pricing. 
With the costs of some drug regimens approaching $1 million, a variety of approaches using different terms are being proposed that loosely fit under the umbrella of “value-based pricing,” authors write (
pp. 2165–6). “The current system, in which prices reflect ‘what the market will bear,’ has been plagued by price hikes on legacy drugs and wide dissociations between prices of drugs and their benefits,” the authors write. “The term value-based pricing has been redefined beyond its original meaning, and now constitutes shorthand for any change to traditional payment models for drugs, regardless of the underlying approach to determining the final price of the product. All of the efforts that are labeled value-based pricing to date remain constrained to branded pharmaceuticals, which account for 11% of prescriptions and 77% of spending on prescription drugs and more specifically to the 2% of drugs that are considered specialty drugs and comprise 43% of net spending. Despite sharing jargon, these concepts vary widely in their capacity to align the price of a drug with its capacity to improve health outcomes.” (A. Kaltenboeck, kaltenba@mskcc.org)
The U.S. pharmaceutical market is being challenged simultaneously by high prices for payers and high access barriers for patients, authors conclude (
pp. 2169–70): “Drug manufacturers require sufficient revenues to sustain research, but can accept lower prices if clinically appropriate patients have good access to their products. Insurers require health care cost moderation but can facilitate patient access to prescribed medications if drugs are priced at value-based benchmark levels. While some payers and manufacturers may prefer the unsatisfactory status quo, others may recognize a mutual interest in more collaborative contracts that reduce prices and barriers to access. Indeed, with fewer barriers for prescribing, it is quite possible that as overall use of a drug increases, overall revenue also may increase rather than decrease. Physicians would benefit from reduced administrative burdens and patients would benefit from access to the medications they need to sustain and improve their health.” (J. C. Robinson, James.Robinson@Berkeley.edu)
Seeking to identify “a more sustainable path for targeted cancer drugs,” authors suggest three steps (
pp. 2167–8): FDA should define minimum clinically meaningful effect sizes, Medicare should negotiate for targeted cancer drugs, and guidelines should prioritize drugs by benefit and price. “Successfully implementing steps to limit the use of high-priced, marginally effective drugs will be difficult; patients with life-threatening diseases may expect access to drugs despite their high costs and limited benefits,” the group concludes. “Nevertheless, the ultimate beneficiaries of these changes will be patients, who deserve the substantial efficacy, reduced toxicity and enhanced value that were the original promise of targeted cancer drugs.” (J. E. Bekelman, bekelman@upenn.edu)
ED Treatment of OUD: Physicians in emergency departments (EDs) have begun initiating buprenorphine therapy i patients with opioid use disorder, according to a news article (pp. 2158–60). While completion of the required education is a barrier to moving into this type of treatment during emergency care, the need is there, given the backlog of cases in addiction clinics: “‘Word spreads very, very fast on the street,’ [one physician] said, so now most patients who come to the ED in search of opioid use disorder treatment must wait 4 to 6 weeks to get into her hospital’s addiction clinic. Between the time they get a dose of buprenorphine in the ED and the time a spot opens for them in the clinic, ‘a lot of people just buy Suboxone [a brand of buprenorphine plus naloxone] on the street,’ which costs less than a packet of heroin.” (R. Rubin)
>>>PNN NewsWatch
FDA yesterday said that it has warned nine online networks, operating a total of 53 websites, that they must stop illegally marketing potentially dangerous, unapproved, and misbranded versions of opioid medications, including tramadol and oxycodone. The agency also has issued warning letters to the parties responsible for liquidcaffeine.com and Dual Health Body and Mind for illegally selling certain highly concentrated caffeine products.

PNN Pharmacotherapy Line
June 7, 2018 * Vol. 25, No. 110
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 June 7 issue of the New England Journal of Medicine (2018; 378).
Medical Management of Early Pregnancy Loss: Mifepristone pretreatment improved the effectiveness of misoprostol management of early pregnancy loss, a study shows (pp. 2161–70). A total of 300 women with pregnancy loss in the first trimester were randomly assigned to mifepristone 200 mg orally, followed by misoprostol 800 μg vaginally (mifepristone-pretreatment group), or misoprostol 800 μg vaginally (misoprostol-alone group). Ultrasound examinations 1 to 4 days later showed the following outcomes: “Complete expulsion after one dose of misoprostol occurred in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8 to 89.3) in the mifepristone-pretreatment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the misoprostol-alone group (relative risk, 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; relative risk, 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P = 0.31); pelvic infection was diagnosed in 1.3% of the women in each group.” (C. A. Schreiber, schreibe@upenn.edu)
“Medical management should never be the only treatment for women with miscarriage; women who are bleeding heavily and women who prefer surgical management should have prompt access to aspiration,” writes an editorialist (
pp. 2232–3). “Symptomatic women should be able to undergo aspiration in emergency departments, and asymptomatic women in the office setting. The treatment of miscarriage in the operating room is not cost-effective or convenient and should be rare. The trial by Schreiber et al. supports a better approach for women who want medical management for miscarriage. To provide better care for the more than half a million U.S. women with miscarriage each year, we need to work on improving availability of this and other office-based treatments.” (C. L. Westhoff)
Rivaroxaban for Stroke Prevention After Idiopathic Embolic Stroke: In patients with embolic strokes of undetermined source — 20% of those with ischemic strokes — rivaroxaban was not superior to aspirin in prevention of recurrent stroke (pp. 2191–201). The NAVIGATE ESUS trial produced these results based on a primary efficacy outcome of first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis: “A total of 7,213 participants were enrolled at 459 sites; 3,609 patients were randomly assigned to receive rivaroxaban and 3,604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P = 0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P <0.001).” (R. G. Hart, robert.hart@phri.ca)
Bezafibrate in Primary Biliary Cholangitis: At 21 French centers, treatment with bezafibrate produced significantly better results among patients with primary biliary cholangitis (formerly primary biliary cirrhosis) (pp. 2171–81). The pan peroxisome proliferator–activated receptors (PPAR) agonist produced these results among 100 patients in the 24-month, phase 3 Bezafibrate in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis (BEZURSO) trial: “Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy.” (C. Corpechot, christophe.corpechot@aphp.fr)

PNN Pharmacotherapy Line
June 8, 2018 * Vol. 25, No. 111
Providing news and information about medications and their proper use

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>>>Chest Highlights
Source:
 June issue of Chest (2018; 153).
Beta-Blockers in COPD: “Cautious and appropriate use of beta-blockers” in patients with moderate to very severe COPD is supported by the phase 3 TONADO 1 and 2 studies (pp. 1315–25). Among 5,162 patients being treated with long-acting bronchodilators, post-hoc analysis shows these outcomes for the subgroup of patients receiving beta-blockers: “In total, 557 of 5,162 patients (11%) received beta-blockers at baseline. Postbronchodilator FEV1at baseline was higher in the beta-blocker group (1.470 L) compared with that in the no beta-blocker group (1.362 L). As expected, patients receiving beta-blockers had a more frequent history of cardiovascular comorbidities and medications. Lung function improved from baseline in patients with or those without beta-blocker treatment, and no relevant between-group differences were observed in trough FEV1 or trough FVC at 24 or 52 weeks. No relevant differences were observed for St. George’s Respiratory Questionnaire results and Transition Dyspnea Index in patients with beta-blockers compared with those in patients without. Safety findings were comparable between groups.” (F. Maltais, Francois.Maltais@fmed.ulaval.ca)
“[These results indicate} there is no risk of treating patients with [cardiovascular disease], suffering from concomitant COPD, with dual bronchodilation when a beta-blocker is added,” editorialists write (
pp. 1289–91). “However, results could have been influenced by less severe COPD and a higher mean baseline postbronchodilator FEV1 in the beta-blocker group. Furthermore, the study did not include patients with significant cardiac disease, and more patients in the beta-blocker group were taking angiotensin-converting enzyme inhibitors, angiotensin II antagonists, and lipid-modifying agents compared with the no-beta-blocker group. These aspects were not irrelevant in potentially affecting the conclusions of the study, although data have been adjusted for these drugs.” (M. Cazzola, mario.cazzola@uniroma2.it)
TB Risk With Metformin: Compared with sulfonylureas, patients on metformin for type 2 diabetes mellitus (T2DM) had a significantly lower risk of tuberculosis (TB) during the first 2 years of treatment, according to this analysis of the Taiwan National Health Insurance Research Database (pp. 1347–57): “Among 40,179 patients with T2DM, 263 acquired TB (0.65%) over a mean follow-up of 6.1 years. In multivariate analysis, the initial 2-year dosage of metformin, but not that of the sulfonylureas, was an independent predictor of TB (60-[cumulative defined daily dose] increase (adjusted hazard ratio [HR], 0.931; 95% CI, 0.877-0.990) after adjustment by cofactors, including adapted diabetes complication severity index. Metformin majors had a significantly lower TB risk than that of sulfonylurea majors before and after matching (HR, 0.477; 95% CI, 0.268–0.850 and HR, 0.337; 95% CI, 0.169–0.673; matched pairs, n = 3,161).…” (W-J Su, wjsu.mail@gmail.com)
>>>Pediatrics Report
Source:
 June issue of Pediatrics (2018; 141).
Pediatric ADHD Medication Exposures: Accidental and intentional exposures of pediatric patients to attention-deficit/hyperactivity disorder drugs are increasingly common, according to this analys of 156,365 incidents reported to U.S. poison control centers in 2000–114 (10.1542/peds.2017-3872): “The overall rate of reported exposures increased 71.2% from 2000 to 2011, followed by a 6.2% decrease from 2011 to 2014. Three-fourths (76.0%) of exposures involved children ≤12 years old. Methylphenidate and amphetamine medications accounted for 46.2% and 44.5% of exposures, respectively. The most common reason for exposure was therapeutic error (41.6%). Intentional medication exposures (including suspected suicide and medication abuse and/or misuse) were reported most often among adolescents (13–19 years old), accounting for 50.2% of exposures in this age group. Overall, the majority of exposed individuals (60.4%) did not receive health care facility treatment; however, 6.2% were admitted to a hospital for medical treatment, and there were 3 deaths. The increasing number and rate of reported ADHD medication exposures during the study period is consistent with increasing trends in ADHD diagnosis and medication prescribing. Exposures associated with suspected suicide or medication abuse and/or misuse among adolescents are of particular concern.” (S. A. King)

PNN Pharmacotherapy Line
June 11, 2018 * Vol. 25, No. 112
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>>>Lancet Highlights
Source:
 June 9 issue of Lancet (2018; 391).
Dabigatran for Myocardial Injury After Noncardiac Surgery: Among patients with myocardial injury after noncardiac surgery (MINS), dabigatran decreased the risk of major vascular complications without increasing major bleeding (pp. 2325–34). Conducted at 84 hospitals in 19 countries, the MANAGE trial compared dabigatran 110 mg twice daily with placebo for a maximum of 2 years or until the study ended. Results based on an efficacy outcome of major vascular complication and a safety outcome of life-threatening, major, or critical organ bleeding showed the following: “Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1,754 patients to receive dabigatran (n = 877) or placebo (n = 877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0.72, 95% CI 0.55–0.93; p = 0.0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0.92, 95% CI 0.55–1.53; p = 0.76).” (P. J. Devereaux, philipj@mcmaster.ca)
Renal Denervation & Blood Pressure Treated With Antihypertensive Drugs: In the first 80 study patients with uncontrolled hypertension while on medications, renal denervation significantly reduced blood pressure compared with sham control, investigators in a randomized trial report (pp. 2346–55). No major safety events occurred, the authors note, and medication nonadherence was common: “Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure −7.0 mm Hg, 95% CI −12.0 to −2.1; p = 0.0059, 24 h diastolic blood pressure −4.3 mm Hg, −7.8 to −0.8; p = 0.0174, office systolic blood pressure −6.6 mm Hg, −12.4 to −0.9; p = 0.0250, and office diastolic blood pressure −4.2 mm Hg, −7.7 to −0.7; p = 0.0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference −6.8 mm Hg, 95% CI −12.5 to −1.1; p = 0.0205), 24 h systolic blood pressure (difference −7.4 mm Hg, −12.5 to −2.3; p=0.0051), office diastolic blood pressure (difference −3.5 mm Hg, −7.0 to −0.0; p = 0.0478), and 24 h diastolic blood pressure (difference −4.1 mm Hg, −7.8 to −0.4; p = 0.0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group.” (D. E. Kandzari, david.kandzari@piedmont.org)
>>>PNN NewsWatch
* A consent decree entered on Friday prohibits Delta Pharma and other defendants from manufacturing, processing, packing, holding, or distributing Delta Pharma’s drugs until they comply with the Federal Food, Drug, and Cosmetic Act and FDA regulations, the agency said.
>>>PNN JournalWatch
Paternal Use of Antidepressants and Offspring Outcomes in Sweden: Nationwide Prospective Cohort Study, in BMJ, 2018: 361: k2233. (S. Sandin, sven.sandin@ki.se)
Genetic Ancestry for Sleep Research: Leveraging Health Inequalities to Identify Causal Genetic Variants, in Chest, 2018: 153: 1478–96. (B. Prasad, bpradsad@uic.edu)
Mobile Health Advances in Physical Activity, Fitness, and Atrial Fibrillation: Moving Hearts, in Journal of the American College of Cardiology, 2018: 71: 10.1016/j.jacc.2018.04.030. Part of a focus seminar on technology in cardiovascular care. (M V. McConnell)
Comparison of Reduced-Dose Prasugrel and Standard-Dose Clopidogrel in Elderly Patients With Acute Coronary Syndromes Undergoing Early Percutaneous Revascularization, in Circulation, 2018: 137: 2435–45. (S. Savonitto, s.savonitto@asst-lecco.it)

PNN Pharmacotherapy Line
June 12, 2018 * Vol. 25, No. 113
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online articles from and June issue of JAMA Internal Medicine (2018; 178).
Inpatient Opioid Standard of Practice Intervention: A provider education intervention shows promise for improving prescribing patterns for inpatients with pain, a study shows, with effective pain relief while using fewer opioids (pp. 759–63). In the pilot study, opioid use in an adult general medical unit was assessed during a 6-month control period and for 3 months after implementation of a local opioid standard of practice, a preference for oral and subcutaneous routes over I.V. administration, and education for attending physicians, nurse practitioners, and physician assistants. Results showed: “The control period included 4,500 patient–days, and the intervention period included 2,459 patient–days. Of 127 patients in the intervention group, 59 (46.5%) were men; mean (SD) age was 57.6 (18.5) years. Intravenous opioid doses were reduced by 84% (0.06 vs 0.39 doses per patient–day, P < .001), and doses of all parenteral opioids were reduced by 55% (0.18 vs 0.39 doses per patient–day, P < .001). In addition, mean (SD) daily parenteral opioid exposure decreased by 49% (2.88 [0.72] vs 5.67 [1.14] morphine-milligram equivalents [MMEs] per patient–day). The daily rate of patients administered any parenteral opioid decreased by 57% (6% vs 14%; P < .001). Doses of opioids given by oral or parenteral route were reduced by 23% (0.73 vs 0.95 doses per patient–day, P = .02), and mean daily overall opioid exposure decreased by 31% (6.30 [4.12] vs 9.11 [7.34] MMEs per patient–day). For hospital days 1 through 3, there were no significant postintervention vs preintervention differences in mean reported pain score for patients receiving opioid therapy: day 1, –0.19 (95% CI, −0.94 to 0.56); day 2, −0.49 (95% CI, −1.01 to 0.03); and day 3, −0.54 (95% CI, −1.18 to 0.09). However, significant improvement was seen in the intervention group on days 4 (−1.07; 95% CI, −1.80 to −0.34) and 5 (−1.06; 95% CI, −1.84 to −0.27).” (A. L. Ackerman, adam.ackerman@ynhh.org)
Buprenorphine Formulations for Opioid Use Disorder: Potential advantages of depot buprenorphine are suggested in a noninferiority trial of weekly and monthly subcutaneous (SC) buprenorphine depot formulations and a daily sublingual (SL) combination of buprenorphine and naloxone in patients with opioid use disorder (pp. 764–73). Participants were randomized to daily SL buprenorphine with naloxone for 24 weeks with matched weekly and monthly SC placebo injections (SL-BPN/NX group) or SL placebo plus weekly (first 12 weeks) or monthly (second 12 weeks) SC buprenorphine (SC-BPN group), with these results: “A total of 428 participants (263 men [61.4%] and 165 women [38.6%]; mean [SD] age, 38.4 [11.0] years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, −4.0% to 9.9%; P < .001). The proportion of opioid-negative urine samples was 1,099 of 3,870 (28.4%) for the SL-BPN/NX group and 1,347 of 3,834 (35.1%) for the SC-BPN group, a 6.7% difference (95% CI, −0.1% to 13.6%; P < .001). The [cumulative distribution function (CDF)] for the SC-BPN group (26.7%) was statistically superior to the CDF for the SL-BPN/NX group (0; P = .004). Injection site adverse events (none severe) occurred in 48 participants (22.3%) in the SL-BPN/NX group and 40 (18.8%) in the SC-BPN group.” (M. R. Lofwall, michelle.lofwall@uky.edu)
Reconsidering GFR Limits on Metformin Use: Responding to a study showing that lactic acidosis occurred with metformin use primarily in patients with estimated glomerular filtration rates (eGFRs) of less than 30 mL/min/1.73 m2 (10.1001/jamainternmed.2018.0292; M. E. Grams, mgrams2@jhmi.edu), editorialists support cautious use of the drug in those with type 2 diabetes who have less severe chronic kidney disease (10.1001/jamainternmed.2018.0301). “Caveats are critical,” they note. “Repeated eGFR measurement [are needed] given the limitation in the accuracy of a single eGFR determination. If receiving metformin, those at higher risk for dehydration due to concomitant medication use (especially sodium-glucose co-transporter 2 inhibitors and diuretics), social circumstances, and comorbid conditions should be carefully monitored for symptoms or worsening renal function.” (L. M. Pogach, leonard.pogach@va.gov)

PNN Pharmacotherapy Line
June 13, 2018 * Vol. 25, No. 114
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 June 12 issue of JAMA (2018; 319).
Medication-Induced Depression: Use of medications that cause depression as an adverse effect is common, according to data from the National Health and Nutrition Examination Surveys conducted in 2005–06 through 2013–14 (pp. 2289–98). Multivariable logistic regression showed associations between use of these medications and concurrent depression in adults: “The study included 26,192 adults (mean age, 46.2 years [95% CI, 45.6–46.7]; women, 51.1%) and 7.6% (95% CI, 7.1%–8.2%) reported depression. The overall estimated prevalence of use of medications with depression as an adverse effect was 37.2%, increasing from 35.0% (95% CI, 32.2%–37.9%) in the cycle years 2005 and 2006 to 38.4% (95% CI, 36.5%–40.3%) in 2013 and 2014 (P for trend = .03). An estimated 6.9% (95% CI, 6.2%–7.6%) reported use of 3 or more concurrent medications with a potential for depression as an adverse effect in 2005 and 2006 and 9.5% (95% CI, 8.4%–10.7%) reported such use in 2013 and 2014 (P for trend = .001). In adjusted analyses excluding users of antidepressants, the number of medications used with depression as possible adverse effects was associated with increased prevalence of concurrent depression. The estimated prevalence of depression was 15% for those reporting use of 3 or more medications with depression as an adverse effect vs 4.7% for those not using such medications (difference, 10.7% [95% CI, 7.2%–14.1%]). These patterns persisted in analyses restricted to adults treated with antidepressants, among hypertensive adults, and after excluding users of any psychotropic medication.” (D. M. Qato, dimaqato@uic.edu)
Recombinant Human Pentraxin 2 in Idiopathic Pulmonary Fibrosis: In a 28-week preliminary study, the decline in lung function among those with idiopathic pulmonary fibrosis (IPF) was slowed by use of the recombinant human pentraxin 2 compared with placebo (pp. 2299–307). The phase 2 international trial included patients with varying levels of pulmonary function and produced these results: “Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in [forced vital capacity] percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was −2.5 vs −4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, −27.7 to 214.7]), quantitative parenchymal features on [high-resolution computed tomography] (normal lung volume difference, −1.2% [90% CI, −4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, −2.2 to 4.3]), or measurement of [diffusing capacity for carbon monoxide] (difference, −0.4 [90% CI, −2.6 to 1.7]). The change in 6-minute walk distance was −0.5 m for patients treated with recombinant human pentraxin 2 vs −31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%).” (G. Raghu, graghu@uw.edu)
Oral Fluconazole in Pregnancy: In Sweden and Norway, nationwide registry data show no relationship between use of fluconazole during pregnancy and stillbirths or neonatal death (pp. 2333–5). A cohort study of more than 2 million pregnancies found “2.7 stillbirths per 1,000 exposed pregnancies and 3.6 per 1,000 unexposed pregnancies (HR, 0.76 [95% CI, 0.52–1.10]), and 1.2 neonatal deaths per 1,000 exposed pregnancies and 1.7 per 1,000 unexposed pregnancies (RR, 0.73 [95% CI, 0.42–1.29.” (B. Pasternak, bjorn.pasternak@ki.se)
Evolution of PBMs: Authors of a Viewpoint article examine the development of pharmacy benefits managers and the impact of mergers and insurer policy changes on drug prices (pp. 2269–70; K. A. Schulman, kevin.schulman@duke.edu).
>>>PNN NewsWatch
* FDA Commissioner Scott Gottlieb, MD, yesterday issued statements on new tools to fight antimicrobial-resistant infections and new efforts to advance medical product communications to support drug competition and value-based health care.

PNN Pharmacotherapy Line
June 14, 2018 * Vol. 25, No. 115
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Online articles and June 14 issue of the New England Journal of Medicine (2018; 378).
Paying for Smoking Cessation: Financial incentives plus free cessation aids were the most effective intervention in a 6-month pragmatic trial of smoking cessation (pp. 2302–10). Smokers at 54 companies were randomly assigned to free cessation aids, free e-cigarettes without a requirement that standard therapies had been tried, free cessation aids plus $600 in rewards for sustained abstinence, free cessation aids plus $600 in redeemable deposits, or usual care, with these results: “Among 6,131 smokers who were invited to enroll, 125 opted out and 6,006 underwent randomization. Sustained abstinence rates through 6 months were 0.1% in the usual-care group, 0.5% in the free cessation aids group, 1.0% in the free e-cigarettes group, 2.0% in the rewards group, and 2.9% in the redeemable deposit group. With respect to sustained abstinence rates, redeemable deposits and rewards were superior to free cessation aids (P <0.001 and P = 0.006, respectively, with significance levels adjusted for multiple comparisons). Redeemable deposits were superior to free e-cigarettes (P = 0.008). Free e-cigarettes were not superior to usual care (P = 0.20) or to free cessation aids (P = 0.43). Among the 1,191 employees (19.8%) who actively participated in the trial (the ‘engaged’ cohort), sustained abstinence rates were four to six times as high as those among participants who did not actively engage in the trial, with similar relative effectiveness.” (S. D. Halpern, shalpern@upenn.edu)
Dengue Serostatus & Dengue Vaccine Safety/Efficacy: Reanalysis of data from three efficacy trials shows adverse effects of a tetravalent dengue vaccine (CYD-TDV) in children who were seronegative at the time of vaccine administration (10.1056/NEJMoa1800820). Case–cohort analysis produced these risks of hospitalization for virologically confirmed dengue (VCD), of severe VCD, and of symptomatic VCD based on dengue serostatus: “Among dengue-seronegative participants 2 to 16 years of age, the cumulative 5-year incidence of hospitalization for VCD was 3.06% among vaccine recipients and 1.87% among controls, with a hazard ratio (vaccine vs. control) through data cutoff of 1.75 (95% confidence interval [CI], 1.14 to 2.70). Among dengue-seronegative participants 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 1.57% among vaccine recipients and 1.09% among controls, with a hazard ratio of 1.41 (95% CI, 0.74 to 2.68). Similar trends toward a higher risk among seronegative vaccine recipients than among seronegative controls were also found for severe VCD. Among dengue-seropositive participants 2 to 16 years of age and those 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 0.75% and 0.38%, respectively, among vaccine recipients and 2.47% and 1.88% among controls, with hazard ratios of 0.32 (95% CI, 0.23 to 0.45) and 0.21 (95% CI, 0.14 to 0.31). The risk of severe VCD was also lower among seropositive vaccine recipients than among seropositive controls.” (S. Sridhar, saranya.sridhar@sanofi.com)
Noting a “massive public backlash” in the Phillippines following disclosure of this vaccine-associated harm at the end of 2017, an editorialist places this in a “trolleyology” perspective given current antivaccine sentiments (
10.1056/NEJMp1804094): “Although it’s impossible to know how many additional lives are risked by potential anti-vax spillover, further quantification will not reveal the morally tenable solution. Trolleyology is thus prophetic — not because it provides an answer, but because philosophers, psychologists, and scientists have failed to find one. Though a ‘rational’ decision entails maximizing benefit and minimizing harm, any such calculus must consider the way our choices make us feel long after decisions are made. To that end, the WHO’s recent recommendation to implement a ‘pre-vaccination screening strategy,’ vaccinating only people who test seropositive, seems, for now, the most socially acceptable solution. Because this strategy requires a readily available and accurate point-of-care test, ideally the recommendation will motivate industry and governments to invest in the infrastructure for such testing. Until then, the challenge remains as practical as it is philosophical. To maximize the gains of medical advances, we must begin to address the barriers that reflect less the limits of science than the quirks of our intuitions.” (L. Rosenbaum)

PNN Pharmacotherapy Line
June 15, 2018 * Vol. 25, No. 116
Providing news and information about medications and their proper use

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>>>Oncology Highlights
Source:
 June issue of the Journal of Clinical Oncology (2018; 36).
Talimogene Laherparepvec in Advanced Melanoma: Compared with ipilimumab alone, talimogene laherparepvec plus ipilimumab produced higher objective response rates in patients with unresectable stages IIIB to IV melanoma, a study shows (pp. 1658–67). The phase 2 trial included 198 participants and tested the anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab plus talimogene laherparepvec, a genetically modified herpes simplex virus type 1 that expresses the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor. A primary end point of investigator-rated objective responses showed the following: “Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related.” (J. Chesney, jason.chesney@louisville.edu)
Pembrolizumab in Patients With Metastatic Melanoma: Durable complete responses were demonstrated for about 2 years following discontinuation of pembrolizumab in promising proportions of patients with metastatic melanoma, according to a dose-ranging trial (pp. 1668–74). Participants had ipilimumab-naive or -treated tumors and were assigned to one of three dose regimens of pembrolizumab. Responses were as follows: “Of 655 treated patients, 105 (16.0%) achieved [complete response (CR)] after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis.” (C. Robert, caroline.robert@gustaveroussy.fr)
>>>Infectious Diseases Report
Source:
 June 15 issue of Clinical Infectious Diseases (2018; 66).
Immunotherapeutic Vaccine for Recurrent Vulvovaginal Candidiasis: Among women with recurrent vulvovaginal candidiasis (RVVC), an immunotherapeutic vaccine (NDV-3A) was safe and highly immunogenic and reduced the frequency of symptomatic RVVC episodes, researchers report (pp. 1928–36). Calling this an “unprecedented study of the effectiveness of a fungal vaccine in humans,” the investigators report these findings in an exploratory randomized, double-blind, placebo-controlled trial of a vaccine containing recombinant Candida albicans adhesin/invasin protein: “The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099).” (J. P. Hennessey, Jr., john_hennessey@novadigm.net)
>>>PNN NewsWatch
FDA yesterday approved the first generic versions of Suboxone (buprenorphine and naloxone) sublingual film for treatment of opioid dependence. Receiving the approvals were Mylan Technologies and Dr. Reddy’s Laboratories.

PNN Pharmacotherapy Line
June 18, 2018 * Vol. 25, No. 117
Providing news and information about medications and their proper use

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>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2018; 361).
Prescription Opioids & Online Illicit Marketplaces: Illicit trading of opioids via online markets (“cryptomarkets&rdquoWinking increased significantly following DEA’s 2014 rescheduling of hydrocodone in the U.S., a study shows (k2270). An analysis of 31 of the world’s largest cryptomarkets operating from Oct. 2013 to July 2016 showed the following: “The sale of prescription opioids through US cryptomarkets increased after the schedule change, with no statistically significant changes in sales of prescription sedatives, prescription steroids, prescription stimulants, or illicit opioids. In July 2016 sales of opioids through US cryptomarkets represented 13.7% of all drug sales (95% confidence interval 11.5% to 16.0%) compared with a modelled estimate of 6.7% of all sales (3.7% to 9.6%) had the new schedule not been introduced. This corresponds to a 4 percentage point yearly increase in the amount of trade that prescription opioids represent in the US market, set against no corresponding changes for comparable products or for prescription opioids sold outside the US. This change was first observed for sales, and later observed for product availability. There was also a change in the composition of the prescription opioid market: fentanyl was the least purchased product during July to September 2014, then the second most frequently purchased by July 2016.” (J. Cunliffe, j.d.cunliffe@kent.ac.uk)
Nicotine Patch Treatment Abstinence & Quitting Smoking: Four weeks of nicotine patch use before a quit date did not clearly enhance smoking cessation rates among 1,792 adult daily smokers, a study shows (k2164). Participants were randomized to either standard smoking cessation pharmacotherapy and behavioral support or the same treatment supplemented by preloading with 4 weeks of 21 mg nicotine patch use before quitting. Results showed the following: “Biochemically validated abstinence at six months was achieved by 157/899 (17.5%) participants in the preloading arm and 129/893 (14.4%) in the control arm: difference 3.0% (95% confidence interval −0.4% to 6.4%), odds ratio 1.25 (95% confidence interval 0.97 to 1.62), P = 0.08 in the primary analysis. There was an imbalance between arms in the frequency of varenicline use as post-cessation treatment, and planned adjustment for this gave an odds ratio for the effect of preloading of 1.34 (95% confidence interval 1.03 to 1.73), P = 0.03: difference 3.8% (0.4% to 7.2%). At four weeks, the difference in prolonged abstinence unadjusted for varenicline use was odds ratio 1.21 (1.00 to 1.48), difference 4.3% (0.0% to 8.7%), P = 0.05, and adjusted for varenicline use was 1.32 (1.08 to 1.62) P = 0.007. At 12 months the odds ratio was 1.28 (0.97 to 1.69), difference 2.7% (−0.4% to 5.8%), P = 0.09 unadjusted for varenicline use and after adjustment was 1.36 (1.02 to 1.80) P = 0.04. 5.9% of participants discontinued preloading owing to intolerance. Gastrointestinal symptoms—chiefly nausea—occurred in 4.0% (2.2% to 5.9%) more people in the preloading arm than control arm. Eight serious adverse events occurred in the preloading arm and eight in the control arm (odds ratio 0.99, 0.36 to 2.75).” (P. Aveyard, paul.aveyard@phc.ox.ac.uk)
>>>PNN NewsWatch
FDA says that at least 43 patients have reported adverse events after receiving eye injections of Guardian’s Pharmacy Services compounded triamcinolone–moxifloxacin product during cataract surgery. The patients reportedly experienced various symptoms, including vision impairment, poor night vision, loss of color perception, and significant reductions in best-corrected visual acuity and visual fields.
>>>PNN JournalWatch
Chronic Obstructive Pulmonary Disease Subpopulations and Phenotyping, in Journal of Allergy and Clinical Immunology, 2018: 141: 1961–71. (L. N. Segal, Leopoldo.Segal@nyumc.org)
Biologics and Chronic Obstructive Pulmonary Disease, in Journal of Allergy and Clinical Immunology, 2018: 141: 1983–91. (I. D. Pavord, ian.pavord@ndm.ox.ac.uk)
Characteristics and Outcomes of Influenza-Associated Encephalopathy Cases Among Children and Adults in Japan, 2010–2015, in Clinical Infectious Diseases, 2018: 66: 1831–7. (K. Oishi, ishik@niid.go.jp">oishik@niid.go.jp)
Predictors of Unemployment After Breast Cancer Surgery: A Systematic Review and Meta-Analysis of Observational Studies, in Journal of Clinical Oncology, 2018: 36: 1868–79. (L. Wang, angli1@mcmaster.ca)

PNN Pharmacotherapy Line
June 19, 2018 * Vol. 25, No. 118
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online article from and June 19 issue of Annals of Internal Medicine (2018; 168).
OUD Medications After Nonfatal Opioid Overdose: In a retrospective study from Massachusetts, few survivors of opioid overdoses received medications for opioid use disorder (MOUD), researchers report, but use of methadone maintenance treatment (MMT) or buprenorphine were associated with reduced all-cause and opioid-related mortality (10.7326/M17-3107). These outcomes were identified in a cohort analysis of seven Massachusetts data sets of 17,658 adults without cancer: “In the 12 months after a nonfatal overdose, 2,040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3,022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1,099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person–years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person–years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio [AHR], 0.47 [CI, 0.32 to 0.71]) and opioid-related mortality (AHR, 0.41 [CI, 0.24 to 0.70]). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 [CI, 0.46 to 0.87]) and opioid-related mortality (AHR, 0.62 [CI, 0.41 to 0.92]). No associations between naltrexone and all-cause mortality (AHR, 1.44 [CI, 0.84 to 2.46]) or opioid-related mortality (AHR, 1.42 [CI, 0.73 to 2.79]) were identified.” (M. R. Larochelle, marc.larochelle@bmc.org)
Opioid Misuse & Subsequent Adverse Outcomes: Among Medicare beneficiaries, those with potential opioid overdose are at increased risk of subsequent opioid overdoses (pp. 837–45). In a 5% sample from 2008–12, measures of opioid misuse were associated with this primary outcome of diagnosis of opioid overdose in the year after a 6-month index period: “Overall, 0.6% to 8.5% of beneficiaries fulfilled a misuse measure. Subsequent opioid overdose was positively associated with successively greater numbers of prescribers or pharmacies or higher opioid quantities during the index period. For example, patients who obtained opioids from 2, 3, or 4 prescribers were increasingly more likely to have an opioid overdose (adjusted absolute risk per 1000 beneficiary–years [aAR], 3.5 [95% CI, 3.3 to 3.7]; 4.8 [CI, 4.5 to 5.2]; or 6.4 [CI, 5.8 to 6.9], respectively) than those with a single prescriber (aAR, 1.9 [CI, 1.8 to 2.0]). Subsequent overdose risk increased meaningfully with any deviation in the single prescriber–single pharmacy opioid use pattern. All misuse measures examined had a positive association with subsequent opioid overdose and death.” (M. L. Barnett, mbarnett@hsph.harvard.edu)
Women’s Health Policy: In a position paper, the American College of Physicians (ACP) supports these recommendations on challenges women face in the U.S. health care system (pp. 874–5; H. Daniel, hdaniel@acponline.org):
* ACP believes that internists are well-suited to provide high-quality women’s health care and that [all] clinicians … should receive appropriate training in health issues of particular relevance to the population of women seen in their practice setting.
* Women should have access to affordable, comprehensive, nondiscriminatory public or private health care coverage that includes evidence-based care over the course of their lifespans without gender-based differences in cost.
* ACP believes in respect for the principle of patient autonomy [and] opposes government restrictions that would erode or abrogate a woman’s right to continue or discontinue a pregnancy.
* ACP opposes legislation or regulations that limit access to comprehensive reproductive health care ….
* ACP supports the goal of universal access to family and medical leave policies that provide a minimum period of 6 weeks’ paid leave …. 
* ACP supports increased availability of effective screening tools for physicians or health care professionals treating survivors of intimate partner or sexual violence [and] increased patient education … and the availability of resources for those affected by these abuses.
* ACP supports efforts to improve the representation of women’s health in clinical research and close [related] knowledge gaps ….

PNN Pharmacotherapy Line
June 20, 2018 * Vol. 25, No. 119
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 June 19 issue of JAMA (2018; 319).
Glycemic Control in Adults With Type 2 Diabetes: After reviewing a clinical guidance from the American College of Physicians on care of nonpregnant adults with type 2 diabetes, authors of a Clinical Guidelines Synopsis conclude (pp. 2430–1; E. L. Tung, eliztung@uchicago.edu): “High-quality, long-term randomized trials have improved knowledge of glycemic control in type 2 diabetes, but important gaps remain. Despite consensus that personalizing goals for glycemic control is important, little evidence exists for how to personalize goals consistently. Similarly, while protocols for deintensification are being developed, the long-term safety and benefits of deintensification are largely unknown. The intensity of glycemic and blood pressure control may be too narrow a focus for diabetes care, given the newer medications (ie, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists) that may have independent cardioprotective effects. A broader risk–benefit calculation based on clinical factors (glycemic control, blood pressure, dyslipidemia, tobacco use, renal function, duration of diabetes, medications) as well patient preferences regarding various risks and therapies may better determine personalized goals in the future.”
Demographics, Urbanization & Obesity: Obesity and/or severe obesity are more common among Americans in rural areas of America than in large cities, according to two articles reporting National Center for Health Statistics analyses.
“In this cross-sectional analysis that included 10,792 adults aged 20 years or older, differences were found in the prevalence of obesity and severe obesity by age group, race and Hispanic origin, and education level,” researchers report (
pp. 2419–29). “The prevalence of obesity was significantly greater among women living in nonmetropolitan statistical areas (non-MSAs; 47.2%) compared with women living in large MSAs (38.1%), and the prevalence of severe obesity in non-MSAs was higher than in large MSAs among men (9.9% vs 4.1%, respectively) and women (13.5% vs 8.1%, respectively).” (C. M. Hales, chales@cdc.gov)
A similar analysis of 6,864 children and adolescents aged 2 to 19 years showed “differences in obesity and severe obesity prevalence by age, race and Hispanic origin, and household education,” the investigators found (
pp. 2410–8). “Differences in obesity by urbanization levels were not significant, but the prevalence of severe obesity was significantly higher in non-MSAs (9.4%) than in large MSAs (5.1%).” (C. L. Ogden, cogden@cdc.gov)
“An Incomplete Prescription”: The two marketplace-oriented approaches announced on May 11 as the Administration’s blueprint for addressing high drug prices “could be helpful,” Viewpoint authors write, but the plan lacks “sufficient detail or power to be useful in the near term, and several long-discussed potential reforms, including those advocated by the president previously, were not put forward” (pp. 2373–4). The two elements are “trying to empower patients and payers to negotiate drug prices more effectively during patent-protected exclusivity periods and trying to promote more price competition,” the group notes. “At a time when many patients in the United States cannot afford to take their medications as prescribed, policy makers will continue to face intense pressure to act. While containing some good ideas, the blueprint put forward by the Trump administration ultimately falls short in embracing long-discussed reforms that could provide meaningful cost savings for patients and payers and help contain health care expenditures.” (A. Sarpatwari, asarpatwari@bwh.harvard.edu)
>>>PNN NewsWatch
Shortages of IV fluids, opioid analgesics, and EpiPen are discussed in a statement posted yesterday on the FDA website. Deputy Center Director Douglas Throckmorton, MD, writes of agency actions to alleviate shortages, “These examples help illustrate some of the many ways the FDA is helping to mitigate and prevent drug shortages, often with a mix of industry cooperation, regular communication, and the flexible use of the FDA’s regulatory authorities. When we are given appropriate notice by manufacturers of a pending supply disruption, the FDA can better use our strategies and tools to help protect the public by preventing and mitigating expected shortages.”

PNN Pharmacotherapy Line
June 21, 2018 * Vol. 25, No. 120
Providing news and information about medications and their proper use

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>>>NEJM Report
Source:
 June 21 issue of the New England Journal of Medicine (2018; 378).
Sodium Thiosulfate for Cisplatin-Induced Hearing Loss: Prophylaxis with sodium thiosulfate lowered the incidence of cisplatin-induced hearing loss among children being treated for standard-risk hepatoblastoma, researchers report (pp. 2376–85). Based on a primary end point of absolute hearing threshold at a minimum age of 3.5 years, these outcomes were noted among participants aged 1 month to 18 years: “A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin–sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin–sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P = 0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin–sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively.” (P. R. Brock, peppybrock@gmail.com)
Ivosidenib for AML: In a phase 1 trial of an oral, targeted, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) in patients with acute myeloid leukemia (AML), ivosidenib 500 mg daily “was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission” (pp. 2386–98). Participants had advanced IDH1-mutated relapsed or refractory AML; responses in the dose-escalation and dose-expansion study were as follows: “Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8).…” (C. D. DiNardo, cdinardo@mdanderson.org)
Treatment of Waldenström’s Macroglobulinemia: In a phase 3 trial of 150 patients with Waldenström’s macroglobulinemia, the combination of ibrutinib plus rituximab produced significantly higher rates of progression-free survival than rituximab alone (pp. 2399–410). The advantage was demonstrated “both among those who had received no previous treatment and among those with disease recurrence,” the investigators conclude. “Atrial fibrillation and hypertension were more common with ibrutinib–rituximab, whereas infusion reactions and IgM flare were more common with placebo–rituximab.” (M. A. Dimopoulos, mdimop@med.uoa.gr)
Competition for the VA: “Privatizing the [Department of Veterans Affairs (VA)] by offering unregulated access to private-sector providers is probably not feasible, necessary, or the best way to care for veterans,” writes the former Secretary of Veterans Affairs and a colleague (pp. 2356–7). Describing “why the VA needs more competition,” the pair conclude, “Although competition alone is not sufficient to improve quality, it can help to modernize performance standards, lead to new management practices within VA medical centers, and move the VA away from the possibility of privatization. Competition also ensures that private-sector providers that wish to care for veterans adhere to the highest quality standards — and formalizing those standards through legislation would allow the VA to better fulfill its responsibility to veterans and taxpayers. Veterans deserve a continually improving health care system, and the best way to ensure that they receive it may be to support the VA at levels that allow it to successfully compete with the private sector.” (D. J. Shulkin)

PNN Pharmacotherapy Line
June 22, 2018 * Vol. 25, No. 121
Providing news and information about medications and their proper use

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>>>Health Affairs Report
Source:
 June issue of Health Affairs (2018; 37).
Robust PDMPs: States with robust prescription drug monitoring programs (PDMPs) had declines in opioid use parameters following implementation of such features in 2012–13, a study shows (pp. 964–74). Using a commercial claims database to examine overall and high-risk opioid prescribing in four states with robust PDMPs and comparator states, the investigators found: “By the end of 2014 the absolute mean morphine-equivalent dosages that providers dispensed declined in a range of 6–77 mg per person per quarter in the four states, relative to comparison states. Only in one of the four states, Kentucky, did the percentage of people who filled opioid prescriptions decline versus its comparator state, with an absolute reduction of 1.6 percent by the end of 2014. Robust PDMPs may be able to significantly reduce opioid dosages dispensed, percentages of patients receiving opioids, and high-risk prescribing.” (R. L. Haffajee, haffajee@umich.edu)
Effects of ACA Medicaid Expansion: Studies of the expansion of Medicaid programs under the Affordable Care Act (ACA) demonstrate improvements in health care with few negative consequences, researchers report (pp. 944–50): “After analyzing seventy-seven published studies, we found that expansion was associated with increases in coverage, service use, quality of care, and Medicaid spending. Furthermore, very few studies reported that Medicaid expansion was associated with negative consequences, such as increased wait times for appointments—and those studies tended to use study designs not suited for determining cause and effect. Thus, there is evidence to document improvements in several areas of health care delivery following the ACA Medicaid expansion. We outline areas for future research that can further reduce current knowledge gaps.” (N. Menachemi, nirmena@iu.edu)
>>>Medical Care Highlights
Source:
 July issue of Medical Care (2018; 56).
Changes in Medicaid Spending Under ACA: Some unexpected changes in Medicaid expenditures have occurred in Oregon in the years since Medicaid expansion under the Affordable Care Act, according to an analysis based in four indices (changes in costs per enrolled member, demographic shifts, prevalence of treated disease/condition, and costs per treated member) (pp. 589–95). “Expenditures on pregnancy/birth and mental conditions accounted for 24% of 2011 spending,” the authors write. “Oregon’s 2012 payment reform was associated with reduced spending attributable primarily to decreased prevalence of treated conditions. The 2014 Medicaid expansion was marked by lower pregnancy and mental health expenditures and higher spending on treatment for substance use and heart disease.” (S. Renfro, renfrst@ohsu.edu)
Gathering Data on Antimicrobial Prescribing Quality: Manual versus electronic medication-use evaluation (MUE) “agreed well for illness severity, antibiotic choice, and duration of therapy in pneumonia at both the individual and facility levels,” investigators conclude in a study of 30 VA facilities (pp. 626–33): “Manual MUE showed additional reviewer-level variation in estimation of initial illness severity and excessive antibiotic use. Electronic MUE allows for reliable, scalable tracking of national patterns of antimicrobial use, enabling the examination of system-wide interventions to improve quality.” (B. E. Jones, barbara.jones@hsc.utah.edu)
>>>PNN NewsWatch
* FDA yesterday approved the Eversense Continuous Glucose Monitoring (CGM) system for use in adults with diabetes and expanded approved uses of the MiniMed 670G hybrid closed looped system to include pediatric patients ages 7 to 13 years with type 1 diabetes. Eversense is the first FDA-approved CGM system to include a fully implantable sensor to detect glucose; it can be worn for up to 90 days. The MiniMed is a diabetes management device that automatically monitors glucose and provides appropriate basal insulin doses with little or no input from the user.
Gaia Ethnobotanical is voluntarily recalling all kratom (Mitragyna speciosa) powder products, lot 0102031800, produced March 18–30, 2018, to the consumer level.

PNN Pharmacotherapy Line
June 25, 2018 * Vol. 25, No. 122
Providing news and information about medications and their proper use

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>>>Lancet Highlights
Source:
 June 24 issue of Lancet (2018; 391).
Upadacitinib in Refractory Rheumatoid Arthritis: Two investigational studies provide evidence of efficacy of the selective Janus kinase 1 inhibitor upadacitinib in patients with difficult-to-treat rheumatoid arthritis.
In a phase 3 trial of patients with moderately to severely active rheumatoid arthritis who had inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), upadacitinib 15 mg or 30 mg in combination with csDMARDs produced significant improvements in clinical signs and symptoms (
pp. 2503–12). The SELECT-NEXT included participants failing treatment with methotrexate, sulfasalazine, or leflunomide. Randomization to a once-daily extended-release formulation of upadacitinib or placebo for 12 weeks produced these results: “At week 12, [20% improvement in American College of Rheumatology criteria (ACR20)] was achieved by 141 (64%; 95% CI 58–70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60–73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29–42) of 221 patients receiving placebo (p <0.0001 for each dose vs placebo). [28-Joint disease activity score using C-reactive protein, or DAS28(CRP)] of 3.2 or less was met by 107 (48%; 95% CI 42–55) patients receiving upadacitinib 15 mg and 105 (48%; 41–55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12–22) patients receiving placebo (p <0.0001 for each dose vs placebo).…” (G. R. Burmester, gerd.burmester@charite.de)
The phase 3 SELECT-BEYOND trial showed “rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis,” authors of a second report conclude (
pp. 2513–24). Patients in this study had inadequate responses to biologic disease-modifying anti-rheumatic drugs (bDMARDs) when they were randomized to upadacitinib or placebo, with these results: “At week 12, ACR20 was achieved by 106 (65%; 95% CI 57–72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49–64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22–35) of 169 patients receiving placebo (p <0.0001 for each dose vs placebo). DAS28(CRP) of 3.2 or less was achieved by 71 (43%; 95% CI 36–51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35–50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9–20) of 169 patients receiving placebo (p <0.0001 for each dose vs placebo).…” (M. C. Genovese, genovese@stanford.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2018; 361).
Vitamin D & Pregnancy-Related Hypertension: Mendelian randomization analyses provide “no strong evidence” linking vitamin D status with development of gestational hypertension or pre-eclampsia, researchers report (k2167). Applying one- and two-sample analyses to triangulate findings from European studies that used different designs, the authors found these relationships: “In the conventional multivariable analysis, the relative risk for pre-eclampsia was 1.03 (95% confidence interval 1.00 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, and 2.04 (1.02 to 4.07) for 25-hydroxyvitamin D levels <25 nmol/L compared with ≥75 nmol/L. No association was found for gestational hypertension. The one sample mendelian randomisation analysis using the total genetic risk score as an instrument did not provide strong evidence of a linear effect of 25-hydroxyvitamin D on the risk of gestational hypertension or pre-eclampsia: odds ratio 0.90 (95% confidence interval 0.78 to 1.03) and 1.19 (0.92 to 1.52) per 10% decrease, respectively. The two sample mendelian randomisation estimate gave an odds ratio for pre-eclampsia of 0.98 (0.89 to 1.07) per 10% decrease in 25-hydroxyvitamin D level, an odds ratio of 0.96 (0.80 to 1.15) per unit increase in the log(odds) of 25-hydroxyvitamin D level <75 nmol/L, and an odds ratio of 0.93 (0.73 to 1.19) per unit increase in the log(odds) of 25-hydroxyvitamin D levels <50 nmol/L.” (M. C. Magnus, Maria.Christine.Magnus@bristol.ac.uk)
>>>PNN JournalWatch
Global Diabetes Prevention Interventions: A Systematic Review and Network Meta-analysis of the Real-World Impact on Incidence, Weight, and Glucose, in Diabetes Care, 2018: 41: 1526–34. (K. I. Galaviz, kgalavi@emory.edu)

PNN Pharmacotherapy Line
June 26, 2018 * Vol. 25, No. 123
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>>>Geriatrics Highlights
Source:
 Early-release articles from the Journal of the American Geriatrics Society (2018; 66).
Direct-Acting Antivirals for Hepatitis C in Older Adults: Drug–drug interactions (DDIs) and adverse events (AEs) occur commonly when adults aged 75 years or older use direct-acting antiviral (DAA) therapy for hepatitis C virus, a study shows (10.1111/jgs.15392). Compared with adults aged 65 to 74 years, investigators found these outcomes in a retrospective review of 113 patients at a viral hepatitis outpatient clinic in 2014–17: “Sustained virologic response rate was 97.7% in individuals aged 65 to 74 and 95.8% in those aged 75 and older. Individuals aged 75 and older were more likely to be taking more than 2 medications per day for chronic conditions (84% vs 62%, p = .02) and more likely to have clinically significant DDIs necessitating cessation or adjustment of medications before commencement of DAA therapy (80% vs 36%, p = .001). Moreover, individuals aged 75 and older were more likely to experience an AE during therapy (50% vs 26%, p = .03) and were more susceptible to developing anemia secondary to ribavirin (60% vs 20%, p = .02).” (M. D. Cannon, mary.cannon@nhs.net)
Cardiovascular Outcomes of Cholinesterase Inhibitors: Used for treating dementia, acetylcholinesterase inhibitors (AChEIs) “may be associated with negative chronotropic and hypertensive effects but also with lower risk of [cardiovascular (CV)] events,” conclude authors of a systematic review and meta-analysis (10.1111/jgs.15415): “Of 4,588 initial hits, 31 studies including 258,540 individuals with dementia and 2,246,592 controls were analyzed. In longitudinal and open-label studies, AChEIs were associated with a significantly greater incidence of hypertension (n = 1,573, 4%, 95% CI = 2–8%, I2 = 47%) and bradycardia (n = 13,703, 2%, 95% CI = 1–6%, I2 = 98%). AChEIs were associated with a decrease in heart rate ([standardized mean difference (SMD)] = –1.77, 95% CI = –3.58–0.03, I2 = 78%) and an increase in PR interval (SMD = 0.10, 95% CI = 0.008–0.19, I2 = 3%) from baseline. During a median follow-up of 116 weeks, AChEIs were associated with a significantly lower risk of CV events (stroke, acute coronary syndrome, CV mortality; HR = 0.63, 95% CI = 0.45–0.88, I2 = 18%), without a significantly greater risk of bradycardic events (HR = 1.40, 95% CI = 0.76–2.59, I2 = 98%).” (A. T. Isik, atisik@yahoo.com)
Hypotensive Drugs, Syncope & Dementia: In a prospective, observational, multicenter study of older adults with dementia, orthostatic hypotension (OH)–related syncopal falls were significantly related to use of specific agents that lower blood pressure, researchers report (10.1111/jgs.15421). The research was conducted in acute care wards, syncope units, and dementia diagnosis centers among adults age 65 years or older. With OH defined as a drop of systolic blood pressure of 30 mm Hg or diastolic blood pressure of 10 mm Hg within 3 minutes of standing from a supine position, the investigators found: “The mean age of the study population (n = 522; women, n = 324) was 83.5 ± 6.1, and the most frequent comorbidity was arterial hypertension (74.5%); 324 (67.8%) participants had had a syncopal fall and 168 (32.2%) a nonsyncopal fall. The mean number of hypotensive drugs administered (2.9 ± 3.1) did not differ between the two groups. Syncopal falls was OH-related in 170 participants (48.0%). OH-related syncopal falls were more frequent in participants receiving nitrates (15.3% vs 9.8%, p = .06), alpha-blockers (16.5% vs 9.8%, p = .04), or combinations of angiotensin-converting enzyme inhibitors (ACE-Is) and diuretics (20.6% vs 13.0%, p = .04), alpha-blockers and diuretics (8.2% vs 3.3%, p = 0.036), and ACE-Is and nitrates (8.2% vs 3.3%, p = .10). Multivariate analysis confirmed a greater risk of OH-related syncopal fall for nitrates (relative risk (RR) = 1.77), combinations of ACE-Is and diuretics (RR = 1.66), and combinations of ACE-Is and nitrates (RR = 2.32).” (P. Abete, p.abete@unina.it)
>>>PNN NewsWatch
FDA yesterday approved the first prescription pharmaceutical formulation of highly purified, Cannabis-derived cannabidiol (CBD). Epidiolex (GW Research Ltd.) is an oral solution indicated for treatment of seizures associated with Lennox–Gastaut syndrome (LGS) or Dravet syndrome in patients 2 years of age or older. CBD does not cause intoxication or euphoria that comes from the tetrahydrocannabinol component of the marijuana plant.

PNN Pharmacotherapy Line
June 27, 2018 * Vol. 25, No. 124
Providing news and information about medications and their proper use

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>>>JAMA Report
Source:
 June 26 issue of JAMA (2018; 319).
Fruquintinib in Previously Treated Metastatic Colorectal Cancer: In the FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, patients with previously treated metastatic colorectal cancer (CRC) had increased overall survival when treated with oral fruquintinib, a vascular endothelial growth factor receptor inhibitor (pp. 2486–96). At 28 Chinese hospitals, randomization to fruquintinib 5 mg or placebo produced these outcomes: “Of the 416 randomized patients (mean age, 54.6 years; 161 [38.7%] women), 404 (97.1%) completed the trial. Median overall survival was significantly prolonged with fruquintinib compared with placebo (9.3 months [95% CI, 8.2–10.5] vs 6.6 months [95% CI, 5.9–8.1]); hazard ratio (HR) for death, 0.65 (95% CI, 0.51–0.83; P < .001). Median progression-free survival was also significantly increased with fruquintinib (3.7 months [95% CI, 3.7–4.6] vs 1.8 months [95% CI, 1.8–1.8] months); HR for progression or death, 0.26 (95% CI, 0.21 to 0.34; P < .001). Grades 3 and 4 treatment-emergent adverse events occurred in 61.2% (170) of patients who received fruquintinib and 19.7% (27) who received placebo. Serious adverse events were reported by 15.5% (43) of patients in the fruquintinib group and 5.8% (8) in the placebo group, with 14.4% (40) of fruquintinib-treated and 5.1% (7) of placebo-treated patients requiring hospitalization.” (S. Qin, qinsk@csco.org.cn)
Baseline Bleeding Risk in Patients Without CVD: Putting risks of aspirin for primary prevention in perspective, a prospective cohort study from New Zealand provides these baseline data on risks of major bleeding in patients without cardiovascular disease (CVD) (pp. 2507–20). “Mean participant age was 54 years (SD, 10 years), 44% were women, and 57% were European. Among the 359,166 individuals in the baseline cohort, 3,976 had a major bleeding event during 1,281,896 person–years of follow-up. Most had gastrointestinal (GI) bleeding (n = 2,910 [73%]). There were 274 fatal bleeding events (7%), of which 153 were intracerebral. The risk of a nonfatal GI bleeding event per 1,000 person–years was 2.19 (95% CI, 2.11–2.27), 1.77 (95% CI, 1.69–1.85) and 1.61 (95% CI, 1.52–1.69), in the baseline, non–high-risk, and nonmedication cohorts, respectively. Case fatality associated with GI bleeding was 3.4% (95% CI, 2.2%–4.1%), 4.0% (95% CI, 3.2%–5.1%), and 4.6% (95% CI, 3.6%–6.0%) in the baseline, non–high-risk, and nonmedication cohorts, respectively.” (V. Selak, v.selak@auckland.ac.nz)
Osteoporosis Screening to Prevent Fractures: Two editorials react to osteoporosis screening recommendations of the U.S. Preventive Services Task Force (USPSTF).
Updating its 2011 recommendations, the task force reaches this conclusion for patients in various age groups (
pp. 2521–31): “The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement)” (S. J. Curry, chair@uspstf.net)
“Fracture prevention is the ultimate goal, and [bone mineral density (BMD)] screening is an effective, low-cost, noninvasive means of identifying men and women at high risk of fracture,” an editorialist writes (
pp. 2483–5). “Yet major deficiencies remain in BMD screening, even among women 65 years and older.… Future research should identify ways of improving BMD screening rates and to improve identification of young women (50–64 years) and older men who would benefit from BMD screening.” (J. A. Cauley, jcauley@edc.pitt.edu)
“As the United States spends more dollars to achieve worse health care outcomes than other industrialized countries, the worst mistakes we can make are to underuse an effective screening protocol that has been made unnecessarily complex, or overuse a prescreening step that adds uncertain value,” a second editorialist concludes (
10.1001/jamainternmed.2018.2776M. Gourlay, margaret_gourlay@med.unc.edu).

PNN Pharmacotherapy Line
June 28, 2018 * Vol. 25, No. 125
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>>>NEJM Report
Source:
 June 28 issue of the New England Journal of Medicine (2018; 378).
Enzalutamide in Castration-Resistant Prostate Cancer: In men with nonmetastatic, castration-resistant prostate cancer and rapidly rising prostate-specific antigen (PSA) levels, the androgen modulator enzalutamide produced “a clinically meaningful and significant 71% lower risk of metastasis or death than placebo,” report investigators in a phase 3 trial (pp. 2465–74). Participants had a PSA doubling rate of 10 months or less and continued androgen-deprivation therapy after randomization to enzalutamide 160 mg or placebo once daily. Based on a primary end point of metastasis-free survival, the researchers found: “A total of 1,401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P <0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P <0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P <0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.” (M. Hussain, maha.hussain@northwestern.edu)
“The FDA approval of apalutamide for nonmetastatic prostate cancer and the anticipated approval of enzalutamide in the same context represent important steps forward for men with rising PSA levels during androgen-deprivation therapy,” writes an editorialist (
pp. 2531–2). “The benefit–risk evaluation suggests that treatment with either drug is better than waiting until the appearance of metastases.” (M. R. Smith)
Dupilumab in Difficult-to-Treat Asthma: Reacting to two trials of dupilumab, a fully human anti–interleukin-4 receptor-alpha monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling, in patients with oral glucocorticoid–treated asthma (pp. 2475–85, K. F. Rabe, k.f.rabe@lungenclinic.de) or moderate-to-severe uncontrolled asthma (pp. 2486–96, M. Castro, castrom@wustl.edu), editorialists call for head-to-head studies of this and other high-cost agents (pp. 2533–4): “We believe that the pharmaceutical companies making these agents owe a debt to the patients with asthma who put themselves at risk to test these new treatments and, as such, are ethically compelled to provide product to well-established public research entities for use in such trials at no cost. Drug companies may be reluctant to risk their franchise on such trials, but with costs for a year of treatment substantially more than a year’s labor at minimum wage in the United States, we deserve to know whether there are clinically important differences among these treatments. An innovative trial design would allow us to look patients in the eye and say with confidence that the drug we are prescribing is one of a family of drugs that are largely equivalent in effectiveness. If we do not take the head-to-head approach, we will end up prescribing the treatment with the most effective marketing. Our patients deserve better than that.” (J. M. Drazen)
Asthma Safety Trials of Long-Acting Beta-2-Agonists: Combined analysis of data from four safety trials shows no increased risks of serious asthma-related events with long-acting beta-2-agonists (LABAs) plus an inhaled glucocorticoid in asthma management than with inhaled glucocorticoids alone, but combination therapy “resulted in significantly fewer asthma exacerbations” among the 36,010 patients (pp. 2497–505; W. W. Busse, wwb@medicine.wisc.edu).
In an accompanying Perspective article, FDA staff explain the history of the agency’s black-box warning for LABAs — first mandated in 2003 — and its Dec. 2017 removal (
pp. 2461–3): “The removal of a boxed warning from a product label is not a common occurrence, but the evidence in this instance was decisive.” (S. M. Seymour)

PNN Pharmacotherapy Line
June 28, 2018 * Vol. 25, No. 125
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
 July issue of Diabetes Care (2018; 41).
Dual-Hormone, Closed-Loop System for Diabetes Care: In 20 physically active adults with type 1 diabetes, episodes of hypoglycemia were reduced by addition of glucagon to a closed-loop insulin system with automated exercise detection, researchers report (pp. 1471–7). All participants received the study’s four interventions in randomized order: dual-hormone, single-hormone, predictive low glucose suspend, and continuation of current care over 4 outpatient days. Each study arm included three moderate-intensity aerobic exercise sessions. Results showed: “The mean time (SD) in hypoglycemia was the lowest with dual-hormone during the exercise period: 3.4% (4.5) vs. 8.3% (12.6) single-hormone (P = 0.009) vs. 7.6% (8.0) predictive low glucose suspend (P <0.001) vs. 4.3% (6.8) current care where pre-exercise insulin adjustments were allowed (P = 0.49). Time in hypoglycemia was also the lowest with dual-hormone during the entire 4-day study: 1.3% (1.0) vs. 2.8% (1.7) single-hormone (P <0.001) vs. 2.0% (1.5) predictive low glucose suspend (P = 0.04) vs. 3.1% (3.2) current care (P = 0.007). Time in range during the entire study was the highest with single-hormone: 74.3% (8.0) vs. 72.0% (10.8) dual-hormone (P = 0.44).” (J. R. Castle, castleje@ohsu.edu)
Gestational Diabetes Mellitus & Diet: The “usual dietary advice” provided to pregnant women with gestational diabetes mellitus (GDM) has “room for improvement,” conclude authors of a systematic review and meta-analysis of 18 trials of 1,151 women (pp. 1346–61): “For modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (−4.07 mg/dL [95% CI −7.58, −0.57]; P = 0.02 and −7.78 mg/dL [95% CI −12.27, −3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (−170.62 g [95% CI −333.64, −7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02).” (H. R. Murphy, helen.murphy@uea.ac.uk)
“The importance of nutrition therapy in GDM is a premise unlikely to be contested,” (
pp. 1343–5). “Yet, the widely accepted approach rooted in carbohydrate restriction was challenged more than a decade ago based on concerns related to higher fat intake and exacerbation of maternal insulin resistance by free fatty acids. The dietary management of diabetes in pregnancy has remained in limbo ever since, with no specific guidelines for nutrition therapy in GDM, a travesty that has resulted in non–evidence-based, fragmented, and inconsistent approaches globally. Action is necessary not only because of the powerful influence of nutrition on fetal programming and development but also because of the ability to positively impact the health of millions of mother–infant dyads. Currently, nutrition therapy appears to have become our Achilles heel, such that despite our strength, we have limped forward in generating clinical evidence to substantiate the potential for nutrition in GDM. More than 13 years after the last American Diabetes Association international conference on GDM, we have made minimal progress. Perhaps [the above] meta-analysis … represents a turning point.” (T. L. Hernandez, teri.hernandez@ucdenver.edu)
>>>PNN NewsWatch
* FDA Commissioner Scott Gottlieb, MD, yesterday issued a statement on fraud enforcements against compounding pharmacies for billing for medically unnecessary compounded drugs, including pain and scar creams. “FDA is inspecting compounding facilities to assess whether drugs that are essentially copies of FDA-approved drugs are being compounded for patients who could use an FDA-approved drug,” Gottlieb said. “As we described in our January 2018 communication, such a practice creates significant public health risks because patients are unnecessarily exposed to drugs that have not been shown to be safe and effective, and it undermines the integrity of the premarket approval processes that Congress put in place to protect patients from unsafe, ineffective, or poor quality drugs.”
* Gottlieb also commented on 
FDA’s efforts to collaborate with internet stakeholders to stop illegal online sale of opioids.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533. Copyright © 2018, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, BSPharm, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.