Jun 2019

PNN April–June 2019

PNN Pharmacotherapy Line
Apr. 1, 2019 * Vol. 26, No. 62
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Mar. 30 issue of Lancet (2019; 393).
Stopping the Global HCV Epidemic: Through attention to blood safety and infection control and a focus on people who inject drugs (PWID) and greater universal screening and treatment with direct-acting antivirals (DAAs), the effort to eliminate the hepatitis C virus (HCV) epidemic can be achieved by the early 2030s, according to a global mathematical model (pp. 1319–29; T. b. Hallett, timothy.hallett@imperial.ac.uk).
PICO: Dynamic transmission model of the global HCV epidemic, calibrated to 190 countries and incorporating data on demography, PWID, current coverage of treatment and prevention programs, natural history of the disease, HCV prevalence, and HCV-attributable mortality.
Results: “By 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14.1 million (95% credible interval 13.0–15.2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640,000 deaths (620,000–670,000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15.1 million (13.8–16.1) new infections and 1.5 million (1.4–1.6) cirrhosis and liver cancer deaths, corresponding to an 81% (78–82) reduction in incidence and a 61% (60–62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implementation of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
BMI & Mortality: A new analysis challenges the generally accepted J-shaped body mass index (BMI)–mortality curve, showing that less weight is associated with greater mortality only in former or current smokers (l1042; S. Burgess, sb452@medschl.cam.ac.uk). For never smokers, less weight was consistently associated with decreased mortality risk.
PICO: Data from the Nord-Trøndelag Health (HUNT) Study (Norway; n = 56,150) and UK Biobank (United Kingdom; n = 366,385).
Results: “12,015 and 10,344 participants died during a median of 18.5 and 7.0 years of follow-up in the HUNT Study and UK Biobank, respectively. Linear mendelian randomisation analyses indicated an overall positive association between genetically predicted BMI and the risk of all cause mortality. An increase of 1 unit in genetically predicted BMI led to a 5% (95% confidence interval 1% to 8%) higher risk of mortality in overweight participants (BMI 25.0–29.9) and a 9% (4% to 14%) higher risk of mortality in obese participants (BMI ≥30.0) but a 34% (16% to 48%) lower risk in underweight (BMI <18.5) and a 14% (−1% to 27%) lower risk in low normal weight participants (BMI 18.5–19.9). Non-linear mendelian randomisation indicated a J shaped relation between genetically predicted BMI and the risk of all cause mortality, with the lowest risk at a BMI of around 22–25 for the overall sample. Subgroup analyses by smoking status, however, suggested an always-increasing relation of BMI with mortality in never smokers and a J shaped relation in ever smokers.”
>>>PNN NewsWatch
* FDA on Friday approved cladribine (Mavenclad, EMD Serono) tablets to treat relapsing forms of multiple sclerosis (MS) in adults, to include relapsing-remitting disease and active secondary progressive disease. Cladribine is not recommended for MS patients with clinically isolated syndrome and is generally a second-line agent because of its safety profile (increased risk of malignancy and fetal harm; contraindicated in those with current malignancy).
>>>PNN JournalWatch
* Medication Adherence: Scope of the Problem, Ways to Measure, Ways to Improve, and the Role of the Pharmacist, in Journal of the American College of Clinical Pharmacy2019; 2: 63–8. (L. K. Sharp, sharpl@uic.edu)
* Best Practices: Incorporating Pharmacy Technicians and Other Support Personnel Into the Clinical Pharmacist’s Process of Care, in 
Journal of the American College of Clinical Pharmacy2019; 2: 74–81. (J. S. Borchert, jborch@midwestern.edu)

PNN Pharmacotherapy Line
Apr. 2, 2019 * Vol. 26, No. 63
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. 2 issue of Annals of Internal Medicine (2019; 170).
Dual Receipt of Prescription Opioids & Overdose Deaths: Veterans who receive opioids through both the VA system and Medicare Part D are at significantly higher risk of overdose deaths, a study shows (pp. 433–42; W. F. Gellad, walid.gellad@va.gov).
PICO: 215 patients who died of a prescription opioid overdose in 2012 or 2013 (cases) and 833 living controls were identified from all veterans enrolled in both VA and Part D who filled at least 1 opioid prescription from either system; exposure was the source of opioid prescriptions within 6 months of the index date, categorized as VA only, Part D only, or VA and Part D (that is, dual use); outcome of unintentional or undetermined-intent death from prescription opioid overdose.
Results: “Among case patients, the mean age was 57.3 years (SD, 9.1), 194 (90%) were male, and 181 (84%) were non-Hispanic white. Overall, 60 case patients (28%) and 117 control patients (14%) received dual opioid prescriptions. Dual users had significantly higher odds of death from prescription opioid overdose than those who received opioids from VA only (odds ratio [OR], 3.53 [95% CI, 2.17 to 5.75]; P < 0.001) or Part D only (OR, 1.83 [CI, 1.20 to 2.77]; P = 0.005).”
Editorial: “Lives lost to opioid overdose are a national tragedy and a notable component of decreased longevity in the United States for 2 years in a row,” editorialists write (pp. 497–8; C. M. Clancy, carolyn.clancy@va.gov). “Last year, 47,000 Americans died of opioid overdose. Although addressing overdoses is imperative, it should not be the only goal. Identifying nonnarcotic alternatives for pain, reducing semiautomatic prescribing for minor procedures, and enhancing our ability to predict which patients are likely to have difficulty using opioids for a short time are also essential. Further, addressing systems issues that arise from dual use and making it easier for providers to access state [prescription drug monitoring programs] data are vital. As Moyo and colleagues note, dual use of opioid prescriptions among veterans is a risk factor for fatal overdose that ‘underscores the importance of care coordination across health care systems to improve opioid prescribing safety.’”
Rituximab in Myalgic Encephalomyelitis/CFS: A phase 3 trial of rituximab in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) failed to confirm clinical improvements related to B-cell depletion intervention (10.7326/M18-1451; Ø. Fluge, ystein.fluge@helse-bergen.no">oystein.fluge@helse-bergen.no).
PICO: At 5 Norwegian hospitals, 151 adult patients with ME/CFS received rituximab induction and treatment infusions or placebo over a 12-month period; primary outcomes of overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months.
Results: “Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, −5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, −0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events.”
>>>PNN NewsWatch
FDA has posted warning letters to four companies who produce homeopathic drug products for significant violations of current good manufacturing practice (CGMP) regulations, including King Bio Inc.; FDA has previously had concerns about the quality of drug products produced by King Bio, the agency said. Products labeled as homeopathic have not been approved by FDA for any use and may not meet modern standards for safety, effectiveness, and quality. Products labeled as homeopathic can be made from a wide range of substances, including ingredients derived from plants, healthy or diseased animal or human sources, minerals, and chemicals, FDA said. These unapproved drugs may cause significant and even irreparable harm if they are poorly manufactured, which can lead to contamination, or may contain active ingredients that are not adequately tested or disclosed to patients, such as belladonna, as noted in previous FDA warnings.

PNN Pharmacotherapy Line
Apr. 3, 2019 * Vol. 26, No. 64
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 2 issue of JAMA (2019; 321).
CABANA—Ablation v. Drugs in Atrial Fibrillation: In patients with atrial fibrillation (AF), a primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest was not significantly changed by use of catheter ablation versus drug therapy, report researchers in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial (pp. 1261–74; D. L. Packer, packer@mayo.edu).
PICO: At 126 centers in 10 countries, participants were randomized to open-label pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators, or standard rhythm and/or rate control drugs guided by contemporaneous guidelines.
Results: “Of the 2,204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1,006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65–1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60–1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74–0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45–0.60]; P < .001).”
CABANA—Quality of Life in Atrial Fibrillation: Compared with drug therapy in patients with AF, catheter ablation therapy produced “clinically important and significant improvements in quality of life at 12 months,” CABANA investigators conclude (pp. 1275–85; D. B. Mark, daniel.mark@duke.edu).
PICO: Prespecified co-primary quality of life end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency and severity scores in 2,204 people with AF.
Results: “The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7–6.9]; P < .001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, −1.7 points [95% CI, −2.3 to −1.2]; P < .001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, −1.5 points [95% CI, −2.0 to −1.1]; P < .001).”
>>>PNN NewsWatch
FDA yesterday announced issuance of two warning letters to operators of websites that illegally market potentially dangerous, unapproved, and misbranded opioid medications, including tramadol. The warning letters issued to azmedicinalshop.com and thedonrx.net request that they immediately cease offering violative drugs for sale to U.S. consumers.
* FDA has scheduled a 
May 13 public hearing to discuss access to affordable insulin products and issues related to the development and approval of biosimilar and interchangeable insulin products. “Driving down drug prices requires a comprehensive approach. But one impactful route is through competition,” FDA Commissioner Scott Gottlieb, MD, wrote in a statement on the topic. “We understand the urgent need to address the high prices and lack of competition in the insulin market. Ultimately the input we receive at the public hearing will help to inform steps the FDA can take to advance access to insulin products, including biosimilar and interchangeable insulin products. We’re also interested in how the agency can encourage the development of biosimilar and interchangeable insulin products while achieving the balance between competition and innovation intended by Congress in the [Biologics Price Competition and Innovation Act].”

PNN Pharmacotherapy Line
Apr. 4, 2019 * Vol. 26, No. 65
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 4 issue of the New England Journal of Medicine (2019; 380).
Andexanet Alfa for Factor Xa Inhibitor Bleeding: Used for acute major bleeding associated with use of a factor Xa inhibitor, andexanet produced excellent or good hemostatic efficacy at 12 hours, according full results from the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study (pp. 1326–35; S. J. Connolly, connostu@phri.ca).
PICO: 352 patients with acute major bleeding within 18 hours after administration of a factor Xa inhibitor; andexanet bolus and 2-hour infusion; coprimary outcomes of percent change in anti–factor Xa activity after andexanet treatment and percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion.
Results: “Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti–factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.”
Levothyroxine in Women With Thyroid Peroxidase Antibodies Before Conception: Testing possible use in euthyroid women with thyroid peroxidase antibodies, researchers report no advantage from levothyroxine supplementation during pregnancy compared with placebo in terms of live births (pp. 1316–25; A. Coomarasamy, a.coomarasamy@bham.ac.uk).
PICO: 952 euthyroid women with thyroid peroxidase antibodies and a history of miscarriage or infertility at 49 U.K. hospitals; levothyroxine 50 mcg or placebo once daily from before conception through end of pregnancy; primary outcome of live birth after 34 weeks’ gestation.
Results: “The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, −0.4 percentage points; 95% CI, −6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14).”
Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome: Benralizumab, a monoclonal antibody against interleukin-5 receptor alpha, produced favorable clinical and hematologic responses in a phase 2 trial of patients with PDGFRA-negative hypereosinophilic syndrome (pp. 1336–46; F. L. Kuang, feili.kuang@nih.gov).
PICO: 20 symptomatic patients with PDGFRA-negative hypereosinophilic syndrome; placebo controlled with double-blinded and open-label phases.
Results: Benralizumab for 12 weeks lowered absolute eosinophil counts and produced sustained clinical and hematologic responses that were sustained for 48 weeks in 74% of the patients.
>>>PNN NewsWatch
FDA 2019 priorities for compounded drugs are as follows, according to a statement from two officials: maintaining quality manufacturing and compliance, regulating compounding from bulk drug substances, finalizing the agency’s memorandum of understanding with states, and clarifying how Section 503A will be applied regarding compounding by hospital and health systems. For the last priority, a public meeting has been scheduled for May 21 to explore when hospitals should register as 503B outsourcing facilities.

PNN Pharmacotherapy Line
Apr. 5, 2019 * Vol. 26, No. 66
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 (2019; 176).
CBT, Medications in Depression, PTSD: Studies and an editorial examine drugs and psychotherapy in management of two difficult-to-treat psychiatric disorders, nonremitting depression and posttraumatic stress disorder (PTSD).
Nonremitting Depression: Patients with major depression who do not respond to initial therapy with antidepressants or cognitive-behavioral therapy (CBT) can benefit from addition of the other treatment modality, a study reports, with no preference for the order in which the interventions are added (pp. 275–86; B. W. Dunlop).
PICO: Previously untreated adults with major depression were randomized to escitalopram, duloxetine, or CBT monotherapy for 12 weeks; 112 patients who did not achieve remission with monotherapy were entered into combination treatment for 12 weeks (41 partial responders and 71 nonresponders); those responding to combination therapy were followed for 18 months.
Results: “Overall, remission rates after subsequent combination therapy were significantly higher among patients who responded to monotherapy but did not achieve remission (61%) than among patients who did not respond to monotherapy (41%). Among patients who responded to monotherapy but did not achieve remission, the remission rate in the CBT plus medication group (89%) was higher than in the medication plus CBT group (53%). However, among patients whose depression did not respond to monotherapy, rates of response and remission were similar between the treatment arms. Higher levels of anxiety, both prior to monotherapy and prior to beginning combination treatment, predicted poorer outcomes for both treatment groups.”
PTSD: Both sertraline and a specific type of CBT — prolonged exposure therapy — were beneficial in patients with PTSD, “with some evidence of an advantage for prolonged exposure” and better results when patients received their preferred treatment, researchers report (pp. 287–96; L. A. Zoellner).
PICO: 200 patients with PTSD viewed standardized treatment rationales before double randomization to choice of treatment or no choice and then to prolonged exposure or sertraline; main outcome measure of interviewer-rated PTSD symptom severity.
Results: “Patients preferred prolonged exposure over sertraline (number needed to benefit [NNTB] = 4.5). Using intent-to-treat analyses (N = 200), both prolonged exposure and sertraline showed large gains that were maintained over 24 months. Although no differential effect was observed on interviewer-rated PTSD severity, there was a significant benefit of prolonged exposure over sertraline on interview-rated loss of PTSD diagnosis (NNTB = 7.0), responder status (NNTB = 5.7), and self-reported PTSD, depression, and anxiety symptoms and functioning (effect sizes, 0.35–0.44). Patients who received their preferred treatment were more likely to be adherent, lose their PTSD diagnosis (NNTB = 3.4), achieve responder status (NNTB = 3.4), and have lower self-reported PTSD, depression, and anxiety symptoms (effect sizes, 0.40–0.72).”
Editorial: In patients with depression or PTSD, “something must be done for patients who do not remit or even respond, and stepping them up to combined treatment by virtue of adding the other monotherapy is as reasonable a choice as any,” writes an editorialist (pp. 259–61; S. D. Hollon, steven.d.hollon@vanderbilt.edu). “[I am struck by] the lack of specificity in our psychological treatments of response to depression, in that spontaneous remission and nonspecific processes account for the bulk of the acute response to treatment among nonpsychotic patients, as opposed to PTSD, in which treatment response (other than the symptom-suppressing response to antidepressant medication just described) is largely specific to trauma-focused treatment. As above, it is not clear whether this is a consequence of patients (PTSD may simply differ from depression) or procedures (trauma-focused CBT for PTSD may simply cut ‘closer to the bone’ than CBT for depression), but that is another question that deserves to be explored.”
>>>PNN NewsWatch
* FDA yesterday expanded the approved indications of palbociclib (Ibrance, Pfizer) for specific types of advanced or metastatic breast cancer to include male patients.

PNN Pharmacotherapy Line
Apr. 8, 2019 * Vol. 26, No. 67
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Cervical Disease After Bivalent HPV Immunization: In Scotland, rates of preinvasive cervical disease have fallen dramatically in the years since implementation of routine immunization with the bivalent human papillomavirus (HPV) vaccine at age 12–13 years, researchers report (l1161; T. Palmer, timothy.palmer@nhs.net).
PICO: Retrospective population study of 138,692 women born in 1988–96 and who had a smear test result recorded at age 20.
Results: “Compared with unvaccinated women born in 1988, vaccinated women born in 1995 and 1996 showed an 89% reduction (95% confidence interval 81% to 94%) in prevalent cervical intraepithelial neoplasia (CIN) grade 3 or worse (from 0.59% (0.48% to 0.71%) to 0.06% (0.04% to 0.11%)), an 88% reduction (83% to 92%) in CIN grade 2 or worse (from 1.44% (1.28% to 1.63%) to 0.17% (0.12% to 0.24%)), and a 79% reduction (69% to 86%) in CIN grade 1 (from 0.69% (0.58% to 0.63%) to 0.15% (0.10% to 0.21%)). Younger age at immunisation was associated with increasing vaccine effectiveness: 86% (75% to 92%) for CIN grade 3 or worse for women vaccinated at age 12–13 compared with 51% (28% to 66%) for women vaccinated at age 17. Evidence of herd protection against high grade cervical disease was found in unvaccinated girls in the 1995 and 1996 cohorts.”
Editorial: Reflecting on the “substantial cross protection [for HPV subtypes] and herd immunity” demonstrated in this study, an editorialist writes, “We must not forget, however, the girls who were not vaccinated and the women who do not currently screen” (l1375; J. M. L. Brotherton, jbrother@vcs.org.au). “We must work towards a world in which all girls and their families are offered, and the majority accept, HPV vaccination, wherever they live. We must also actively develop, resource, and scale-up more effective, feasible, and culturally acceptable strategies for cervical screening, such as self collection of specimens, if we are ever to effectively reduce the global burden of cervical cancer.”
>>>Lancet Report
Source:
 Apr. 6 issue of Lancet (2019; 393).
Veverimer in Metabolic Acidosis Associated With CKD: In adults with nondialysis-dependent chronic kidney disease, metabolic acidosis was effectively and safely corrected with veverimer, a nonabsorbed, counterion-free, polymeric drug that selectively binds and removes hydrochloric acid from the gastrointestinal lumen (pp. 1417–27; D. E. Wesson, donald.wesson@bswhealth.org).
PICO: At 37 international sites, 217 participants were randomized to double-blind veverimer 6 g/d or placebo for 12 weeks; composite primary efficacy endpoint of week 12 difference in proportion of patients achieving an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22–29 mmol/L.
Results: “The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23–49; p <0.0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia).”
>>>PNN JournalWatch
* Lytic Therapy for Retained Traumatic Hemothorax, in Chest2019; 155: 805–15. (B. S. Hendriksen, bhendriksen@pennstatehealth.psu.edu)
* Bronchiectasis, in 
Chest2019; 155: 825–33. (P. J. McShane, pmcshane@medicine.bsd.uchicago.edu)
* Cardiovascular Safety Trials for All New Diabetes Mellitus Drugs? Ten Years of FDA Guidance Requirements to Evaluate Cardiovascular Risk, in 
Circulation2019; 139: 1741–3. (C. C. Low Wang, cecilia.lowwang@ucdenver.edu)
* Quality Metrics for Antimicrobial Stewardship Programs, in 
Pediatrics2019; 143: 10.1542/peds.2018-2372. (M. Science)

PNN Pharmacotherapy Line
Apr. 9, 2019 * Vol. 26, No. 68
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 (2019; 179).
Rationing During Drug Shortages: Medication shortages occur frequently, hospital pharmacists report in a national survey, and various methods are used for allocation and rationing of available product (10.1001/jamainternmed.2018.8251; A. Hantel, ahantel@medicine.bsd.uchicago.edu).
PICO: 19-item survey of 719 ASHP members who were pharmacy managers or leaders in early 2018.
Results: “Most respondents (664 [92.4%]) reported an average of less than 1 month from notification to active shortage, 250 (34.9%) described having no administrative mechanism to respond to shortages, 96 (13.3%) reported a standing committee that included physicians, and 20 (2.8%) included an ethicist.… Notably, medication hoarding was reported by 584 respondents (81.3%).
“More than one-third of respondents (247 [34.4%]) reported an episode of rationing within the past year.… During rationing, 128 respondents (51.8%) reported that the treating team alone decided on allocation methods, whereas 119 (48.2%) used committees, 12 (4.9%) of which included an ethicist. Only 89 patients (36.0%) were informed that their care included rationing.”
Quality of Chronic-Disease Guidelines in Primary Care: Clinical practice guidelines (CPGs) applicable to primary care practice are of widely variable quality, a systematic review shows, and fewer than 25% of included CPGs were rated as high quality (pp. 553–60; D. O. de Melo, melo.daniela@unifesp.br).
PICO: Systematic assessment of 421 CPGs for management of common noncommunicable diseases in primary care using the validated Appraisal of Guidelines for Research and Evaluation Instrument, version II (AGREE-II) tool and multiple logistic regression to identify factors associated with quality of CPGs.
Results: “Of the 421 CPGs reviewed, 23.5% (99) were classified as high quality. Among included guidelines, clarity of presentation (70%) and scope and purpose (61%) had the highest median AGREE-II scores. The domains with the lowest median scores were applicability (22%) and rigor of development (33%). Factors associated with high-quality CPGs included having more than 20 authors (odds ratio, 9.08; 95% CI, 3.35–24.62), development at governmental institutions (odds ratio, 10.38; 95% CI, 2.72–39.60), and reporting funding (odds ratio, 10.34; 95% CI, 4.77–22.39). Year of publication, region, guideline version, and scope were not associated with quality among included CPGs.”
Editorial: “These findings are sobering and suggest that development of high-quality clinical practice guidelines appears to be beyond the capacity of the small groups of content experts who have historically created many widely used guidelines,” write editorialists (p. 561; J. S. Ross, joseph.ross@yale.edu). “The findings also question the utility of guidelines developed by professional societies, particularly those with financial relationships with industry. Clinicians appear to be best served when government organizations take on the development of clinical practice guidelines, and should be tasked with ensuring and updating high-quality guidelines to meet [Institute of Medicine] standards, retiring low-quality guidelines, and resolving conflicts between discordant existing guidelines. Fewer clinical practice guidelines should be developed going forward, and those that are developed should have sufficient expert engagement, technical support, and resources. As a profession, we rely on rigorous and transparent methods to answer scientific questions; our approach to summarizing research into clinical practice guidelines should be no less thorough.”
>>>PNN NewsWatch
FDA yesterday approved dolutegravir plus lamivudine (Dovato, ViiV Healthcare) as the first complete regimen for the treatment of HIV-1 infection in adults with no antiretroviral treatment history and with no known or suspected substitutions associated with resistance to the individual components of the product.
* In a 
news release and safety communication alert, FDA yesterday warned against using test strips — including those for blood glucose meters and INR/warfarin monitoring — from a previous owner or not authorized for sale in the U.S. because they may potentially cause infection or lead to inaccurate test results, which can cause serious harm, including death.

PNN Pharmacotherapy Line
Apr. 10, 2019 * Vol. 26, No. 69
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 9 issue of JAMA (2019; 321).
Vitamin D as Cancer Therapy? While vitamin D supplementation failed to improve 5-year, relapse-free survival in a study of 417 patients with digestive tract cancers (pp. 1361–9; M. Urashima, urashima@jikei.ac.jp), a second trial yielded intriguing results for high doses of vitamin D3 in patients being treated for metastatic colorectal cancer (CRC; pp. 1370–9; K. Ng, kimmie_ng@dfci.harvard.edu).
PICO: Double-blind phase 2 randomized clinical trial of high- versus standard-dose vitamin D3 in 139 U.S. patients with advanced or metastatic CRC in 2012–16; primary end point of progression-free survival (PFS).
Results: “The median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02).… The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, −2.6 ng/mL [95% CI, −6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001).…”
Editorial: “The possible effects of longer-term administration of vitamin D supplementation among patients with advanced-stage colorectal cancer remain unstudied,” editorialists write (pp. 1354–5; J. A. Baron, jabaron@med.unc.edu). “Confirmatory trials are needed to evaluate these preliminary findings.…”
Sexually Transmitted Infections During HIV Prophylaxis: In the Pre-exposure Prophylaxis Expanded (PrEPX) Study, a subset of gay and bisexual male participants had high and increasing numbers of bacterial sexually transmitted infections (STIs) after they began HIV preexposure prophylaxis (pp. 1380–90; M. W. Traeger, michael.traeger@burnet.edu.au).
PICO: 2,981 Australian participants on oral tenofovir disoproxil fumurate and emtricitabine, quarterly HIV/STI testing, and clinical monitoring; primary outcome of chlamydia, gonorrhea, or syphilis incidence.
Results: “Among the 2,981 individuals (median age, 34 years [interquartile range, 28–42]), 98.5% identified as gay or bisexual males, 29% used PrEP prior to enrollment, 89 (3%) withdrew and were censored at date of withdrawal, leaving 2,892 (97.0%) enrolled at final follow-up. During a mean follow-up of 1.1 years (3185.0 person–years), 2,928 STIs were diagnosed among 1,427 (48%) participants (1,434 chlamydia, 1,242 gonorrhea, 252 syphilis). STI incidence was 91.9 per 100 person–years, with 736 participants (25%) accounting for 2,237 (76%) of all STIs. Among 2,058 participants with complete data for multivariable analysis, younger age, greater partner number, and group sex were associated with greater STI risk, but condom use was not. Among 1,378 participants with preenrollment testing data, STI incidence increased from 69.5 per 100 person–years prior to enrollment to 98.4 per 100 person–years during follow-up (IRR, 1.41 [95% CI, 1.29–1.56]). After adjusting for testing frequency, the increase in incidence from 1 year preenrollment to follow-up was significant for any STI (adjusted IRR, 1.12 [95% CI, 1.02–1.23]) and for chlamydia (adjusted IRR, 1.17 [95% CI, 1.04–1.33]).”
Editorial: “Offering PrEP to patients and preventing STIs should not be viewed as a trade-off,” editorialists write (pp. 1356–8; M. Gandhi, monica.gandhi@ucsf.edu). “The HIV and STI epidemics comprise a syndemic that is now addressable. The tools are now available to end the HIV epidemic, including treatment as prevention and PrEP. Increased PrEP prescribing should lead to more frequent STI screening, which should eventually lead to a reduction in overall STI prevalence. The onus is now on health care systems and clinicians to promote and implement the comprehensive sexual health services that are needed to achieve the elimination of HIV transmissions and the end of the current STI epidemic.”
>>>PNN NewsWatch
Romosozumab-aqqg (Evenity, Amgen) was approved by FDA to treat osteoporosis in postmenopausal women at high fracture risk.

PNN Pharmacotherapy Line
Apr. 11, 2019 * Vol. 26, No. 70
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Early-release and Apr. 11 articles from the New England Journal of Medicine (2019; 380).
Pembrolizumab for PML: For treatment of patients with progressive multifocal leukoencephalopathy (PML), further study of immune checkpoint inhibitors is warranted, authors conclude based on a demonstration-of-concept study conducted at NIH (10.1056/NEJMoa1815039; I. Cortese, corteseir@ninds.nih.gov). PML, an opportunistic JC virus brain infection “is typically fatal unless immune function can be restored,” the investigators explain. “Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance.”
PICO: 8 adults with PML with different underlying conditions; pembrolizumab every 6 to 8 weeks.
Results: “Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti–JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement.”
Editorial: Commenting on these results and two letters to the editor reporting experiences with immune checkpoint inhibitors in PML (10.1056/NEJMc1817193, S. Rauer, sebastian.rauer@uniklinik-freiburg.de10.1056/NEJMc1816198, G. Martin-Blondel, martin-blondel.g@chu-toulouse.fr), an editorialist writes, “The findings from magnetic resonance imaging (MRI) in these case reports deserve consideration, since a decrease in the size of the lesions was interpreted as treatment efficacy” (10.1056/NEJMe1904140; I. J. Koralnik). “However, in some cases, the PML lesions were replaced with atrophy, a finding consistent with destruction of white matter by PML rather than with elimination of the lesions. Furthermore, the absence of contrast enhancement on MRI suggests that the immune checkpoint blockers may not have been potent enough to trigger the immune reconstitution inflammatory syndrome (IRIS). This may be partly a result of the timing of administration in the course of PML. For example, in another case report of a patient who had Hodgkin’s lymphoma, an inflammatory form of PML developed within 24 hours after the first injection of nivolumab, a presentation known as ‘unmasking IRIS.’ The brain biopsy showed infiltration of CD4+ and CD8+ T cells within the lesion.”
Verubecestat for Prodromal Alzheimer’s Disease: Based on a study terminated early for futility, researchers report that “verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer’s disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo” (pp. 1408–20; M. F. Egan, michael.egan@merck.com).
PICO: 104-week trial of verubecestat or placebo in patients with memory impairment and elevated brain amyloid levels but not meeting the case definition of dementia; primary outcome of change from baseline to week 104 in the score on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB).
Results: “The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group.…”
Editorial: “The disheartening results with [beta-site amyloid precursor protein–cleaving enzyme 1 (BACE-1)] inhibitors follow on the heels of a press announcement on March 21, 2019, that aducanumab, an antiamyloid antibody that has been shown to lower levels of A-beta, was deemed a failure after a planned interim futility analysis,” (pp. 1476–8; D. S. Knopman). “The dissociation between A-beta lowering and cognitive benefits with both BACE-1 inhibition and antiamyloid antibody therapy is troubling. To be blunt, A-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”

PNN Pharmacotherapy Line
Apr. 12, 2019 * Vol. 26, No. 71
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Chest Highlights
Source:
 Apr. issue of Chest (2019; 155).
Triple Combination Therapy in COPD: A meta-analysis shows significant benefits from triple combination therapy in patients with COPD when a long-acting muscarinic receptor antagonist (LAMA) is added to inhaled corticosteroid (ICS)/long-acting beta-2-agonist (LABA) therapy (pp. 758–70; M. Cazzola, mario.cazzola@uniroma2.it).
PICO: 13 randomized controlled trials of 15,519 patients with COPD; primary end points of the effect of triple therapy on trough FEV1, risk of acute exacerbation of COPD (AECOPD), and risk of cardiovascular serious adverse events (SAEs).
Results: “ICS/LABA/LAMA combination improved trough FEV1 (mean difference, +104.86 mL; 95% CI, 86.74–122.99; high quality of evidence) and protected against AECOPD (relative risk, 0.78; 95% CI, 0.71–0.85; high quality of evidence) vs ICS/LABA combination. For every approximately four patients treated with triple therapy, one increased FEV1 > 100 mL, and approximately 26 patients had to be treated for 1 year with ICS/LABA/LAMA combination to prevent one AECOPD, compared with ICS/LABA combination. Adding a LAMA to ICS/LABA therapy did not modulate the risk of cardiovascular SAEs (moderate quality of evidence).”
Pirfenidone & Multiple Disease Progression Events in Idiopathic Pulmonary Fibrosis: In patients with idiopathic pulmonary fibrosis, pirfenidone “significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo,” researchers report, indicating that continued treatment is beneficial despite single disease progression events (pp. 712–9; S. D. Nathan, steven.nathan@inova.org).
PICO: Post-hoc analysis of pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND and CAPACITY phase 3 trials; disease progression events defined as relative decline in % predicted FVC ≥ 10%, absolute decline in [6-min walk distance (6MWD)] ≥50 m, respiratory hospitalization, or death from any cause.
Results: “The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002).”
>>>Cardiology Report
Source:
 Apr. 16 issue of the Journal of the American College of Cardiology (2019; 73).
RAAS Inhibition & Reduced GI Bleeding With LVADs: In patients with continuous-flow left ventricular assist devices (CF-LVADs), ACE inhibitor/ARB therapy is associated with lower risk of major gastrointestinal bleeds (GIBs), a study shows (10.1016/j.jacc.2019.01.051; M. P. Converse).
PICO: ACE inhibitor/ARB exposure status landmarked at 30 days after patients received HeartMate II CF-LVADs in 2009–16; major GIBs defined as endoscopically confirmed bleeds requiring ≥2 U of packed red blood cells or resulting in death.
Results: “Patients who received an ACE inhibitor/ARB within 30 days post-operatively had a 57% reduction in the risk of major GIB (adjusted hazard ratio [aHR]: 0.43; 95% confidence interval [CI]: 0.19 to 0.97; p = 0.042) and a 63% reduction in the risk of [arteriovenous malformations (AVM)]–related GIB (aHR: 0.37; 95% CI: 0.16 to 0.84; p = 0.017). When the mean daily post-operative lisinopril-equivalent ACE inhibitor/ARB dose was >5 mg, the risk of major GIB decreased in a dose-threshold manner (aHR: 0.28; 95% CI: 0.09 to 0.85; p = 0.025).”
>>>PNN NewsWatch
* Citing postmarketing studies, FDA is ordering Sprout Pharmaceuticals to update the boxed warning, contraindication, warnings and precautions, and adverse reactions sections of labeling for flibanserin (Addyi) to reflect that women should discontinue drinking alcohol at least 2 hours before taking the drug at bedtime or to skip the flibanserin dose that evening. Women should not consume alcohol at least until the morning after taking flibanserin at bedtime.

PNN Pharmacotherapy Line
Apr. 15, 2019 * Vol. 26, No. 72
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Apr. 13 issue of Lancet (2019; 393).
Laser Trabeculoplasty for Ocular Hypertension/Glaucoma: Compared with topical ophthalmic products, selective laser trabeculoplasty yielded superior outcomes in the Laser in Glaucoma and ocular HyperTension (LiGHT) study, researchers report, supporting this intervention for first-line treatment for open angle glaucoma and ocular hypertension (pp. 1505–16; G. Gazzard, gus.gazzard@moorfields.nhs.uk).
PICO: Observer-masked, randomized controlled trial of 652 treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities in 2012–14; randomized to initial selective laser trabeculoplasty or eye drops based on glaucoma severity; primary outcome of health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D).
Results: “Average EQ-5D score was 0.89 (SD 0.18) in the selective laser trabeculoplasty group versus 0.90 (SD 0.16) in the eye drops group, with no significant difference (difference 0.01, 95% CI −0.01 to 0.03; p = 0.23). At 36 months, 74.2% (95% CI 69.3–78.6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intraocular pressure at more visits (93.0%) than in the eye drops group (91.3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20,000 per quality-adjusted life-year gained.”
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Sotagliflozin in Type 1 Diabetes: “In type 1 diabetes, sotagliflozin improves glycaemic and non-glycaemic outcomes and reduces hypoglycaemia rate and severe hypoglycaemia,” conclude authors of a meta-analysis of six randomized controlled trials of the dual SGLT 1/2 inhibitor that included 3,238 adult patients (l1328; G. Musso, giovanni_musso@yahoo.it). “The risk of diabetic ketoacidosis could be minimised by appropriate patient selection and down-titration of the basal insulin dose.”
Type 2 Diabetes With Steroid 5-alpha-Reductase Inhibitors: Intraclass differences are evident with respect to risks of developing type 2 diabetes during 5-alpha-reductase inhibitor therapy for benign prostatic hyperplasia, according to an analysis of the U.K. Clinical Practice Research Datalink and the Taiwanese National Health Insurance Research Database (l1204; R. Andrew, ruth.andrew@ed.ac.uk). “The risk of developing new onset type 2 diabetes appears to be higher in men with benign prostatic hyperplasia exposed to 5-alpha-reductase inhibitors than in men receiving tamsulosin, but did not differ between men receiving dutasteride and those receiving finasteride,” the authors conclude. “Additional monitoring might be required for men starting these drugs, particularly in those with other risk factors for type 2 diabetes.”
>>>PNN NewsWatch
FDA on Friday granted accelerated approval to erdafitinib (Balversa, Janssen), for treatment of adult patients with locally advanced or metastatic bladder cancer with FGFR3 or FGFR2 genetic alterations that has progressed during or following prior platinum-containing chemotherapy. Erdafitinib is the first FGFR kinase inhibitor approved by FDA. Patients should be selected for therapy with erdafitinib using the companion diagnostic therascreen FGFR RGQ RT-PCR Kit (Qiagen Manchester, Ltd.), the agency said.
>>>PNN JournalWatch
* Screening and Management of Depression in Patients With Cardiovascular Disease: JACC State-of-the-Art Review, in Journal of the American College of Cardiology2019; 73: 10.1016/j.jacc.2019.01.041. (M. K. Jha)
* Management of Cancer-Associated Anemia With Erythropoiesis-Stimulating Agents: ASCO/ASH Clinical Practice Guideline Update, in 
Journal of Clinical Oncology2019; 10. 1200/JCO.18.02142. (ASCO, guidelines@asco.org)
* Treatments of Cold Urticaria: A Systematic Review, in 
Journal of Allergy and Clinical Immunology2019; 143: 1311–31. (S. Hunnangkul, s_hunnangkul@hotmail.com)

PNN Pharmacotherapy Line
Apr. 16, 2019 * Vol. 26, No. 73
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. 16 issue of Annals of Internal Medicine (2019; 170).
Acute Cannabis-Associated Illness by Route of Exposure: In Colorado, inhaled cannabis exposure was associated with more emergency department (ED) visits than ingestion of edible products, but the latter produced a greater frequency of acute psychiatric symptoms and more ED visits than expected, a study shows (pp. 531–7; A. A. Monte, andrew.monte@ucdenver.edu).
PICO: ED visits by adults for cannabis-related conditions at a Colorado academic hospital in 2012–16.
Results: “There were 9,973 visits with an ICD-9-CM or ICD-10-CM code for cannabis use. Of these, 2,567 (25.7%) visits were at least partially attributable to cannabis, and 238 of those (9.3%) were related to edible cannabis. Visits attributable to inhaled cannabis were more likely to be for cannabinoid hyperemesis syndrome (18.0% vs. 8.4%), and visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% vs. 10.9%), intoxication (48% vs. 28%), and cardiovascular symptoms (8.0% vs. 3.1%). Edible products accounted for 10.7% of cannabis-attributable visits between 2014 and 2016 but represented only 0.32% of total cannabis sales in Colorado (in kilograms of tetrahydrocannabinol) during that period.”
Editorial: “These findings also underscore the urgent need for greater oversight of manufacturing practices, labeling standards, and quality control of cannabis products marketed to the public,” editorialists write (pp. 569–70; N. D. Volkow, nvolkow@nida.nih.gov). “We must recognize that the full range of potential adverse health consequences from cannabis consumption are not fully understood. Research is needed not only to rigorously ascertain evidence about potential beneficial effects of cannabis but also to carefully characterize its potential negative effects.”
Improving the Affordable Care Act: In a position paper, the American College of Physicians “recommends action to enhance and expand eligibility for health insurance financial subsidies; stabilize health insurance marketplaces; provide sustained funding for outreach, education, and enrollment assistance activities; test and implement a mechanism to encourage enrollment; expand Medicaid in all states; and establish a public insurance option to increase competition” (10.7326/M18-3401; R. A. Crowley, rcrowley@acponline.org). “The coverage reforms of the Patient Protection and Affordable Care Act have fundamentally changed the U.S. health care system. The law’s health insurance regulations, which include protections for persons with preexisting conditions, have made health insurance more accessible. The premium tax credit and cost-sharing subsidies have made nongroup coverage more affordable. The essential health benefit package and coverage for preventive services without cost sharing have made insurance more comprehensive. Perhaps most important, the Medicaid expansion extended coverage to millions of low-income adults. Despite these gains, more needs to be done to bring the United States closer to achieving universal coverage.”
Low Scam Awareness & Risk of Alzheimer Dementia: A prospective study links decreased scam awareness with increased risk for incident Alzheimer dementia, mild cognitive impairment, and Alzheimer disease pathology in the brain (10.7326/M18-2711; P. A. Boyle, Patricia_Boyle@rush.edu).
PICO: Community-based prospective study of 935 older adults initially free of dementia; questionnaire measurement of scam awareness; neuropathology after death.
Results: “During a mean of about 6 years (SD, 2.4) of observation, 151 persons (16.1%) developed Alzheimer dementia. Low scam awareness was associated with increased risk for Alzheimer dementia (hazard ratio [HR], 1.56 [95% CI, 1.21 to 2.01]; P <0.001), such that each 1-unit increase in scam score (indicating lower awareness) was associated with about a 60% increase in dementia risk. Low scam awareness was also associated with increased risk for mild cognitive impairment (HR, 1.47 [CI, 1.20 to 1.81]; P <0.001). These associations persisted even after adjustment for global cognitive function. Finally, low scam awareness was associated with a higher burden of Alzheimer pathology in the brain, particularly beta-amyloid (estimated increase [± SE] in beta-amyloid per 1-unit increase in scam score, 0.22 ± 0.10 unit; P = 0.029).”

PNN Pharmacotherapy Line
Apr. 17, 2019 * Vol. 26, No. 74
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 16 issue of JAMA (2019; 321).
Oral Semaglutide in Type 2 Diabetes: Compared with sitagliptin, higher oral doses of the glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide produced significantly greater reductions in glycated hemoglobin over 26 weeks, researchers report (pp. 1466–80; M. Davies, melanie.davies@uhl-tr.nhs.uk).
PICO: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks in 2016–18; once-daily oral semaglutide 3, 7, or 14 mg or sitagliptin 100 mg; primary end point of change in glycated hemoglobin.
Results: “Among 1,864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n = 879 [47.2%] women), 1,758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, –0.3% [95% CI, –0.4% to –0.1%] and –0.5% [95% CI, –0.6% to –0.4%], respectively; P < .001 for both) and body weight (differences, –1.6 kg [95% CI, –2.0 to –1.1 kg] and –2.5 kg [95% CI, –3.0 to –2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.”
Editorial: These and other recent findings “indicate that the introduction of semaglutide, the first oral preparation of a GLP-1RA for which the subcutaneous agent has shown positive cardiovascular benefit, should be an important addition to the growing list of pharmacologic options for type 2 diabetes,” writes an editorialist (pp. 1457–8; I. B. Hirsch, ihirsch@uw.edu). “What should not be overlooked is the successful development of technology to permit oral availability of peptide-based drugs. The oral formulation of semaglutide requires an absorption enhancer that should be a model for other drugs. The most compelling example would be insulin, for which development of an oral formulation has been attempted for decades with a variety of approaches: enzyme inhibitors, absorption enhancers, chemical modification for endogenous receptor-mediated absorption, and mucoadhesive polymers.”
Mouthwash for Radiotherapy-Related Oral Mucositis Pain: Compared with placebo, doxepin mouthwash or diphenhydramine–lidocaine–antacid mouthwash significantly reduced radiotherapy-related oral mucositis pain during the first 4 hours after administration, but not to a clinically important degree, a study shows (pp. 1481–90; R. C. Miller, robertmiller@umm.edu).
PICO: Phase 3 randomized trial of 275 patients with oral mucositis pain after head and neck radiotherapy in 2014–16; doxepin or diphenhydramine–lidocaine–antacid mouthwash or placebo; primary end point of total oral mucositis pain reduction 4 hours after a single dose.
Results: “Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine–lidocaine–antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2–6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1–5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo.” More drowsiness, unpleasant taste, and stinging or burning was reported with doxepin mouthwash compared with placebo.
Editorial: “More high-quality prospective research is needed to refine the available treatments, to address all types of oral mucositis, to provide head-to-head comparisons of active treatments (in addition to comparisons with placebo), and, when applicable, to assess if the intervention carries a risk for severe, late adverse events,” editorialists write (pp. 1459–61; S. Elad, selad@urmc.rochester.edu). “Technological advances in the treatment of cancer, such as using proton-beam radiotherapy for head and neck cancers, may substantially reduce the extent of oral mucositis. Until these advances are routinely used, the search for an effective, safe therapy for oral mucositis and its associated pain needs to continue.”

PNN Pharmacotherapy Line
Apr. 18, 2019 * Vol. 26, No. 75
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 18 issue of the New England Journal of Medicine (2019; 380).
Cardioversion Timing in Recent-Onset Atrial Fibrillation: Commenting on a study showing noninferiority of a wait-and-see approach in comparison with early cardioversion for patients seen in the emergency department with recent-onset, symptomatic atrial fibrillation (pp. 1499–508; H. J. G. M. Crijns, hjgm.crijns@mumc.nl), editorialists make these points (pp. 1578–9; J. S. Healey): “Since the early-cardioversion strategy did not significantly increase the rate of sinus rhythm at 4 weeks, it is implausible that such treatment would improve long-term outcomes, a finding that is consistent with the results comparing long-term rate control with pharmacologic rhythm control. However, long-term prognosis can be improved with oral anticoagulation and risk-factor modification, which can be initially addressed in the emergency department visit and then effectively managed with routine specialist follow-up. Therapy to prevent recurrent hospitalization for atrial fibrillation is another key component of long-term care, since most patients who present to the emergency department have recurrent atrial fibrillation. The management of atrial fibrillation in the emergency department is not only a sprint to eliminate symptoms and facilitate safe discharge but also the start of a marathon to improve long-term outcomes for patients.”
Antithrombotic Therapy After ACS or PCI in Atrial Fibrillation: The need for personalized pharmacotherapy is apparent based on the results of the AUGUSTUS trial of antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) (pp. 1509–24; R. D. Lopes, renato.lopes@duke.edu).
PICO: International trial with 2-by-2 factorial design; patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor, to receive apixaban or a vitamin K antagonist, and to receive aspirin or matching placebo for 6 months; primary outcome of major or clinically relevant nonmajor bleeding.
Results: “Enrollment included 4,614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P <0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P <0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group.”
Editorial: “Although guideline committees will now have to grapple with incorporating the results of the AUGUSTUS trial into specific recommendations, it is clear that a one-size-fits-all policy is unlikely to apply in these patients,” an editorialist concludes (pp. 1580–1; S. R. Mehta). “Clinical decision making should continue to be based on a balanced assessment of three competing risks: cardioembolic stroke, coronary ischemic events, and bleeding. This assessment should include not only demographic and clinical variables regarding these risks but also the clinical setting as well as the angiographic complexity of PCI and risks associated with the procedure. In patients with a low risk of thrombotic events (e.g., those undergoing elective PCI who do not have high-risk clinical or angiographic features) or a high risk of bleeding, early omission of aspirin therapy and treatment with a direct oral anticoagulant plus clopidogrel is entirely warranted. However, in patients undergoing complex, multivessel, or high-risk PCI or in those presenting with high-risk acute coronary syndrome, aspirin should probably not be routinely omitted for at least several weeks or longer, depending on bleeding risk.”

PNN Pharmacotherapy Line
Apr. 19, 2019 * Vol. 26, No. 76
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Oncology Report
Source:
 Early-online article from the Journal of Clinical Oncology (2019; 37).
Opioid Use Among Older Cancer Survivors: Six years after diagnosis of colorectal, lung, or breast cancers, survivors were no more likely to be chronic users of opioids than control participants, a study shows (10.1200/JCO.18.00938; T. Salz, salzt@mskcc.org).
PICO: Opioid-naive survivors of colorectal, lung, and breast cancers diagnosed in 2008–13 were matched with noncancer controls; rates of high-dose opioid use (average ≥90 morphine milligram equivalents daily) compared between cases and controls with chronic use.
Results: “In the first year after the index date (survivor’s diagnosis date), chronic use among colorectal and lung cancer survivors exceeded chronic use among controls (colorectal cancer: odds ratio, 1.34; 95% CI, 1.22 to 1.47; lung cancer: odds ratio, 2.55; 95% CI, 2.34 to 2.77). Differences in chronic use between survivors and controls declined each year after the index date. Chronic use among breast cancer survivors was less than that of controls each year after the index date. Survivors with chronic use were more likely to have a high daily dose than controls with chronic use in the first 3 to 5 years.”
>>>Infectious Diseases Report
Source:
 Apr. 15 issue of Clinical Infectious Diseases (2019; 68).
IDO Activity & HIV Reservoir Size During ART: Activity of indoleamine 2,3-dioxygenase (IDO) — an immunoregulatory enzyme that metabolizes tryptophan to immunosuppressive kynurenines and an emerging target in HIV research — is positively correlated with total HIV DNA in blood during antiretroviral therapy (ART), researchers report (pp. 1274–81; H. Lu, luhongzhou@fudan.edu.cn).
PICO: In 127 patients living with HIV and receiving ART, total HIV DNA in peripheral blood mononuclear cells (PBMCs), tryptophan and kynurenine concentrations, and microbial translocation markers were measured.
Results: “Elevated IDO activity prior to ART correlated with on-ART HIV DNA (r = 0.35, P = .004), but was not associated with pre-ART HIV DNA. A median duration of 15 months of ART significantly decreased IDO activity; however, these levels were still higher than those observed in HIV-uninfected controls. Among treated participants, IDO activity positively correlated with their concurrent HIV DNA (r = 0.36, P < .0001). Multivariate model showed an independent association of pre-ART CD4/CD8 ratio (adjusted odds ratio [aOR], 0.75 per 0.1 increase [95% confidence interval {CI}, .62–.91]) and on-ART IDO activity (aOR, 1.09 per nM/μM increase [95% CI, 1.04–1.14]) with higher levels of HIV DNA on-ART. A lack of association of the microbial translocation markers was observed with the size of HIV reservoir. HIV DNA positively correlated with the proportions of activated CD4 T and CD8 T cells and exhausted CD4 T cells.”
Immunosuppression & Indirect Effects of Pneumococcal Childhood Vaccination: Analysis of invasive pneumococcal disease (IPD) cases shows the importance of childhood vaccination with pneumococcal conjugate vaccines (PCVs) in both immunocompetent and immunosuppressed individuals (pp. 1367–73; A. Steens, anneke.steens@fhi.no).
PICO: Case–cohort study of 7,926 IPD cases reported to the Norwegian Surveillance System for Communicable Diseases in 2005–14 and 249,998 individuals randomly selected from the National Registry in 2012; immunosuppressive treatment groups identified based on dispensed prescriptions retrieved from the Norwegian Prescription Database; incidences and age-adjusted relative risks (RR).
Results: “IPD incidences decreased in all groups. The PCV13 incidence decreased by 5–12% across groups. The non-PCV13 incidence increased by 4–10%, mostly in individuals on chemotherapy (overlapping 95% confidence intervals). In the PCV13 era, the RR for IPD was highest (significant) and the percentage of cases caused by the polysaccharide vaccine PPV23 serotypes lowest (numerical) in individuals on chemotherapy (RR = 20.4, PPV23 = 52%), followed by individuals on corticosteroids (RR = 6.2, PPV23 = 64%), other immunosuppressants (RR = 5.6, PPV23 = 68%), and no immunosuppressants (RR = 1 [reference], PPV23 = 74%).”

PNN Pharmacotherapy Line
Apr. 23, 2019 * Vol. 26, No. 78
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 the Annals of Internal Medicine (2019; 170).
Long-Term Weight Loss With Metformin: Participants in the Diabetes Prevention Program (DPP) who received metformin had greater long-term weight loss (LTWL) during the Outcomes Study (DPPOS) phase of the study, compared with intensive lifestyle intervention (ILS), or placebo (10.7326/M18-1605; K. M. Gadde, Kishore.gadde@pbrc.edu).
PICO: At 27 DPP and DPPOS clinics, 1,066 participants who lost at least 5% of baseline weight in the first year were followed for 15 years.
Results: “After 1 year, 289 (28.5%) participants in the metformin group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the placebo group had lost at least 5% of their weight. After the masked treatment phase ended, the mean weight loss relative to baseline that was maintained between years 6 and 15 was 6.2% (95% CI, 5.2% to 7.2%) in the metformin group, 3.7% (CI, 3.1% to 4.4%) in the ILS group, and 2.8% (CI, 1.3% to 4.4%) in the placebo group. Independent predictors of LTWL included greater weight loss in the first year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and higher fasting plasma glucose levels at baseline in the placebo group.”
>>>Vaccine Highlights
Source:
 May 1 issue of Vaccine (2019; 37).
Intraseason Decline in Influenza VE: In general practice, the 2016 influenza vaccine showed good effectiveness during the Southern Hemisphere season, a study shows, but vaccine effectiveness (VE) was higher in the months closer to administration, “indicating [that] immunization close to influenza season offered optimal protection” (pp. 2634–41; A. K. Regan).
PICO: Using a test-negative design in a case–control study, data from three routine syndromic sentinel surveillance systems in general practices in Australia were used to estimate VE.
Results: “A total of 1,085 patients tested for influenza in 2016 were included in the analysis, of whom 447 (41%) tested positive for influenza. The majority of detections were influenza A/H3N2 (74%). One-third (31%) of patients received the 2016 southern hemisphere formulation influenza vaccine. Overall, VE was estimated at 40% (95% CI: 18–56%). VE estimates were highest for patients immunized within two months prior to symptom onset (VE: 60%; 95% CI: 26–78%) and lowest for patients immunized >4 months prior to symptom onset (VE: 19%; 95% CI: −73–62%).”
>>>Gerontology Report
Source:
 Apr. issue of The Gerontologist (2019; 59).
Bilingual Text & Pictograms on Rx Medication Labels: Among older adults in Singapore, use of bilingual text with or without International Pharmaceutical Federation pictograms on prescription medication labels (PMLs) was associated with improved understanding of instructions (pp. 378–90; R. Malhotra, rahul.malhotra@duke-nus.edu.sg). These results strongly suggest application of this intervention in practice, the investigators conclude, adding, “The key findings warrant further assessment of issues related to label design and content, including adapting FIP pictograms for elderly Singaporeans, as well as other nonlabel-related factors that may limit their understanding of PMLs.”
>>>PNN NewsWatch
* Torrent Pharmaceuticals is expanding its recall for Losartan Potassium Tablets USP and Losartan Potassium/Hydrochlorothiazide Tablets, USP, to the consumer level because of the detection of trace amounts of N-methylnitrosobutyric acid in a Hetero Labs active pharmaceutical ingredient, FDA said.
* “We cannot state strongly enough – the overwhelming scientific evidence shows that vaccines are among the most effective and safest interventions to both prevent individual illness and protect public health,” Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research, said in a 
statement released yesterday. “Vaccinating against measles, mumps and rubella not only protects us and our children, it protects people who can’t be vaccinated, including children with compromised immune systems due to illness and its treatment, such as cancer.”

PNN Pharmacotherapy Line
Apr. 24, 2019 * Vol. 26, No. 79
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 Apr. 23/30 issue of JAMA (2019; 321).
Medicaid Prices, Market Share & Spending on Long-Acting Insulins: Competition among long-acting insulin products is linked to lower Medicaid reimbursements in a market-share analysis (pp. 1627–9; I. Hernandez, inh3@pitt.edu). Based on the results, the authors conclude, “These findings [lend] support to policies that expedite biosimilar approval and market entry. More savings should be expected once biosimilars are labeled as ‘interchangeable’ and can be automatically substituted at the pharmacy.”
PICO: Mean amount reimbursed per 100 IU and market share as reflected in fee-for-service and managed care Medicaid state drug utilization data from quarter 1 (Q1) 2005 to Q2 2018, for insulin glargine 100 international units (IU)/mL (Basaglar and Lantus); insulin detemir; insulin glargine–lixisenatide; insulin glargine 300 IU/mL; and insulin degludec.
Results: Following early dominance, “the market shares of Lantus and insulin detemir decreased [from 80% and 20%] to 42% and 14%, respectively. By Q1 2018, the market share of Basaglar reached 34% of all IU for long-acting insulins, or 44% of all IU for insulin glargine, 100 IU/mL. In Q1 2018, insulin glargine, 300 IU/mL, and insulin degludec each accounted for 5% of IU for long-acting insulins and insulin glargine–lixisenatide for 0.1%.
“Reimbursement rates for Lantus and insulin detemir increased in parallel in 2006–2014 by an average of 13% annually but stabilized following new product entry. Without accounting for inflationary or supplemental rebates, Basaglar reimbursement rates have been 15% to 16% lower than those of Lantus since its entry. From Q4 2016 to Q2 2018, Basaglar entry resulted in savings of more than $70 million to Medicaid, or around 4.4% of expenditures on insulin glargine, 100 IU/mL.”
Canadian Experiences With Drug Price Regulation: “As Canadian payers are struggling to cope with high-cost pharmaceuticals, many are questioning the effectiveness of the [Patented Medicine Prices Review Board (PMPRB)] in meeting the government’s policy objectives,” Viewpoint authors write (pp. 1565–6; F. Xie, fengxie@mcmaster.ca). A PMPRB amendment introduces economic factors such as cost-utility analysis in an effort to regulate drug prices. “With an increasing number of high-cost, potentially breakthrough drugs being marketed worldwide, there is a need to establish a price regulation mechanism to control drug prices and ensure the sustainability of the Canadian and other health care systems,” the authors conclude. “The proposed amendment to Canadian patented drug price regulation is a first but important step to addressing rising drug costs. An effective approach to controlling drug prices must regulate the amount of profit each pharmaceutical R&D investment dollar can generate and ultimately requires a concerted effort at the international level.”
Editorial: One of three related Viewpoint articles notes that “in providing care for the expanding older population, ‘What matters most?’ cannot mean any therapy at any price” (pp. 1567–8; J. H. Gurwitz, jerry.gurwitz@umassmed.edu). “Aligning the price of new therapies with demonstrated added benefits is an important step on the road to a health system that can guarantee sustainable access to effective therapies for older patients. Policies around pricing and coverage must be developed in a transparent fashion with adequate consideration of the views of patients and families. Pricing and coverage decisions must also reflect that ‘high-value,’ high-cost treatments applicable to large numbers of older patients will require measures to ensure that the potential budgetary consequences do not impinge on patients’ access to treatment and the affordability of their care.”
>>>PNN NewsWatch
Alvogen is voluntarily recalling two lots (180060 and 180073) of Fentanyl Transdermal System 12 mcg/h transdermal patches (manufactured by 3M Drug Delivery Systems) to the consumer level because cartons labeled 12 mcg/h Fentanyl Transdermal System patches have been found that contain 50 mcg/h patches. The 50 mcg/h patches that were included in these cartons are individually labeled as 50 mcg/h.
* An 
FDA statement describes improvements made in recent months to the voluntary system of product recalls and outlines plans for future enhancements.

PNN Pharmacotherapy Line
Apr. 25, 2019 * Vol. 26, No. 80
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Apr. 25 issue of the New England Journal of Medicine (2019; 380).
Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm: For treating blastic plasmacytoid dendritic-cell neoplasm (BPDCN) — an aggressive blood cancer — tagraxofusp produced clinical responses but also serious adverse events (pp. 1628–37; N. Pemmaraju, npemmaraju@mdanderson.org). BPDCN is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123); tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin.
PICO: Open-label, multicohort study of 47 patients with untreated or relapsed BPDCN; intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle with treatment continued until disease progression or unacceptable toxic effects; primary outcome of combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. 
Results: “Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups.”
Transplants from HCV-Infected Donors to Uninfected Recipients: Using an antiviral regimen for 4 weeks starting shortly after transplantation, patients without hepatitis C virus (HCV) infection were able to receive HCV-infected heart and lung grafts, researchers report (pp. 1606–17; A. E. Woolley, awoolley@bwh.harvard.edu).
PICO: Sofosbuvir–velpatasvir preemptively administered to the organ recipients for 4 weeks, beginning within a few hours after transplantation; primary outcome of a composite of a sustained virologic response at 12 weeks after completion of antiviral therapy for HCV infection and graft survival at 6 months after transplantation.
Results: “A total of 44 patients were enrolled: 36 received lung transplants and 8 received heart transplants. The median viral load in the HCV-infected donors was 890,000 IU per milliliter (interquartile range, 276,000 to 4.63 million). The HCV genotypes were genotype 1 (in 61% of the donors), genotype 2 (in 17%), genotype 3 (in 17%), and indeterminate (in 5%). A total of 42 of 44 recipients (95%) had a detectable hepatitis C viral load immediately after transplantation, with a median of 1800 IU per milliliter (interquartile range, 800 to 6180). Of the first 35 patients enrolled who had completed 6 months of follow-up, all 35 patients (100%; exact 95% confidence interval, 90 to 100) were alive and had excellent graft function and an undetectable hepatitis C viral load at 6 months after transplantation; the viral load became undetectable by approximately 2 weeks after transplantation, and it subsequently remained undetectable in all patients. No treatment-related serious adverse events were identified. More cases of acute cellular rejection for which treatment was indicated occurred in the HCV-infected lung-transplant recipients than in a cohort of patients who received lung transplants from donors who did not have HCV infection. This difference was not significant after adjustment for possible confounders.”
>>>PNN NewsWatch
Legacy Pharmaceutical Packaging is expanding its consumer-level recall of 3 repackaged lots of Losartan Tablets USP 50 mg to include one additional lot. The lots have trace amounts of the N-Nitroso N-Methyl 4-amino butyric acid carcinogen.

PNN Pharmacotherapy Line
Apr. 29, 2019 * Vol. 26, No. 82
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 Apr. 27 issue of Lancet (2019; 393).
Biosimilar CT-P13 v. Originator Infliximab in Crohn Disease: In a comparative trial, the biosimilar CP-P13 was noninferior to the originator product infliximab in management of patients with Crohn disease, providing “a new option for the treatment,” investigators conclude (pp. 1699–707; Y-H Kim, bowelkim@gmail.com).
PICO: Randomized, double-blind, phase 3 noninferiority study of 220 patients with active Crohn’s disease not responsive to or intolerant of nonbiological treatments; CT-P13 or infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks up to week 54; primary endpoint of proportion of patients with a decrease of 70 points or more in Crohn’s Disease Activity Index (CDAI) from baseline to week 6; noninferiority margin of −20%.
Results: “CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69.4%, 95% CI 59.9 to 77.8] of 111) and infliximab (81 [74.3%, 95% CI 65.1 to 82.2] of 109; difference −4.9% [95% CI −16.9 to 7.3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13–CT-P13 group, 34 [62%] in the CT-P13–infliximab group, 37 [69%] in the infliximab–infliximab group, and 40 [73%] in the infliximab–CT-P13 group).”
Predicting Standardized Pediatric Colitis Response: Initial clinical activity and treatment response by 4 weeks can be used to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis, researchers report (pp. 1708–20; J. S. Hyams, jhyams@connecticutchildrens.org).
PICO: Patients aged 4–17 years with newly diagnosed ulcerative colitis at 29 U.S. and Candian centers; standardized mesalazine or corticosteroids, with pre-established criteria for escalation to thiopurine immunomodulators or anti-tumor necrosis factor–alpha (TNF-alpha) therapy; primary outcome of week 52 corticosteroid-free remission with no therapy beyond mesalazine.
Results: “150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNF-alpha therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n = 386, logistic model area under the curve [AUC] 0.70, 95% CI 0.65–0.75; specificity 77%, 95% CI 71–82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis.…”
>>>PNN NewsWatch
Belimumab (Benlysta, GSK-SmithKline) I.V. infusion has been approved by FDA for treatment of children with systemic lupus erythematosus (SLE). The first FDA approval of a treatment for pediatric patients with SLE, this agent has been approved for use in adults since 2011. The drug should not be administered with live vaccines. A Medication Guide informs patients of the risks associated with the drug, including a warning for mortality, serious infections, hypersensitivity, and depression based on clinical data in adults.
* The 
“Remove the Risk” campaign is an FDA educational campaign targeting women ages 35–64 about the important role they play in removing and properly disposing of unused prescription opioids from their homes. This new initiative is part of FDA’s continued efforts to address the nationwide opioid crisis and aims to help decrease unnecessary exposure to opioids and prevent new addiction. Women in this age group are most likely to oversee household health care decisions and often serve as the gatekeepers to opioids and other prescription medications in the home.
>>>PNN JournalWatch
* The Forgotten Middle: Many Middle-Income Seniors Will Have Insufficient Resources For Housing And Health Care, in Health Affairs, 2019; 38: 10.1377/hlthaff.2018.05233. (C. F. Pearson, Pearson-caroline@norc.org)
* 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis, in 
Arthritis & Rheumatology, 2019; 71: 10.1002/art.40884. (S. Ringold, Sarah.Ringold@seattlechildrens.org)

PNN Pharmacotherapy Line
Apr. 30, 2019 * Vol. 26, No. 83
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Report
Source:
 Early-online/May issue of Diabetes Care (2019; 42).
Update to Standards of Medical Care: In an update to the “living” Standards of Medical Care in Diabetes — 2019, the American Diabetes Association makes these medication-related changes:
Section 10 is updated based on the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) outcomes, which determined the addition of icosapent ethyl to statin therapy for patients with high triglyceride levels reduced cardiovascular events. The Standards of Care now include a recommendation that icosapent ethyl be considered for patients with diabetes and atherosclerotic cardiovascular disease or other cardiac risk factors on a statin with controlled LDL-C, but with elevated triglycerides (135–499) to reduce cardiovascular risk.
* Sections 
910, and 11 are revised based on findings from The Dapagliflozin Effect on Cardiovascular Events-Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58) Trial, in which dapagliflozin treatment showed a reduction of hospitalization for heart failure and a reduction in progression of chronic kidney disease (CKD).
* Based on a revision to the prescribing information for dapagliflozin, for patients with diabetes and CKD, the approved use per estimated glomerular filtration rate is revised from ≥60 mL/min/1.73 sq m to ≥45 mL/min/1.73 sq m in 
Section 11 of the Standards of Care.
Dapagliflozin, Liver Fat & Tissue Insulin Sensitivity: In patients with obesity and liver fat, 8 weeks of dapagliflozin therapy reduced both the volumes of visceral adipose tissue and liver proton density fat fraction (PDFF), researchers report (pp. 931–7; P. Nuutila, pirjo.nuutila@utu.fi).
PICO: Randomized, double-blind, parallel group, placebo-controlled study of 32 patients with type 2 diabetes and HbA1c 6.5–10.5% (48–91 mmol/mol) and 3 months or more of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or both; randomized to dapagliflozin 10 mg or placebo daily for 8 weeks; measures included tissue insulin sensitivity, positron emission tomography during hyperinsulinemic-euglycemic clamp; PDFF and adipose tissue volumes.
Results: “After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA1c −0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (−3.74%, P < 0.01), liver volume (−0.10 L, P < 0.05), visceral adipose tissue volume (−0.35 L, P < 0.01), interleukin-6 (−1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (−96 ng/L, P = 0.03).”
SMBG in Youth-Onset Type 2 Diabetes: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, adherence with self-monitoring of blood glucose (SMBG) was poor and declined over time, and low adherence was associated with higher glycated hemoglobin levels (pp. 903–9; B. H. Braffett, braffett@bsc.gwu.edu).
PICO: 699 participants taking oral medications were asked to perform SMBG twice daily; after reaching the primary outcome (PO) HbA1c ≥8% (64 mmol/mol) over 6 months or an inability to wean from temporary insulin because of metabolic decompensation, insulin glargine was started.
Results: “SMBG declined over time and was inversely related to HbA1c (P < 0.0001). Of 298 youth who reached PO and started insulin, 282 had SMBG data. At PO, mean ± SD age was 15.8 ± 2.3 years, BMI 35.5 ± 7.9 kg/sq m, and HbA1c 9.6 ± 2.0% (81 ± 21.9 mmol/mol); 65.3% were female. Median [% days when meter was used] was 40% at PO, which increased to 49% after 6 months and fell to 41% after 1 year on insulin. At PO, 22% of youth checked ≥80% of days, which increased to 25% and fell to 19% after 6 and 12 months using insulin, respectively. At PO, compared with those who checked <80%, youth who checked ≥80% were younger and with a lower BMI, HbA1c, and blood pressure. SMBG ≥80% was associated with ≥1% reduction in HbA1c at 6 and 12 months after insulin initiation.”

PNN Pharmacotherapy Line
May 1, 2019 * Vol. 26, No. 84
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Nephrology Report
Source:
 April and May issues of the American Journal of Kidney Diseases (2019; 73).
I.V. Sodium Bicarbonate for Severe Metabolic Acidemia: A recent Lancet study is a welcome addition to the literature on use of bicarbonate in treatment of acute metabolic acidosis, write authors of a commentary (pp. 572–5; N. E. Madias, nicolaos.madias@steward.org): “Although far from definitive, this study supports treating severe metabolic acidemia (largely caused by lactic acidosis) with intravenous sodium bicarbonate solution, particularly in patients with advanced [acute kidney injury]. However, additional controlled studies will be required to establish the impact of base on the clinical outcomes of severe metabolic acidemia. We would recommend that future studies use a target arterial blood pH of 7.20 to 7.25. Because such trials tend to produce a blood pH higher than the target, setting a goal of ≥7.30, as in the Jaber et al study, is likely to predispose to alkalemia and its attendant consequences. The bicarbonate was administered as a hypertonic 4.2% solution, presumably to limit the quantity of fluid given. Some studies have shown that hypertonicity per se can suppress cardiac function and therefore an isotonic solution might be preferred. This issue is worth exploring.”
Muscle Relaxant Use Among Hemodialysis Patients: In patients on hemodialysis, use of muscle relaxants is common and associated with altered mental status and falls, researchers report (pp. 525–32; J. H. Ishida, julie.ishida@ucsf.edu).
PICO: Observational cohort study of 140,899 adults on Medicare who were receiving hemodialysis in 2011; primary outcomes of time to first emergency department visit or hospitalization for altered mental status, fall, or fracture.
Results: “10% of patients received muscle relaxants in 2011. 11%, 6%, 3%, and 13% had an episode of altered mental status, fall, fracture, and death, respectively. Muscle relaxant use was associated with higher risk for altered mental status (HR, 1.39; 95% CI, 1.29–1.51) and fall (HR, 1.18; 95% CI, 1.05–1.33) compared to no use. Muscle relaxant use was not statistically significantly associated with higher risk for fracture (HR, 1.17; 95% CI, 0.98–1.39). Muscle relaxant use was associated with lower hazard of death (HR, 0.85; 95% CI, 0.76–0.94). However, hazards were higher for altered mental status or death (HR, 1.17; 95% CI, 1.10–1.25), fall or death (HR, 1.14; 95% CI, 1.06–1.22), and fracture or death (HR, 1.10; 95% CI, 1.01–1.20).”
Need for Phosphate Labeling on Foods: “Mandatory labeling of phosphate content on all packaged foods and drugs would enable identification of healthy low-phosphate foods and medications and permit critically important control of total phosphate intake,” according to authors of a commentary on “dietary phosphate and the forgotten kidney patient” (pp. 542–51; J. Uribarri, jaime.uribarri@mssm.edu). “Simple changes in regulatory policy and labeling are warranted and would enable better management of dietary intake of phosphate at all stages of kidney disease, as well as potentially reduced health risks in the general population.”
>>>PNN NewsWatch
FDA yesterday approved the combination of glecaprevir and pibrentasvir (Mavyret, AbbVie) tablets to treat all six genotypes of hepatitis C virus (HCV) in children ages 12 to 17. The product was previously approved to treat HCV in adults in 2017. With this approval, dosing information is provided for glecaprevir/pibrentasvir for the treatment of adult or pediatric patients 12 years and older, or weighing at least 99 pounds, who are infected with any of six identified HCV genotypes either without cirrhosis or with compensated cirrhosis.
* Boxed warnings are being added to the labeling of several 
prescription medications for insomnia — eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, and Zolpimist) cautioning of serious injuries and deaths resulting from sleepwalking, sleep driving, and engaging in other activities while not fully awake, such as unsafely using a stove. In addition to the boxed warning, FDA is requiring the addition of a contraindication to not use these medicines in patients who have experienced an episode of complex sleep behaviors after taking them. The actions are based on 66 cases reported to FDA that include 46 reports of nonfatal serious injuries associated with use of the drugs.

PNN Pharmacotherapy Line
May 2, 2019 * Vol. 26, No. 85
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 2 New England Journal of Medicine (2019; 380).
bb2121 Therapy in Relapsed/Refractory Multiple Myeloma: In patients with relapsed or refractory multiple myeloma, antitumor activity was documented in initial clinical trials of bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA) (pp. 1726–37; J. N. Kochenderfer, kochendj@mail.nih.gov).
PICO: Phase 1 study of patients with relapsed or refractory multiple myeloma; bb2121 infused at four doses of CAR-positive T cells in a dose-escalation phase and a range of doses in an expansion phase; primary end point of safety.
Results: “Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10−4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion.”
Hypoparathyroidism Case Report: A case of hypothyroidism in a previously healthy 31-year-old woman is presented (pp. 1738–47; R. I. Gafni, gafnir@mail.nih.gov). The patient presented with progressive paresthesias and numbness of her hands, neck, face, and back; 6 months later, carpopedal spasms in the hands and feet occurred during exercise, which rapidly progressed to difficulty breathing and full body tetany. On admission, the patient had hypocalcemia and hyperphosphatemia, with an undetectable parathyroid hormone level.
Results: “Urgent treatment with intravenous calcium (calcium gluconate, if administered through a peripheral intravenous catheter) is appropriate. We would also promptly initiate oral calcium carbonate and calcitriol therapy in divided doses to minimize symptoms of hypocalcemia and to maintain an albumin-adjusted blood calcium level near the low end of the normal range and 24-hour urinary calcium excretion in the weight-adjusted normal range. If treatment with calcium and calcitriol was ineffective at controlling symptoms of hypocalcemia, we would consider treatment with PTH 1–84, as well as calcium and vitamin D supplementation as needed. The patient’s strong family history of autoimmunity suggests an autoimmune cause of hypoparathyroidism and necessitates screening and surveillance for other autoimmune disease in this patient.”
Drug Rebates & Discounts in Medicare Part D: In discussing the potential impact of a proposed rule for discounts in the Medicare Part D program, Perspective authors assess problems with the current rebate-based system (pp. 1688–90; W. F. Gellad): “First, rebates reward increasing list prices. Because rebates are based on a percentage of list prices, when those prices rise, rebates rise and plans benefit. Second, though rebates may lower premiums for all plan members, they lead to higher out-of-pocket costs for patients who need drugs with very high list prices, who cannot receive discounts directly. Rebates, critics argue, lower premiums for the healthy at the expense of out-of-pocket costs for the sick. Third, the common use of rebates in Part D makes it less attractive for plans to switch to less expensive biosimilars or generic drugs.”
>>>PNN NewsWatch
FDA yesterday licensed Dengvaxia (Sanofi Pasteur), the first vaccine approved for prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in 9- to 16-year-olds with laboratory-confirmed previous dengue infection living in endemic areas (including American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands).

PNN Pharmacotherapy Line
May 3, 2019 * Vol. 26, No. 86
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
 May issue of the American Journal of Psychiatry (2019; 176).
Predictors & Moderators of Depression Remission: More specific augmentation, combinations, and switching strategies for antidepressants in major depressive disorder could result if preliminary findings from the U.S. Department of Veterans Affairs (VA) Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) study are confirmed, investigators conclude (pp. 348–57; S. Zisook).
PICO: Multisite, randomized, single-blind trial of 1,522 Veterans Health Administration patients who did not have an adequate response to at least one course of antidepressant treatment meeting minimal standards for dosage and duration; participants received one of three possible next-step treatments for 12 weeks: switch to another antidepressant—sustained-release bupropion; combination with another antidepressant—sustained-release bupropion; or augmentation with an antipsychotic—aripiprazole. 
Results: “Remission was more likely for individuals who were employed, less severely and chronically depressed, less anxious, not experiencing complicated grief symptoms, did not experience childhood adversity, and had better quality of life and positive mental health. Two features suggested specific next-step treatment selections: age ≥65 years (for whom augmentation with aripiprazole was more effective than switch to bupropion) and severe mixed hypomanic symptoms (for which augmentation with aripiprazole and combination with bupropion were more effective than switch to bupropion).”
Clinical Utility of Irritability in Depression: Irritability is an important predictive symptom of major depressive disorder that is not adequately reflected in current symptom measures, researchers report (pp. 358–66; M. K. Jha).
PICO: Mixed-model analyses assessed changes in irritability from baseline to week 4 after controlling for depression severity.
Conclusion: “Early reductions in irritability, when combined with changes in depressive symptom severity, provide a robust estimate of likelihood of remission or no meaningful benefit in outpatients with major depression.”
>>>Pediatrics Highlights
Source:
 May issue of Pediatrics (2019; 143).
Parental Psychotropic Use When Children Have Cancer: Medical teams should be aware of stress responses in parents of children diagnosed with cancer, authors conclude in a study showing increased parental use of psychotropic medications (10.1542/peds.2018-2605; H. Salem).
PICO: Case–control study 6,744 parents of children with cancer from the Danish Cancer Registry in 1998–2014 and 65,747 parents of matched children who were cancer free; for subgroup analysis, 3,290 parents of children with cancer from the Childhood Cancer Registry in 2003–15.
Results: “Parents of children with cancer were at increased risk for a first prescription of psychotropic medication compared with parents of children who were cancer free up to 2 years after the diagnosis, the risk being highest in the first year (HR, 1.83 [95% confidence interval (CI), 1.66–2.01]). Parents of children with cancer, especially parents who lost their child, had an increased risk for a first prescription of hypnotics (HR, 6.91; 95% CI, 3.50–13.66) and anxiolytics (HR, 4.55, 95% CI, 1.57–13.17) in the first year after diagnosis.”
>>>PNN NewsWatch
* In this week’s MMWR (2019; 68: 388–95), an increasing number of overdose deaths involving cocaine and psychostimulants with or without opioids illustrate the increasing complexity of America’s current overdose crisis. The contribution of opioids to increases in stimulant-involved deaths underscores the importance of continued opioid overdose surveillance and prevention measures such as current efforts to expand naloxone availability to people at risk, authors suggest. Overdose deaths involving these substances have increased across age groups, racial/ethnic groups, county urbanization levels, and many states. Death rates involving cocaine and psychostimulants with and without involvement of opioids have increased. Early increases in psychostimulant-involved deaths occurred largely without involvement of opioids, but recent data show increasing synthetic opioid involvement.

PNN Pharmacotherapy Line
May 6, 2019 * Vol. 26, No. 87
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 May 4 issue of Lancet (2019; 393).
Pembrolizumab in Non-Small-Cell Lung Cancer: Based on benefit-to-risk findings from the KEYNOTE-042 trial, first-line therapy with pembrolizumab can be extended to patients with locally advanced or metastatic non-small-cell lung cancer without sensitizing EGFR or ALK alterations and with low programmed death ligand 1 (PD-L1) tumor proportion score (TPS), investigators conclude (pp. 1819–30; T. S. K. Mok, tony@clo.cuhk.edu.hk).
PICO: Randomized, open-label, phase 3 study in 32 countries; adults with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitizing EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater; block randomization to pembrolizumab or the investigator’s choice of platinum-based chemotherapy; primary endpoints of overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater in the intention-to-treat population.
Results: “1,274 patients …with a PD-L1 TPS of 1% or greater were … included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater.… Median follow-up was 12.8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0.69, 95% CI 0.56–0.85, p = 0.0003; ≥20% 0.77, 0.64–0.92, p = 0.0020, and ≥1% 0.81, 0.71–0.93, p = 0.0018). The median survival values by TPS population were 20.0 months (95% CI 15.4–24.9) for pembrolizumab versus 12.2 months (10.4–14.2) for chemotherapy, 17.7 months (15.3–22.1) versus 13.0 months (11.6–15.3), and 16.7 months (13.9–19.7) versus 12.1 months (11.3–13.3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.”
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Preterm Birth & CKD Risk: Preterm and early-term birth are strong risk factors for the development of chronic kidney disease (CKD) from childhood into mid-adulthood, researchers report based on a national cohort study (l1346; C. Crump, casey.crump@mssm.edu).
PICO: 4 million singleton births in Sweden in 1973–2014; gestational age at birth as recorded in the Swedish birth registry.
Results: “Preterm birth and extremely preterm birth (<28 weeks) were associated with nearly twofold and threefold risks of CKD, respectively, from birth into mid-adulthood (adjusted hazard ratio 1.94, 95% confidence interval 1.74 to 2.16; P <0.001; 3.01, 1.67 to 5.45; P <0.001). An increased risk was observed even among those born at early term (37–38 weeks) (1.30, 1.20 to 1.40; P <0.001). The association between preterm birth and CKD was strongest at ages 0–9 years (5.09, 4.11 to 6.31; P <0.001), then weakened but remained increased at ages 10–19 years (1.97, 1.57 to 2.49; P <0.001) and 20–43 years (1.34, 1.15 to 1.57; P <0.001).…”
Pre-eclampsia & Risk of Later Kidney Disease: In a registry-based cohort study from Denmark, pre-eclampsia — particularly early preterm pre-eclampsia— was strongly associated with several chronic renal disorders in mothers later in life (l1516; H. Boyd, hoy@ssi.dk). “More research is needed to determine which women are most likely to develop kidney disease after pre-eclampsia, what mechanisms underlie the association, and what clinical follow-up and interventions (and in what timeframe post-pregnancy) would be most appropriate and effective,” the authors conclude.
>>>PNN JournalWatch
* Scientific Issues Relevant to Improving the Diagnosis, Risk Assessment, and Treatment of Major Depression, in American Journal of Psychiatry, 2019; 176: 342–7. (A. F. Schatzberg)
* Research Gaps in Primary Pediatric Hypertension, in 
Pediatrics, 2019; 143: 10.1542/peds.2018-3517. (P. Taylor-Zapata)
* Cost-effectiveness of Palivizumab for Respiratory Syncytial Virus: A Systematic Review, in 
Pediatrics, 2019; 143: 10.1542/peds.2018-4064. (S. Mac)

PNN Pharmacotherapy Line
May 7, 2019 * Vol. 26, No. 88
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 May 7 issue of Annals of Internal Medicine (2019; 170).
Intensive Hepatitis C Care for PWID on Opioid Agonists: People who inject drugs (PWID) can be effectively treated while in opioid agonist therapy (OAT) programs, researchers report, with results better in models using directly observed therapy (DOT) rather than self-administered individual treatment (SIT) (pp. 594–603; A. Litwin, alain.litwin@prismahealth.org).
PICO: Randomized controlled trial of intensive interventions (DOT and group treatment [GT]) or SIT at 3 OAT programs in New York; primary measure of adherence using electronic blister packs.
Results: “Mean age was 51 years; 65% of participants had positive results on urine drug testing during the 6 months before treatment, and 75% reported ever injecting drugs. Overall adherence, estimated from mixed-effects models using the daily timeframe, was 78% (95% CI, 75% to 81%) and was greater among participants randomly assigned to DOT (86% [CI, 80% to 92%]) than those assigned to SIT (75% [CI, 70% to 81%]; difference, 11% [CI, 5% to 18%]; Bonferroni-corrected P = 0.001). No significant difference in adherence was observed between participants randomly assigned to GT (80% [CI, 74% to 86%]) and those assigned to SIT (difference, 4.7% [CI, −2% to 11%]; Bonferroni-corrected P = 0.29). The HCV treatment completion rate was 97%, with no differences among groups (P = 0.53). Overall [sustained virologic response (SVR)] was 94% (CI, 89% to 97%); the SVR rate was 98% in the DOT group, 94% in the GT group, and 90% in the SIT group (P = 0.152).”
Dietary Supplements & Mortality in U.S. Adults: The health advantages of dietary supplement use by Americans are explored in a study that finds no relation to mortality benefits (pp. 604–13; F. F. Zhang, fang_fang.zhang@tufts.edu).
PICO: Prospective cohort study using 1999–2010 National Health and Nutrition Examination Survey data and National Death Index data for 30,899 U.S. adults aged 20 years or older who answered questions on dietary supplement use.
Results: “During a median follow-up of 6.1 years, 3,613 deaths occurred, including 945 [cardiovascular disease (CVD)] deaths and 805 cancer deaths. Ever-use of dietary supplements was not associated with mortality outcomes. Adequate intake (at or above the Estimated Average Requirement or the Adequate Intake level) of vitamin A, vitamin K, magnesium, zinc, and copper was associated with reduced all-cause or CVD mortality, but the associations were restricted to nutrient intake from foods. Excess intake of calcium was associated with increased risk for cancer death (above vs. at or below the Tolerable Upper Intake Level: multivariable-adjusted rate ratio, 1.62 [95% CI, 1.07 to 2.45]; multivariable-adjusted rate difference, 1.7 [CI, −0.1 to 3.5] deaths per 1,000 person–years), and the association seemed to be related to calcium intake from supplements (≥1000 mg/d vs. no use: multivariable-adjusted rate ratio, 1.53 [CI, 1.04 to 2.25]; multivariable-adjusted rate difference, 1.5 [CI, −0.1 to 3.1] deaths per 1,000 person–years) rather than foods.”
>>>PNN NewsWatch
FDA has approved tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax) capsules for treatment of cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM) in adults. These are the first FDA-approved treatments for ATTR-CM. Vyndaqel and Vyndamax have the same active moiety, tafamidis, but they are not substitutable on a milligram-to-milligram basis and their recommended doses differ. Approval of the products was granted to Pfizer subsidiary FoldRx.
Amifampridine (Ruzurgi, Jacobus Pharmaceutical Company) tablets were approved yesterday by FDA for treatment of Lambert–Eaton myasthenic syndrome (LEMS) in patients ages 6 to 16 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The only other treatment approved for LEMS is only approved for use in adults.
* Eight 
zoonotic diseases of national concern in the U.S. are the focus of a new federal collaborative report. Released by CDC and other agencies, the U.S. One Health Zoonotic Disease Prioritization report addresses the threats posed by zoonotic influenza, salmonellosis, West Nile virus, plague, emerging coronaviruses such as severe acute respiratory syndrome and Middle East respiratory syndrome, rabies, brucellosis, and Lyme disease.

PNN Pharmacotherapy Line
May 8, 2019 * Vol. 26, No. 89
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 7 issue of JAMA (2019; 321).
Single Aspirin Dose & Sensitivity of Fecal Immunochemical Tests: Sensitivity of newer fecal immunochemical tests (FITs) are not affected by single doses of aspirin administered before testing, researchers report, with detection of advanced colorectal neoplasms similar to those in study participants receiving placebo (pp. 1686–92; H. Brenner, h.brenner@dkfz-heidelberg.de).
PICO: Administration of a single tablet of aspirin 300 mg or placebo 2 days before fecal sampling for fecal immunochemical tests; primary outcome of sensitivity of a quantitative fecal immunochemical test at 2 predefined cutoffs (10.2 and 17-μg Hb/g stool) for detecting advanced neoplasms (colorectal cancer or advanced adenoma).
Results: “Among 2,422 randomized patients (mean [SD] age, 59.6 [7.9] years; 1219, 50%, men), 2,134 were included in the analysis (78% for primary screening colonoscopy, 22% for diagnostic colonoscopy). Advanced neoplasms were identified in 224 participants (10.5%), including 8 participants (0.4%) with [colorectal cancer] and 216 participants (10.1%) with advanced adenoma. Sensitivity was 40.2% in the aspirin group and 30.4% in the placebo group (difference 9.8%, 95% CI, −3.1% to 22.2%, P = .14) at cutoff 10.2-μg Hb/g stool and 28.6% in the aspirin and 22.5% in the placebo group (difference 6.0%, 95% CI, −5.7% to 17.5%, P = .32) at cutoff 17-μg Hb/g stool.”
Aclidinium & Major Cardiovascular Events in High-Risk COPD: In the ASCENT-COPD Randomized Clinical Trial, aclidinium reduced chronic obstructive pulmonary disease (COPD) exacerbations and did not result in an inferior risk of major adverse cardiovascular events (MACE), compared with placebo (pp. 1693–701; R. A. Wise, rwise@jhmi.edu).
PICO: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study at 522 sites in North America; 3,630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized to aclidinium bromide (n = 1,812) or placebo (n = 1,818) by dry-powder inhaler, twice daily for up to 3 years; follow-up for up to 3 years until at least 122 MACEs occurred; primary safety end point of time to first MACE over up to 3 years; primary efficacy end point of the annual COPD exacerbation rate during the first year of treatment.
Results: “Among 3,589 patients analyzed (mean age, 67.2 years; 58.7% male), 2,537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0–1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0–1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68–0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48–0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]).”
>>>PNN NewsWatch
Pregnancy-related deaths can occur up to a year after a woman gives birth – but whenever they occur, most of these deaths are preventable, according to a new CDC Vital Signs report. Heart disease and stroke caused 34% of pregnancy-related deaths. Other leading causes included infections and severe bleeding. Of the 700 pregnancy-related deaths that happen each year in the United States, nearly 31% happen during pregnancy, 36% happen during delivery or the week after, and 33% happen 1 week to 1 year after delivery. The data confirm persistent racial disparities: Black and American Indian/Alaska Native women were about 3 times as likely to die from a pregnancy-related cause as white women. However, the new analysis also found that most deaths were preventable, regardless of race or ethnicity.

PNN Pharmacotherapy Line
May 9, 2019 * Vol. 26, No. 90
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 9 issue of the New England Journal of Medicine (2019; 380).
Extended Alteplase Thrombolysis Following Stroke: In the EXTEND trial, image-guided use of alteplase at 4.5 to 9 hours following onset of stroke symptoms resulted in no or minor neurologic deficits, researchers report (pp. 1795–803; G. A. Donnan, geoffrey.donnan@unimelb.edu.au).
PICO: Placebo-controlled trial of 225 patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging; randomized to I.V. alteplase or placebo 4.5–9.0 hours after the onset of stroke or on awakening with stroke within 9 hours of the midpoint of sleep; primary outcome of 0 or 1 on the modified Rankin scale at 90 days.
Results: “The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.”
Editorial: “The era of time-based treatment with intravenous alteplase in patients with acute stroke may finally be drawing to a close,” an editorialist writes (pp. 1865–6; R. S. Marshall). “As the only approved pharmacologic treatment for acute stroke, and one that has been used since 1995, alteplase is still limited to patients whose stroke began within 4.5 hours before the infusion.… Faced with these time constraints and the promise of better outcomes with earlier treatment, a generation of stroke practitioners championed earlier stroke recognition, faster transport to stroke centers, and more efficient stroke diagnostic protocols in the emergency department. The battle cry of ‘Time is brain!’ reigned unopposed, until now.”
Progesterone for Bleeding in Early Pregnancy: Among women treated for bleeding during early pregnancy, live births were no more common in those receiving vaginal progesterone than with placebo, a study shows (pp. 1815–24; A. Coomarasamy, a.coomarasamy@bham.ac.uk).
PICO: 4,152 women with vaginal bleeding in early pregnancy at 48 U.K. hospitals; randomized to vaginal suppositories with progesterone 400 mg or matching placebo twice daily from the time of presentation with bleeding through 16 weeks’ gestation; primary outcome of birth of a live-born baby after at least 34 weeks’ gestation.
Results: “The percentage of women with available data for the primary outcome was 97% (4,038 of 4,153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1,513 of 2,025 women) in the progesterone group and 72% (1,459 of 2,013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups.”
Editorial: “In retrospect, it is likely that the initial rationale for hormonal therapy — that is, the observed fall in pregnancy hormone levels before pregnancy loss — was, in fact, a consequence rather than a cause of pregnancy failure,” writes an editorialist (pp. 1867–8; M. F. Greene). “The subsequent enthusiasm for hormonal therapy was driven by overestimation of the incidence of pregnancy loss in the absence of therapy and by reports of seeming success in uncontrolled case series. The current randomized, placebo-controlled trial of treatment for threatened abortion provides much-needed information regarding both the true risk of pregnancy loss in the absence of treatment and the small, statistically insignificant difference in the incidence of live births between treatment and expectant management in a contemporary context.”
>>>PNN NewsWatch
* Draft guidances on study design on use of medications during breastfeeding and pregnancy have been released by FDA, two agency staffers write in a statement issued yesterday.

PNN Pharmacotherapy Line
May 10, 2019 * Vol. 26, No. 91
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Chest Highlights
Source:
 May issue of Chest (2019; 155).
ED Door-to-Antibiotic Time & Mortality From Sepsis: Delays in emergency department (ED) door-to-antibiotic initiation times are associated with increased long-term, risk-adjusted rates of mortality in patients presenting to the ED with sepsis, researchers report (pp. 938–46; I. D. Peltan, ithan.peltan@utah.edu).
PICO: Retrospective cohort study of nontrauma adult ED patients with clinical sepsis at four hospitals in 2013–17; multivariable logistic regression used to measure the adjusted association between door-to-antibiotic time and 1-year mortality.
Results: “Among 10,811 eligible patients, median door-to-antibiotic time was 166 min (interquartile range, 115–230 min), and 1-year mortality was 19%. After adjustment, each additional hour from ED arrival to antibiotic initiation was associated with a 10% (95% CI, 5–14; P < .001) increased odds of 1-year mortality. The association remained linear when each 1-h interval of door-to-antibiotic time was independently compared with door-to-antibiotic time ≤ 1 h and was similar for hospital, 30-day, and 90-day mortality. Mortality at 1 year was higher when door-to-antibiotic times were > 3 h vs ≤ 3 h (adjusted OR, 1.27; 95% CI, 1.13–1.43) but not > 1 h vs ≤ 1 h (adjusted OR, 1.26; 95% CI, 0.98–1.62).”
AF in Inpatients With End-Stage COPD on Home Oxygen: To care for hospitalized patients with end-stage COPD who increasingly have comorbid atrial fibrillation (AF), better management strategies are needed, a study shows, particularly for older adults (pp. 918–27; J. He, hejia63@yeah.net).
PICO: Retrospective analysis of the 2003–14 Nationwide Inpatient Sample for all patients 18 years of age or older with a primary diagnosis of COPD on home oxygen who were hospitalized for COPD exacerbation; multivariate-adjusted models evaluating the association of AF with clinical factors, cost, length of stay, and hospital outcomes.
Results: In 1,345,270 patients, “244,488 (18.2%) had AF. The AF prevalence increased from 12.9% in 2003 to 21.3% in 2014 (P < .0001) and varied by age, sex, race, income, insurance type, and hospital region. Advancing age, female sex, white race, high income, and large hospital size were associated with increased odds of AF. Presence of AF was a risk predictor for in-hospital death…, acute respiratory failure…, invasive mechanical ventilation…, noninvasive mechanical ventilation…, acute kidney injury…, sepsis…, and stroke…. AF was also associated with increased cost and length of stay.”
Editorial: For such patients, editorialists advise “a streamlined approach to holistic AF management … (the so-called ABC pathway),” (pp. 888–9; G. Y. H. Lip, gregory.lip@liverpool.ac.uk): “‘A’—avoid stroke with anticoagulation; ‘B’—better symptom management, with patient-centred decisions on rate or rhythm control; and ‘C’—cardiovascular risk and comorbidity management, including attention to lifestyle factors. Stroke prevention with oral anticoagulation is a clear priority for the management of patients with AF.”
>>>PNN NewsWatch
* In this week’s MMWR (2019; 68: 413–5), a new CDC analysis finds a 300% increase in hepatitis A virus infections in the U.S. in recent years. In addition to two foodborne outbreaks of hepatitis A in 2016 and an increase of cases among men who have sex with men (MSM), widespread outbreaks among people reporting drug use or homelessness in 16 states have overwhelmingly driven the recent surge in cases. For all hepatitis A outbreaks, vaccination is the most effective strategy for halting ongoing transmission and preventing future outbreaks. The CDC Advisory Committee on Immunization Practices recommends routine vaccination for adults at increased risk for exposure to hepatitis A, including: MSM, persons who use drugs, and persons who are homeless.
* Implications of a recent report on absorption of 
topically applied sunscreens (JAMA. 2019; 10.1001/jama.2019.5586) are discussed in an FDA perspectives article posted this week. FDA experts note that the agency has issued a proposed rule “aimed at bringing over-the-counter sunscreens up to date with the latest scientific standards. As part of this rule, the FDA is asking industry and other interested parties for additional safety data on 12 active sunscreen ingredients currently available in marketed products.”

PNN Pharmacotherapy Line
May 13, 2019 * Vol. 26, No. 92
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 May 11 issue of Lancet (2019; 393).
Atrasentan & Renal Events in Type 2 Diabetes & CKD: The selective endothelin A receptor antagonist atrasentan reduced the risk of renal events in selected patients with diabetes and chronic kidney disease, researchers report in the SONAR study (pp. 1937–47; H. J. L. Heerspink, h.j.lambers.heerspink@umcg.nl).
PICO: Double-blind, randomized, placebo-controlled trial at 689 sites in 41 countries; 11,087 adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1.73 sq m of body surface area, and urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximal or tolerated renin–angiotensin system inhibition for at least 4 weeks; atrasentan 0.75 mg orally daily during an enrichment period in 5,117 participants; 2,648 participants with UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period; responders randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo; primary endpoint of a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1.73 sq m sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders.
Results: “Median follow-up was 2.2 years (IQR 1.4–2.9). 79 (6.0%) of 1,325 patients in the atrasentan group and 105 (7.9%) of 1,323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49–0.88]; p = 0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1,325 patients in the atrasentan group and 34 (2.6%) of 1,323 patients in the placebo group (HR 1.33 [95% CI 0.85–2.07]; p = 0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75–1.59]; p = 0.65).”
Perioperative Chemotherapy in Gastric Adenocarcinoma: In patients with locally advanced, resectable gastric or gastro-esophageal junction adenocarcinoma, perioperative docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin, and docetaxel) improved overall survival compared with a standard regimen (pp. 1948–57; S-E Al-Batran, albatran@ikf-khnw.de).
PICO: Controlled, open-label, phase 2/3 trial of 716 patients with locally advanced, resectable gastric or gastro-esophageal junction adenocarcinoma; randomized to either three preoperative and three postoperative 3-week cycles of epirubicin and cisplatin on day 1 plus either fluorouracil or capecitabine 1on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil as 24-h infusion on day 1 (FLOT; experimental group); primary outcome of overall survival (superiority) in intention-to-treat population.
Results: “Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0.77; 95% confidence interval [CI; 0.63 to 0.94]; median overall survival, 50 months [38.33 to not reached] vs 35 months [27.35 to 46.26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.”
PNN JournalWatch
* Changes in, and Factors Associated With, Frequency of Sex in Britain: Evidence From Three National Surveys of Sexual Attitudes and Lifestyles (Natsal), in BMJ, 2019; 365: l1525. (K. Wellings, kaye.wellings@lshtm.ac.uk)
* Arrhythmia-Induced Cardiomyopathy: 
JACC State-of-the-Art Review, in Journal of the American College of Cardiology, 2019; 73: 2328 ff. (J. F. Huizar)
* Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial, in 
Journal of the American College of Cardiology, 2019; 73: 2243–50. (K. A. A. Fox, k.a.a.fox@ed.ac.uk)
* Rhinoviruses and Their Receptors, in 
Chest, 2019; 155: 1018–25. (S. Basnet, basnet@wisc.edu)

PNN Pharmacotherapy Line
May 14, 2019 * Vol. 26, No. 93
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Internal Medicine Report
Source:
 Early-online articles from JAMA Internal Medicine (2019; 179).
Ignoring Beers Criteria Leads to a Prescribing Cascade: “We can and must do better,” concludes a clinical pharmacist in reflecting on likely misdiagnoses and inappropriate prescribing of Beers list medications in her 87-year-old mother (10.1001/jamainternmed.2019.1288; K. H. DeRhodes, khderhodes@novanthealth.org). “We were fortunate. My mother’s cognition returned to her baseline. I have instructed all family members and her primary care physician that no Beers List medications are to be prescribed unless absolutely necessary. How many family members without a medical background are caring for their elderly loved ones and are unaware of this problem? They do not know about Beers List medications. They rely on medical professionals like us to recognize and protect them from preventable ADRs, as we are trained to do.”
Pharmacy Naloxone Distribution & Fatal Overdoses: Adoption of state laws that permit pharmacists to dispense naloxone directly and under their own authority is associated with declines in fatal opioid-related overdoses, according to authors of a research letter who analyzed state-level data for 2005–16 (10.1001/jamainternmed.2019.0272; R. Abouk, aboukr@wpunj.edu).
Restricting Calcium in Phosphate Binders in ESRD Hemodialysis: The high cost benefit of sevelamer carbonate products is questioned in a study showing no increased cardiovascular safety compared with calcium-based phosphate binders in older patients with end-stage renal disease (ESRD) who are on hemodialysis (10.1001/jamainternmed.2019.0045; R. J. Desai, rdesai@bwh.harvard.edu).
PICO: Observational cohort study using the U.S. Renal Data System linked to Medicare claims data in 2012–13 for patients 65 years or older with ESRD within 180 days after starting hemodialysis.
Results: “After propensity score weighting, 2,639 patients initiating sevelamer treatment (1,184 men [44.9%]; mean [SD] age, 75.6 [6.9] years) and 2,065 patients initiating calcium acetate treatment (930 men [45.0%]; mean [SD] age, 75.5 [7.1] years) were included in the analysis. Crude incidence rates (IRs) for cardiovascular events of 458 per 1,000 person-years for sevelamer and 464 per 1,000 person-years for calcium acetate were observed. After propensity score fine-stratification weighting, HRs of 0.96 (95% CI, 0.84–1.10) for cardiovascular events were observed. Results were consistent within subgroups of age (<75 y: primary outcome, HR, 1.02; 95% CI, 0.85–1.24; vs ≥75 years: primary outcome, HR, 0.83; 95% CI, 0.69–1.01) and sex (primary outcome in men: HR, 1.02; 95% CI, 0.83–1.26).”
Editorial: Asking “how did we get here,” an editorialist writes (10.1001/jamainternmed.2019.0043; I. H. de Boer, deboer@u.washington.edu). “[This] study … provides evidence that calcium-based phosphate binders are unlikely to increase cardiovascular events or mortality to a meaningful degree compared with sevelamer, at least as initial therapy and up to 3 years of follow-up. Given the extensive burden of phosphate binders required to lower serum phosphate concentrations, the use of calcium acetate as a first-line agent would result in substantial health care savings and potential redirection of resources toward more effective areas. Nonetheless, over the long term, moderating the total dose of calcium-based binders remains prudent when harm is possible and the benefits of phosphate binders in general remain unproven.”
>>>PNN NewsWatch
* FDA has published a final guidance to industry on demonstrating interchangeability of biosimilars with reference products. In advance of a hearing on biosimilar and interchangeable insulin products held yesterday at FDA, Acting Commissioner Ned Sharpless, MD, wrote, “In advancing the broader policy efforts for biosimilar and interchangeable products, soon we will also be issuing additional guidance on the agency’s recommendations on the design and evaluation of comparative analytical studies and other important scientific considerations needed to support a demonstration that a biological product is biosimilar to a reference product.”
Novartis has announced a voluntary recall of three lots of Promacta (eltrombopag) 12.5 mg for oral suspension to the consumer level because of a risk of potential peanut flour contamination at a third-party contract manufacturing site.

PNN Pharmacotherapy Line
May 15, 2019 * Vol. 26, No. 94
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 14 issue of JAMA (2019; 321).
Management of Preexisting Diabetes in Pregnancy: In a review of evidence-based approaches to managing preexisting type 1 or type 2 diabetes in pregnancy, authors write (pp. 1811–9; A. L. Peters, annepete@med.usc.edu): “Medications known to be unsafe in pregnancy, such as angiotensin-converting enzyme inhibitors and statins, should be discontinued. Women with obesity should be screened for obstructive sleep apnea, which is often undiagnosed and can result in poor outcomes. Blood pressure goals must be considered carefully because lower treatment thresholds may be required for women with nephropathy. During pregnancy, continuous glucose monitoring can improve glycemic control and neonatal outcomes in women with type 1 diabetes. Insulin is first-line therapy for all women with preexisting diabetes; injections and insulin pump therapy are both effective approaches. Rates of severe hypoglycemia are increased during pregnancy; therefore, glucagon should be available to the patient and close contacts should be trained in its use. Low-dose aspirin is recommended soon after 12 weeks’ gestation to minimize the risk of preeclampsia. The importance of discussing long-acting reversible contraception before and after pregnancy, to allow for appropriate preconception planning, cannot be overstated.”
Limiting Number of Open Records in EHR Systems: Limiting the number of open patient records to 1 did not significantly reduce the number of orders entered for the wrong patient in an electronic health record (EHR) system, researchers report, compared with allowing 4 open records (pp. 1780–7; J. S. Adelman, jsa2163@cumc.columbia.edu). However, interpretation of study results was limited because clinicians in the 4-record group entered most orders while only 1 patient record was open.
PICO: Randomized clinical trial of 3,356 clinicians at a large New York health system in 2015–17 in emergency department (ED), inpatient, and outpatient settings; EHR configuration limited to number of open patient records to 1 or 4.
Results: “The study included 12,140,298 orders, in 4,486,631 order sessions, placed for 543,490 patients. There was no significant difference in wrong-patient order sessions per 100,000 in the restricted vs unrestricted group, respectively, overall (90.7 vs 88.0; odds ratio [OR], 1.03 [95% CI, 0.90-1.20]; P = .60) or in any setting (ED: 157.8 vs 161.3, OR, 1.00 [95% CI, 0.83-1.20], P = .96; inpatient: 185.6 vs 185.1, OR, 0.99 [95% CI, 0.89-1.11]; P = .86; or outpatient: 7.9 vs 8.2, OR, 0.94 [95% CI, 0.70-1.28], P = .71). The effect did not differ among settings (P for interaction = .99). In the unrestricted group overall, 66.2% of the order sessions were completed with 1 record open, including 34.5% of ED, 53.7% of inpatient, and 83.4% of outpatient order sessions.”
Editorial: “More broadly, studies like that performed by Adelman and colleagues point the way to the creation of a digital learning health system, in which the results of the interactions between clinicians (and, increasingly, patients and families) and the EHR are analyzed to help guide the strategies that lead to the highest value and most satisfying care,” editorialists write (pp. 1771–3; R. M. Wachter, robert.wachter@ucsf.edu). “Having spent tens of billions of dollars digitizing the health care system, it is essential to take advantage of the unique capacity of digital tools to allow clinicians and health care systems to learn from every click.”
Polygenic Scores: Use of polygenic scores — a “mathematical aggregate of risk conferred by many DNA variants to estimate the likelihood of a specific outcome, such as disease onset” — “will become part of clinical care in the near future,” write authors of a Genomics and Precision Health article (pp. 1820–1; L. P. Sugrue, leo.sugrue@ucsf.edu).
>>>PNN NewsWatch
FDA has posted warning letters to five companies who produce products labeled as homeopathic for significant violations of current good manufacturing practice regulations. Four of the warning letters pertain to companies who jointly produced a product labeled as homeopathic that posed a significant safety risk to consumers because their purportedly sterile products were not shown to be sterile. An additional letter outlines a company’s failure to have systems in place to assure proper design, monitoring, and control of manufacturing processes.

PNN Pharmacotherapy Line
May 16, 2019 * Vol. 26, No. 95
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 16 issue of the New England Journal of Medicine (2019; 380).
Dabigatran & Stroke Prevention After Embolic Stroke of Undetermined Source: For preventing recurrent stroke in patients with recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin, researchers report (pp. 1906–17; H-C Diener, hans.diener@uk-essen.de).
PICO: Multicenter, randomized, double-blind trial of patients who had had an embolic stroke of undetermined source; dabigatran 150 or 110 mg twice daily or aspirin 100 mg once daily; primary outcome of recurrent stroke; primary safety outcome of major bleeding.
Results: “A total of 5,390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2,695 patients) or aspirin (2,695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively.”
Alpelisib in Advanced Breast Cancer: In a phase 3 trial of patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously, the PI3K-alpha-specific inhibitor alpelisib plus fulvestrant prolonged progression-free survival compared with placebo plus fulvestrant (pp. 1929–40; F. André, fabrice.andre@gustaveroussy.fr).
PICO: Randomized placebo-controlled trial of patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously; alpelisib 300 mg/d plus fulvestrant 500 mg every 28 days and once on day 15; primary end point of progression-free survival.
Results: “A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib–fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo–fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P <0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort without PIK3CA-mutated cancer was greater with alpelisib–fulvestrant than with placebo–fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib–fulvestrant group vs. 0.7% in the placebo–fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib–fulvestrant group, as compared with 0.3% of those in the placebo–fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively.”
Continuing Daily Aspirin: Based on a case vignette of a 72-year-old man with hypertension and hyperlipidemia, authors take a point–counterpoint approach in assessing the need for continuing daily aspirin 81 mg (pp. 1967–70; A. Fernandes).
Yes: “I do not think that Mr. Evans’s age automatically rules aspirin out, since the totality of data does not suggest a significant modification of the effect of low-dose aspirin according to age.”
No: “Given the increased risk of intracranial bleeding with aspirin, I would recommend not prescribing aspirin and instead focusing on controlling his blood pressure, reducing his cholesterol level, and encouraging him to live a healthy lifestyle to protect against a stroke.”

PNN Pharmacotherapy Line
May 17, 2019 * Vol. 26, No. 96
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 June 1 issue of Clinical Infectious Diseases (2019; 68).
Long-Acting Opioid Use & Risk of Serious Infections: Clinicians need to be cognizant of an increased risk of serious infections among patients on long-acting opioids, according to a report based on Tennessee Medicaid data (pp. 1862–9; A. D. Weise, andrew.d.wiese.1@vumc.org).
PICO: Retrospective cohort study of Tennessee Medicaid enrollees age ≥18 years initiating long-acting opioids in 1995–2015; hospitalizations for serious infection identified and analyzed using multivariable Poisson regression models; infection risk compared for patients using long-acting opioids with known immunosuppressive properties (morphine, fentanyl, methadone) and without known immunosuppressive properties (oxycodone, oxymorphone, tramadol).
Results: “Among the 61,240 patients initiating opioids with immunosuppressive properties and 22,811 patients initiating opioids without immunosuppressive properties, we identified 1,906 serious infections. Nonimmunosuppressive opioid users had a lower rate of infections than immunosuppressive opioid users (aIRR:0.78 [CI: 0.66–0.91]). Among individual opioids, oxycodone users had a lower rate of infection than morphine users (aIRR:0.73 [CI: 0.60–0.89]). There were no significant differences in the infection risk between other opioids and morphine.”
>>>Oncology Report
Source:
 Early-online articles from the Journal of Clinical Oncology (2019).
Comparative Efficacy of Agents for Chronic Cancer Pain: Significant differences among current regimens for cancer pain are identified in a Bayesian network meta-analysis (10.1200/JCO.18.01567; R. Huang). The authors conclude, “Our evidence suggests that certain nonopioid analgesics and nonsteroidal anti-inflammatory drugs can serve as effectively as opioids in managing chronic cancer pain.”
Editorial: “Although it is important to identify effective and safe nonopioid treatments for cancer pain, avoiding opioids altogether may not be in the best interest of every patient,” (10.1200/JCO.19.00936; E. M. Lavoie Smith). “Future research is needed to uncover innovative, patient-centric, multidimensional solutions that target numerous biopsychosocial factors. Attention to the triad of common sense clinical practice—efficacy, feasibility, and risk avoidance—will protect us from misinterpreting high-level scientific evidence that could lead us down the wrong path. Future collaboration among diverse stakeholders (eg, patients, clinicians, scientists, policymakers) will be important as we strive to find mechanism-targeted approaches, identify and manage high-risk populations, and enforce principle-based policies that maximize the safety, comfort, and quality of life of people with cancer.”
>>>Vaccine Highlights
Source:
 May 27 issue of Vaccine (2019; 37).
Influenza Vaccination & Healthcare Utilization: In older adults, influenza vaccination may result in reduced healthcare utilization, authors of a systematic review of 22 studies conclude, but the variability among studies precludes a clear conclusion on effectiveness of the influenza vaccine on this parameter (pp. 3179–89; C. Quach, c.quach@umontreal.ca).
Results: “Overall, two studies (9%) were deemed at moderate risk of bias, thirteen (59%) at serious risk of bias and seven (32%) at critical risk of bias. For outpatient visits, we found modest evidence of protection by the influenza vaccine. For all-cause hospitalization outcomes, we found a wide range of results, mostly deemed at serious risk of bias. The included studies suggested that the vaccine may protect older adults against influenza hospitalizations and cardiovascular events. No article meeting our inclusion criteria explored the use of antibiotics and [hospitalizations for influenza-like illness]. The high heterogeneity between studies hindered the aggregation of data into a meta-analysis.”
>>>PNN NewsWatch
FDA yesterday approved dalteparin sodium (Fragmin, Pfizer) injection for subcutaneous use to reduce the recurrence of symptomatic venous thromboembolism in infants and children 1 month of age or older.

PNN Pharmacotherapy Line
May 20, 2019 * Vol. 26, No. 97
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2019; 364).
Habitual Glucosamine Use & CVD Risk: Habitual users of the dietary supplement glucosamine had a significantly lower risk of cardiovascular disease (CVD) events in a decade-long longitudinal study (l1628; L. Qi, lqi1@tulane.edu).
PICO: Prospective cohort study of 466,039 participants in the UK Biobank without CVD at baseline who provided baseline (2006–10) information on glucosamine use and were followed up to 2016; incident CVD death, heart disease, and stroke).
Results: “During a median follow-up of seven years, there were 10,204 incident CVD events, 3,060 CVD deaths, 5,745 coronary heart disease events, and 3,263 stroke events. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, drug use, and other supplement use, glucosamine use was associated with a significantly lower risk of total CVD events (hazard ratio 0.85, 95% confidence interval 0.80 to 0.90), CVD death (0.78, 0.70 to 0.87), coronary heart disease (0.82, 0.76 to 0.88), and stroke (0.91, 0.83 to 1.00).”
Breast Cancer & Hormone Use in Transgender People: Trans women have an increased risk of breast cancer, compared with cisgender men, that appears to be related to a “relatively short duration of hormone treatment,” researchers report (l1652; M, den Heijer, m.denheijer@vumc.nl). The similarity of the risk to that of cisgender women suggests that breast cancer screening guidelines for cisgender people are sufficient in trans individuals, the authors conclude.
PICO: Retrospective, nationwide Dutch cohort study of 2,260 adult trans women (male sex assigned at birth, female gender identity) and 1,229 adult trans men (female sex assigned at birth, male gender identity) who received gender-affirming hormone treatment at clinics; incidence and characteristics of breast cancer.
Results: “The total person time in this cohort was 33,991 years for trans women and 14,883 years for trans men. In the 2,260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7–37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1,229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).”
Chronic Tramadol After Acute Pain: Given patterns of chronic use of tramadol following prescriptions for acute pain, governing bodies should consider reclassifying the drug, authors conclude, and providers should “use as much caution when prescribing tramadol in the setting of acute pain as for other short acting opioids” (l1849; M. M. Jeffery, Jeffery.Molly@mayo.edu).
PICO: Observational study of U.S. administrative claims data in 2009–18; opioid-naive patients (n = 357,884) undergoing elective surgery; risk of persistent opioid use after discharge for patients treated with tramadol alone compared with other short-acting opioids.
Results: “Receipt of tramadol alone was associated with a 6% increase in the risk of additional opioid use relative to people receiving other short acting opioids (incidence rate ratio 95% confidence interval 1.00 to 1.13; risk difference 0.5 percentage points; P = 0.049), 47% increase in the adjusted risk of persistent opioid use (1.25 to 1.69; 0.5 percentage points; P <0.001), and 41% increase in the adjusted risk of a CONSORT chronic opioid use episode (1.08 to 1.75; 0.2 percentage points; P = 0.013).”
>>>PNN NewsWatch
* In a safety communicationFDA warns patients and health professionals of risks associated with the use of unapproved or unauthorized devices for diabetes management, including continuous glucose monitoring systems, insulin pumps, and automated insulin dosing systems.
>>>PNN JournalWatch
* Mass Gatherings Medicine: Public Health Issues Arising From Mass Gathering Religious and Sporting Events, in Lancet, 2019; 393: 2073–84. (A. Zumla, a.zumla@ucl.ac.uk)

PNN Pharmacotherapy Line
May 21, 2019 * Vol. 26, No. 98
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 (2019; 170).
Steroids v. Biologics After Arthroscopy in RA: In an observational study of patients with rheumatoid arthritis (RA), glucocorticoid use — particularly in dosages of more than 10 mg/d — was associated with greater risk of adverse outcomes, compared with biologics (10.7326/M18-2217; M. D. George, michael.george@uphs.upenn.edu).
PICO: Retrospective cohort study of adults with RA who were having elective inpatient total knee or hip arthroplasty and had a recent infusion of or prescription for abatacept, adalimumab, etanercept, infliximab, rituximab, or tocilizumab before surgery; Medicare and Truven MarketScan administrative data in 2006–15; risks for hospitalized infection within 30 days and prosthetic joint infection (PJI) within 1 year after surgery.
Results: “Among 9,911 patients treated with biologics, 10,923 surgical procedures were identified. Outcomes were similar in patients who received different biologics. Compared with an 8.16% risk for hospitalized infection with abatacept, predicted risk from propensity-weighted models ranged from 6.87% (95% CI, 5.30% to 8.90%) with adalimumab to 8.90% (CI, 5.70% to 13.52%) with rituximab. Compared with a 2.14% 1-year cumulative incidence of PJI with abatacept, predicted incidence ranged from 0.35% (CI, 0.11% to 1.12%) with rituximab to 3.67% (CI, 1.69% to 7.88%) with tocilizumab. Glucocorticoids were associated with a dose-dependent increase in postoperative risk for all outcomes. Propensity-weighted models showed that use of more than 10 mg of glucocorticoids per day (vs. no glucocorticoid use) resulted in a predicted risk for hospitalized infection of 13.25% (CI, 9.72% to 17.81%) (vs. 6.78%) and a predicted 1-year cumulative incidence of PJI of 3.83% (CI, 2.13% to 6.87%) (vs. 2.09%).”
Editorial: “The study has provided convincing evidence to support lack of variability in postoperative infection risk across the available biologic therapies, with the aforementioned caveat about insufficient experience to date with rituximab and tocilizumab,” editorialists write (10.7326/M19-1088; G. Hawker, g.hawker@utoronto.ca). “The findings should also be reassuring regarding the lack of evidence for increased infection risk with methotrexate–biologic cotherapy, which almost half of the study population was receiving. However, the study does not resolve the question of whether withholding biologic therapies in the perioperative period actually reduces patients’ overall risk for infection complications. Instead, it provides compelling evidence, once again, of the substantial risk for serious postoperative infections associated with glucocorticoid use. There is a critical need for research to elucidate the risks and benefits of withholding biologics to optimize patient outcomes.”
Pharmacogenetics in Precision Prescribing: In a Cases in Precision Medicine article, authors discuss “the current clinical utility of pharmacogenetic testing in the context of a patient who requires anticoagulation with warfarin,” reaching these conclusions (10.7326/M18-2357; W. K. Chung, wkc15@columbia.edu):
* Although evidence for the clinical utility of genotype-based warfarin therapy is conflicting, data exist to support the use of pharmacogenetic testing in persons of European ancestry. If genetic information is readily available, genotype-based warfarin therapy should be applied on the basis of recommendations from the Clinical Pharmacogenetics Implementation Consortium guidelines.
Warfarindosing.org provides a calculator in which physicians can enter a patient’s genetic and clinical information to determine the appropriate warfarin dosage.
* Because of the long turnaround times for pharmacogenetic testing, it is not feasible for patients with an emergent need for warfarin.
* Pharmacogenetics currently is not recommended when prescribing warfarin for persons of African ancestry because of the lack of clinical studies in this population.
* Evidence is available to support genotype-guided prescribing for a limited number of drugs, including abacavir, thiopurines, carbamazepine (Asian populations), allopurinol (Asian populations), and ivacaftor. Overall, however, the evidence is insufficient to support genotype-guided prescribing for most other medications with available pharmacogenetic tests.

PNN Pharmacotherapy Line
May 22, 2019 * Vol. 26, No. 99
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 21 issue of JAMA (2019; 321).
Aflibercept in Diabetic Macular Edema: Watch and wait is a reasonable first step in patients with diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) and good visual acuity, a study shows (pp. 1880–94; A. R. Glassman, drcrstat2@jaeb.org; aglassman@jaeb.org).
PICO: Trial at 91 US and Canadian sites of 702 adults with type 1 or type 2 diabetes who had 1 study eye with CI-DME and visual acuity of 20/25 or better; in 2013–18, eyes randomly assigned to intravitreous aflibercept 2.0 mg as frequently as every 4 weeks, focal/grid laser photocoagulation, or observation; aflibercept required for eyes in other groups when visual acuity declined; primary outcome of 5-letter visual acuity decrease at 2 years.
Results: “For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, −2% [95% CI, −9% to 5%]; relative risk, 0.88 [95% CI, 0.57–1.35; P = .79]; aflibercept vs observation risk difference, −3% [95% CI, −11% to 4%]; relative risk, 0.83 [95% CI, 0.55–1.27; P = .79]; laser photocoagulation vs observation risk difference, −1% [95% CI, −9% to 6%]; relative risk, 0.95 [95% CI, 0.64–1.41; P = .79]). Antiplatelet Trialists’ Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups.”
Editorial: “It is the patient who has the most to gain from these study results,” writes an editorialist (pp. 1873–5; E. Y. Chew, echew@nei.nih.gov). “Some patients may not need intraocular injections of anti-VEGF therapies, which carry a risk, albeit small, of endophthalmitis. The cost of the drugs as well as the monetary cost associated with increased frequency of eye examinations associated with anti-VEGF therapies would be avoided. This approach could not only reduce the increased economic burden associated with intraocular injection therapy, but also could reduce the demands and psychological burden of treatment for diabetic retinopathy for the patients, their families, and society.”
Improved Asthma, Lipids Factors in Children: A pair of studies show the benefits of interventions on pediatric asthma and childhood lipids/apolipoprotein B levels. 
Asthma Study: The asthma data come from the Southern California Children’s Health Study, which assessed the impact of air pollution decline over the 1993 to 2014 time period (pp. 1906–15; E. Garcia, garc991@usc.edu). In three waves of the longitudinal cohort study, 525 cases of asthma were identified among 4,140 children. Decreases in ambient nitrogen dioxide and particulate matter less than 2.5 µm were associated with decreased incidence of childhood asthma; levels of ozone and larger particulate matter lowered asthma rates but did not reach significance.
Editorial: “[Current] efforts … to deny that air pollution is dangerous to health, to the benefit of vested interested parties such as the oil and coal companies, clearly comes at the expense of human health,” editorialists write (pp. 1875–7; G. D. Thurston, george.thurston@nyu.edu). “Scientists and physicians must recognize the threat that such science denial represents and speak out vigorously against it. As this new study by Garcia et al shows, the health of the nation’s children benefits from cleaner air.”
Lipids Study: Between 1999 and 2016, lipids and apolipoprotein B levels improved in the National Health and Nutrition Examination Surveys for youths aged 6 to 19 years, researchers report (pp. 1895–905; A. M. Perak, amarma@luriechildrens.org): “Decreasing linear trends were observed in mean levels of total cholesterol (from 164 mg/dL to 155 mg/dL), non–high-density lipoprotein cholesterol (from 108 mg/dL to 100 mg/dL), low-density lipoprotein cholesterol (from 92 mg/dL to 86 mg/dL), triglycerides (from 78 mg/dL to 63 mg/dL), and apolipoprotein B (from 70 mg/dL to 67 mg/dL), and increasing linear trends were observed in mean levels of high-density lipoprotein cholesterol (from 52.5 mg/dL to 55.0 mg/dL).”

PNN Pharmacotherapy Line
May 23, 2019 * Vol. 26, No. 100
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 Early-release articles from the New England Journal of Medicine (2019; 380).
Managing Mild Asthma: Two studies and an editorial examine current strategies for treatment of patients with mild asthma.
Study 1: “The majority of [295] patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo,” researchers conclude (10.1056/NEJMoa1814917; S. C. Lazarus, lazma@ucsf.edu). “These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level.”
Study 2: “In an open-label trial involving [668] adults with mild asthma, budesonide–formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations,” authors conclude (10.1056/NEJMoa1901963; R. Beasley, richard.beasley@mrinz.ac.nz).
Editorial: “Both [trials] showed that patients with mild asthma whose only asthma treatment was a [short-acting beta-2-agonist (SABA)] as needed for relief of asthma symptoms were at considerable risk for exacerbations,” concludes an editorialist (10.1056/NEJMe1905354; G. W. K. Wong). “Given all these results, we should carefully review the current guideline recommendations for treating mild asthma. Evidence is building to question the role of as-needed SABAs as the step 1 treatment for mild intermittent asthma.…”
Early Neuromuscular Blockade in ARDS: In patients with moderate-to-severe acute respiratory distress syndrome (ARDS), early and continuous cisatracurium infusion produced similar 90-day mortality rates as a usual-care approach with lighter sedation targets, report investigators in the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial (10.1056/NEJMoa1901686; D. C. Angus, angusdc@upmc.edu).
PICO: 48-hour continuous cisatracurium infusion with concomitant deep sedation (intervention group) or usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group); primary end point of in-hospital, all-cause death at 90 days.
Results: “The trial was stopped at the second interim analysis for futility. We enrolled 1,006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, −0.3 percentage points; 95% confidence interval, −6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months.”
Editorial: “Therapeutic strategies in ARDS should ideally be tailored to the specific underlying disease or injury mechanism at any given point in time, rather than being applied uniformly to all patients,” editorialists write (10.1056/NEJMe1905627; A. S. Slutsky). “Early paralytic agents for ARDS? Given their long-term neuromuscular safety profile in the ROSE trial, we suggest that paralytic agents can sometimes be used, when physiologically and clinically indicated.”
>>>PNN NewsWatch
* Federal judges have entered consent decrees against PharMedium Services and PharmD Solutions, two compounding operations, FDA said yesterday. The consent decree involving PharMedium prohibits the company and the other defendants from, among other things, manufacturing, holding, or distributing PharMedium’s drugs at or from its Tennessee facility until it completes corrective actions and receives authorization from FDA. The company has ceased operations at its Mississippi facility, and its Texas and New Jersey facilities must, among other things, hire an independent expert to review PharMedium’s operations to ensure compliance with the law.

PNN Pharmacotherapy Line
May 24, 2019 * Vol. 26, No. 101
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Medical Care Report
Source:
 June issue of Medical Care (2019; 57).
Vaccine Costs, Income: Office- and clinic-based providers of vaccinations overall have small positive incomes from the services, but some providers likely lose money on immunizations, researchers report (pp. 410–6; B. Yarnoff).
PICO: 4 internal medicine, 4 family medicine, 2 pediatric, 2 obstetrics and gynecology (OBGYN) practices, and 2 community health clinics in North Carolina; time-motion assessment of vaccination-related activities in the provider office; survey of providers on vaccine management costs.
Results: “Across all provider settings, mean cost per vaccine administration was $14 with substantial variation by practice setting (pediatric: $10; community health clinics: $15; family medicine: $17; OBGYN: $23; internal medicine: $23). When receiving the maximum payment, all provider settings had positive income for vaccination services. When receiving the minimum reported payments for vaccination services, pediatric and family medicine practices had positive income, internal medicine and OBGYN practices had approximately equal costs and payments, and community health clinics had losses or negative income.”
Opioid Prescribing by NPs, Physicians in Medicare: Tailored pain-management and opioid-prescribing educational programs may be needed for different types of health professionals who provide care to Medicare beneficiaries, a study concludes (pp. 482–9; U. Muench).
PICO: Medicare beneficiaries without cancer diagnosis, hospice care, or end-stage renal disease who in 2009–13 were residing in states in which nurse practitioners (NPs) prescribe controlled substances without physician oversight; measured whether beneficiaries received any opioid prescriptions; acute (<90 d supply) and chronic (≥90 d supply) use at baseline (2009–10) and follow-up (2012–13); potential misuse of opioid prescribing using a daily morphine milligram equivalent dose of >100 mg, overlapping prescriptions of opioids >7 days, and overlapping prescriptions of opioids with benzodiazepines >7 days.
Results: “Beneficiaries managed by NPs were less likely to receive an opioid [odds ratio (OR), 0.87; P <0.001], were less likely to be acute users at baseline (OR, 0.84; P <0.001), and were more likely to receive a high daily opioid dose of morphine milligram equivalent >100 mg compared with physician-managed beneficiaries (OR, 1.11; P = 0.048).”
>>>Health Affairs Highlights
Source:
 May issue of Health Affairs, a theme issue on “social determinants, children, and more” (2019; 38).
External Reference Pricing In Medicare Part D: A study compares prices for a market basket of brand-name drugs in the U.S. to those in the U.K., Japan, and the Canadian province of Ontario to determine how much Medicare could save if it based Part D drug prices on amounts paid in other countries (pp. 804–11; S-Y Kang, Soyeon.Kang@jhu.edu).
Summary: “Many countries use external reference pricing to help determine drug prices. However, external reference pricing has received little attention in the US—perhaps because the US is often the first adopter of drugs. External reference pricing could be used to set prices for drugs that were already established in the market. We compared the price differentials between the US and the UK, Japan, and Ontario (Canada) for single-source brand-name drugs that had been on the market for at least three years. We found that the prices averaged 3.2–4.1 times higher in the US after rebates were considered. The price differential for individual drugs varied from 1.3 to 70.1. The longer a drug remained on the market, the greater the differential. The estimated savings to Medicare Part D of adopting the average price of drugs in the reference countries was $72.9 billion in 2018. Medicare could use external reference pricing in Part D to improve affordability for patients.”
>>>PNN NewsWatch
* CDC has released 8 tips for safe and healthy summertime work and play. Categories of advice are international travel, swimming, young workers, heat and sunburn, children’s activities, vaccines, food safety, and insect protections.
PNN will not be published on Mon., May 27, Memorial Day.

PNN Pharmacotherapy Line
May 28, 2019 * Vol. 26, No. 102
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Prednisolone Tapering for First-Episode Nephrotic Syndrome: In children with steroid-sensitive nephrotic syndrome, extension of the initial course of prednisolone treatment from 8 to 16 weeks did not improve clinical outcomes, a phase 3 study shows, but short-term economic benefits were demonstrated (l1800; N. J. A. Webb, nicholas.webb@mft.nhs.uk).
PICO: At 125 U.K. National Health Service district general hospitals and tertiary pediatric nephrology centers, 237 pediatric patients with a first episode of steroid-sensitive nephrotic syndrome were randomized to 8- or 16-week courses of prednisolone; primary outcome measure of time to first relapse over a minimum follow-up of 24 months.
Results: “No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P = 0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P = 0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P = 0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P = 0.81). Total prednisolone dose after completion of the trial drug was 6,674 mg for the extended course versus 5,475 mg for the standard course (P = 0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P = 0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval −0.005 to 0.037) and cost savings (difference −£1673 ($2160; 1930 euros), 95% confidence interval −£3455 to £109).”
>>>PNN NewsWatch
FDA on Friday approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis), the first gene therapy approved to treat children younger than 2 years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality. SMA is a rare genetic disease caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the survival motor neuron (SMN) protein – a protein found throughout the body, which is critical for the maintenance and function of motor neurons. Without sufficient functional SMN protein, the motor neurons die, leading to debilitating and often fatal muscle weakness. Children with this condition have problems holding their heads up, swallowing, and breathing, beginning as early as birth or by 6 months of age. FDA granted this application fast track, breakthrough therapy, and priority review designations. The product also received orphan drug designation.
* Also approved on Friday by 
FDA were alpelisib (Piqray, Novartis) tablets, to be used in combination with the FDA-approved endocrine therapy fulvestrant, to treat men and postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer (as detected by a companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, which was also approved) following progression on or after an endocrine-based regimen.
>>>PNN JournalWatch
* Comparisons Between Oral Anticoagulants Among Older Nonvalvular Atrial Fibrillation Patients, in Journal of the American Geriatrics Society, 2019; 10.1111/jgs.15956. (S. Deitelzweig)
* Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation, in 
Journal of the American Geriatrics Society, 2019; 10.1111/jgs.15982. (S. Sukumar)
* Delirium, Dementia, and In-Hospital Mortality: The Results From the Italian Delirium Day 2016, A National Multicenter Study, in 
Journals of Gerontology, Series A, 2019; 74: 910–6. (G. Bellelli, guiseppe.bellelli@unimib.it)
* “The Lesser of Two Evils” Versus “Medicines not Smarties”: Constructing Antipsychotics in Dementia, in 
The Gerontologist, 2019; 59: 570–9. (P. Donyai, p.donyai@reading.ac.uk)
* Reducing Ageism: Education About Aging and Extended Contact With Older Adults, in 
The Gerontologist, 2019; 59: 580–8. (A. Lytle, alytle@steven.edu)

PNN Pharmacotherapy Line
May 29, 2019 * Vol. 26, No. 103
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 May 28 issue of JAMA (2019; 321).
Specialty Drug Pricing & Out-of-Pocket Part D Spending: “The number of orally administered anticancer medications covered under Part D has increased since 2010, with mean monthly point-of-sale prices for anticancer drugs reaching nearly $14,000 in 2018,” researchers report. “Anticancer drug prices have increased beyond inflation between 2010 and 2018, resulting in higher out-of-pocket spending for patients despite the Part D coverage gap closing” (pp. 2025–7; S. B. Dusetzina, s.dusetzina@vanderbilt.edu).
PICO: Medicare formulary and pricing files for fourth quarter 2010 through fourth quarter 2018; point-of-sale prices (excluding rebates and discounts) for a single fill of each anticancer medication; comparison of prices in 2010 (or the first year a newer product was observed in the data) and 2018; percentage prices changes net of inflation based on Consumer Price Index.
Results: “In 2010, 13 anticancer medications were covered by Part D and 54 in 2018. The mean price per fill in 2010 was $7,438 vs $13,992 in 2018. In 2018, 48 of 54 medications had monthly prices exceeding $10,000 per fill and 21 had prices exceeding $15,000 per fill. Across all drugs and varying years of approval (pre-2010 through 2018), mean prices rose by 5.8% per year above inflation. Changes in mean per-fill price from the first observed fill year to 2018 was 40.4% overall, ranging from a reduction of 44% for generic imatinib ($8,570 in 2016 vs $4,822 in 2018) to an increase of 306% for gefitinib ($1,960 in 2010 vs $7,960 in 2018).
“Despite efforts to close the coverage gap between 2010 and 2019, mean expected out-of-pocket spending in 2019 benefit designs increased for 12 of 13 orally administered anticancer drugs available in both years (mean 12-month out-of-pocket spending in 2010 was $8,794 and in 2019 is expected to be $10,470; mean increase, $1,676). Estimated annual out-of-pocket spending in 2019 is expected to be lowest for lapatinib ($7,220) and highest for lenalidomide ($15,472).”
Increasing Vaccinations Using Law, Science & Words: Viewpoint authors call for increasing U.S. vaccine coverage through strategies based on law, science, and communication (pp. 1969–70; L. O. Gostin, gostin@law.georgetown.edu). After describing the factors behind the current measles outbreaks, the authors advocate for tightening state vaccination laws, communicating facts and not falsehoods, ensuring “coverage of safe vaccinations for a healthy nation,” increasing corporate responsibility to screen out false antivaccine messages, and ending or tightening religious and philosophical exemptions.
Novel Clinical Phenotypes in Sepsis: Four clinical phenotypes are identified in patients with sepsis that correlated with host–response patterns and clinical outcomes, and simulations suggest these phenotypes may help in understanding heterogeneity of treatment effects (pp. 2003–17; C. W. Seymour, seymourcw@upmc.edu).
PICO: Retrospective analysis of data sets from electronic health records for 63,858 patients in three observational cohorts using statistical, machine learning, and simulation tools.
Results: “Four novel sepsis phenotypes (alpha, beta, gamma, and delta) with different demographics, laboratory values, and patterns of organ dysfunction were derived, validated, and shown to correlate with biomarkers and mortality. In the simulations using data from 3 randomized clinical trials involving 4,737 patients, the outcomes related to the treatments were sensitive to changes in the distribution of these phenotypes.”
Editorial: “[This study] represents the brave new world of attempting to apply patient data, machine learning, and artificial intelligence to better understand complex, serious clinical problems,” editorialists write (pp. 1981–2; W. A. Knaus, wknaus@virginia.edu). “However, the ultimate answer to the question ‘will this approach improve patient outcomes?’ remains unknown.”
>>>PNN NewsWatch
Heritage Pharmaceuticals Inc. is voluntarily recalling Amikacin Sulfate Injection, USP, 1 g/4 mL (250 mg/mL), lot VEAC025, exp. date: Oct. 2019, and Prochlorperazine Edisylate Injection, USP, 10 mg/2 mL (5 mg/mL), lot VPCA172, exp. date Apr. 2020, to the consumer level because of detection of microbial growth in unreleased sublots.

PNN Pharmacotherapy Line
May 30, 2019 * Vol. 26, No. 104
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 May 30 issue of the New England Journal of Medicine (2019; 380).
Ibrutinib & Venetoclax for First-Line Treatment of CLL: In high-risk and older patients with chronic lymphocytic leukemia (CLL), the combination of venetoclax and ibrutinib proved an effective oral regimen, according to an investigator-initiated phase 2 study (pp. 2095–103; N. Jain, njain@mdanderson.org).
PICO: Untreated high-risk and older patients with CLL with one or more of these features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older; treated with ibrutinib 420 mg once daily for 3 cycles, followed by weekly dose escalations of venetoclax to 400 mg once daily for 24 cycles; responses assessed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria.
Results: “A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHVTP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.”
Editorial: “Extended follow-up of this important study will provide many more insights into targeted therapy of CLL,” writes an editorialist (pp. 2169–71; A. Wiestner). “Important questions include the following: Can treatment ever be safely stopped? Are there subgroups with a poor prognosis that require additional therapy? What is the nature and mechanism of ibrutinib and venetoclax resistance? And does substituting a different BTK inhibitor for ibrutinib preserve activity with a lower risk of toxic effects?”
Initial Therapy in Older Patients with Multiple Myeloma: Among patients with newly diagnosed multiple myeloma, addition of daratumumab to lenalidomide and dexamethasone reduced the risk of disease progression or death significantly (pp. 2104–15; ).
PICO: 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation received daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group); primary end point of progression-free survival.
Results: “At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P <0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P <0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P <0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).”
Editorial: “Selection of an appropriate regimen [for treatment of multiple myeloma in such patients] will become a more challenging and complex process that is based on the unique clinical characteristics of a given patient,” an editorialist concludes (pp. 2172–3; J. Laubach). “These developments … are welcomed enthusiastically, because it stands to reason that the expanding number of effective induction regimens will improve clinical outcomes among older patients with multiple myeloma.”

PNN Pharmacotherapy Line
May 31, 2019 * Vol. 26, No. 105
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Care Report
Source:
 Early-online articles from and June issue of Diabetes Care (2019; 42).
International Consensus on SGLT Inhibitor Use in T1D: An international consensus report reviews current data regarding sodium–glucose cotransporter (SGLT) inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes (pp. 1147–54; C. G. Parkin, chris@cgparkin.org).
Summary: “SGLT inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk.”
Editorial: “The increase in absolute risk of DKA, even in closely supervised patients participating in clinical trials, raises a serious concern that DKA will be even more common if SGLT inhibitors are used in routine clinical practice by practitioners who do not have the expertise and resources of the clinical trialists to implement the complex recommendations necessary to mitigate risk for DKA,” editorialists write in advising clinicians to “proceed with extreme caution” (pp. 991–3; J. I. Wolfsdorf, joseph.wolfsdorf@childrens.harvard.edu). “It would be prudent to limit adjunctive use of SGLT inhibitors in type 1 diabetes to specialists well versed in the risks associated with such therapy and who have the requisite resources to educate, train, and support carefully selected patients.”
Fish Oil and/or Probiotics in Gestational Diabetes Mellitus: In women with overweight or obesity, the risk of gestational diabetes mellitus (GDM) was unchanged by interventions using fish oil and/or probiotic supplements, researchers report (pp. 1009–17; O. Pellonperä, uti.pellonpera@utu.fi">outi.pellonpera@utu.fi).
PICO: 439 women (mean 13.9 ± 2.1 gestational weeks [gw]) randomized to fish oil + placebo, probiotics + placebo, fish oil + probiotics, and placebo + placebo; fish oil (1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid) and probiotic supplements (Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each) were provided for daily consumption from randomization beyond delivery; primary outcomes of the incidence of GDM diagnosed with oral glucose tolerance test targeted at 24–28 gw and the change in fasting glucose between randomization and late pregnancy (mean 35.2 ± 0.9 gw).
Results: “No differences were found among the intervention groups in the maternal and neonatal pregnancy outcomes or side effects related to the intervention (P > 0.05). The proportion of women with GDM (94 of 377; fish oil + placebo, 23 of 96, 24.0%; probiotics + placebo, 25 of 99, 25.3%; fish oil + probiotics, 26 of 91, 28.6%; and placebo + placebo, 20 of 91, 22.0%) and the change in glucose, insulin, or HOMA2-IR (n = 364) did not differ among the intervention groups (P > 0.11 for all comparisons).”
>>>PNN NewsWatch
* In a statement posted yesterday, FDA said it is opening a public docket to solicit feedback on possibly requiring that certain immediate-release opioid analgesics be made available in fixed-quantity, unit-of-use blister packaging. The action would be based on new authority granted in the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities (SUPPORT) Act.
FDA said yesterday it is putting R3 Stem Cell, LLC, on notice for marketing unapproved stem cell products for treating serious conditions.
Novis PR LLC is recalling 5 lots of Pecgen DMX, 16 oz, a liquid cough syrup, to the consumer level because of a typographical error in the label’s dosage information.

PNN Pharmacotherapy Line
June 3, 2019 * Vol. 26, No. 106
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 June 1 issue of Lancet (2019; 393).
Oral Immunotherapy for Peanut Allergy: In the Peanut Allergen immunotherapy, Clarifying the Evidence (PACE) systematic review and meta-analysis, patients with peanut allergy had more allergic and anaphylactic reactions with oral immunotherapy than with avoidance or placebo, despite effectively inducing desensitization, researchers report (pp. 2222–32; D. K. Chu, chudk@mcmaster.ca).
PICO: Randomized controlled trials of oral immunotherapy versus no oral immunotherapy for peanut allergy, without language restrictions; main outcomes of anaphylaxis, allergic or adverse reactions, epinephrine use, and quality of life; GRADE approach used to assess certainty.
Results: “12 trials (n = 1,041; median age across trials 8.7 years [IQR 5.9–11.2]) showed that oral immunotherapy versus no oral immunotherapy increased anaphylaxis risk (risk ratio [RR] 3.12 [95% CI 1.76–5.55], I2 = 0%, risk difference [RD] 15.1%, high-certainty), anaphylaxis frequency (incidence rate ratio [IRR] 2.72 [1.57–4.72], I2 = 0%, RD 12.2%, high-certainty), and epinephrine use (RR 2.21 [1.27–3.83], I2 = 0%, RD 4.5%, high-certainty) similarly during build-up and maintenance (p interaction = 0.92). Oral immunotherapy increased serious adverse events (RR 1.92 [1.00–3.66], I2 = 0%, RD 5.7%, moderate-certainty), and non-anaphylactic reactions (vomiting: RR 1.79 [95%CI 1.35–2.38], I2 = 0%, high-certainty; angioedema: 2.25 [1.13–4.47], I2 = 0%, high-certainty; upper tract respiratory reactions: 1.36 [1.02–1.81], I2 = 0%, moderate-certainty; lower tract respiratory reactions: 1.55 [0.96–2.50], I2 = 28%, moderate-certainty). Passing a supervised challenge, a surrogate for preventing out-of-clinic reactions, was more likely with oral immunotherapy (RR 12.42 [95% CI 6.82–22.61], I2 = 0%, RD 36.5%, high-certainty). Quality of life was not different between groups (combined parents and self report RR 1.21 [0.87–1.69], I2 = 0%, RD 0.03%, low-certainty). Findings were robust to IRR, trial sequential, subgroup, and sensitivity analyses.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
PPI Use & Mortality in Veterans: Among U.S. veterans, use of PPIs was associated with a small excess risk of all-cause mortality and death from cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer (l1580; Z. Al-Aly, zalaly@gmail.com).
PICO: Longitudinal observational cohort study of new users of PPIs (n=157,625) or H2 blockers (n = 56,842) in 2002–04; follow for 10 years; main outcome measures of all-cause mortality and cause-specific mortality associated with taking PPIs.
Results: “There were 45.20 excess deaths (95% confidence interval 28.20 to 61.40) per 1,000 patients taking PPIs. Circulatory system diseases (number of attributable deaths per 1,000 patients taking PPIs 17.47, 95% confidence interval 5.47 to 28.80), neoplasms (12.94, 1.24 to 24.28), infectious and parasitic diseases (4.20, 1.57 to 7.02), and genitourinary system diseases (6.25, 3.22 to 9.24) were associated with taking PPIs. There was a graded relation between cumulative duration of PPI exposure and the risk of all cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases. Analyses of subcauses of death suggested that taking PPIs was associated with an excess mortality due to cardiovascular disease (15.48, 5.02 to 25.19) and chronic kidney disease (4.19, 1.56 to 6.58). Among patients without documented indication for acid suppression drugs (n=116,377), taking PPIs was associated with an excess mortality due to cardiovascular disease (22.91, 11.89 to 33.57), chronic kidney disease (4.74, 1.53 to 8.05), and upper gastrointestinal cancer (3.12, 0.91 to 5.44).…”
>>>PNN JournalWatch
* A Public Health Crisis: Electronic Cigarettes, Vape, and JUUL, in Pediatrics, 2019; 143: 10.1542/peds.2018-2741. (S. C. Walley)
* Opioids and the Urgent Need to Focus on the Health Care of Young Adults, in 
Pediatrics, 2019; 143: 10.1542/peds.2019-0835. (S. T. Callahan)
* Pharmacogenomic Variants and Drug Interactions Identified Through the Genetic Analysis of Clozapine Metabolism, in 
American Journal of Psychiatry, 2019; 176: 477–86. (A. F. Pardiñas)
* Tolerance to Sodium in Patients With CKD-Induced Metabolic Acidosis: Does the Accompanying Anion Matter?, in 
American Journal of Kidney Diseases, 2019; 73: 858–65. (D. A. Bushinsky, david_bushinsky@urmc.rochester.edu)


PNN Pharmacotherapy Line
June 4, 2019 * Vol. 26, No. 107
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 4 issue of Annals of Internal Medicine (2019; 170).
Access to Office-Based Buprenorphine Treatment: In areas with high rates of opioid-related mortality, getting a new appointment with physician who offers office-based treatment or rapid buprenorphine therapy can be difficult for patients who are actively using heroin or with Medicaid coverage, a study shows (10.7326/M18-3457; M. L. Barnett, mbarnett@hsph.harvard.edu).
PICO: Real-world “secret shopper” audit survey in U.S. jurisdictions with high burden of opioid-related mortality in July through Nov. 2018; 546 buprenorphine prescribers were contacted twice by “patients” posing as uninsured or with Medicaid; outcomes of rates of new appointments offered, whether buprenorphine prescription was possible at the first visit, and wait times.
Results: “Among 1,092 contacts with 546 clinicians, schedulers were reached for 849 calls (78% response rate). Clinicians offered new appointments to 54% of Medicaid contacts and 62% of uninsured–self-pay contacts, whereas 27% of Medicaid and 41% of uninsured–self-pay contacts were offered an appointment with the possibility of buprenorphine prescription at the first visit. The median wait time to the first appointment was 6 days (interquartile range [IQR], 2 to 10 days) for Medicaid contacts and 5 days (IQR, 1 to 9 days) for uninsured–self-pay contacts. These wait times were similar regardless of clinician type or payer status. The median wait time from first contact to possible buprenorphine induction was 8 days (IQR, 4 to 15 days) for Medicaid and 7 days (IQR, 3 to 14 days) for uninsured–self-pay contacts.”
Editorial: “This study captured real-time barriers patients may encounter when trying to find a buprenorphine provider,” (10.7326/M19-1429; P. A. Lagisetty, lagiset@med.umich.edu). “It emphasized that timely treatment access varies according to payer status, state, and the provider’s treatment capacity, warranting further study on disparities in treatment access in these areas. To better inform policy, future efforts should evaluate state policies regarding reimbursement for buprenorphine therapy as well as existing access to treatment. In the interim, however, the findings demonstrate that many existing buprenorphine providers are willing to provide timely care to new patients. The more pressing challenge may be to engage and connect patients to these prescribers.”
2018 Cholesterol Clinical Practice Guidelines: The writing committee for the American Heart Association and American College of Cardiology (AHA/ACC) 2018 clinical practice guideline on cholesterol management provides a synopsis of its recommendations (pp. 779–83; N. J. Stone, n-stone@northwestern.edu).
Recommendation: “The guideline endorses a heart-healthy lifestyle beginning in childhood to reduce lifetime risk for [atherosclerotic cardiovascular disease]. It contains several new features compared with the 2013 guideline. For secondary prevention, patients at very high risk may be candidates for adding nonstatin medications (ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors) to statin therapy. In primary prevention, a clinician–patient risk discussion is still strongly recommended before a decision is made about statin treatment. The AHA/ACC risk calculator first triages patients into 4 risk categories. Those at intermediate risk deserve a focused clinician–patient discussion before initiation of statin therapy. Among intermediate-risk patients, identification of risk-enhancing factors and coronary artery calcium testing can assist in the decision to use a statin. Compared with the 2013 guideline, the new guideline gives more attention to percentage reduction in low-density lipoprotein cholesterol as a treatment goal and to long-term monitoring of therapeutic efficacy. To simplify monitoring, nonfasting lipid measurements are allowed.”
>>>PNN NewsWatch
* FDA has approved ceftolozane/tazobactam (Zerbaxa, Merck) for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in adult patients. The product was initially approved in 2014 to treat complicated intra-abdominal infections and for complicated urinary tract infections.
FDA is warning consumers about safety of the supplement ingredient vinpocetine, particularly when used by women of childbearing age.

PNN Pharmacotherapy Line
June 5, 2019 * Vol. 26, No. 108
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 June 4 issue of JAMA (2019; 321).
Neladenoson in Heart Failure With Preserved Ejection Fraction: New approaches to use of the first-in-class partial adenosine A1 receptor agonist neladenoson bialanate are needed if the agent is to be developed further, authors conclude following a negative phase 2b clinical trial in patients with heart failure with preserved ejection fraction (HFpEF) (pp. 2102–12; S. J. Shah, sanjiv.shah@northwestern.edu).
PICO: At 76 centers in the U.S., Europe, and Japan, 305 patients with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were randomized to placebo or neladenoson 5, 10, 20, or 40 mg for 20 weeks of treatment; primary end point of change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m).
Results: “Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, −12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, −10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, −2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, −1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, −5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]).”
Absorption of Sunscreen Active Ingredients: Application of 4 commercially available sunscreens under maximal use conditions produced plasma concentrations that exceed the threshold established by FDA for potentially waiving some nonclinical toxicology studies for sunscreens, researchers report (pp. 2082–91; D. G. Strauss, david.strauss@fda.hhs.gov).
PICO: Randomized clinical trial of of two sunscreen sprays, a lotion, and a cream in 24 healthy volunteers at a U.S. phase 1 clinical pharmacology unit; primary outcome of the maximum plasma concentration of avobenzone. 
Results: “For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen.”
Editorial: “[This study] will likely raise concerns in the medical community, as well as among sunscreen users,” editorialists write (pp. 2077–9; K. Shinkai, Kanade.shinkai@ucsf.edu).
>>>PNN NewsWatch
FDA yesterday expanded the approved indications of galcanezumab-gnlm (Emgality, Lilly) solution for injection to include treatment of episodic cluster headache in adults. The self-injected product was first approved by the FDA in September 2018 for preventive treatment of migraine in adults.
* A federal district judge has granted the government’s motion for summary judgment against two Florida 
US Stem Cell Clinics and the company’s chief scientific officer, FDA said yesterday. The court held that the defendants in that case adulterated and misbranded a stem cell drug product made from a patient’s adipose tissue.

PNN Pharmacotherapy Line
June 6, 2019 * Vol. 26, No. 109
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 June 6 issue of the New England Journal of Medicine (2019; 380).
15-Year Follow-up on Intensive Glucose Control in T2D: Adding to a prior report of 5.6-year experiences with intensive glucose control in patients with type 2 diabetes, VADT investigator found “no evidence of a legacy effect or a mortality benefit with intensive glucose control” during 15 years’ of follow-up (pp. 2215–24; P. D. Reaven, peter.reaven@va.gov).
PICO: Observational follow-up conducted by monitoring central VA databases for cardiovascular events, hospitalizations, and deaths among VADT participants (complete cohort) after the conclusion of the original clinical trial; participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort); prespecified primary outcome of a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes; death from any cause was a prespecified secondary outcome.
Results: “There were 1,655 participants in the complete cohort and 1,391 in the survey cohort. During the trial (which originally enrolled 1,791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).”
Editorial: “A major implication of the VADT follow-up study is that older patients with advanced diabetes should not expect long-term cardiovascular benefits from intensive glycemic control,” (pp. 2266–7; K. J. Lipska). “Instead, interventions that clearly reduce cardiovascular risk — such as smoking cessation, blood-pressure control, statin therapy, use of antiplatelet agents, and the use of glucose-lowering agents with proven cardiovascular benefits in patients with established cardiovascular disease — should be prioritized. Although a glycemic legacy effect may exist for younger patients, the current era of comprehensive cardiovascular risk-factor control may reduce, if not eliminate, legacy effects. Glycemic goals that are likely to produce both cardiovascular and microvascular benefits and minimize harms, consistent with patient preferences and values, may be the most effective, evidence-based, and safest strategy for patients with type 2 diabetes.”
Setting Realistic — and Perhaps Lower — Expectations for Azithromycin in Malaria: “The azithromycin story is a salutary reminder that large initial effects may subsequently settle on a more modest effect size, as John Ioannides has convincingly reargued and as was made famous by Francis Galton in the late 19th century through his description of regression toward the mean,” editorialists write (pp. 2264–5; N. Bar-Zeev) in reaction to two clinical studies (pp. 2197–206; D. Chandramohan, daniel.chandramohan@lshtm.ac.uk (pp. 2207–14; T. M. Lietman, tom.lietman@ucsf.edu). “How should delivery of azithromycin be targeted? Do only some populations benefit? When and why? Should trial end points be more specific or more circumspect? Even if benefits are confirmed for some, will antimicrobial resistance cause harm to others? Perhaps our hopes for azithromycin should be more modest.”
Measles Vaccination: Two Perspective articles describe efforts to control the ongoing measles epidemic through public health mandates (10.1056/NEJMp1905941; J. D. Cantor) and allowing adolescent consent for vaccines over parental objections (10.1056/NEJMp1905814, R. D. Silverman).

PNN Pharmacotherapy Line
June 7, 2019 * Vol. 26, No. 110
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Pediatrics Report
Source:
 June issue of Pediatrics (2019; 143).
Nonmedical Immunizations & School-Entry Vaccine Status: The percentage of incoming kindergarteners up-to-date on vaccinations in California increased after the implementation of Senate Bill 277 (SB277) in 2016, but with a replacement effect, researchers report (10.1542/peds.2018-3301; P. L. Delamater). 
PICO: Magnitude and composition of the population of kindergarteners not up-to-date on vaccinations before and after the implementation of SB277; correlations between previous geographic patterns of nonmedical exemptions and patterns of the remaining entry mechanisms for kindergarteners not up-to-date after law’s implementation.
Results: “In the first year after SB277 was implemented, the percentage of kindergartners entering school not up-to-date on vaccinations decreased from 7.15% to 4.42%. The conditional entrance rate fell from 4.43% to 1.91%, accounting for much of this decrease. Other entry mechanisms for students not up-to-date, including medical exemptions and exemptions for independent study or homeschooled students, largely replaced the decrease in the personal belief exemption rate from 2.37% to 0.56%. In the second year, the percentage of kindergartners not up-to-date increased by 0.45%, despite additional reductions in conditional entrants and personal belief exemptions. The correlational analysis revealed that previous geographic patterns of vaccine refusal persisted after the law’s implementation.”
Opioid Prescribing in Ambulatory Care Settings: Among adolescents and young adults, rates of opioid prescribing in emergency departments (EDs) and outpatient clinics remain high, a study shows, particularly for certain emergency conditions (10.1542/peds.2018-1578; J. D. Hudgins).
PICO: Visits to EDs and outpatient clinics for adolescents (13–17 years old) and young adults (18–22 years old) in the National Hospital Ambulatory Medical Care Survey and National Ambulatory Medical Care Survey data for 2005–15; rates of opioid prescribing over time examined with logistic regression.
Results: “Nearly 57 million visits (5.7%; 95% CI 5.4% to 6.0%) by adolescents and young adults were associated with an opioid prescription. The rate of opioid prescribing was 14.9% (95% CI 14.4% to 15.6%) for ED visits and 2.8% (95% CI 2.5% to 3.1%) for outpatient clinic visits. There was a small but significant decrease in the rate of opioid prescriptions among ED visits (odds ratio 0.96; 95% CI 0.95 to 0.98); no change was seen for outpatient clinic visits. Among ED visits, opioid-prescribing rates were highest among adolescents and young adults with dental disorders (59.7% and 57.9%, respectively), followed by adolescents with clavicle (47.0%) and ankle fractures (38.1%).”
Outpatient Opioids in Children With Special Needs: In children and youth with special health care needs (CYSHCN), outpatient opioid exposure (OE) is common, according to data from 2016 (10.1542/peds.2018-2199; J. A. Feinstein). The authors conclude that future researchers should “examine the appropriateness of opioid prescribing, particularly in emergency departments, as well as assess for drug interactions with chronic medications and reasons for insufficient follow-up.”
PICO: Retrospective cohort study of 2,597,987 CYSHCN aged 0-to-18 years from 11 states continuously enrolled in Medicaid in 2016 with ≥1 chronic condition; OE included any filled single or multiple prescription for opioids. Health care encounters assessed within 7 days before and 7 and 30 days after OE.
Results: “Among CYSHCN, 7.4% had OE. CYSHCN with OE versus without OE were older (ages 10–18 years: 69.4% vs 47.7%), had more chronic conditions (≥3 conditions: 49.1% vs 30.6%), and had more polypharmacy (≥5 other medication classes: 54.7% vs 31.2%), P < .001 for all. Most (76.7%) OEs were single fills with a median duration of 4 days (interquartile range: 3–6). The most common OEs were acetaminophen-hydrocodone (47.5%), acetaminophen-codeine (21.5%), and oxycodone (9.5%). Emergency department visits preceded 28.8% of OEs, followed by outpatient surgery (28.8%) and outpatient specialty care (19.1%). Most OEs were preceded by a diagnosis of infection (25.9%) or injury (22.3%). Only 35.1% and 62.2% of OEs were associated with follow-up visits within 7 and 30 days, respectively.”

PNN Pharmacotherapy Line
June 10, 2019 * Vol. 26, No. 111
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Ticagrelor + Aspirin for Minor Stroke or TIA: Carriers of the CYP2C19 loss-of-function allele can benefit from use of ticagrelor plus aspirin following minor stroke or transient ischemic attack (TIA), researchers report based on a comparison with clopidogrel plus aspirin (l2211; Y. Wang, yilong528@gmail.com).
PICO: Multicenter trial of 675 patients in China in 2015–17; ticagrelor (180 mg loading dose, then 90 mg twice daily) or clopidogrel (300 mg loading dose, then 75 mg daily) on a background of aspirin (100 mg daily for the first 21 days) within 24 hours of symptom onset of acute minor stroke or TIA; primary outcome of proportion of patients with high platelet reactivity at 90 days.
Results: “At 90 days, high platelet reactivity occurred in 35 (12.5%) of 280 patients in the ticagrelor/aspirin group and 86 (29.7%) of 290 patients in the clopidogrel/aspirin group (risk ratio 0.40; 95% confidence interval 0.28 to 0.56; P <0.001), and in 10.8% versus 35.4% (0.31; 0.18 to 0.49; P <0.001) of patients carrying CYP2C19 loss-of-function alleles. Stroke occurred in 21 (6.3%) of 336 patients in the ticagrelor/aspirin group and 30 (8.8%) of 339 patients in the clopidogrel/aspirin group (hazard ratio 0.70; 95% confidence interval 0.40 to 1.22; P = 0.20). Patients with large artery atherosclerosis in the ticagrelor/aspirin group had a lower stroke recurrence at 90 days than those in the clopidogrel/aspirin group (6.0% v 13.1%; hazard ratio 0.45, 95% confidence interval 0.20 to 0.98; P = 0.04). No difference was seen in the rates of major or minor haemorrhagic events between the ticagrelor/aspirin and clopidogrel/aspirin groups (4.8% v 3.5%; P = 0.42).”
>>>Lancet Report
Source:
 June 8 issue of Lancet (2019; 393).
Upadacitinib in Active RA: In comparison with continuing methotrexate SELECT-MONOTHERAPY participants with rheumatoid arthritis who had responded inadequately, upadacitinib monotherapy improved clinical and functional outcomes (pp. 2303–11; J. S. Smolen, josef.smolen@meduniwien.ac.at).
PICO: Patients with refractory active rheumatoid arthritis were randomized to once-daily monotherapy of upadacitinib or methotrexate at their existing dose; at week 14, patients on methotrexate were randomized to once-daily upadacitinib 15 or 30 mg; primary endpointsof proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3.2 or lower. 
Results: “At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35–48) in the continued methotrexate group, 147 (68%) of 217 patients (62–74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65–77) receiving upadacitinib 30 mg (p <0.0001 for both doses vs continued methotrexate). DAS28(CRP) 3.2 or lower was met by 42 (19%) of 216 (95% CI 14–25) in the continued methotrexate group, 97 (45%) of 217 (38–51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46–60) receiving upadacitinib 30 mg (p <0.0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg.” Herpes zoster was reported in 1 patient on continued methotrexate, three on upadacitinib 15 mg, and 6 on upadacitinib 30 mg, and 3 malignancies were reported.
>>>PNN NewsWatch
FDA and the Federal Trade Commission issued a warning letter to four firms for allegedly marketing flavored e-liquids to youth without the nicotine warning statement.
* Please note 
PNN’s new address and phone number below.
>>>PNN JournalWatch
* Prevention of Opioid Overdose, in New England Journal of Medicine, 2019; 380: 2246–55. (K. M. Babu, kavita.babu@umassmemorial.org)
* Clinical and Therapeutic Implications of Cancer Stem Cells, in 
New England Journal of Medicine, 2019; 380: 2237–45. (M. F. Clarke, mfclarke@stanford.edu)
* Procalcitonin-Guided Antibiotic Discontinuation and Mortality in Critically Ill Adults, in 
Chest, 2019; 155: 1109–18. (D. J. Pepper, dominiquepepper@gmail.com)
* Past, Present, and Future Research on the Lung Microbiome in Inflammatory Airway Disease, in 
Chest, 2019; 155: 10.1016/j.chest.2019.05.011. (L. J. Caverly)

PNN Pharmacotherapy Line
June 11, 2019 * Vol. 26, No. 112
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>> Internal Medicine Report
Source:
 Early-online articles from JAMA Internal Medicine (2019; 179).
GI Events Associated With Sodium Polystyrene Sulfonate: Among ambulatory older adults, use of sodium polystyrene sulfonate was associated with “a higher risk of hospitalization for serious adverse GI events,” leading authors to conclude, “These findings require confirmation and suggest caution with the ongoing use of sodium polystyrene sulfonate” (10.1001/jamainternmed.2019.0631; M. M. Sood, msood@toh.on.ca).
PICO: Population-based, retrospective matched cohort study of eligible adults ≥66 years of age in Ontario who were dispensed sodium polystyrene sulfonate in 2003–15; primary outcome of a composite of adverse GI events (hospitalization or emergency department visit with intestinal ischemia/thrombosis, GI ulceration/perforation, or resection/ostomy) within 30 days of initial sodium polystyrene sulfonate prescription
Results: “From a total of 1,853,866 eligible adults, 27,704 individuals were dispensed sodium polystyrene sulfonate (mean [SD] age, 78.5 [7.7] years; 54.7% male), and 20,020 sodium polystyrene sulfonate users were matched to 20,020 nonusers. Sodium polystyrene sulfonate use compared with nonuse was associated with a higher risk of an adverse GI event over the following 30 days (37 events [0.2%]; incidence rate, 22.97 per 1,000 person–years vs 18 events [0.1%]; incidence rate, 11.01 per 1,000 person–years) (hazard ratio, 1.94; 95% CI, 1.10–3.41). Results were consistent in additional analyses, including the subpopulation with baseline laboratory values (hazard ratio, 2.91; 95% CI, 1.38–6.12), and intestinal ischemia/thrombosis was the most common type of GI injury.”
Editorial: “Evidence for positive outcomes with cation-exchange resins is weak, and accumulating evidence suggests that sodium polystyrene sulfonate increases risk for serious GI adverse events such as intestinal necrosis,” editorialists write (10.1001/jamainternmed.2019.1291; D. Grady). “Despite this, sodium polystyrene sulfonate is still commonly used to treat moderate hyperkalemia when no treatment or alternative treatments should be preferred. Newer cation-exchange agents are entering clinical use, but data describing their success in reducing hyperkalemia are limited, and there is very little data regarding long-term safety.”
Needs-Tailored Asthma Intervention in Older Adults: In the SAMBA study, a comprehensive, patient-tailored asthma self-management support intervention improved outcomes in a group of 391 older adults (10.1001/jamainternmed.2019.1201; A. D. Federman, alex.federman@mssm.edu).
PICO: Three-arm randomized clinical trial of adults 60 years or older in New York City with persistent, uncontrolled asthma randomized to home-based intervention, clinic-based intervention, or control (usual care).
Results: “Intervention patients had significantly better asthma control, quality of life, medication adherence, and inhaler technique than control patients. The proportion of intervention patients with an emergency department visit for asthma was 6% vs 12% in the control group, a significant difference.”
>>> PNN NewsWatch
FDA yesterday granted accelerated approval to polatuzumab vedotin-piiq (Polivy, Genentech), in combination with bendamustine and a rituximab product (“BR&rdquoWinking to treat adult patients with diffuse large B-cell lymphoma (DLBCL) that has progressed or returned after at least two prior therapies. This new agent is a novel antibody–drug conjugate that binds to a specific protein (CD79b) found only on B cells and then releases the chemotherapy drug into those cells. DLBCL is the most common type of non-Hodgkin lymphoma.
* The incidence of 
pediatric herpes zoster (HZ) was significantly lower among children who received varicella vaccine, according to a population-based study reported this week in Pediatrics (10.1542/peds.2018-2917; S. Weinmann; accompanying editorial). Electronic health records from six integrated health care organizations showed a 78% lower incidence of HZ among in 2003–14 among vaccinated children than among unvaccinated children (38 versus 170 per 100,000 person–years). The investigators write that the study reinforces “the benefit of routine varicella vaccination to prevent pediatric HZ.”

PNN Pharmacotherapy Line
June 12, 2019 * Vol. 26, No. 113
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 June 11 issue of JAMA (2019; 321).
PrEP for Prevention of HIV Infection: The U.S. Preventive Services Task Force (USPSTF) presents its recommendations on preexposure prophylaxis (PrEP) for the prevention of HIV infection and evidence used in its deliberations.
Evidence Report: “In adults at increased risk of HIV infection, PrEP with oral tenofovir disoproxil fumarate monotherapy or tenofovir disoproxil fumarate/emtricitabine was associated with decreased risk of acquiring HIV infection compared with placebo or no PrEP, although effectiveness decreased with suboptimal adherence,” conclude authors of the evidence report (pp. 2214–30; R. Chou, chour@ohsu.edu). A systematic review on PrEP and its use of antiretroviral therapy (ART) shows the following: “Fourteen [randomized controlled trials] (N = 18,837), 8 observational studies (N = 3,884), and 7 studies of diagnostic accuracy (N = 32,279) were included. PrEP was associated with decreased risk of HIV infection vs placebo or no PrEP after 4 months to 4 years (11 trials; relative risk [RR], 0.46 [95% CI, 0.33–0.66]; I2 = 67%; absolute risk reduction [ARD], −2.0% [95% CI, −2.8% to −1.2%]). Greater adherence was associated with greater efficacy (RR with adherence ≥70%, 0.27 [95% CI, 0.19–0.39]; I2 = 0%) in 6 trials. PrEP was associated with an increased risk of renal adverse events (12 trials; RR, 1.43 [95% CI, 1.18–1.75]; I2 = 0%; ARD, 0.56% [95% CI, 0.09%–1.04%]) and gastrointestinal adverse events (12 trials; RR, 1.63 [95% CI, 1.26–2.11]; I2 = 43%; ARD, 1.95% [95% CI, 0.48%–3.43%]); most adverse events were mild and reversible. Instruments for predicting incident HIV infection had moderate discrimination (area under the receiver operating characteristic curve, 0.49–0.72) and require further validation. Adherence to PrEP in the United States in men who have sex with men varied widely (22%–90%).”
Recommendations: “The USPSTF recommends offering PrEP with effective antiretroviral therapy to persons at high risk of HIV acquisition. (A recommendation),” concludes the panel (pp. 2203–13; D. K. Owens, chair@uspstf.net), which provided this explanation of its review: “The USPSTF found convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition. The USPSTF also found convincing evidence that adherence to PrEP is highly associated with its efficacy in preventing the acquisition of HIV infection; thus, adherence to PrEP is central to realizing its benefit. The USPSTF found adequate evidence that PrEP is associated with small harms, including kidney and gastrointestinal adverse effects. The USPSTF concludes with high certainty that the magnitude of benefit of PrEP with oral tenofovir disoproxil fumarate–based therapy to reduce the risk of acquisition of HIV infection in persons at high risk is substantial.”
Editorial: “While the first USPSTF guideline on HIV screening was a modest update of its prior work, the preexposure prophylaxis (PrEP) guideline is new,” write editorialists (pp. 2172–4; P. A. Volberding, Paul.Volberding@ucsf.edu). “The Recommendation Statement is extremely timely, given a national initiative to end the HIV epidemic, and the accompanying evidence report shows PrEP to be both safe and highly effective in preventing HIV acquisition. The USPSTF is, again, deliberate in making its recommendation; PrEP, with the pill combining tenofovir disoproxil fumarate and emtricitabine, was approved by the US Food and Drug Administration in 2012 and first recommended by the Centers for Disease Control and Prevention in 2014. Although uptake of this prevention strategy has been increasing in the United States, implementation challenges remain, driven in part by cost and access. Currently, less than 10% of individuals with an indication for PrEP are receiving this medication. The gap between indication and use is most pronounced among black and Latino men who have sex with men, despite a higher number of HIV diagnoses in these groups. The evidence developed by the task force in support of the new guideline, and the strong A recommendation, should serve to promote policies to expand PrEP access to those at risk, including men who have sex with men, women, and people who inject drugs.”
>>>PNN NewsWatch
* The contaminant-related recall of bulk losartan potassium tablets has been expanded by Teva.

PNN Pharmacotherapy Line
June 13, 2019 * Vol. 26, No. 114
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 June 13 New England Journal of Medicine (2019; 380).
Canagliflozin & Renal Outcomes in T2D/CKD: In the CREDENCE trial, the risk of kidney failure and cardiovascular events was reduced by use of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes and albuminuric chronic kidney disease (pp. 2295–306; V. Perkovic, vperkovic@georgeinstitute.org.au).
PICO: Double-blind, randomized trial of patients with type 2 diabetes, estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area, and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000); also treated with renin–angiotensin system blockade; primary outcome of a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.
Results: “The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4,401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1,000 patient–years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P <0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P <0.001). There were no significant differences in rates of amputation or fracture.”
Editorial: “Overall, the importance of CREDENCE, a well done and large clinical trial, cannot be overstated,” editorialists write (pp. 2371–3; J. R. Ingelfinger). “Such data are certain to be welcomed by patients with diabetes and chronic kidney disease and by the clinicians who treat them.”
Chemoradiotherapy in Advanced Endometrial Cancer: Addition of radiation to adjuvant chemotherapy failed to significantly alter outcomes in women with advanced endometrial cancer, researchers report (pp. 2317–26; D. Matei, daniela.matei@northwestern.edu).
PICO: Randomized phase 3 trial of 707 patients with stage III or IVA endometrial carcinoma; 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) or six cycles of combination chemotherapy alone; median follow-up period of 47 months; primary end point of relapse-free survival.
Results: “At 60 months, the Kaplan–Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86).…”
Safer Opioid Prescribing: Citing instances of misuse of the CDC’s 2016 Guideline for Prescribing Opioids for Chronic Pain, Perspective authors write (pp. 2285–7; D. Dowell): “The CDC is evaluating the (intended and unintended) impact of the guideline and other health system strategies on clinician and patient outcomes and is committed to updating recommendations when new evidence is available. The CDC is funding the Agency for Healthcare Research and Quality to conduct systematic reviews on the effectiveness of opioid, nonopioid pharmacologic, and nonpharmacologic treatments for acute and chronic pain. Results of these reviews will assist in identifying research priorities and determining when evidence gaps are sufficiently addressed to warrant a guideline update or expansion. Until then, we encourage implementation of recommendations consistent with the guideline’s intent.”

PNN Pharmacotherapy Line
June 14, 2019 * Vol. 26, No. 115
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Psychiatry Report
Source:
 June issue of American Journal of Psychiatry (2019; 176).
Flexibly Dosed Esketamine Nasal Spray in Resistant Depression: In treatment-resistant depression, esketamine nasal spray was safe and effective with a rapid onset of action (pp. 428–38; V. Popova).
PICO: Phase 3, double-blind, active-controlled, multicenter study of 197 adults with moderate-to-severe nonpsychotic depression and history of nonresponse to 2 or more antidepressants in current episode; esketamine nasal spray 56 or 84 mg twice weekly + antidepressant or antidepressant + placebo nasal spray; primary efficacy endpoint of change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score.
Results: “Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means = −4.0, SE = 1.69, 95% CI = −7.31, −0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.”
Cariprazine Treatment of Bipolar Depression: The dopamine D3/D2 and 5-HT1A receptor partial agonist cariprazine was “effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression,” researchers report (pp. 439–48; W. Earley).
PICO: Double-blind placebo-controlled study of adults who met DSM-5 criteria for bipolar I disorder and a current depressive episode; placebo (N = 158) or cariprazine at 1.5 mg/day (N = 157) or 3.0 mg/day (N = 165); primary and secondary efficacy parameters of changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively.
Results: “Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were −2.5 (95% CI = −4.6, −0.4) for cariprazine at 1.5 mg/day and −3.0 (95% CI = −5.1, −0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, −0.2 [95% CI = −0.5, 0.0] for the 1.5 mg/day group and −0.3 [95% CI = −0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups.”
>>>Cardiology Highlights
Source:
 June issue of Journal of the American College of Cardiology (2019; 73).
Aspirin for Primary Cardiovascular Prevention: Following publication of revised guidelines and other summaries of available evidence, authors provide further support for the benefits and risks of aspirin therapy in primary prevention of cardiovascular (CV) events (pp. 2915–29; H. K. Abdelaziz).
PICO: 15 randomized controlled trials of 165,502 participants.
Results: “Compared with control, aspirin was associated with similar all-cause death (RR: 0.97; 95% confidence interval [CI]: 0.93 to 1.01), CV death (RR: 0.93; 95% CI: 0.86 to 1.00), and non-CV death (RR: 0.98; 95% CI: 0.92 to 1.05), but a lower risk of nonfatal [myocardial infarction] (RR: 0.82; 95% CI: 0.72 to 0.94), [transient ischemic attack] (RR: 0.79; 95% CI: 0.71 to 0.89), and ischemic stroke (RR: 0.87; 95% CI: 0.79 to 0.95). Aspirin was associated with a higher risk of major bleeding (RR: 1.5; 95% CI: 1.33 to 1.69), intracranial bleeding (RR: 1.32; 95% CI: 1.12 to 1.55), and major GI bleeding (RR: 1.52; 95% CI: 1.34 to 1.73), with similar rates of fatal bleeding (RR: 1.09; 95% CI: 0.78 to 1.55) compared with the control subjects.”

PNN Pharmacotherapy Line
June 17, 2019 * Vol. 26, No. 116
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 June 15 issue of Lancet (2019; 393).
Burosumab in X-Linked Hypophosphatemia: Children with X-linked hypophosphatemia fared better when treated with burosumab than with conventional therapy, researchers report (pp. 2416–27; E. A. Imel, eimel@iu.edu).
PICO: Randomized, open-label, phase 3 trial of 61 children with X-linked hypophosphatemia aged 1–12 years; subcutaneous burosumab or conventional therapy; primary endpoint of change in rickets severity at week 40.
Results: “For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1.9 [SE 0.1] with burosumab vs +0.8 [0.1] with conventional therapy; difference 1.1, 95% CI 0.8–1.5; p <0.0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.”
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2019; 364).
Gabapentinoids & Adverse Outcomes: In an observational study, gabapentinoids were associated with increased risk of suicidal behavior and other adverse outcomes, with pregabalin associated with higher hazards of these outcomes than gabapentin (l2147; S. Fazel, seena.fazel@psych.ox.ac.uk).
PICO: Population-based cohort study of 191,973 people with records in the Swedish Prescribed Drug Register who received gabapentinoids (pregabalin or gabapentin) in 2006–13; primary outcome measures of suicidal behavior, unintentional overdoses, head/body injuries, road traffic incidents and offenses, and arrests for violent crime.
Results: “During the study period, 10,026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17,144 (8.9%) experienced an unintentional overdose, 12,070 (6.3%) had a road traffic incident or offence, 70,522 (36.7%) presented with head/body injuries, and 7,984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behaviour and deaths from suicide (age adjusted hazard ratio 1.26, 95% confidence interval 1.20 to 1.32), unintentional overdoses (1.24, 1.19 to 1.28), head/body injuries (1.22, 1.19 to 1.25), and road traffic incidents and offences (1.13, 1.06 to 1.20). Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was associated with increased hazards of all outcomes, whereas gabapentin was associated with decreased or no statistically significant hazards. When stratifying on age, increased hazards of all outcomes were associated with participants aged 15 to 24 years.”
>>>PNN NewsWatch
* At FDA’s request, U.S. Marshals seized more than 300,000 containers of dietary supplements with the brand names Life Rising, Holicare, or HopeStream and worth an estimated $3.5 million from Life Rising Corporation because of failure to conform to dietary supplement current good manufacturing practice requirements, FDA said.
>>>PNN JournalWatch
* Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-analysis of Observational Studies , in Clinical Infectious Diseases, 2019; 68: 2135–43. (H. L. Sings, heather.sings@pfizer.com)
Clostridium difficile in Immunocompromised Hosts: A Review of Epidemiology, Risk Factors, Treatment, and Prevention, in Clinical Infectious Diseases, 2019; 68: 2144–53. (S. L. Revolinski, srevolin@mcw.edu)
* Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update, in 
Journal of Clinical Oncology, 2019; 10.1200/JCO.19.00946. (A. A. Khorana)
* From Neurobiology to Novel Medications: A Principled Approach to Translation, in 
American Journal of Psychiatry, 2019; 176: 425–7. (J. A. Gordon)
* Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia, in 
American Journal of Psychiatry, 2019; 176: 457–67. (W. F. Martin)

PNN Pharmacotherapy Line
June 18, 2019 * Vol. 26, No. 117
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 18 issue of Annals of Internal Medicine (2019; 170).
Inpatient Opioids & Postdischarge Opioid Use: Opioids are commonly administered to opioid-naive inpatients, an observational study shows, and this increases their risk for long-term use after discharge (10.7326/M18-2864; J. M. Donohue, jdonohue@pitt.edu).
PICO: Retrospective cohort study using electronic health record data for 2010–14 at 12 Pennsylvania hospitals in; 148,068 opioid-naive patients (191,249 admissions); number of days and patterns of inpatient opioid use; any outpatient opioid use 90 and 365 days after discharge.
Results: “Opioids were administered in 48% of admissions. Patients were given opioids for a mean of 67.9% (SD, 25.0%) of their stay. Location of administration of first opioid on admission, timing of last opioid before discharge, and receipt of nonopioid analgesics varied substantially. After adjustment for potential confounders, 5.9% of inpatients receiving opioids had outpatient use at 90 days compared with 3.0% of those without inpatient use (difference, 3.0 percentage points [95% CI, 2.8 to 3.2 percentage points]). Opioid use at 90 days was higher in inpatients receiving opioids less than 12 hours before discharge than in those with at least 24 opioid-free hours before discharge (7.5% vs. 3.9%; difference, 3.6 percentage points [CI, 3.3 to 3.9 percentage points]). Differences based on proportion of the stay with opioid use were modest (opioid use at 90 days was 6.4% and 5.4%, respectively, for patients with opioid use for ≥75% vs. ≤25% of their stay; difference, 1.0 percentage point [CI, 0.4 to 1.5 percentage points]). Associations were similar for opioid use 365 days after discharge.”
Editorial: “Although opioid stewardship is an important goal, it is unlikely to have a substantial effect by itself on the crisis of opioid-related harms,” editorialists write (10.7326/M19-1394; M. R. Larochelle, Marc.LaRochelle@bmc.org). “A modeling study estimated that accelerating reductions in incident prescription opioid misuse would only decrease overdose deaths by up to 5% over the next 5 to 10 years. The lack of effect is partially due to the high prevalence of persons with opioid use disorder and the transition from prescription opioids to heroin and fentanyl as the types most commonly implicated in overdose death. Efforts to deliver harm reduction services and treatment for opioid use disorder are also urgently needed.”
Adverse Events & White Coat Hypertension: Commenting on a systematic review and meta-analysis of cardiovascular events and mortality in white coat hypertension (WCH; pp. 853–62; J. B. Cohen, jco@pennmedicine.upenn.edu), editorialists write (pp. 890–2; D. Shimbo, ds2231@cumc.columbia.edu). “For adults taking antihypertensive medication, the results are clear. White coat effect is not associated with increased risk, and out-of-office monitoring seems warranted to prevent intensification of antihypertensive treatment. For adults not taking antihypertensive medication, the risk for [cardiovascular] events and all-cause mortality is only moderately increased, and this risk is substantially lower than that associated with sustained hypertension. Therefore, out-of-office [blood pressure (BP)] monitoring is useful for distinguishing between WCH and sustained hypertension among persons with high office BP.”
American College of Physicians Clinical Guideline Development: In an update of methods for developing clinical guidelines and guidance statements, the American College of Physicians includes these elements: more stringent policies regarding disclosure of interests and conflict management; inclusion of public perspective; full adoption of GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods; more standardized reporting formats that consider value of care, patient comorbid conditions, patient values and preferences, costs; and further clarification of guidance statement methods (10.7326/M18-3290; A. Qaseem, aqaseem@acponline.org).
>>>PNN NewsWatch
FDA yesterday approved an additional indication for liraglutide (Victoza, Novo Nordisk) injection: treatment of pediatric patients 10 years or older with type 2 diabetes. Liraglutide, initially marketed in 2010, is the first noninsulin drug approved to treat type 2 diabetes in pediatric patients since metformin in 2000.

PNN Pharmacotherapy Line
June 19, 2019 * Vol. 26, No. 118
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Infectious Diseases Report
Source:
 July 1 issue of Clinical Infectious Diseases (2019; 69).
Looking for 20 New Antibiotics by 2020: Efforts to achieve 20 new antibacterial drugs by 2020 “may well be achieved,” authors associated with the Infectious Diseases Society of America write, but “this success could be the ‘last hurrah’ for robust antibiotic development” (pp. 1–11; H.W. Boucher, hboucher@tuftsmedicalcenter.org). “Pharmaceutical sponsor and investor disengagement continues to worsen, such that the prognosis for a sustainable antibiotic [research and development] infrastructure will be bleak in the absence of further economic incentives for antibiotic development. In the meantime, clinicians must protect currently available antibacterial drugs through robust antibiotic stewardship and infection prevention.”
Antibiotic Decision-Making by Surgical v. Medical Teams: Differing approaches are needed to influence antibiotic decision-making by surgical versus acute medical teams, researchers report (pp. 12–20; E. Charani, e.charani@imperial.ac.uk).
PICO: London teaching hospital in 2015–17; ethnographic observational study with 500 hours of direct observations and face-to-face interviews with 23 key informants of antibiotic decision-making by acute medical and surgical teams.
Results: “In medicine, accepted norms of the decision-making process are characterized as collectivist (input from pharmacists, infectious disease, and medical microbiology teams), rationalized, and policy-informed, with emphasis on de-escalation of therapy. The gaps in antibiotic decision-making in acute medicine occur chiefly in the transition between the emergency department and inpatient teams, where ownership of the antibiotic prescription is lost. In surgery, team priorities are split between 3 settings: operating room, outpatient clinic, and ward. Senior surgeons are often absent from the ward, leaving junior staff to make complex medical decisions. This results in defensive antibiotic decision-making, leading to prolonged and inappropriate antibiotic use.”
Influenza Point-of-Care Tests: Point-of-care tests (POCTs) for influenza influence therapy, a study shows, but their real-world use is challenging (pp. 24–33; J. J. Lee, joseph.lee@phc.ox.ac.uk).
PICO: Systematic review and random-effects meta-analysis of trials of influenza POCTs versus usual care in ambulatory care settings; 7 randomized and 6 nonrandomized studies, most of them conducted in pediatric emergency departments.
Results: “In randomized trials, POCTs had no effect on admissions (RR 0.93, 95% CI 0.61–1.42, I2 = 34%), returning for care (RR 1.00 95% CI = 0.77–1.29, I2 = 7%), or antibiotic prescribing (RR 0.97, 95% CI 0.82–1.15, I2 = 70%), but increased prescribing of antivirals (RR 2.65, 95% CI 1.95–3.60; I2 = 0%). Further testing was reduced for full blood counts (FBC) (RR 0.80, 95% CI 0.69–0.92 I2 = 0%), blood cultures (RR 0.82, 95% CI 0.68–0.99; I2 = 0%) and chest radiography (RR 0.81, 95% CI 0.68–0.96; I2 = 32%), but not urinalysis (RR 0.91, 95% CI 0.78–1.07; I2 = 20%). Time in the emergency department was not changed. Fewer non-randomized studies reported these outcomes, with some findings reversed or attenuated (fewer antibiotic prescriptions and less urinalysis in tested patients).”
>>>PNN NewsWatch
Premier Pharmacy Labs of Weeki Wachee, FL, is voluntarily recalling all unexpired products, intended to be sterile, due to a lack of sterility assurance.
* Efforts to “improve transparency and predictability for generic drug applicants” are intended “to help increase timely access to high-quality, lower cost 
generic drugs,” Acting FDA Commissioner Norman E. “Ned” Sharpless, M.D., wrote in a statement posted yesterday. “The agency’s previous efforts to help bolster the competitiveness of the generics market include: taking significant steps to support complex generic drug development and application review; prioritizing the review of certain generics; and publishing a list of off-patent, off-exclusivity brand drugs. Each of these efforts was aimed at getting more competitors into the market, which might drive down prices for consumers – all the while making sure generics meet the FDA’s approval standards and will be manufactured under our rigorous quality standards.”

PNN Pharmacotherapy Line
June 20, 2019 * Vol. 26, No. 119
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 June 20 issue of the New England Journal of Medicine (2019; 380).
Guiding Adjuvant Therapy for Breast Cancer: Added to a 21-gene recurrence score, clinical-risk stratification was useful in identifying premenopausal women who could benefit from more effective adjunctive therapy for breast cancer, researchers report (pp. 2395–405; J. A. Sparano, jsparano@montefiore.org).
PICO: Prospective trial of 9,427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, scored using an assay of 21 genes and clinical risk of recurrence of breast cancer scored as low or high on the basis of the tumor size and histologic grade; initial endocrine therapy was tamoxifen alone in most of the premenopausal women age 50 years or younger.
Results: “The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (± SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7 ± 1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3 ± 2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2 ± 3.3%).”
Editorial: “Distinguishing between results that warrant a change in practice and those that do not will not be a ‘precise’ process,” editorialists write (pp. 2472–4; D. J. Hunter). “Medicine in the molecular era will be no more ‘precise’ than in prior eras — evidence synthesis, clinical judgment, and patient preferences all factor in. Although regulatory bodies such as the Food and Drug Administration may continue to insist on statistically significant results from randomized trials in licensing decisions, communicating information from trials beyond prespecified and primary objectives remains important, and judicious use of these data should continue to inform clinical practice.”
Perspective: “We … know that effects of the environment — by which we mean things that change, such as exercise, diet, smoking habits, the air we breathe, and the chemicals (including medications) to which we are exposed — generally multiply the risk of disease for all of us, whether we have low or high inherited risk,” authors of a Perspective article write (pp. 2391–3; D. J. Hunter). “Thus, when a polygenic risk score (PRS) is combined with other known risk factors, the risk distribution tends to flatten out, and the combination of high PRS and high environmental risk predicts the highest overall risk. To a great extent, it is not only the genetic hand you are dealt but also how you play that hand that makes the big difference in health outcomes.”
Nonnarcotic Methods of Pain Management: “For the management of acute pain, the use of multiple approaches that do not include opioids and the establishment of acute pain services for postoperative pain management can reduce opioid-related adverse effects and dependence,” an author writes in a review of nonnarcotic pain management (pp. 2440–8; N. B. Finnerup, finnerup@clin.au.dk). “Patient education, psychological treatments, and avoidance of opioids may be useful for the management of chronic pain.”
>>>PNN NewsWatch
RXQ Compounding is voluntarily recalling all sterile human and animal products within expiry to the user level due to lack of sterility process assurance. In addition, RXQ is voluntarily ceasing all sterile production at its current Athens, Ohio, location as it transitions into a new outsourcing facility.

PNN Pharmacotherapy Line
June 21, 2019 * Vol. 26, No. 120
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Geriatrics Report
Source:
 June issue of the Journal of the American Geriatrics Society (2019; 67).
Medication Appropriateness in Vulnerable Older Adults: Advocating for a “healthy skepticism of appropriate polypharmacy,” authors of a special article discuss “the concept of ‘inappropriate’ vs ‘appropriate’ polypharmacy” (pp. 1123–7; T. R. Fried, terri.fried@yale.edu): “Few studies have examined the health outcomes associated with adding and/or removing medications to address this debate directly. The criteria used to identify underutilized medications are based on results of randomized controlled trials that may not be generalizable to older adults. Several randomized controlled trials and many more observational studies provide evidence that these criteria overestimate medication benefits and underestimate harms. In addition, evidence suggests that the marginal effects of medications added to an already complex regimen differ from their effects when considered individually. Although in selected circumstances adding medications results in benefit to patients, patients with multimorbidity and frailty/disability have susceptibilities that can decrease the likelihood of medication benefit and increase the likelihood of harms. The identification of appropriate polypharmacy requires more robust criteria to evaluate the net effects of complex medication regimens.”
Diabetic Peripheral Neuropathy Meds & Fall Risk: In older adults with diabetic peripheral neuropathy (DPN), use of tricyclic antidepressants (TCAs) or gamma-aminobutyric acid (GABA) analogs is associated with increased risk of falls and possibly fractures, researchers report (pp. 1174–81; A. C. Randolph, acrandol@utmb.edu).
PICO: Historical cohort study of TCA/GABA-analog users (n = 5,550) and nonusers (n = 22,200) in a nationally representative 5% Medicare sample in 2008–10.
Results: “After matching, users and nonusers were largely similar. After covariate adjustment, TCA/GABA-analog use was associated with a statistically significant increase in fall risk (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 1.03–1.20), but was not associated with fracture risk (adjusted HR = 1.09; 95% CI = 0.99–1.19) in the conventional analysis. Treating TCA/GABA-analog use as a time-dependent covariate resulted in statistically significant associations of TCA/GABA-analog use with both fall and fracture risk (HR = 1.26 [95% CI = 1.17–1.36]; and HR = 1.12 [95% CI = 1.02–1.24], respectively).”
Polypharmacy, Gait Performance, & Falls: Gait disturbances appeared to play a role in the medication-related falls pathway in an observational study of older adults (pp. 1182–8; M. Montero-Odasso, mmontero@uwo.ca).
PICO: Community-dwelling older adults (n = 249; 76.6 ± 8.6 y; 63% women) at an Ontario clinic.
Results: “The number of medications was cross-sectionally associated with poor gait performance…. Prospectively, the number of medications was associated with overall gait decline …. These associations remained true after adjusting for age, sex, and accounting for ‘confounding by indication bias’ by using a comorbidity propensity score adjustment. Each additional medication taken, significantly increased gait decline risk by 12% to 16% and fall incidence risk by 5% to 7%. Mediation analyses revealed that gait impairments in stride length, step length, and step width mediated the strength of the association between medications and fall incidence.”
>>>PNN NewsWatch
* FDA will hold a public hearing on Sept. 17 to discuss a draft guidance regarding the agency’s benefit-risk assessment of opioid analgesics, Acting FDA Commissioner Norman E. “Ned” Sharpless, M.D., said in a statement yesterday. “This meeting will include a discussion of whether an applicant for a new opioid analgesic should be required to demonstrate that its product has an advantage over existing drugs in order to be approved and, if so, what new authorities the FDA would need to impose such a requirement,” the Commissioner wrote. “In addition, the agency will discuss whether new preapproval incentives (in addition to existing incentives, such as breakthrough designation) are needed to better support and encourage development of all therapeutics … intended to treat pain or addiction.” 
* Citing lack of sterility assurance, 
Infusion Options in Brooklyn, NY, is voluntarily recalling all unexpired sterile products to the hospital level.

PNN Pharmacotherapy Line
June 24, 2019 * Vol. 26, No. 121
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Lancet Report
Source:
 June 22 issue of Lancet (2019; 393).
Gentamicin v. Ceftriaxone for Gonorrhea: In the G-ToG trial, investigators conclude, “Gentamicin is not appropriate as first-line treatment for gonorrhoea but remains potentially useful for patients with isolated genital infection, or for patients who are allergic or intolerant to ceftriaxone, or harbour a ceftriaxone-resistant isolate” (pp. 2511–20; J. D. C. Ross, jonathan.ross@uhb.nhs.uk).
PICO: Multicenter, parallel-group, pragmatic, randomized, noninferiority trial of adults aged 16–70 years with uncomplicated genital, pharyngeal, or rectal gonorrhea; I.M. gentamicin 240 mg or ceftriaxone 500 mg, each with oral azithromycin 1 g; primary outcome of clearance of Neisseria gonorrhoeae at all initially infected sites, defined as a negative nucleic acid amplification test 2 weeks after treatment.
Results: “At 2 weeks after treatment, infection had cleared for 299 (98%) of 306 participants in the ceftriaxone group compared with 267 (91%) of 292 participants in the gentamicin group (adjusted risk difference −6.4%, 95% CI −10.4% to −2.4%). Of the 328 participants who had a genital infection, 151 (98%) of 154 in the ceftriaxone group and 163 (94%) of 174 in the gentamicin group had clearance at follow-up (adjusted risk difference −4.4%, −8.7 to 0). For participants with a pharyngeal infection, a greater proportion receiving ceftriaxone had clearance at follow-up (108 [96%] in the ceftriaxone group compared with 82 [80%] in the gentamicin group; adjusted risk difference −15.3%, −24.0 to −6.5). Similarly, a greater proportion of participants with rectal infection in the ceftriaxone group had clearance (134 [98%] in the ceftriaxone group compared with 107 [90%] in the gentamicin group; adjusted risk difference −7.8%, −13.6 to −2.0). Thus, we did not find that a single dose of gentamicin 240 mg was non-inferior to a single dose of ceftriaxone 500 mg for the treatment of gonorrhoea, when both drugs were combined with a 1 g dose of oral azithromycin. The side-effect profiles were similar between groups, although severity of pain at the injection site was higher for gentamicin (mean visual analogue pain score 36 of 100 in the gentamicin group vs 21 of 100 in the ceftriaxone group).”
>>>PNN NewsWatch
* On Friday, FDA expanded the indication for tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals) tablets for treatment of pediatric patients ages 6 years or older with cystic fibrosis with two copies of the F508del mutation or who have at least one of the mutations in the cystic fibrosis transmembrane conductance regulator gene that is responsive to one of these drug. The product had been approved last year for treatment of patients ages 12 and older with those same specific genetic mutations.
Bremelanotide (Vyleesi, AMAG Pharmaceuticals) has been approved by FDA for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women.
>>>PNN JournalWatch
* Global Alcohol Exposure Between 1990 and 2017 and Forecasts Until 2030: A Modelling Study, in Lancet, 2019; 393: 2493–502. (J. Manthey, jakob.manthey@tu-dresden.de)
* Prevalence of Vaping and Smoking Among Adolescents in Canada, England, and the United States: Repeat National Cross Sectional Surveys, in 
BMJ, 2019; 365: l2219. (D. Hammond, dhammond@uwaterloo.ca)
* Cigarette Consumption Estimates for 71 Countries From 1970 to 2015: Systematic Collection of Comparable Data to Facilitate Quasi-Experimental Evaluations of National and Global Tobacco Control Interventions, in 
BMJ, 2019; 365: l2231. (M. J. P. Poirier, mathieu.poirier@globalstrategylab.org)
* An Opinion Paper of the Cardiology Practice and Research Network of the American College of Clinical Pharmacy (ACCP): Recommendations for Training of Cardiovascular Pharmacy Specialists in Post-graduate Year 2 Residency Programs, in 
Journal of the American College of Clinical Pharmacy, 2019; 2: 10.1002/jac5.1148. (T. M. H. Ng, tienng@usc.edu)
* A Review of Health-Related Outcomes from Community Pharmacist Interventions in Patients with Chronic Obstructive Pulmonary Disease, in 
J. Am. College of Clinical Pharmacy, 2019; 2: 10.1002/jac5.1151. (K. L. Barefield, kimberlba@pcom.edu)
* Alteplase Therapy for Acute Ischemic Stroke in Pregnancy: Two Case Reports and a Systematic Review of the Literature, in 
Pharmacotherapy, 2019; 39: 10.1002/phar.2278. (G. V. Fontaine, Fontaine.gabe@gmail.com)
* Care Management For Older Adults: The Roles Of Nurses, Social Workers, And Physicians, in 
Health Affairs, 2019; 38: 941–9. (K. Donelan, kdonelan@mgh.harvard.edu)

PNN Pharmacotherapy Line
June 25, 2019 * Vol. 26, No. 122
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Vaccine Highlights
Source:
 Early-online articles from Vaccine (2019; 37).
Pediatric Influenza Vaccine Effectiveness in 2013–18: Vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) was greater against influenza type B in some seasons when used in a two-dose series, researchers report, adding that both one- and two-dose regimens were generally effective and reduced hospitalizations due to influenza type A (10.1016/j.vaccine.2019.05.090; M. Shinjoh, m-shinjo@z2.keio.jp).
PICO: VE assessed using a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results in children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT for all five seasons since 2013–14.
Results: “In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A.”
LAIV in Pediatric Patients With Asthma: Lower respiratory events (LREs) no more common among pediatric patients with asthma who received inactivated influenza vaccine (IIV) or live attenuated influenza vaccine (LAIV), a pre/post study shows (10.1016/j.vaccine.2019.05.081; J. D. Nordin, James.D.Nordin@healthpartners.com).
PICO: Pre/post guideline retrospective cohort study of children ages 2–17 years with asthma receiving influenza vaccines in 2007–16; medically attended LREs within 21 and 42 days of immunization.
Results: “The cohort included 7,851 influenza vaccinations in 4,771 children with asthma. Among patients in the LAIV guideline group, the proportion receiving LAIV increased from 23% to 68% post-guideline implementation, versus an increase from 7% to 11% in the control group. Age and baseline asthma severity adjusted [ratio of rate ratio (ROR)] showed no increase in LREs, primarily asthma exacerbations, following implementation of the LAIV guideline: overall aROR (95% Confidence Interval): 0.74 (0.43–1.29) for LRE within 21 days of vaccination, 0.77 (0.53–1.14) for LRE within 42 days of vaccination.…”
>>>Allergy/Immunology Report
Source:
 June issue of the Journal of Allergy and Clinical Immunology (2019; 143).
IgE Antagonism by IgG in Chronic Rhinosinusitis: In patients with chronic rhinosinusitis with nasal polyps (CRSwNP), polyclonal IgE idiotypes “are functional, promote IgE-mediated proallergic inflammation, and are partially antagonized by corresponding IgG idiotypes,” authors conclude in a research article (pp. 2086–94.e2; M. H. Shamji, m.shamji@imperial.ac.uk).
PICO: IgE levels compared in nasal polyp homogenates from patients with grass pollen allergy with CRSwNP and nonallergic control participants; local IgE and IgG repertoires evaluated using Immunoglobulin 454 sequencing.
Results: “We show that IgG plays a key role in controlling IgE-mediated inflammatory responses in patients with nasal polyps. Depletion of IgG from nasal homogenates resulted in an increase in CD23-mediated IgE-facilitated allergen binding to B cells but also enhanced Fc-epsilon-RI-mediated allergen-driven basophil activation and histamine release. A similar response was observed in relation to specific IgE antibodies to Staphylococcus aureus enterotoxins. The capacity of IgG in nasal polyps to limit IgE-mediated inflammation is based on the fact that IgG repertoires widely share the antigen targets with the IgE repertoires in both allergic and nonallergic subjects.”

PNN Pharmacotherapy Line
June 26, 2019 * Vol. 26, No. 123
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>JAMA Report
Source:
 June 25 issue of JAMA (2019; 321).
Dual Antiplatelet Therapy in Patients Receiving PCI: Studies of dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary interventions support the use of shorter, less intensive regimens, but conclude that confirmatory data are needed (pp. 2414–27, T. Kimura, taketaka@kuhp.kyoto-u.ac.jppp. 2428–37, J-Y Hahn, jyhahn@skku.edu).
Study 1 PICO: Noninferiority STOPDAPT-2 trial of 3,045 patients in Japan; 1 month of DAPT compared with standard 12 months of DAPT; composite end point of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months.
Study 1 Results: “One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, −1.34% [95% CI, −2.57% to −0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42–0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, −0.55% [95% CI, −1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, −1.13% [95% CI, −1.84% to −0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority).”
Study 2 PICO: Open-label, noninferiority, randomized SMART-CHOICE trial of 2,993 patients in Korea; aspirin plus a P2Y12 inhibitor for 3 months and then a P2Y12 inhibitor alone or DAPT for 12 months; primary end point of major adverse cardiac and cerebrovascular events (composite of all-cause death, MI, or stroke) at 12 months.
Study 2 Results: “Major adverse cardiac and cerebrovascular events occurred in 42 patients in the P2Y12 inhibitor monotherapy group and in 36 patients in the DAPT group (2.9% vs 2.5%; difference, 0.4% [1-sided 95% CI, –∞% to 1.3%]; P = .007 for noninferiority). There were no significant differences in all-cause death (21 [1.4%] vs 18 [1.2%]; hazard ratio [HR], 1.18; 95% CI, 0.63–2.21; P = .61), MI (11 [0.8%] vs 17 [1.2%]; HR, 0.66; 95% CI, 0.31–1.40; P = .28), or stroke (11 [0.8%] vs 5 [0.3%]; HR, 2.23; 95% CI, 0.78–6.43; P = .14) between the 2 groups. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group (2.0% vs 3.4%; HR, 0.58; 95% CI, 0.36–0.92; P = .02).”
Editorial: “It is likely that shorter DAPT duration will gain more support with the accumulating evidence of lack of excess ischemic complications, especially when used in conjunction with contemporary stents, optimal implantation techniques, and aggressive atherosclerosis risk factor reduction,” editorialists write in reaction to these studies (pp. 2409–11; D. J. Moliterno, moliterno@uky.edu). “It is important to emphasize that a degree of selectivity is needed when considering a short DAPT approach, particularly in reference to clinical presentation and underlying risk of ischemic complications. Whether aspirin or P2Y12 monotherapy should follow shorter-course DAPT remains unclear. The present studies using clopidogrel monotherapy have demonstrated a meaningful reduction in bleeding, but direct comparison with aspirin monotherapy is not available to fully resolve this question. The Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention Study (TWILIGHT) will report the outcomes of approximately 9,000 high-risk patients randomized to 1 month of DAPT including ticagrelor followed by ticagrelor monotherapy compared with 12 months of DAPT. This study should provide data to help address some of the remaining issues regarding monotherapy. Until then, and while it is possible to shorten the DAPT duration in selected cases, the evidence is not sufficient to fully cut the cord with traditional DAPT or aspirin monotherapy—not for all patients and not just yet.”
>>>PNN NewsWatch
Kratom products are the topic of warning letters sent by FDA to two marketers/distributors that the agency says are illegally selling these unapproved, misbranded drug products.

PNN Pharmacotherapy Line
June 27, 2019 * Vol. 26, No. 124
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>NEJM Report
Source:
 June 27 New England Journal of Medicine (2019; 380).
Early Sedation with Dexmedetomidine in Critical Care: In the SPICE III trial, early use of dexmedetomidine for critical-care sedation yielded an all-cause mortality rate at 90 days similar to that with usual care, and supplemental sedatives were required to achieve the prescribed level of sedation, researchers report (pp. 2506–17; Y. Shehabi, yahya.shehabi@monashhealth.org).
PICO: Open-label, randomized trial of 4,000 critically ill adults who had been on ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day; dexmedetomidine as sole/primary sedative or usual care (propofol, midazolam, or other sedatives); primary outcome of rate of death from any cause at 90 days.
Results: “In a modified intention-to-treat analysis involving 3,904 patients, the primary outcome event occurred in 566 of 1,948 (29.1%) in the dexmedetomidine group and in 569 of 1,956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, −2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively.…”
Editorial: “The SPICE III trial should be viewed as a call to study clinical decision making as it pertains to depth of sedation and pharmacologic choices,” editorialists write (pp. 2577–8; D. B. Coursin). “Understanding these behaviors could enhance trial design and analysis and heighten insight into improving clinical practice. Deep sedation immobilizes patients, limits communication, increases costs and mortality, and reduces the likelihood of meaningful recovery. Understanding the differences in how sedation is administered and what drives these variations is essential in providing improved care.…”
Nintedanib for Systemic Sclerosis–Associated ILD: Compared with placebo in patients who have interstitial lung disease (ILD) with systemic sclerosis, the tyrosine kinase inhibitor nintedanib slowed the decline in forced vital capacity (FVC) (pp. 2518–28; O. Distler, liver.distler@usz.ch">oliver.distler@usz.ch).
PICO: Randomized, double-blind, placebo-controlled trial of 576 patients with ILD with systemic sclerosis; nintedanib 150 mg orally twice daily or placebo; primary end point of annual rate of FVC decline.
Results: “In the primary end-point analysis, the adjusted annual rate of change in FVC was −52.4 ml per year in the nintedanib group and −93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the [St. George’s Respiratory Questionnaire] at week 52 did not differ significantly between the trial groups, with differences of −0.21 (95% CI, −0.94 to 0.53; P = 0.58) and 1.69 (95% CI, −0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.”
>>>PNN NewsWatch
Shared decision-making regarding adult vaccines by patients and clinicians was the common thread in two votes on Wednesday by the CDC Advisory Committee on Immunization Practices. ACIP removed its recommendation for a single dose of the 13-valent pneumococcal conjugate vaccine at age 65 and replaced it with a recommendation for shared decision-making for immunocompetent older adults; the vaccine would still be recommended in adults with immunocompromising conditions. In reviewing its recommendations for catch-up human papillomavirus virus vaccination, ACIP voted to recommend shared decision-making regarding use in adults ages 27 through 45 years. The panel also voted to extend the recommended age range for catch-up HPV vaccine for men through age 26 (from the current 21); this matches current recommendations for women.

PNN Pharmacotherapy Line
June 28, 2019 * Vol. 26, No. 125
Providing news and information about medications and their proper use

Click here for a PDF of this issue.

>>>Diabetes Care Report
Source:
 Early-online articles from and July issue of Diabetes Care (2019; 42).
Antidiabetic Drugs & Mortality in Pancreatic-Condition Diabetes: In patients with postpancreatitis diabetes mellitus (PPDM), metformin provided a survival benefit, an observational study shows, but reverse causality may explain a lack of benefit of the drug in those with pancreatic cancer–related diabetes (PCRD) (dc190145; J. Cho).
PICO: 1,862 individuals with PCRD or PPDM identified from nationwide pharmaceutical dispensing data for 2006–15 linked to hospital discharge data; hazard ratios from multivariable Cox regression analysis; 6-month lag used to minimize reverse causality.
Results: “In individuals with PCRD, ever users of metformin (adjusted hazard ratio 0.54; 95% CI 0.46–0.63) and ever users of insulin (adjusted hazard ratio 0.46; 95% CI 0.39–0.55) had significantly lower risks of mortality compared with never users of antidiabetic medications. These associations attenuated toward the null with the use of a 6-month lag. In individuals with PPDM, ever users of metformin had a significantly lower risk of mortality (adjusted hazard ratio 0.51; 95% CI 0.36–0.70), whereas ever-users of insulin did not have a significantly changed risk of mortality (adjusted hazard ratio 0.75; 95% CI 0.49–1.14) compared with never users of antidiabetic medications. The former association remained significant with the use of a 6-month lag.”
Oral Semaglutide in Type 2 Diabetes: With a safety profile consistent with other GLP-1 agonists, oral semaglutide provided superior and clinically relevant improvements in glycemic control and weight in adult patients with type 2 diabetes (T2D), compared with placebo (dc190749; V. R. Aroda).
PICO: 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial of adults with T2D at 93 sites in 9 countries; once-daily oral semaglutide 3 mg, 7 mg, 14 mg or placebo; primary endpoint of change from baseline to week 26 in HbA1c.
Results: “Oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand: −0.6% [3 mg], −0.9% [7 mg], −1.1% [14 mg]; trial product estimand: −0.7% [3 mg], −1.2% [7 mg], −1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy: −0.1 kg [3 mg], −0.9 kg [7 mg], −2.3 kg [14 mg; P < 0.001]; trial product: −0.2 kg [3 mg], −1.0 kg [7 mg; P = 0.01], −2.6 kg [14 mg; P < 0.001]).”
Depression Treatment in Type 2 Diabetes: Compared with usual care (UC) in patients with type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD), Program ACTIVE II behavioral treatment interventions yielded clinically meaningful improvements in depression outcomes, researchers report (pp. 1185–93; M. de Groot, mdegroot@iu.edu).
PICO: 2 × 2 factorial randomized controlled trial design; 140 adults with T2DM for 1 year or more and diagnosed with MDD received cognitive behavioral therapy (CBT), community-based exercise (EXER), CBT+EXER, or UC; primary outcomes of depression remission rate and change in glycemic control (HbA1c).
Results: “The mean age was 56.0 years (SD 10.7). Participants were female (77%), white (71%), and married (52%). After controlling for education and antidepressant use, odds of achieving full MDD remission in the intervention groups were 5.0–6.8 times greater than UC (P <0.0167). The CBT+EXER group demonstrated improved HbA1c compared with UC. For participants with a baseline HbA1c ≥7.0%, exploratory post hoc subgroup analysis showed that the CBT+EXER group had a 1.1% improvement in HbA1c (P <0.0001) after controlling for covariates.”
>>>PNN NewsWatch
* Eculizumab (Soliris, Alexion Pharmaceuticals) injection for intravenous use has been approved by FDA for treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults who are anti-aquaporin-4 antibody positive. NMOSD is an autoimmune disease of the central nervous system mainly affecting the optic nerves and spinal cord.
*
FDA has approved dupilumab (Dupixent, Regeneron) for treatment of adults with nasal polyps accompanied by chronic rhinosinusitis.
*
FDA is also warning that certain Medtronic MiniMed insulin pumps are being recalled due to potential cybersecurity risks.