Jun 2017

PNN April–June 2017

PNN Pharmacotherapy Line
Apr. 3, 2017 * Vol. 24, No. 63
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 1 issue of Lancet (2017; 389).
Prophylactic Hydration With Iodinated Contrast Material: Prehydrating patients with compromised renal function before administration of iodinated contrast material may be of little clinical benefit despite extra costs, a study shows (pp. 1312–22). Concluding that “no prophylaxis [was] non-inferior and cost-saving in preventing contrast-induced nephropathy,” authors of the AMACING trial report these results in a comparison with hydration of high-risk adult patients: “Between June 17, 2014, and July 17, 2016, 660 consecutive patients were randomly assigned to receive no prophylaxis (n = 332) or intravenous hydration (n = 328). 2–6 day serum creatinine was available for 307 (92%) of 332 patients in the no prophylaxis group and 296 (90%) of 328 patients in the intravenous hydration group. Contrast-induced nephropathy was recorded in eight (2.6%) of 307 non-hydrated patients and in eight (2.7%) of 296 hydrated patients. The absolute difference (no hydration vs hydration) was −0.10% (one-sided 95% CI −2.25 to 2.06; one-tailed p = 0.4710). No hydration was cost-saving relative to hydration. No haemodialysis or related deaths occurred within 35 days. 18 (5.5%) of 328 patients had complications associated with intravenous hydration.” (E. C. Nijssen, estelle.nijssen@mumc.nl)
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Pump v. Syringe in Insulin Therapy: Providing insulin pumps to patients with poor glycemic control of type 1 diabetes is not justified until “the effects of training on participants’ level of engagement in intensive self management have been determined,” conclude investigator in the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial (j1285). At eight secondary care centers in England and Scotland, adults willing to begin intensive insulin treatment were assigned in clusters and pairs to pump or multiple daily injection therapy, with these results: “317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was −0.85% with pump treatment and −0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was −0.24% (−2.7 mmol/mol) in favour of pump users (95% confidence interval −0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24 months.” (S. Heller, s.heller@sheffield.ac.uk)
Antenatal Corticosteroids in Preterm Infants: A prospective cohort study at 300 U.S. neonatal intensive care units demonstrates lower mortality and morbidity among most preterm infants receiving antenatal corticosteroids (j1039): “Infants exposed to antenatal corticosteroids (n =81,832) had a significantly lower rate of death before discharge at each gestation 29 weeks or less, 31 weeks, and 33–34 weeks compared with infants without exposure (range of adjusted odds ratios 0.32 to 0.55). The number needed to treat with antenatal corticosteroids to prevent one death before discharge increased from six at 23 and 24 weeks’ gestation to 798 at 34 weeks’ gestation. The rate of survival without major hospital morbidity was higher among infants exposed to antenatal corticosteroids at the lowest gestations. Infants exposed to antenatal corticosteroids had lower rates of severe intracranial hemorrhage or death, necrotizing enterocolitis stage 2 or above or death, and severe retinopathy of prematurity or death compared with infants without exposure at all gestations less than 30 weeks and most gestations for infants born at 30 weeks’ gestation or later.” (W. A. Carlo, wcarlo@peds.uab.edu)
>>>PNN NewsWatch
* Citing a defective activation part,
Meridian Medical Technologies is voluntarily recalling 13 lots of Mylan’s EpiPen and EpiPen Jr (epinephrine injection) Auto-Injector. 
>>>PNN JournalWatch
* Maternal Immunization, in
New England J. Medicine, 2017; 376: 1256–67. (S. B. Omer, somer@emory.edu)

PNN Pharmacotherapy Line
Apr. 4, 2017 * Vol. 24, No. 64
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. 4 issue of the Annals of Internal Medicine (2017; 166).
Management of Low Back Pain: Clinical guidelines for managing low back pain are presented, along with supporting systematic reviews and an editorial.
“New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain,” authors of a pharmacologic review conclude (
pp. 480–92). “For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms,” the group adds. “Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective.” (R. Chou, chour@ohsu.edu)
Review of studies on nonpharmacologic options leads authors to this synthesis (
pp. 493–505): “New evidence indicates that tai chi (strength of evidence [SOE], low) and mindfulness-based stress reduction (SOE, moderate) are effective for chronic low back pain and strengthens previous findings regarding the effectiveness of yoga (SOE, moderate). Evidence continues to support the effectiveness of exercise, psychological therapies, multidisciplinary rehabilitation, spinal manipulation, massage, and acupuncture for chronic low back pain (SOE, low to moderate). Limited evidence shows that acupuncture is modestly effective for acute low back pain (SOE, low). The magnitude of pain benefits was small to moderate and generally short term; effects on function generally were smaller than effects on pain.” (R. Chou, chour@ohsu.edu)
Based on these findings, the American College of Physicians makes three recommendations (
pp. 514–30; A. Qaseem, aqaseem@acponline.org):
* Given that most patients with acute or subacute low back pain improve over time regardless of treatment, clinicians and patients should select nonpharmacologic treatment with superficial heat (moderate-quality evidence), massage, acupuncture, or spinal manipulation (low-quality evidence). If pharmacologic treatment is desired, clinicians and patients should select nonsteroidal anti-inflammatory drugs or skeletal muscle relaxants (moderate-quality evidence). (Grade: strong recommendation)
* For patients with chronic low back pain, clinicians and patients should initially select nonpharmacologic treatment with exercise, multidisciplinary rehabilitation, acupuncture, mindfulness-based stress reduction (moderate-quality evidence), tai chi, yoga, motor control exercise, progressive relaxation, electromyography biofeedback, low-level laser therapy, operant therapy, cognitive behavioral therapy, or spinal manipulation (low-quality evidence). (Grade: strong recommendation)
* In patients with chronic low back pain who have had an inadequate response to nonpharmacologic therapy, clinicians and patients should consider pharmacologic treatment with nonsteroidal anti-inflammatory drugs as first-line therapy, or tramadol or duloxetine as second-line therapy. Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence)
“If clinicians and their professional societies cannot demonstrate that their recommendations are improving the delivery of high-value services, what are the alternatives?” asks an editorialist (
pp. 533–4). “Likely what is needed is an ‘all-of-the-above’ approach: more pragmatic trials to evaluate proven therapies and their combinations in real-world settings; efforts to reduce the use of low-value services, such as payer coverage policies based on guideline recommendations; patient engagement through shared decision making; and pressure on insurers to cover nonpharmacologic, noninvasive therapies that have shown benefit. Nevertheless, rigorous reviews of existing evidence and their application in practice guidelines remain an underpinning that should drive efforts not only to decrease the use of therapies without demonstrated benefit but also to show that the therapies being used improve real-world outcomes for patients with low back pain.” (S. J. Atlas, satlas@mgh.harvard.edu)

PNN Pharmacotherapy Line
Apr. 5, 2017 * Vol. 24, No. 65
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 4 issue of JAMA (2017; 317).
2-Year Outcomes With Low-Dose Hydrocortisone in Extremely Preterm Neonates: Neurodevelopment at 2 years of age was not affected by early hydrocortisone therapy in the Early Low-Dose Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial (pp. 1329–37). Previous studies have associated dexamethasone treatment of extremely preterm neonates with neurodevelopmental impairment at 2 years, the investigators note, but their study identified these outcomes when neonates were randomized to low-dose hydrocortisone or placebo in 2010 through 2016: “Of 1,072 neonates screened, 523 were assigned to hydrocortisone (n = 256) or placebo (n = 267) and 406 survived to 2 years of age. A total of 379 patients (93%; 46% female) were evaluated (194 in the hydrocortisone group and 185 in the placebo group) at a median corrected age of 22 months (interquartile range, 21–23 months). The distribution of patients without neurodevelopmental impairment (73% in the hydrocortisone group vs 70% in the placebo group), with mild neurodevelopmental impairment (20% in the hydrocortisone group vs 18% in the placebo group), or with moderate to severe neurodevelopmental impairment (7% in the hydrocortisone group vs 11% in the placebo group) was not statistically significantly different between groups (P = .33). The mean global developmental quotient score was not statistically significantly different between groups (91.7 in the hydrocortisone group vs 91.4 in the placebo group; between-group difference, 0.3 [95% CI, −2.7 to 3.4]; P = .83). The incidence of cerebral palsy or other major neurological impairments was not significantly different between groups.” (O. Baud, olivier.baud@rdb.aphp.fr)
“Early use of low-dose hydrocortisone holds promise as an intervention to prevent bronchopulmonary dysplasia,” an editorialist writes (
pp. 1317–8). “However, a systematic review found steroid-related short-term complications, including gastrointestinal bleeding and perforation, although those complications were not seen in the current trial. A reevaluation of early neonatal therapy is warranted. Other trial investigators should confirm the findings of the PREMILOC trial, using a very low dose of hydrocortisone and powering their studies to investigate safety outcomes. The PREMILOC investigators are planning later outcome studies when patients are aged 5 to 7 years. Until those and other trials are completed, the value of early hydrocortisone to safely prevent bronchopulmonary dysplasia appears promising but remains unclear.” (N. Marlow, n.marlow@ucl.ac.uk)
Dexmedetomidine in Mechanical Ventilation With Sepsis: The light sedative dexmedetomidine made no difference in mortality or ventilator-free days when compared with placebo in patients undergoing ventilation, researchers report (pp. 1321–8). Among 201 patients, dexmedetomidine or placebo showed these effects: “The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38–1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5–24] days; control group: median, 18 [interquartile range, 0.5–23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%–58% vs 20%–39%; P = .01); other outcomes were not significantly different between groups. Adverse events occurred in 8 (8%) and 3 (3%) patients in the dexmedetomidine and control groups, respectively.” (H. Yamamura, yamamura@hirosaki-u.ac.jp)
Treatment of Obsessive-Compulsive Disorder: “The dissemination of computer-based cognitive behavioral therapy and improved evidence supporting it represent a major advancement in treatment of” obsessive–compulsive disorder, a review article concludes (pp. 1358–67). SSRIs remain a preferred initial therapy, and “increasing evidence that supports the safety and efficacy of neuroleptics and neuromodulatory approaches in treatment-resistant cases provides alternatives for patients whose condition does not respond to first-line interventions.” (C. A. Mathews, carolmathews@ufl.edu)

PNN Pharmacotherapy Line
Apr. 6, 2017 * Vol. 24, No. 66
Providing news and information about medications and their proper use
>>>NEJM Report
Source:
Apr. 6 issue of the New England Journal of Medicine (2017; 376).
Immunomodulation + Transplantation for Myeloma: High-dose chemotherapy plus transplantation extended progression-free survival in patients with multiple myeloma, compared with chemotherapy alone, but researchers report that overall survival was not changed significantly (pp. 1311–20). In the IFM 2009 Study, 700 patients were assigned to induction therapy with three cycles of lenalidomide, bortezomib, and dexamethasone (RVD) and then consolidation therapy with either five additional cycles of RVD or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD, with these results: “Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P <0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P = 0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P <0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy.” (M. Attal, attal.michel@iuct-oncopole.fr)
Summarizing the findings of this trial and noting the $120,000 per year cost of lenalidomide, editorialists conclude, “Transplantation resulted in a deeper and longer initial treatment response than did a nontransplantation approach” (
pp. 1378–9). “However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative. While some questions about initial therapy remain unanswered, we owe a big ‘merci’ to the IFM investigators for the important issues addressed in this study.” (C. A. Schiffer)
Body Weight in Coronary Disease: Using data from the Treating to New Targets (TNT) trial, investigators find that fluctuations in body weight among patients with coronary artery disease “was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors” (pp. 1332–40). Data from the lipid-lowering trial showed these patterns for a primary outcome of any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina): “Among 9,509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2,091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P = 0.01), any cardiovascular event (2,727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P <0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P <0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models.” (S. Bangalore, sripalbangalore@gmail.com)
FDA on Medical-Device Clinical Trials: Successful introduction of medical devices in the U.S. requires robust data on the innovation’s benefit–risk profile, FDA authors write, and sometimes the needed data are beyond those that the agency can require in premarketing studies (pp. 1350–7). The authors call on the industry and practitioners to provide additional evidence through trials, registries, and data analyses. (O. Faris, owen.faris@fda.hhs.gov)

PNN Pharmacotherapy Line
Apr. 7, 2017 * Vol. 24, No. 67
Providing news and information about medications and their proper use
>>>Psychiatry Report
Source: Apr. issue of the American Journal of Psychiatry (2017; 174).
Treatment-Emergent Mania With Methylphenidate in Bipolar Disorder: Swedish national registries demonstrate no association of methylphenidate use by patients with bipolar disorder who are receiving mood-stabilizing medications with treatment-emergent mania, researchers report (pp. 341–8). Data on 2,307 adults who began methylphenidate treatment in 2006 and 2014 show these patterns: “Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within 3 months of medication initiation (hazard ratio=6.7, 95% CI=2.0–22.4), with similar results for the subsequent 3 months. By contrast, for patients taking mood stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio = 0.6, 95% CI = 0.4–0.9). Comparable results were observed when only hospitalizations for mania were counted.” (A. Viktorin)
Computerized Cognitive Training for Dementia in Older Adults: Computerized cognitive training (CCT) is an effective intervention in patients with mild cognitive impairment or dementia that should be studied further in larger trials, according to results of a systematic review and meta-analysis (pp. 329–40): “The overall effect [of CCT] on cognition in mild cognitive impairment across 17 trials was moderate (Hedges’ g = 0.35, 95% CI = 0.20–0.51). There was no evidence of publication bias or difference between active- and passive-controlled trials. Small to moderate effects were found for global cognition, attention, working memory, learning, and memory, with the exception of nonverbal memory, and for psychosocial functioning, including depressive symptoms. In dementia, statistically significant effects were found on overall cognition (k = 11, g = 0.26, 95% CI = 0.01–0.52) and visuospatial skills, but these were driven by three trials of virtual reality or Nintendo Wii.” (N. T. M. Hill)
>>>Pediatrics Highlights
Source: Apr. issue of Pediatrics (2017; 139).
Antibiotic Prescribing for Community-Acquired Pneumonia: Antibiotics prescribed for pediatric patients with community-acquired pneumonia (CAP) varied widely in a retrospective cohort study and in ways “unlikely related to the microbiologic etiology of CAP” (10.1542/peds.2016-2331). Concluding that anti-infective stewardship efforts should be informed by “drivers of off-guideline prescribing,” investigators report these data from an outpatient pediatric primary care network in 2009–13: “Of 10,414 children, 4,239 (40.7%) received amoxicillin, 4,430 (42.5%) received macrolides and 1,745 (16.8%) received broad-spectrum antibiotics. The factors associated with an increased odds of receipt of macrolides compared with amoxicillin included patient age ≥5 years (adjusted odds ratio [aOR]: 6.18; 95% confidence interval [CI]: 5.53–6.91), previous antibiotic receipt (aOR: 1.79; 95% CI: 1.56–2.04), and private insurance (aOR: 1.47; 95% CI: 1.28–1.70). The predicted probability of a child being prescribed a macrolide ranged significantly between 0.22 and 0.83 across clinics. The nonclinical characteristics associated with an increased odds of receipt of broad-spectrum antibiotics compared with amoxicillin included suburban practice (aOR: 7.50; 95% CI: 4.16–13.55) and private insurance (aOR: 1.42; 95% CI: 1.18–1.71).” (L. K. Handy)
Impact of Pneumonia Treatment Guideline: Local implementation efforts were an important factor in adoption of antibiotic recommendations made in the 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America pneumonia guideline — more so than hospital organizational readiness to change — according to analysis of inpatient antibiotic prescribing in 28 children’s hospitals (10.1542/peds.2016-3231; D. J. Williams).
>>>PNN NewsWatch
*
FDA yesterday allowed the marketing of the 23andMe Personal Genome Service Genetic Health Risk tests for 10 diseases or conditions. These are the first direct-to-consumer tests authorized by FDA to provide information on an individual’s genetic predisposition to certain medical diseases or conditions.
*
Isomeric Pharmacy Solutions is voluntarily recalling all lots of sterile products it has compounded and packaged and that remain within expiry to the hospital/user level because of FDA concerns of a lack of sterility assurance.

PNN Pharmacotherapy Line
Apr. 10, 2017 * Vol. 24, No. 68
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 8 issue of Lancet (2017; 389).
Liraglutide in Prediabetes: Used for risk and weight reduction in patients with prediabetes and obesity, liraglutide 3 mg daily showed promising results in the SCALE Obesity and Prediabetes trial (pp. 1399–409). Among adults with body mass indices of 30 mg/sq m or more (or 27 kg/sq m with comorbidities), these results were generated over 3 years of treatment in the placebo-controlled study: “We randomly assigned 2,254 patients to receive liraglutide (n = 1,505) or placebo (n = 749). 1,128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1,472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2.7 times longer with liraglutide than with placebo (95% CI 1.9 to 3.9, p <0.0001), corresponding with a hazard ratio of 0.21 (95% CI 0.13–0.34). Liraglutide induced greater weight loss than placebo at week 160 (–6.1 [SD 7.3] vs −1.9% [6.3]; estimated treatment difference −4.3%, 95% CI −4.9 to −3.7, p <0.0001). Serious adverse events were reported by 227 (15%) of 1,501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group.” (C. W. le Roux, carel.leroux@ucd.ie)
>>>Circulation Report
Source: Apr. 4 issue of Circulation (2017; 135).
Genetic Variants in QT Prolongation Risk: A genetic QT score comprising 61 common genetic variants explains a significant proportion of QT prolongation and predicts risk of torsades de pointes, researchers report (pp. 1300–10). Concluding that larger studies are needed, the group reports these results from genetic analyses of 22 individuals who participated in a larger crossover trial of three QT-prolonging drugs with 15 time-matched QT/plasma drug concentration measurements: “The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55; 95% confidence interval, 0.09–0.81; P = 0.02), 23% in response to quinidine (r = 0.48; 95% confidence interval, −0.03 to 0.79; P = 0.06), and 27% in response to ranolazine (r = 0.52; 95% confidence interval, 0.05–0.80; P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2 = 12%, P = 1×10−7).” (D. G. Strauss, david.strauss@fda.hhs.gov)
>>>PNN NewsWatch
*
FDA on Friday approved supplemental applications for sofosbuvir (Sovaldi) and ledipasvir/sofosbuvir (Harvoni) to treat hepatitis C virus (HCV) infections in children ages 12 to 17 years. Both Gilead products were previously approved to treat HCV in adults.
>>>PNN JournalWatch
* Management of Ventricular Arrhythmias in Patients With Advanced Heart Failure, in
Journal of the American College of Cardiology, 2017; 69: 10.1016/j.jacc.2017.01.047. (P. Santangeli) 
* Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery, in
Journal of the American College of Cardiology, 2017; 69: 10.1016/j.jacc.2017.02.012. (S. Banerjee)
* Interstitial Lung Disease in the Elderly, in
Chest, 2017; 151: 838–44. (K. C. Patterson) 
* Use of Management Pathways or Algorithms in Children With Chronic Cough: CHEST Guideline and Expert Panel Report, in
Chest, 2017; 151: 875–83.
(A. B. Chang) 
* Management of Children With Chronic Wet Cough and Protracted Bacterial Bronchitis: CHEST Guideline and Expert Panel Report, in
Chest, 2017; 151: 884–90.
(A. B. Chang) 
* Urine Culture Follow-up and Antimicrobial Stewardship in a Pediatric Urgent Care Network, in
Pediatrics, 2017; 139: 10.1542/peds.2016-2103. (D. Saha) 
* Dinutuximab for Maintenance Therapy in Pediatric Neuroblastoma, in
American Journal of Health-System Pharmacy, 2017; 74: 563–7. (J. Kolesar, jill.kolesar@uky.edu)

PNN Pharmacotherapy Line
Apr. 11, 2017 * Vol. 24, No. 69
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. issue of JAMA Internal Medicine (2017; 177).
Antibiotic Selection for Clostridium difficile Infection: In a comparative effectiveness trial of patients with Clostridium difficile infection (CDI), vancomycin significantly reduced 30-day mortality rates  in severe cases, compared with metronidazole, researchers report (pp. 546–53). Retrospective data for VA patients with stool tests positive for C. difficile toxins showed these patterns when analyzed in this propensity-matched cohort study: “A total of 47,471 patients (mean [SD] age, 68.8 [13.3] years; 1,947 women [4.1%] and 45,524 men [95.9%]) developed CDI, were treated with vancomycin or metronidazole, and met criteria for entry into the study. Of 47,147 eligible first treatment episodes, 2,068 (4.4%) were with vancomycin. Those 2,068 patients were matched to 8,069 patients in the metronidazole group for a total of 10,137 included patients. Subcohorts were constructed that comprised 5,452 patients with mild to moderate disease and 3,130 patients with severe disease. There were no differences in the risk of recurrence between patients treated with vancomycin vs those treated with metronidazole in any of the disease severity cohorts. Among patients in the any severity cohort, those who were treated with vancomycin were less likely to die (adjusted relative risk, 0.86; 95% CI, 0.74 to 0.98; adjusted risk difference, –0.02; 95% CI, –0.03 to –0.01). No significant difference was found in the risk of mortality between treatment groups among patients with mild to moderate CDI, but vancomycin significantly reduced the risk of all-cause 30-day mortality among patients with severe CDI (adjusted relative risk, 0.79; 95% CI, 0.65 to 0.97; adjusted risk difference, –0.04; 95% CI, –0.07 to –0.01).” (V. W. Stevens, vanessa.stevens@hsc.utah.edu)
Warfarin for Atrial Fibrillation After Head Bleeds: A nationwide observational cohort study from Denmark shows that resumption of warfarin in patients with atrial fibrillation (AF) may carry more risks in those who have had spontaneous hemorrhagic strokes than in those with traumatic intracranial hemorrhages (ICHs) (pp. 563–70). “Resumption of warfarin therapy after spontaneous hemorrhagic stroke in patients with AF was associated with a lower rate of ischemic events and a higher rate of recurrent ICH,” the authors conclude. “Among patients with a traumatic ICH, a similar lower rate of ischemic events was found; however, a lower relative risk for recurrent ICH despite resuming warfarin treatment was also revealed.” (P. Brønnum Nielsen, pbn@rn.dk)
Testosterone Replacement Therapy in Older Men: An editorialist (pp. 459–60; E. Orwoll, orwoll@ohsu.edu) reaches these conclusions in response to three research articles assessing the effects of testosterone replacement therapy (TRT) in older men on bone density and strength (pp. 471–9; P. J. Snyder, pjs@mail.med.upenn.edu), anemia (pp. 480–90; P. J. Snyder, pjs@mail.med.upenn.edu), and cardiovascular risks (pp. 491–9; T. C. Cheetham, tcraigcheetham@icloud.com):
* “Testosterone replacement may be sufficient to forestall the need for osteoporosis therapies in those with borderline [bone mineral densities] who will otherwise be treated with testosterone. The management of older men with hypogonadism and more severe osteoporosis is more challenging.”
* “In older men with unexplained anemia, or anemia of known etiology but without adequate response to therapy, an assessment of gonadal status would be warranted. If hypogonadism is present, testosterone replacement should be considered.”
* “At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement in older hypogonadal men have not been adequately resolved.”
CNS Polypharmacy Among Older Adults: Polypharmacy involving medications that affect the central nervous system (CNS) doubled between 2004 and 2013, an analysis of data from the National Ambulatory Medical Care Surveys shows (pp. 583–5). Patients aged 65 years or older who were taking three or more psychoactive drugs from the Beers list accounted for 1.4% of outpatient visits in 2013, compared with 0.6% in 2004. The largest increase in CNS polypharmacy was observed in rural areas, and women were disproportionately receiving CNS polypharmacy. (D. T. Maust, maustd@umich.edu)

PNN Pharmacotherapy Line
Apr. 12, 2017 * Vol. 24, No. 70
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 11 issue of JAMA (2017; 317).
Norepinephrine Shortage & Septic Shock Mortality: Mortality rates were higher among patients hospitalized for septic shock during the 2011 shortage of first-line agent norepinephrine, according to an analysis of the Premier Healthcare Database (pp. 1433–42). A retrospective cohort study of 26 hospitals shows phenylephrine was the most commonly administered alternative vasopressor, leading to these results: “Among 27,835 patients (median age, 69 years [interquartile range, 57–79 years]; 47.0% women) with septic shock in 26 hospitals that demonstrated at least 1 quarter of norepinephrine shortage in 2011, norepinephrine use among cohort patients declined from 77.0% (95% CI, 76.2%–77.8%) of patients before the shortage to a low of 55.7% (95% CI, 52.0%–58.4%) in the second quarter of 2011; phenylephrine was the most frequently used alternative vasopressor during this time (baseline, 36.2% [95% CI, 35.3%–37.1%]; maximum, 54.4% [95% CI, 51.8%–57.2%]). Compared with hospital admission with septic shock during quarters of normal use, hospital admission during quarters of shortage was associated with an increased rate of in-hospital mortality (9,283 of 25,874 patients [35.9%] vs 777 of 1,961 patients [39.6%], respectively; absolute risk increase = 3.7% [95% CI, 1.5%–6.0%]; adjusted odds ratio = 1.15 [95% CI, 1.01–1.30]; P = .03).” (H. Wunsch, hannah.wunsch@sunnybrook.ca)
“This precarious situation did not arise by design, but rather through a complicated set of actions and unintended consequences,” editorialists write (
pp. 1415–7). “In 1984, the Drug Price Competition and Patent Term Restoration Act (also known as the Hatch–Waxman Act) introduced a new approval mechanism to incentivize pharmaceutical companies to manufacture generic drugs. The principal burden for approval under the Hatch–Waxman Act is to demonstrate bioequivalence. Consequently, the only differentiating feature among generic drugs is price. The Hatch–Waxman Act worked extremely well, with generic drugs increasing from 18.6% of prescriptions in 1984 to 85.4% of prescriptions in 2016, driven by payers negotiating for lower prices and generating substantial savings for patients. However, for generic sterile injectable drugs, the market does not recognize quality differences in production, which inadvertently incentivizes manufacturers to adopt a reactive approach to quality management.” (J. M. Donohue, jdonohue@pitt.edu)
Universal Health Coverage Without Single-Payer System: Requirements that Americans purchase insurance “are as old as the Republic,” according to Viewpoint authors (pp. 1409–10). “In 1790, President George Washington required that ship owners purchase medical insurance for their seamen, and Medicare has long assessed penalties on healthy people who do not enroll by age 65 years,” the group writes, adding these observations about countries that have achieved universal coverage without use of a single-payer system: “Health insurance models in Switzerland, Singapore, and Germany suggest that an individual mandate, with adequate subsidies, can achieve affordable universal coverage. But the recipe for their success also includes firm penalties. They also suggest that the [Affordable Care Act’s] individual mandate failed to pool risk adequately, in large part because its penalties were too weak. In 2014, approximately 7.5 million individuals paid the penalty rather than purchasing insurance, and of the approximately 15 million uninsured people who were ineligible for Medicaid, an estimated 7.1 million would pay a penalty lower than the cost of the least expensive plan.… ” (R. J. Boxer, rboxer@mednet.ucla.edu)
>>>PNN NewsWatch
*
FDA has approved valbenazine (Ingrezza, Neurocrine Biosciences) to treat adults with tardive dyskinesia. This is the first drug approved for this common drug adverse effect.In a clinical trial of 234 participants, valbenazine improved the severity of abnormal involuntary movements to a significantly greater degree than did placebo. Valbenazine can cause serious side effects including sleepiness and QT prolongation. Its use should be avoided in patients with congenital long QT syndrome or with abnormal heartbeats associated with a prolonged QT interval. Those taking valbenazine should not drive, operate heavy machinery, or perform other dangerous tasks until it is known how the drug affects them.

PNN Pharmacotherapy Line
Apr. 13, 2017 * Vol. 24, No. 71
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 13 issue of the New England Journal of Medicine (2017; 376).
Trends in Mortality, Incidence of Diabetes: In two research articles and an editorial, authors examine trends in diabetes and their implications.
From Sweden come data showing a declining incidence of cardiovascular outcomes in people with diabetes but less so for fatal outcomes among those with the type 2 condition (
pp. 1407–18). The national registry showed significant declines in 1998 through 2014 for all-cause mortality, cardiovascular mortality, coronary heart disease mortality, and hospitalizations for cardiovascular disease in patients with diabetes. “Patients with type 1 diabetes had roughly 40% greater reduction in cardiovascular outcomes than controls, and patients with type 2 diabetes had roughly 20% greater reduction than controls,” the authors add. “Reductions in fatal outcomes were similar in patients with type 1 diabetes and controls, whereas patients with type 2 diabetes had smaller reductions in fatal outcomes than controls.” (A. Rawshani, aidin.rawshani@gu.se)
American youth — particularly those in minority ethnic and racial groups — had significantly increased incidence of diabetes in 2012 than in 2002, researchers report (
pp. 1419–29). Figures from five U.S. study centers combined with census data show the following: “A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2,846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002–2003 to 21.7 cases per 100,000 youths per year in 2011–2012, P = 0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non-Hispanic whites (4.2% vs. 1.2%, P <0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002–2003 to 12.5 cases per 100,000 youths per year in 2011–2012, P <0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non-Hispanic whites (0.6%) was lower than that among non-Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P <0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P = 0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P <0.001) and that of type 2 diabetes was 4.8% (P <0.001).” (E. J. Mayer-Davis, ejmayer-davis@unc.edu)
“What do the marked increase in the incidence of diabetes and more people at risk imply about therapy?” editorialists ask (
pp. 1473–4). “Over the past several decades, there have been important studies focusing on the treatment of type 1 and type 2 diabetes. For example, the Diabetes Control and Complications Trial (DCCT) showed that intensive glycemic control improved outcomes in persons with type 1 diabetes mellitus, as did the United Kingdom Prospective Diabetes Study (UKPDS) in persons with type 2 diabetes. Despite a growing understanding about the pathogenesis of each condition, knowledge about how best to lower the number of new cases and how best to treat problems in persons with diabetes, once they arise, has been elusive.
“It is clear that we are far from controlling the negative effects of diabetes on health worldwide. As the prevalence increases, we clearly need new approaches to reduce the burden of this disease on public health.” (J. R. Ingelfinger)
Inclisiran for Elevated LDL Cholesterol: A small interfering RNA that targets PCSK9 messenger RNA, inclisiran lowered PCSK9 and LDL cholesterol levels among 501 patients with high cardiovascular risks and elevated LDL cholesterol levels, a phase 2 study shows (pp. 1430–40). “The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180,” the investigators write. “At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens.” (K. K. Ray, k.ray@imperial.ac.uk)

PNN Pharmacotherapy Line
Apr. 14, 2017 * Vol. 24, No. 72
Providing news and information about medications and their proper use
>>>Infectious Diseases Report
Source: Apr 15 issue of Clinical Infectious Diseases (2017; 64).
Relapse After HCV Treatment in Patients With HIV: Used for treating acute hepatitis C virus (HCV) genotype-1 infection in patients who also have HIV-1 infection, sofosbuvir–ribavirin has a high relapse rate, according to an open-label, two-cohort, 12-week clinical trial of safety and efficacy (pp. 1035–42): “Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2,280,000 IU/mL (interquartile range, 272,000–4,230,000). Ten participants (59%) achieved the primary outcome of [sustained viral response at 12 weeks (SVR12)] (90% confidence interval, 36%–78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment.” (S. Naggie, susanna.naggie@duke.edu)
Risk of Eardrum Perforation With Quinolone Ear Drops in Children With Tubes: Analysis of Medicaid data for children with tympanostomy tube (TT) placement in 29 U.S. states shows that exposure to quinolone ear drops is associated with increased risk of eardrum perforations requiring tympanoplasty, researchers report (pp. 1052–8). The data, from 1999 to 2006, also show that the risk is exacerbated by corticosteroids: “A total of 96,595 children entered the study cohort. Patients exposed to quinolone ear drops had a higher risk of perforation, with an adjusted hazard ratio of 1.61 (95% confidence interval [CI], 1.15–2.26). The adjusted hazard ratios were 1.49 (95% CI, 1.05–2.09) for ofloxacin, 1.94 (95% CI, 1.32–2.85) for ciprofloxacin plus hydrocortisone, and 2.00 (95% CI, 1.18–3.41) for ciprofloxacin plus dexamethasone.” (A. Alrwisan)
>>>Oncology Highlights
Source: Apr. issue of the Journal of Clinical Oncology (2017; 35).
Cholesterol-Lowering Drugs & Reduced Breast Cancer Recurrence: Observational associations of reduced breast cancer recurrence in women taking cholesterol-lowering medications (CLMs) should be explored in prospective randomized trials, investigators write (pp. 1179–88). In the Breast International Group (BIG) phase 3 trial BIG 1-98, postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer (n = 8,010) had these outcomes in 1998–2003 while being treated with tamoxifen: “Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen–letrozole (n = 189), letrozole–tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer–free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence–free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03).” (S. Borgquist, signe.borgquist@med.lu.se)
>>>PNN NewsWatch
* Standard Homeopathic Company this week agreed to a recall of
Hyland’s Baby Teething Tablets and Hyland’s Baby Nighttime Teething Tablets, as requested in January after FDA found inconsistent amounts of belladonna in the products.
*
Illicitly manufactured fentanyl, an important factor in a 150% increase in opioid overdose deaths in Massachusetts in 2012–15, often causes death within seconds to minutes after the person injects or insufflates the drug, an article in this week’s MMWR reports. Based on an analysis of factors surrounding 196 opioid overdose deaths, the authors conclude, “The high percentage of fatal overdoses occurring at home with no naloxone present, coupled with the rapid onset of overdose symptoms after using fentanyl through injection or insufflation, underscores the urgent need to expand initiatives to link persons at high risk for overdose (such as persons using heroin, persons with past overdoses, or persons recently released from incarceration) to harm reduction services and evidence-based treatment.”

PNN Pharmacotherapy Line
Apr. 17, 2017 * Vol. 24, No. 73
Providing news and information about medications and their proper use
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Short-Term Oral Corticosteroids: The use and adverse effects of short-term courses of oral corticosteroids in the U.S. is quantified through analysis of commercial insurance claims, with researchers reporting that 1 in 5 Americans receive the agents in a 3-year period (j1415). Adverse effects are common, as detailed in these results for the initial 30 days and the 31–90-day risk period after prescription: “Of 1,548,945 adults, 327,452 (21.1%) received at least one outpatient prescription for short term use of oral corticosteroids over the three year period. Use was more frequent among older patients, women, and white adults, with significant regional variation (all P <0.001). The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of drug initiation, there was an increase in rates of sepsis (incidence rate ratio 5.30, 95% confidence interval 3.80 to 7.41), venous thromboembolism (3.33, 2.78 to 3.99), and fracture (1.87, 1.69 to 2.07), which diminished over the subsequent 31–90 days. The increased risk persisted at prednisone equivalent doses of less than 20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P <0.001).” (A. K. Waljee, awaljee@med.umich.edu)
>>>Allergy/Immunology Report
Source: Apr. issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Mepolizumab in Severe Eosinophilic Asthma: Compared with placebo in four studies of 1,388 patients with severe eosinophilic asthma, mepolizumab reduced exacerbations and emergency department visits by one-half, a meta-analysis shows (pp. 1167–.75e2): “Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30–0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33–0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively.” (S. W. Yancey, steve.w.yancey@gsk.com)
Microbiota in Asthma & Allergic Disease: Authors of two review articles examine evidence of the effects of microbiota on development of asthma and allergies.
“Microbiota in the gut and lungs can influence both the inception and progress of asthma,” writes an author (
pp. 1071–81). “In babies and infants the presence of pathogenic bacteria in the lungs and gut has been associated with subsequent development of allergic sensitization and asthma. Lung microbiota are present in the airways of healthy subjects but are dysregulated in adults with asthma, with a reduced diversity and community composition that has been linked to severity and inflammatory phenotypes. Causality between certain gut microbiota and the development of allergic asthma has been shown in experiments conducted in neonatal mice. Manipulation of the airway microbiome, particularly in early life, might be a strategy to prevent or treat asthma, although the results of studies of probiotics used together with prebiotics have been overall negative. A better understanding of the regulation of both the lung and gut microbiota to derive appropriate targets for prevention or treatment of asthma is needed.” (K. F. Chung, f.chung@imperial.ac.uk)
PRACTALL 2017 — an initiative of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology — “is focused on what has been established regarding the role of the microbiome in patients with asthma, atopic dermatitis, and food allergy,” authors write (
pp. 1099–110). “This is complemented by outlining important knowledge gaps regarding its role in allergic disease and delineating strategies necessary to fill these gaps.” (T. A. Fleisher, tfleishe@mail.nih.gov)
>>>PNN JournalWatch
* Eight Habits of Highly Effective Antimicrobial Stewardship Programs to Meet the Joint Commission Standards for Hospitals, in
Clinical Infectious Diseases, 2017; 64: 1134–9. (D. A. Goff) 
* Somatic
BRCA1/2 Recovery as a Resistance Mechanism After Exceptional Response to Poly (ADP-ribose) Polymerase Inhibition, in Journal of Clinical Oncology, 2017; 35: 1240–9. (A. M. Oza, amit.oza@uhn.ca)
PNNInfo@mac.com www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Apr. 18, 2017 * Vol. 24, No. 74
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: Apr. 18 issue of the Annals of Internal Medicine (2017; 166).
Glucocorticoid Injections in Chronic Low Back Pain: At three tertiary care centers in France, a single glucocorticoid intradiscal injection (GC IDI) in patients with chronic low back pain (LBP) provided relief at month 1 but not 12, researchers report (pp. 547–56). Comparing prednisolone acetate 25 mg with no intervention during discography, investigators identified these differences: “At 1 month after the intervention, the percentage of responders (LBP intensity <40 [on an 11-point scale from 0 to 100]) was higher in the GC IDI group (36 of 65 [55.4%]) than the control group (21 of 63 [33.3%]) (absolute risk difference, 22.1 percentage points [95% CI, 5.5 to 38.7 percentage points]; P = 0.009). The groups did not differ in LBP intensity at 12 months and in most secondary outcomes at 1 and 12 months.” (S. Poiraudeau, serge.poiraudeau@aphp.fr)
 “In patients with an acute pain episode that coincides with Modic 1 changes on magnetic resonance imaging, [GC IDI] may be an option for short-term pain relief,” editorialists write (
pp. 601–2). “However, in patients with chronic pain, glucocorticoid injection clearly is not effective over the long term. The question then arises about the utility of using an invasive treatment for short-term relief in the setting of an acute condition with a favorable natural history or for an acute flare of a chronic condition.” (D. J. Kennedy, djkenned@stanford.edu)
Anakinra in Chronic Fatigue Syndrome: Symptoms of chronic fatigue syndrome (CFS) were not improved by 4 weeks of subcutaneous anakinra therapy, researchers report in a previously released manuscript (see PNN, Mar. 7; pp. 557–64). Cytokine inhibition was tested in 50 women aged 18–59 years of age with CFS and severe fatigue, with these results during 4 weeks of treatment and 20 weeks of follow-up: “At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in … fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).” (M. E. Roerink, Megan.Roerink@radboudumc.nl)
Synopsis of 2017 ADA Standards for Medical Care of Diabetes: Pharmacologic management of type 2 diabetes based on this year’s guidelines from the American Diabetes Association are summarized in a Clinical Guidelines article (pp. 572–8): “Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes (A rating). Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in patients treated with metformin, especially those with anemia or peripheral neuropathy (B rating). Providers should consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic, have a hemoglobin A1c (HbA1c) level of 10% or greater, or have a blood glucose level of 16.7 mmol/L (300 mg/dL) or greater (E rating). If noninsulin monotherapy at the maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months, adding a second oral agent, a glucagon-like peptide-1–receptor agonist, or basal insulin should be considered (A rating). For patients with type 2 diabetes who are not achieving glycemic goals, insulin therapy should be instituted without delay (B rating). A patient-centered approach should be used to guide the choice of pharmacologic agents (E rating).” (J. J. Chamberlain, jimchammd@yahoo.com)
Canadian Survival Advantage in Cystic Fibrosis: Reacting to a cohort study showing that Canadians with cystic fibrosis live a median of 10 years longer than Americans (pp. 537–46; A. L. Stephenson, stephensona@smh.ca), editorialists propose that the difference might be the result of lack of health care services among impoverished people in the U.S. (pp. 599–600; P. A. Flume, flumepa@musc.edu).

PNN Pharmacotherapy Line
Apr. 19, 2017 * Vol. 24, No. 75
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 18 issue of JAMA (2017; 317).
Maternal Depression, Prenatal Antidepressant Use & Autism: Two research articles and an editorial attempt to clarify the relationship among development of autism and maternal depression and use of antidepressants during pregnancy.
Contrary to prior studies —including a
JAMA Pediatrics analysis from Quebec republished in this issue (pp. 1568–9; B. H. King, bryan.king@ucsf.edu) — a retrospective cohort study of public prescription drugs dispensed in Ontario to pregnant women shows no increased risk of autism spectrum disorder associated with prenatal use of serotonergic antidepressants (pp. 1544–52). Among 35,906 singleton births with mean gestational age of 38.7 weeks, 2.0% of 2,837 children exposed in utero to antidepressants developed autism spectrum disorder. “The incidence of autism spectrum disorder was 4.51 per 1,000 person–years among children exposed to antidepressants vs 2.03 per 1,000 person–years among unexposed children (between-group difference, 2.48 [95% CI, 2.33–2.62] per 1,000 person–years; hazard ratio [HR], 2.16 [95% CI, 1.64–2.86]; adjusted HR, 1.59 [95% CI, 1.17–2.17]). After inverse probability of treatment weighting based on the high-dimensional propensity score, the association was not significant (HR, 1.61 [95% CI, 0.997-2.59]).” (S. N. Vigod, simone.vigod@wchospital.ca)
Among Swedish children born in 1996–2012, those exposed to antidepressants during the first trimester had “a small increased risk of preterm birth but no increased risk [after data adjustment] of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder,” researchers report (
pp. 1553–62). The study, which included 1.6 million births to nearly 950,000 mothers, found these relationships among first-trimester antidepressant use and adverse outcomes: “6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years.” (B. M. D’Onofrio, bmdonofr@indiana.edu)
“[These studies] serve as a reminder that regardless of antidepressant treatment, children of mothers with depression remain at increased risk for developmental disturbances (
pp. 1533–4). “Although maternal depression (both prenatal and postnatal) remains a key determinant of child development, its effect is far from simple and may not be directly related to maternal behavior or decision making about treatment. Identifying how maternal mood and related genetic and environmental factors shape developmental risk is needed, moving away from a focus on antidepressant medications alone and toward whether some mothers and their children might actually benefit from prenatal maternal antidepressant treatment.” (T. F. Oberlander, toberlander@bcchr.ca)
Oral Dexamethasone for Acute Sore Throat: Two days after administration, a single oral dose of dexamethasone 10 mg relieved symptoms of sore throat among 565 acutely ill adults, a study shows (pp. 1535–43). At 42 family practices in England, patients with acute sore throat not requiring antibiotics had these outcomes when randomized to dexamethasone or placebo: “At 24 hours, 65 participants (22.6%) in the dexamethasone group and 49 (17.7%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 4.7% (95% CI, −1.8% to 11.2%) and a relative risk of 1.28 (95% CI; 0.92 to 1.78; P = .14). At 24 hours, participants receiving dexamethasone were not more likely than those receiving placebo to have complete symptom resolution. At 48 hours, 102 participants (35.4%) in the dexamethasone group vs 75 (27.1%) in the placebo group achieved complete resolution of symptoms, for a risk difference of 8.7% (95% CI, 1.2% to 16.2%) and a relative risk of 1.31 (95% CI, 1.02 to 1.68; P = .03). This difference also was observed in participants not offered delayed antibiotic prescription, for a risk difference of 10.3% (95% CI, 0.6% to 20.1%) and a relative risk of 1.37 (95% CI, 1.01 to 1.87; P = .046). There were no significant differences in any other secondary outcomes.” (G. N. Hayward, gail.hayward@phc.ox.ac.uk)
PNNInfo@mac.com www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Apr. 20, 2017 * Vol. 24, No. 76
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 20 issue of the New England Journal of Medicine (2017; 376).
Risks & Benefits of Bococizumab: A humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), bococizumab is used to reduce elevated LDL cholesterol levels. Two research articles and a letter examine pharmacotherapy with this agent.
Problems with development of antidrug antibodies and wide variations in cholesterol reduction even in patients without the antibodies are evident in data from six large clinical trials, researchers report (
pp. 1517–26). Among 4,300 patients with hyperlipidemia, these outcomes were recorded with bococizumab 150 mg or placebo subcutaneously every 2 weeks for up to 12 months: “At 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, −55.2 percentage points). Significant between-group differences were also observed in total cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (P <0.001 for all comparisons). However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels. In addition, among patients with no antidrug antibodies, there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks. Major cardiovascular events occurred in 57 patients (2.5%) who received bococizumab and in 55 (2.7%) who received placebo (hazard ratio, 0.96; 95% confidence interval, 0.66 to 1.39; P = 0.83). The most common adverse event among patients who received bococizumab was injection-site reaction (12.7 per 100 person–years).” (P. M. Ridker, jean-claude.tardif@icm-mhi.org)
Significantly improved outcomes occurred in two randomized trials of bococizumab only for patients with higher risks, an analysis shows (
pp. 1527–39). The trials had 27,438 participants and showed these results based on a primary end point of nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death: “In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08)…” (P. M. Ridker, pridker@partners.org)
Differing views on antibodies to and efficacy of bococizumab are provided in a letter to the editor from companies developing the investigational drug (
pp. 1589–90). Despite those benefits though, “immunogenicity led to the discontinuation of clinical development of bococizumab,” the authors write. (E. M. Roth, eroth@sterlingresearch.org)
Eltrombopag for Aplastic Anemia: Compared with a historical cohort, the synthetic thrombopoietin-receptor agonist eltrombopag produced higher rates of hematologic response among patients with severe aplastic anemia, a 92-patient, a phase 1-2 study shows (pp. 1540–50; D. M. Townsley, townsleydm@nhlbi.nih.gov).
Risankizumab for Plaque Psoriasis: Risankizumab was superior to ustekinumab for symptom relief in a phase 2 trial of 166 patients with moderate-to-severe plaque psoriasis (pp. 1551–60). Week 12 results showed 77% of patients on risankizumab had a reduction of 90% or more on a standard scale, compared with 40% of those on ustekinumab. (K. A. Papp, kapapp@probitymedical.com)
>>>PNN NewsWatch
*
Organic Herbal Supply is recalling several products following FDA analyses showing presence of tadalafil or flibanserin, FDA said.
PNN Pharmacotherapy Line
Apr. 21, 2017 * Vol. 24, No. 77
Providing news and information about medications and their proper use
>>>Geriatrics Report
Source: Apr. Journal of the American Geriatrics Society (2017; 65).
Natriuretic Peptides in Heart Failure: In addition to ejection fraction (EF) and comorbidities, N-terminal pro b-type natriuretic peptide (NT-proBNP) was associated with significantly poorer prognoses in 279 older adults hospitalized for decompensation of chronic established heart failure in two Italian facilities (pp. 822–6). Study participants, all older than 75 years of age, had these mortality outcomes: “In-hospital, 12-month and 5-year mortality were, respectively, 10%, 36%, and 77%. NT-proBNP, [estimated glomerular filtration rate], hemoglobin, diabetes, systolic blood pressure, and moderate to severe tricuspid regurgitation were independently associated with long-term prognosis and were entered into a multivariate model, with a C-index of 0.765 for the determination of high-risk patients. The C-index for NT-proBNP to predict mortality at 2 and 12 months was 0.740 and 0.756, respectively. The optimal cutoff point[s] for predicting mortality at 2 and 12 months [were] 8,444 pg/mL (hazard ratio 5.33) and 8,275 pg/mL (hazard ratio 6.03), respectively.” (A. Passantino, andrea.passantino@fsm.it)
“The role of natriuretic peptides in mortality risk stratification in older [heart failure (HF)] patients seems clear,” editorialists write (
pp. 691–2). “We need more information about natriuretic peptides and cardiovascular and non-cardiovascular cause of death, and information on the use of natriuretic peptides to risk stratify for rehospitalization or advanced therapies such as cardiac resynchronization devices, implantable cardioverter defibrillators (ICDs), and mechanical circulatory support. Finally, the role of natriuretic peptides in end of life decision making warrants consideration. For example, the decision to turn off an ICD may be informed by a natriuretic peptide level which indicates very high short term morality regardless of a defibrillator shock. As the population ages, managing the HF epidemic will place continued demands on the healthcare system so continued efforts to clarify the use of natriuretic peptides to inform that care and improve the lives of older patients with HF will be crucial.” (A. Sharma)
>>>PNN NewsWatch
*
FDA is restricting the use of codeine and tramadol medicines in children by requiring several changes to the labels of all prescription medicines containing these drugs. These new actions further limit the use of these medicines beyond the 2013 FDA restriction of codeine use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids. Specifically, FDA has added (1) a contraindication to the drug labels of codeine and tramadol alerting that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 years; (2) a new contraindication to the tramadol label warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids; (3) a warning to the drug labels of codeine and tramadol to recommend against their use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems; and (4) a strengthened warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants such as excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.
*
CDC has released the General Best Practice Guidelines for Immunization as an online report. It helps vaccination providers to assess vaccine benefits and risks, use recommended administration practices, understand the most effective strategies for ensuring that vaccination coverage in the population remains high, and communicate the importance of vaccination to reduce the effects of vaccine-preventable disease.
* Moving beyond medication reconciliation to the
“correct medication list” is the topic of a JAMA Viewpoint article released online in advance of print publication. “Achieving this list would involve multiple levels of reconciliation,” the authors write, adding that it is inappropriate to continue listing medications the patient cannot afford or does not want, that some drugs need to be discontinued, and that the burden of adherence should be addressed.
PNN Pharmacotherapy Line
Apr. 24, 2017 * Vol. 24, No. 78
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 22 issue of Lancet (2017; 389).
Doxycycline for Bullous Pemphigoid: Compared with oral prednisolone, doxycycline is noninferior “for short-term blister control in bullous pemphigoid and significantly safer in the long-term,” authors of a pragmatic study conclude (pp. 1630–8). Adult patients with the potentially fatal blistering-skin disorder had these outcomes: “Between March 1, 2009, and Oct. 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 U.K. and seven German dermatology centres. Mean age was 77.7 years (SD 9.7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18.6% (90% CI 11.1–26.1) favouring prednisolone (upper limit of 90% CI, 26.1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19.0% (95% CI 7.9–30.1), p = 0.001.” (H. C. Williams, hywel.williams@nottingham.ac.uk)
>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Dexamethasone in Gastrointestinal Surgery: In a U.K. trial of patients undergoing large or small bowel surgery, addition of an intravenous dose of dexamethasone 8 mg at the induction of anesthesia significantly reduced the incidence of postoperative nausea and vomiting at 24 hours and the need for rescue antiemetics for up to 72 hours (j1455). Among 1,350 patients, the pragmatic, parallel-group trial yielded these results: “Vomiting within 24 hours of surgery occurred in 172 (25.5%) participants in the dexamethasone arm and 223 (33.0%) allocated standard care (number needed to treat (NNT) 13, 95% confidence interval 5 to 22; P = 0.003). Additional postoperative antiemetics were given (on demand) to 265 (39.3%) participants allocated dexamethasone and 351 (51.9%) allocated standard care (NNT 8, 5 to 11; P <0.001). Reduction in on demand antiemetics remained up to 72 hours. There was no increase in complications.” (L. Magill, e.l.magill@bham.ac.uk)
Active Commuting & Morbidity/Mortality: People who cycle or walk to work have improved health outcomes, a study shows, including lower risk of cardiovascular disease (CVD), cancer, and all-cause mortality with cycling, according to a prospective, population-based study (j1456). U.K. Biobank data from 22 sites showed these associations: “2,430 participants died (496 were related to CVD and 1,126 to cancer) over a median of 5.0 years (interquartile range 4.3–5.5) follow-up. There were 3,748 cancer and 1,110 CVD events. In maximally adjusted models, commuting by cycle and by mixed mode including cycling were associated with lower risk of all cause mortality (cycling hazard ratio 0.59, 95% confidence interval 0.42 to 0.83, P = 0.002; mixed mode cycling 0.76, 0.58 to 1.00, P <0.05), cancer incidence (cycling 0.55, 0.44 to 0.69, P <0.001; mixed mode cycling 0.64, 0.45 to 0.91, P = 0.01), and cancer mortality (cycling 0.60, 0.40 to 0.90, P = 0.01; mixed mode cycling 0.68, 0.57 to 0.81, P <0.001). Commuting by cycling and walking were associated with a lower risk of CVD incidence (cycling 0.54, 0.33 to 0.88, P = 0.01; walking 0.73, 0.54 to 0.99, P = 0.04) and CVD mortality (cycling 0.48, 0.25 to 0.92, P = 0.03; walking 0.64, 0.45 to 0.91, P = 0.01).…” (J. M. R. Gill, jason.gill@glasgow.ac.uk)
>>>PNN NewsWatch
* Moving beyond its traditional electronics business, Samsung on Friday received FDA approval for a
biosimilar for Remicade (infliximab) , the Wall Street Journal reports. This second follow-on product for the rheumatoid arthritis agent has the trade name Renflexis.
* Lot 70952A of
Phenobarbital Tablets, USP, 15 mg, has been recalled by C. O. Truxton because of a confirmed customer complaint of a bottle containing 30-mg tablets.
>>>PNN JournalWatch
* Rheumatoid Arthritis and Risk of Malignant Lymphoma: Is the Risk Still Increased?, in
Arthritis & Rheumatology, 2017; 69: 700–8. (K. Hellgren, karin.hellgren@karolinska.se)
* States With Prescription Drug Monitoring Mandates Saw a Reduction in Opioids Prescribed to Medicaid Enrollees, in
Health Affairs, 2017; 36: 733–41. (Y. Bao, yub2003@med.cornell.edu)
PNN Pharmacotherapy Line
Apr. 25, 2017 * Vol. 24, No. 79
Providing news and information about medications and their proper use
>>>Diabetes Report
Source: May issue of Diabetes Care (2017; 40).
Sulfonylureas & Cardiovascular Outcomes: Despite dozens of studies of sulfonylureas’ effects on cardiovascular outcomes, a careful look at the methodological strength of observational data shows that more accurate measures of cardiovascular safety are needed (pp. 706–14). Only 6 of 19 studies had no major design-related biases, the authors report. In those trials, “sulfonylureas were associated with an increased risk of cardiovascular events and mortality in the majority of studies with no major design-related biases,” the authors write. “Among studies with important biases, the association varied significantly with respect to the comparator, the outcome, and the type of bias. With the introduction of new antidiabetic drugs, the use of appropriate design and analytical tools will provide their more accurate cardiovascular safety assessment in the real-world setting.” (L. Azoulay, laurent.azoulay@mcgill.ca)
“Metaphorically, the jury is still deliberating as to whether all sulfonylureas are unsafe based on worrisome evidence from studies of tolbutamide and glyburide,” editorialists conclude (
pp. 629–31). “Gliclazide, glipizide, and glimepiride are reliably effective in lowering glucose, but are they too dangerous to use? As suggested by Azoulay and Suissa, more skillful analysis of observational data are possible, and some randomized trial experience is soon to be reported. If new evidence supports a not guilty verdict, the modern sulfonylureas should regain respect and continue to be an important option for controlling glucose.” (M. C. Riddle, riddlem@ohsu.edu)
Canagliflozin & Phentermine for Weight Management: The combination of canagliflozin (CANA) plus phentermine (PHEN) “produced meaningful reductions in body weight and was generally well tolerated in individuals who were overweight or obese without type 2 diabetes,” a study shows (pp. 632–9). A 26-week, phase 2a trial produced these outcomes among 335 participants who received the drug combination, the drugs separately, or placebo (PBO): “CANA/PHEN provided statistically superior weight loss from baseline versus PBO at week 26 (least squares mean difference –6.9% [95% CI –8.6 to –5.2]; P < 0.001). CANA/PHEN also provided statistically superior achievement of weight loss ≥5% and reduction in systolic blood pressure compared with PBO. CANA/PHEN was generally well tolerated, with a safety and tolerability profile consistent with that of the individual components.” (P. Hollander, priscilh@baylorhealth.edu)
Pancreas Safety During Dulaglutide Development: During phase 2/3 trials of the glucagon-like peptide 1 receptor agonist dulaglutide, acute pancreatitis occurred at a rate similar to that in patients on placebo, researchers report (pp. 647–54). Among 6,005 patients with type 2 diabetes receiving dulaglutide, active comparators, or placebo, these outcomes were identified: “Overall, 203 events from 151 patients underwent adjudication (dulaglutide group n = 108; comparator group including placebo n = 43). Acute pancreatitis was confirmed by adjudication in seven patients (dulaglutide n = 3, placebo n = 1, sitagliptin n = 3). Exposure-adjusted incidence rates were as follows: dulaglutide group 0.85 patients/1,000 patient–years, placebo group 3.52 patients/1,000 patient–years, sitagliptin group 4.71 patients/1,000 patient–years. No events of pancreatitis were confirmed by adjudication in patients treated with exenatide twice daily, metformin, or glargine. Increases in median values of lipase and pancreatic amylase within the normal range were observed with all treatments except glargine. These changes were not associated with [adverse events].” (Z. Milicevic, milicevic_zvonko@lilly.com)
>>>PNN NewsWatch
* Hospira is voluntarily recalling one lot (58382EV) of
25% Dextrose Injection, USP, (Infant) prefilled syringe to the hospital/user level due to the presence of particulate matter, identified as human hair, found within an internal sample syringe, FDA reports.
* Pharmacists’ expanding role in self-care is the subject of
a new FIP report. “Pharmacy as a gateway to care: Helping people towards better health” reviews consumer interest in health care, presents a collection of evidence of pharmacy services related to self-care and the value pharmacists bring to health systems, and lays out drivers of self-care and “profound” changes in the way health systems operate. 
PNN Pharmacotherapy Line
Apr. 26, 2017 * Vol. 24, No. 80
Providing news and information about medications and their proper use
>>>JAMA Report
Source: Apr. 25 issue of JAMA (2017; 317).
Dosing Schedule for Quadrivalent HPV Vaccine: While waning of vaccine effectiveness is evident by 3 years after immunization, data from a study of dosing of quadrivalent human papillomavirus (HPV) vaccine support shifting from three to two doses (pp. 1687–8). The CDC Advisory Committee on Immunization Practices made that recommendation last year for all three formulations of HPV vaccines available in the U.S. In the current report, a post hoc analysis of data from a phase 3 postlicensure, noninferiority immunogenicity trial at three Canadian centers in 2007–08 shows the following: “Of 520 girls originally randomized, 101 provided serum samples at 60 months (50 receiving 2 doses and 51 receiving 3 doses). Seropositivity at 60 months for both 2 doses and 3 doses was above 95% for all genotypes except HPV 18. At 60 months, responses for HPV 6, HPV 11, and HPV 16 were all noninferior in the 2-dose vs 3-dose groups. Between 36 and 60 months, there was a significant reduction in [geometric mean titers (GMTs)] across all HPV types for both the 2-dose and 3-dose groups based on paired sample t test. However, there was no significant difference in the reduction between groups. For all 4 types in both groups, there was a decline in GMT titers to 60 months, but there was no difference (P >.05) between the trend in decline between 2 and 3 doses.” (G. Ogilvie, gina.ogilvie@cw.bc.ca)
OTC Mechanical Nasal Dilators: In an article reprinted from JAMA Facial Plastic Surgery, authors of a systematic review conclude that external nasal dilator strips available over the counter are an effective alternative to surgical intervention for internal nasal valve obstruction for some patients (pp. 1684–5). Published data on 33 available OTC mechanical dilators showed these results: “An analysis of each product’s mechanism revealed 4 broad classes: external nasal dilator strips, nasal stents, nasal clips, and septal stimulators. A review demonstrated 5 studies supporting the use of external nasal dilator strips, 4 studies supporting the use of nasal clips, 1 study supporting the use of nasal stents, and no studies supporting the use of septal stimulators.” (S. S. Pawar, spawar@mcw.edu)
Trends in Infective Endocarditis: While the overall incidence of infective endocarditis is stable, etiologies shifted in 1998–2013 to more nonnosocomial sources of health-care-associated conditions, according to epidemiologic data from California and New York state (pp. 1652–60). Sources of nonnosocomial health-care-associated infections are intravenous therapies (including chemotherapy), specialized nursing facilities, hemodialysis, or hospitalization for 2 days or more in the 90 days before admission of infective endocarditis. Also, the proportion of patients with native-valve endocarditis decreased (from 74.5% to 68.4%), while prosthetic-valve endocarditis and cardiac device–related endocarditis increased (from 12.0% to 13.8% and from 1.3% to 4.1%, respectively). (J. Chikwe, joanna.chikwe@mountsinai.org)
Lack of Evidence Guiding Marijuana Therapy: After taking an 8-hour course required in Florida before physicians can recommend medical marijuana to their patients, an internist practicing in Key West found that he had little evidence to make him comfortable with this intervention, according to a news article (pp. 1611–3). “‘The course has no dosing data. You go to the smallest amount possible and then work your way up,’ Norris explained. ‘It’s like trying to prescribe St John’s wort instead of Prozac.’ The lack of clear dosing guidelines also makes it difficult to determine whether a patient is misusing medical marijuana.…
“Norris, who has a sign hanging in his waiting room stating ‘this is not a pain clinic,’ is unmoved by callers claiming that since their state approved an amendment legalizing medical marijuana, it is now their constitutional right to get it. ‘They think I’m supposed to just go ahead and write the scripts, and I’m not doing that.’” (R. Rubin)
>>>PNN NewsWatch
*
FDA yesterday posted online warning letters to 14 U.S.-based companies that it said were illegally selling more than 65 products that fraudulently claim to prevent, diagnose, treat, or cure cancer. The products are marketed and sold without FDA approval, most commonly on websites and social media platforms, the agency said.
PNN Pharmacotherapy Line
Apr. 27, 2017 * Vol. 24, No. 81
Providing news and information about medications and their proper use
>>>NEJM Report
Source: Apr. 27 issue of the New England Journal of Medicine (2017; 376).
Cytokine BAFF Overexpression & Autoimmunity Risk: Patients with a DNA variant had higher risks of developing multiple sclerosis and systemic lupus erythematosus (SLE) in a genomewide-association, case–control study from Sardinia, Italy (pp. 1615–26): “A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT [to] A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.” (F. Cucca, fcucca@uniss.it)
“It will be a challenge for the future to assess whether the insertion–deletion variant of
TNFSF13B can be used to stratify patients for a specific therapy,” editorialists write (pp. 1680–1). “Although the data from the current study clearly point in this direction, the discriminatory power of this solitary [single-nucleotide polymorphism] may not be sufficient for clinical decision making. However, it seems reasonable to study whether stratification of patients according to the variant of TNFSF13B could be useful for clinical trials that assess B-cell–directed therapies.” (T. Korn)
Uninterrupted Dabigatran in Atrial Fibrillation Ablation: Compared with uninterrupted warfarin in patients undergoing ablation for atrial fibrillation, continued dabigatran produced significantly fewer bleeding episodes, researchers report (pp. 1627–36). In a randomized, open-label trial with blinded adjudicated end-point assessments, dabigatran 150 mg twice daily or warfarin titrated to INRs of 2.0 to 3.0 produced these results based on bleeding in the 8 weeks after ablation: “The trial enrolled 704 patients across 104 sites; 635 patients underwent ablation. Baseline characteristics were balanced between treatment groups. The incidence of major bleeding events during and up to 8 weeks after ablation was lower with dabigatran than with warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk difference, −5.3 percentage points; 95% confidence interval, −8.4 to −2.2; P <0.001). Dabigatran was associated with fewer periprocedural pericardial tamponades and groin hematomas than warfarin. The two treatment groups had a similar incidence of minor bleeding events. One thromboembolic event occurred in the warfarin group.” (H. Calkins, hcalkins@jhmi.edu)
Adalimumab/Methotrexate for Uveitis in Juvenile Idiopathic Arthritis: In a study of children and adolescents with active juvenile idiopathic arthritis (JIA)–associated uveitis, adalimumab provided better control of inflammation when added to methotrexate, but the anti-TNF agent also produced a much higher incidence of adverse effects, including serious ones (pp. 1637–46). Based on a primary end point of time to treatment failure, the study showed: “The prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed 16 treatment failures in 60 patients (27%) in the adalimumab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P <0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalimumab than in those receiving placebo (10.07 events per patient–year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient–year [95% CI, 5.26 to 7.77]), as were serious adverse events (0.29 events per patient–year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient–year [95% CI, 0.00 to 0.40]).” (A. V. Ramanan, avramanan@hotmail.com)
>>>PNN NewsWatch
*
Correction: Yesterday’s PNN incorrectly stated that vaccine effectiveness waned in the JAMA study of two versus three doses of HPV vaccine. While geometric mean titers indicated declining antibodies to the four HPV types, breakthrough cases of cervical cancer or other HPV diseases were not observed; studies of long-term vaccine efficacy are pending.
PNN Pharmacotherapy Line
Apr. 28, 2017 * Vol. 24, No. 82
Providing news and information about medications and their proper use
>>>Nephrology Report
Source: May issue of the American J. Kidney Diseases (2017; 69).
Self-Managed Sodium Restriction in CKD: At four Dutch hospitals, patients with moderately decreased renal function who were randomized to regular care plus self-management of sodium restriction had modestly improved outcomes over those managed with regular care alone (pp. 576–86). The intervention — education, motivational interviewing, coaching, and self-monitoring of blood pressure (BP) and sodium — yielded these results: “At baseline, mean sodium excretion rate was 163.6 ± 64.9 (SD) mmol/24 h; mean estimated glomerular filtration rate was 49.7 ± 25.6 mL/min/1.73 m2; median protein excretion rate was 0.8 (IQR, 0.4–1.7) g/24 h; and mean 24-hour ambulatory systolic and diastolic BPs were 129 ± 15 and 76 ± 9 mm Hg, respectively. Compared to regular care only (n = 71), at 3 months, the intervention group (n = 67) showed reduced sodium excretion rate (mean change, −30.3 [95% CI, −54.7 to −5.9] mmol/24 h), daytime ambulatory diastolic BP (mean change, −3.4 [95% CI, −6.3 to −0.6] mm Hg), diastolic office BP (mean change, −5.2 [95% CI, −8.4 to −2.1] mm Hg), protein excretion (mean change, −0.4 [95% CI, −0.7 to −0.1] g/24h), and improved self-efficacy (mean change, 0.5 [95% CI, 0.1 to 0.9]). At 6 months, differences in sodium excretion rates and ambulatory BPs between the groups were not significant, but differences were detected in systolic and diastolic office BPs (mean changes of −7.3 [95% CI, −12.7 to −1.9] and −3.8 [95% CI, −6.9 to −0.6] mm Hg, respectively), protein excretion (mean changes, −0.3 [95% CI, −0.6 to −0.1] g/24h), and self-efficacy (mean change, 0.5 [95% CI, 0.0 to 0.9]). No differences in kidney function, medication, and health-related quality of life were observed.” (Y. Meuleman, meulemany@fsw.leidenuniv.nl)
Belatacept in Kidney Transplant Recipients: Phase 2 trial participants with kidney transplants who were switched from a calcineurin inhibitor (CNI) to belatacept had acceptable safety outcomes at 36 months posttransplantation, researchers report (pp. 587–94). Medications were changed between 6 and 36 months after transplant; a previous study showed improved kidney function at 12 months postconversion. Safety data at 36 months for 173 patients were as follows: “Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure−adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person–years) and malignancies (3.01 vs 3.41 per 100 person–years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person–years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07 mL/min/1.73 m2 per year; P for time-by-treatment interaction effect = 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65–9.65; P = 0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14–7.07; P = 0.9).” (Josep M. Grinyó, jgrinyo@ub.edu)
>>>PNN NewsWatch
* In its first liver-cancer indication approval in almost a decade,
FDA yesterday expanded the approved use of regorafinib (Stivarga, Bayer) to include treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
*
FDA also approved cerliponase alfa (Brineura, BioMarin Pharmaceutical) as a treatment for a specific form of Batten disease. Brineura is the first FDA-approved treatment to slow loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2, also known as tripeptidyl peptidase-1 deficiency.
* Label changes for
general anesthetics and sedatives in children younger than 3 years of age have been approved by FDA. A new warning states that exposure to these medicines for lengthy periods of time or over multiple surgeries or procedures may negatively affect brain development in children younger than 3 years, and the pregnancy and pediatric use sections of the label now cautions of widespread neuronal damage in young animals and pregnant animals exposed to the drugs for more than 3 hours.

PNN Pharmacotherapy Line
May 1, 2017 * Vol. 24, No. 83
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: Apr. 29 issue of Lancet (2017; 389).
Risankizumab Induction Therapy in Crohn’s disease: Blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in moderate-to-severe Crohn’s disease, according to findings of a short-term study of risankizumab (pp. 1699–709). In an international phase 2 study, patients with moderate-to-severe Crohn’s disease had these outcomes after randomization to placebo or risankizumab 200 or 600 mg: “Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15.0%, 95% CI 0.1 to 30.1; p = 0.0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9.0%, −8.3 to 26.2; p = 0.31) and 15 (37%) of 41 who received the 600 mg dose (20.9%, 2.6 to 39.2; p = 0.0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn’s disease. No deaths occurred.” (B. G. Feagan, brian.feagan@robartsinc.com)
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Mortality Risk of Opioid Substitution Treatment: A systematic review and meta-analysis of 19 cohorts in published studies of 122,885 people taking methadone over 1.3–13.9 years and 15,831 people treated with buprenorphine for 1.1–4.5 years reached this conclusion (j1550): “Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.” (G. Barrio, gbarrio@isciii.es)
>>>PNN NewsWatch
*
FDA on Friday approved midostaurin (Rydapt, Novartis) for treatment of adults with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation, FLT3, in combination with chemotherapy. The drug is approved for use with a companion diagnostic, the LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies), which is used to detect the FLT3 mutation in patients with AML. Midostaurin is also approved for treatment of adults with advanced systemic mastocytosis, which includes aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic neoplasm, and mast cell leukemia.
>>>PNN JournalWatch
* Inappropriate Medication in Non-Hospitalized Patients With Renal Insufficiency: A Systematic Review, in
Journal of the American Geriatrics Society, 2017; 65: 853–62. (M. Dörks, michael.doerks@uni-oldenburg.de
* Proton Pump Inhibitor Use and Risk of Hip Fracture in Kidney Transplant Recipients, in
American Journal of Kidney Diseases, 2017; 69: 595–601. (C. R. Lenihan, clenihan@stanford.edu
* E-Prescribing and Adverse Drug Events: An Observational Study of the Medicare Part D Population With Diabetes, in
Medical Care, 2017; 55: 456–62. (M. H. Gabriel) 
* Chronic Health Outcomes and Prescription Drug Copayments in Medicaid, in
Medical Care, 2017; 55: 520–7. (D. Kostova) 
* Antibiotic Prophylaxis for Urinary Tract Infection–Related Renal Scarring: A Systematic Review, in
Pediatrics, 2017; 139: 0.1542/peds.2016-3145. (I. K. Hewitt)
* Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-4317. (H. S. Fischer)
PNN Pharmacotherapy Line
May 2, 2017 * Vol. 24, No. 84
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: May 2 issue of the Annals of Internal Medicine (2017; 166).
Oral Direct-Acting Agent Therapy for Hepatitis C Virus: FDA-approved oral direct-acting antiviral (DAA) regimens produce high sustained virologic response (SVR) rates for all six hepatitis C virus (HCV) genotypes and for patient populations historically considered difficult to cure, conclude authors of a systematic review article (pp. 637–48). These details reflect data from 43 English-language studies of trials lasting at least 8 weeks of interferon-free regimens for HCV in adults: “Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child–Turcotte–Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without.” (O. Falade-Nwulia, ofalade1@jhmi.edu)
“These findings provide hope that HCV infection is now a fully treatable condition that, with sufficient efforts, can be eliminated as an important medical problem in the United States,” an editorialist writes (
pp. 675–6). “Amid the optimism about HCV therapy, however, a few caveats need to be mentioned.” The  caveats include concerns that the response rates were close to, but not equal to, 100%; many persons remain unaware of their infection until cirrhosis or end-stage liver disease arises; rare but serious adverse events have been reported; and the word “cure” may imply that further concern or follow-up is not needed. (J. H. Hoofnagle)
Benefits & Harms of Osteoporosis Medications in Chronic Kidney Disease: “Effects of osteoporosis medications on [bone mineral density (BMD)], fracture risk, and safety among patients with [chronic kidney disease (CKD)] are not clearly established,” conclude authors of a systematic review and meta-analysis article (pp. 649–58): “There were 13 trials (n = 9,850) that included kidney transplant recipients (6 trials), patients who had stage 3 to 5 CKD or were receiving dialysis (3 trials), or postmenopausal women with CKD (4 trials). Evidence showed that bisphosphonates may slow loss of BMD among transplant recipients (moderate [strength of evidence (SOE)]), but their effects on fractures and safety in transplant recipients and others with CKD are unclear. Raloxifene may prevent vertebral fractures but may not improve BMD (low SOE). Effects of teriparatide and denosumab on BMD and fractures are unclear (very low SOE), and these medications may increase risk for some safety outcomes.” (L. M. Wilson, lisawilson@jhmi.edu)
Administrative Tasks in Health Care: An American College of Physicians (ACP) position paper presents seven recommendations on how to assess administrative requirements and tasks that affect physician time, practice, and system cost, and patient care (pp. 659–61). ACP first calls on “stakeholders external to the physician practice or health care clinician environment who develop or implement administrative tasks (such as payers, governmental and other oversight organizations, vendors and suppliers, and others) to provide financial, time, and quality-of-care impact statements for public review and comment” for all existing and new administrative tasks. “Administrative tasks that cannot be eliminated from the health care system must be regularly reviewed, revised, aligned, and/or streamlined in a transparent manner, with the goal of minimizing burden, by all stakeholders involved,” the authors continue. “Stakeholders, including public and private payers, must collaborate with professional societies, frontline clinicians, patients, and electronic health record vendors to aim for performance measures that minimize unnecessary clinician burden, maximize patient and family centeredness, and integrate the measurement of and reporting on performance with quality improvement and care delivery.” Other recommendations call for efficiency and research on the effects of administrative tasks. (S. M. Erickson, serickson@acponline.org)
PNN Pharmacotherapy Line
May 3, 2017 * Vol. 24, No. 85
Providing news and information about medications and their proper use
>>>JAMA Report
Source: May 2 issue of JAMA, a theme issue on conflicts of interest (2017; 317).
Conflicts of Interest: In one of numerous Viewpoints on conflicts of interest in medicine, health care, education, research, and publication, a writer asks, “Why does it matter?” (pp. 1717–8): “Physicians, like others, have many types of possible financial interests. As clinicians, their basic income may be salary, capitation, or fee-for-service. A surgeon paid fee-for-service clearly has a financial stake in whether a patient agrees to surgery. This is transparent to the patient and may be readily balanced by seeking a second opinion from a disinterested expert. Consultant fees, honoraria, and other financial interests may arise in relation to other professional roles. Authors of a published article, for example, may disclose an institutional affiliation, sources of other relevant income, and funders of the research. What is acceptable for an author and remedied by disclosure may differ from more lax standards required for a reviewer who is merely advising the editors and from more stringent standards for selecting an editorialist who will interpret the meaning of the research for clinical practitioners. Standards for disclosure and inclusion may be even more stringent for experts chosen to develop professional guidelines or regulations that can directly affect practice.…
“The Gallup poll reports that nurses, pharmacists, and physicians are among the professions most trusted by the US public. Especially at a time when the place of science is challenged in public policy and decision making, it is incumbent on the health professions to champion their reliance on evidence and disinterested expertise. Adherence to carefully considered, transparent, and evenhanded policies on conflict of interest can help physicians earn and maintain their trusted place in the minds of the public and policy makers.” (H. V. Fineberg,
harvey.fineberg@moore.org)
Trying to distinguish between “potential or perceived” and “true or actual” COIs are misguided, argue authors of a second article (
pp. 1721–2): “Distinctions between potential and actual COI are rooted in a basic misunderstanding of the concept of a COI and its ethical significance. These invidious distinctions should be avoided. A COI exists when a secondary interest has the potential to bias a physician’s or a researcher’s primary interest in pursuing patient well-being and generalizable knowledge. Physicians and others must use clear and consistent terms to describe the severity of a COI, the policies that are used to manage a COI, and the standards for identifying a COI. Achieving greater conceptual clarity is essential to develop policies that effectively regulate COIs without unduly limiting financial interactions that do not constitute COIs. Only in this way can the integrity of medical research and practice be protected.” (M. S. McCoy, mmcco@mail.med.upenn.edu)
>>>Pediatrics Report
Source: May issue of Pediatrics (2017; 139).
Support for Vaccinations: Three articles provide useful information and insights regarding pediatric immunizations.
Vaccinating children against influenza saves lives, report authors who assessed the risk reduction using a case–cohort analysis of U.S. data for 2010–14 (
10.1542/peds.2016-4244). “Overall [vaccine effectiveness (VE)] against death was 65% (95% CI, 54% to 74%). Among 153 deaths in children with underlying high-risk medical conditions, 47 (31%) were vaccinated. VE among children with high-risk conditions was 51% (95% CI, 31% to 67%), compared with 65% (95% CI, 47% to 78%) among children without high-risk conditions.” (B. Flannery)
A retrospective study from Kaiser Northern California “strongly supports the United States’ current recommendation to administer Tdap during each pregnancy” (
10.1542/peds.2016-4091). “Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life,” the investigators conclude. “Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life.” (R. Baxter)
Adults who get vaccinated are more likely to have their children immunized, according to data from the Oregon ALERT Immunization Information System (
10.1542/peds.2016-2883). The authors conclude that “encouraging parental immunization is a potential tool for increasing children’s immunization rates.” (S. G. Robison)
PNN Pharmacotherapy Line
May 4, 2017 * Vol. 24, No. 86
Providing news and information about medications and their proper use
>>>NEJM Report
Source: May 4 issue of the New England Journal of Medicine (2017; 376).
Cardiovascular Outcomes With Evolocumab: In a trial of 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg/mL or more who were receiving statin therapy, addition of the PCKS9 inhibitor evolocumab lowered LDL cholesterol levels to a median of 30 mg/dL, researchers report (pp. 1713–22). In the FOURIER trial, subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly produced these outcomes: “At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P <0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary [efficacy] end point (1,344 patients [9.8%] vs. 1,563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P <0.001) and the key secondary [efficacy] end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P <0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).” (M. S. Sabatine, msabatine@partners.org)
“It is anticipated that the results of the FOURIER trial will soon be implemented in international guidelines regarding the treatment of high-risk patients, directing clinicians in the use of this new and expensive class of drugs,” an editorialist writes (
pp. 1790–1). “The FOURIER trial is a landmark trial providing formal evidence that treatment targeted at PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved by lipid-lowering treatment alone. However, in this trial, the duration of evolocumab treatment was rather short. The efficacy, with regard to atherosclerotic cardiovascular disease, of PCSK9 inhibition treatment that is started shortly after an acute event still needs to be determined, as does the efficacy of the treatment in other categories of high-risk patients. End-point studies of alirocumab and other monoclonal antibodies against PCSK9 (bococizumab and LY3015014) are under way, and an RNA interference therapeutic agent that inhibits PCSK9 synthesis and lowers plasma LDL cholesterol levels has been tested in a phase 1 study.” (R. P. F. Dullaart)
Tofacitinib in Ulcerative Colitis: The oral small-molecule Janus kinase inhibitor tofacitinib produced significant improvements as induction and maintenance treatment of ulcerative colitis in 3 placebo-controlled, phase 3 trials (pp. 1723–36). The OCTAVE Induction 1 and 2 trials and the OCTAVE Sustain trial included 598, 541, and 593 patients, respectively, and produced these results: “In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P = 0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P <0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P <0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.” (W. J. Sandborn, wsandborn@ucsd.edu)
“Regardless of its eventual place in the treatment algorithm for ulcerative colitis, tofacitinib is a new class of therapy that has efficacy” and a “promising step forward,” an editorialist writes (
pp. 1792–3; S. Friedman).
PNN Pharmacotherapy Line
May 5, 2017 * Vol. 24, No. 87
Providing news and information about medications and their proper use
>>>Psychiatry Report
Source: May issue of the American Journal of Psychiatry (2017; 174).
Pediatric Antidepressant Efficacy: Studies funded by the National Institute of Mental Health support antidepressant efficacy in children and adolescents for a variety of pediatric internalizing conditions, concludes the author of a review article (pp. 430–7). In contrast, industry-funded research has a number of flaws that limit applicability of the results, as noted in this summary: “In this review, the author discusses several scientific and clinical complexities that are important to understand in reviewing the antidepressant literature: the strengths and weaknesses of meta-analyses; the scientific and regulatory context for the large number of antidepressant trials in the late 1990s and early 2000s; and the distinction between a negative trial, where the treatment does not demonstrate efficacy, and a failed trial, where methodological problems make it impossible to draw any conclusion about efficacy. It is the premise of this review that meta-analyses that include the large number of industry-sponsored antidepressant trials distort the picture of antidepressant efficacy for teen depression. Industry-sponsored child and adolescent depression trials suffer from a number of implementation challenges and should be considered failed trials that are largely uninformative and not eligible to be included in efficacy meta-analyses. In contrast to the industry-sponsored trials, depression trials funded by the National Institute of Mental Health (NIMH) (N = 2) are characterized by many methodological strengths, lower placebo response rates (30%−35%), and meaningful between-group differences (25%−30%) that support antidepressant efficacy. The NIMH-funded trials, taken together with the demonstrated efficacy of the serotonin reuptake inhibitors for childhood-onset obsessive-compulsive disorder and the anxiety disorders, suggest a broad and important role for antidepressant medications in pediatric internalizing conditions.” (J. T. Walkup, jtw9001@med.cornell.edu)
“One can understand the controversy surrounding SSRIs by noting the context from which it arose,” editorialists write (
pp. 407–8). “When considering this context, it is also important to remember the large burden to patients, families, and communities associated with pediatric mental disorders. Most importantly, when clinicians look beyond controversy to their patients’ clinical burden, Walkup’s perspective helps us carefully evaluate the efficacy data to choose the best treatment for children and adolescents with major depression, anxiety disorders, and OCD, and in particular, to consider the SSRIs as a reasonable therapeutic option for many of our patients.” (D. S. Pine, daniel.pine@nih.gov)
Overdoses/Poisonings With Antidepressants: Data from the National Poison Data System for 2000–14 show a large increase in overdoses with and nonintentional exposures to drugs used to treat depression, researchers report (pp. 438–50): “During this 15-year period, there were 962,222 single substance exposures to the 48 medications studied. Serious outcomes rose 2.26-fold and in linear fashion over the 15 years. While tricyclic and monoamine oxidase inhibitor medications were associated with high morbidity and mortality, several newer agents also appeared hazardous. Lithium, quetiapine, olanzapine, bupropion, and carbamazepine were associated with high morbidity indices. Lithium, venlafaxine, bupropion, quetiapine, olanzapine, ziprasidone, valproic acid, carbamazepine, and citalopram were associated with higher mortality indices.” (J. C. Nelson, craig.nelson@ucsf.edu)
>>>PNN NewsWatch
* “Insurers and markets, rather than government, should be empowered to find ways to provide health insurance to a broad set of people at affordable prices,” writes a
Wall Street Journal reporter in analyzing yesterday’s Obamacare repeal-and-replace vote in the U.S. House of Representatives. “Republicans are betting that these changes will engender competition, draw healthier people into the insurance pool and cut premium prices overall. Democrats, who uniformly opposed the bill Thursday, said many participants and providers in the health system will face higher costs and be worse off than under [Obamacare].”
* May is
Lyme Disease Awareness Month and the beginning of the period through July when people will get more tick bites and tick-borne diseases than any other time of year in the U.S., says CDC.
PNN Pharmacotherapy Line
May 8, 2017 * Vol. 24, No. 88
Providing news and information about medications and their proper use
>>>Lancet Highlights
Source: May 6 issue of Lancet (2017; 389).
Antithrombotic Treatment After ACS: Combined with a P2Y12 inhibitor, low-dose rivaroxaban versus low-dose aspirin produced similar risks of clinically significant bleeding in patients with acute coronary syndromes, researchers report (pp. 1799–808). Participants at 371 clinical centers in 21 countries were randomized to rivaroxaban 2.5 mg or aspirin 100 mg daily; investigators chose between clopidogrel or ticagrelor for P2Y12 therapy. Results showed: “Between April 22, 2015, and Oct 14, 2016, 3,037 patients with acute coronary syndromes were randomly assigned; 1,518 to receive aspirin and 1,519 to receive rivaroxaban. 1,704 patients (56%) were in the ticagrelor and 1,333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239–354). [Thrombolysis in myocardial infarction] non–[coronary artery bypass grafting] clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1,519 vs 74 participants [5%] of 1,518; HR 1.09 [95% CI 0.80–1.50]; p = 0.5840).” Based on these findings, the authors conclude, “A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.” (E. M. Ohman, ohman001@mc.duke.edu)
>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Postapproval Drug Studies: For 117 new drugs approved by FDA in 2005–12 based on a single pivotal trial and/or surrogate markers, controlled studies published later often did not support the evidence relied on for the initial approval, a systematic review shows (j1680): “We identified 758 published controlled studies over a median of 5.5 years (interquartile range 3.4–8.2) after approval, most of which (554 of 758; 73.1%) were studies for indications approved on the basis of surrogate markers of disease. Most postapproval studies used active comparators—67 of 77 (87.0%) indications approved on the basis of single pivotal trials, 365 of 554 (65.9%) approvals based on surrogate marker trials, and 100 of 127 (78.7%) approvals based on single surrogate trials—and examined surrogate markers of efficacy as primary endpoints—51 of 77 (66.2%), 512 of 554 (92.4%), and 110 of 127 (86.6%), respectively. Overall, no postapproval studies were identified for 43 of the 123 (35.0%) approved indications. The median total number of postapproval studies identified was 1 (interquartile range 0–2) for indications approved on the basis of a single pivotal trial, 3 (1–8) for indications approved on the basis of pivotal trials that used surrogate markers of disease as primary endpoints, and 1 (0–2) for single surrogate trial approvals, and the median aggregate number of patients enrolled in postapproval studies was 90 (0–509), 533 (122–3633), and 38 (0–666), respectively. The proportion of approved indications with one or more randomized, controlled, double blind study using a clinical outcome for the primary endpoint that was published after approval and showed superior efficacy was 18.2% (6 of 33), 2.0% (1 of 49), and 4.9% (2 of 41), respectively.” (J. S. Ross, joseph.ross@yale.edu)
>>>PNN NewsWatch
*
FDA on Friday approved edaravone (Radicava, Mitsubishi Tanabe Pharma America) to treat patients with amyotrophic lateral sclerosis (Lou Gehrig’s disease). 
>>>PNN JournalWatch
* Acute Kidney Injury in Patients with Cancer, in
New England Journal of Medicine, 2017; 376: 1770–81. (M. H. Rosner, mhr9r@virginia.edu
* Antiphospholipid Syndrome: Role of Vascular Endothelial Cells and Implications for Risk Stratification and Targeted Therapeutics, in
Journal of the American College of Cardiology, 2017; 69: 2317–30. (M. T. Corban) 
* Shift Work and Shift Work Sleep Disorder: Clinical and Organizational Perspectives, in
Chest, 2017; 151: 1156–72. (E. Wickwire) 
* Is Rapid Health Improvement Possible? Lessons From the Million Hearts Initiative, in
Circulation, 2017; 135: 1677–80. (J. S. Wright, janet.wright@cms.hhs.gov
* First-Trimester Artemisinin Derivatives and Quinine Treatments and the Risk of Adverse Pregnancy Outcomes in Africa And Asia: A Meta-analysis of Observational Studies, in
PLOS Med, 2017; 14(5): e1002290. (A. Stergachis, stergach@uw.edu)
PNN Pharmacotherapy Line
May 9, 2017 * Vol. 24, No. 89
Providing news and information about medications and their proper use
>>>Internal Medicine Report
Source: May issue of JAMA Internal Medicine (2017; 177).
Thiazolidinediones in Nonalcoholic Steatohepatitis: The thiazolidinedione pioglitazone has shown indications of improving advanced fibrosis in nonalcoholic steatohepatitis (NASH), even in patients without diabetes, authors of a meta-analysis report (pp. 633–40): “This study analyzed 8 [randomized controlled trials (RCTs)] (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25–7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12–2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17–4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04–10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02–3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95–5.93; P < .001; I2= 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%–4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy.” (G. Musso, giovanni_musso@yahoo.it)
Until more data are available, “it may make sense to consider the use of pioglitazone in patients with type 2 diabetes who have NASH and evidence of advanced fibrosis,” editorialists write (
pp. 640–1). “Treating such patients would not incur any incremental risk of adverse events because they might already be taking pioglitazone as part of the management of their diabetes, while potentially benefiting from its putative benefits in NASH. For most patients with NASH, prior guidance to reduce weight, exercise, and refrain from heavy consumption of alcohol would seem prudent until we have data showing therapies that improve clinical outcomes.” (H. F. Yee, Jr., hal.yee@ucsf.edu)
Suicidality & Depression With 5-Alpha-Reductase Inhibitors: Administrative medication use data from Ontario show that men using 5-alpha reductase inhibitors are not at increased risk of suicide, but they do have increase rates of self-harm and depression, researchers report (pp. 683–91). In a retrospective, matched-cohort study of 93,197 men aged 66 years or older, those receiving new prescriptions for agents in this drug class had the following outcomes: “Men who used 5-alpha-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53–1.45). Risk of self-harm was significantly increased during the initial 18 months after 5-alpha-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34–2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5-alpha-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73–2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08–1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100,000 patient–years and 237 per 100,000 patient–years, respectively. The type of 5-alpha-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression.” (B. Welk, bkwelk@gmail.com)
Magnesium Oxide & Nocturnal Leg Cramps: Compared with placebo in a randomized controlled trial of older adults, supplements of magnesium oxide were not significantly better for prevention of nocturnal leg cramps (NLCs) (pp. 617–23). “The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC,” the authors conclude. (U. Milman, uzimy@netvision.net)
>>>PNN NewsWatch
* Following FDA analysis showing presence of anabolic steroids and steroid like substances, all lots of
GEC Laxoplex dietary supplement capsules distributed between Feb. 2, 2015 and May 2, 2017, have been recalled by Genetic Edge Compounds to the retail and consumer levels, the agency said.
PNN Pharmacotherapy Line
May 10, 2017 * Vol. 24, No. 90
Providing news and information about medications and their proper use
>>>JAMA Report
Source: May 9 issue of JAMA (2017; 317).
Selumetinib in Non–Small Cell Lung Cancer: The mitogen-activated protein kinase (MEK) inhibitor selumetinib provided no additional benefit when paired with docetaxel in a trial of 510 patients with advanced KRAS-mutant non–small cell lung cancer (NSCLC), researchers report (pp. 1844–53). In 2013–16, participants in a multinational clinical trial with this type of neoplasm were randomized to docetaxel plus placebo or both active drugs, with these results: “At the time of data cutoff, 447 patients (88%) had experienced a progression event and 346 deaths (68%) had occurred. Median progression-free survival was 3.9 months (interquartile range [IQR], 1.5–5.9) with selumetinib + docetaxel and 2.8 months (IQR, 1.4–5.5) with placebo + docetaxel (difference, 1.1 months; hazard ratio [HR], 0.93 [95% CI, 0.77–1.12]; P = .44). Median overall survival was 8.7 months (IQR, 3.6–16.8) with selumetinib + docetaxel and 7.9 months (IQR, 3.8–20.1) with placebo + docetaxel (difference, 0.9 months; HR, 1.05 [95% CI, 0.85–1.30]; P = .64). Objective response rate was 20.1% with selumetinib + docetaxel and 13.7% with placebo + docetaxel (difference, 6.4%; odds ratio, 1.61 [95% CI, 1.00–2.62]; P = .05). Median duration of response was 2.9 months (IQR, 1.7-4.8; 95% CI, 2.7–4.1) with selumetinib + docetaxel and 4.5 months (IQR, 2.3-7.3; 95% CI, 2.8–5.6) with placebo + docetaxel. Adverse events of grade 3 or higher were more frequent with selumetinib + docetaxel (169 adverse events [67%] for selumetinib + docetaxel vs 115 adverse events [45%] for placebo + docetaxel; difference, 22%).” (P. A. Jänne, pasi_janne@dfci.harvard.edu)
Characterizing these results as “the end of the beginning for targeted therapies,” editorialists write that such agents are “are critical to the future management of patients with
KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations” (pp. 1835–7): “Molecular testing is rapidly evolving and circulating tumor DNA testing will facilitate tumor testing and may allow for serial monitoring and use of surrogate end points for drug development. The next generation of targeted therapies will likely focus on the primary oncogenic molecular event and the acquired resistance mechanisms, and will be more potent and specific for the oncogenic driver. This will ideally improve efficacy and reduce off-target toxicities.” (T. E. Stinchcombe, thomas.stinchcombe@duke.edu)
Quinine Exposure & All-Cause Mortality: Long-term exposure to quinine — either as a treatment for leg cramps or as an ingredient in drinks such as bitter lemon or tonic water — is associated with increased risk of death, a study shows, especially from sudden cardiac death (pp. 1907–9). A U.K. primary care database, The Health Improvement Network (THIN), shows these outcomes among adults who received quinine salt prescriptions for at least 1 year in 1990–2014: “Exposed persons received a median 203 mg/d (interquartile range, 163–252) of quinine. There were 11,598 deaths (4.2 per 100 person–years) among the 44,699 exposed individuals vs 26,753 (3.2 per 100 person–years) among the 130,496 unexposed individuals (adjusted hazard ratio [HR], 1.24 [95% CI, 1.21–1.27]). The increase in the risk of death was more pronounced in those younger than 50 years (adjusted HR, 3.06 [95% CI, 2.51–3.73]), whatever the indication for prescription. A dose-effect was found for exposure of 200 to 299 mg/d (adjusted HR, 1.25 [95% CI, 1.20–1.30]), 300 to 399 mg/d (adjusted HR, 1.83 [95% CI, 1.72–1.94]), and 400 mg/d or more (adjusted HR, 2.24 [95% CI, 1.95–2.58]) compared with less than 200 mg/d (P value for trend, <.001).” (L. Fardet, laurence.fardet@aphp.fr)

* A pro-industry approach is expected from the new Commissioner of Food and Drugs, Scott Gottlieb, MD, who was confirmed by the Senate yesterday 57–42. His support of faster approvals of generic drugs and looser restrictions on off-label marketing could become a factor in the drug-pricing discussion, and he supports “more widespread use of expedited approval reviews for brand-name drugs, the Wall Street Journal reports. The “veteran health-care investor and physician” has opposed importation of drugs by consumers from Canada and other countries.
PNN Pharmacotherapy Line
May 11, 2017 * Vol. 24, No. 91
Providing news and information about medications and their proper use
>>>Pharmacotherapy Report
Source: Early-release articles from Pharmacotherapy (2017; 37).
Postoperative Naloxone Nausea/Vomiting Prophylaxis: Based on a meta-analysis of nine randomized controlled trials, investigators conclude that low-dose naloxone “plays no role in preventing [postoperative nausea and vomiting (PONV)]” (10.1002/phar.1930). The drug reduces postoperative nausea, the authors note, but this does not “translate into decreases in postoperative vomiting,” as explained in this summary of data on 946 adult and pediatric patients: “Naloxone demonstrated a reduced risk of postoperative nausea (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.67–0.95, p = 0.01) in a pooled analysis of eight of the nine studies. However, naloxone did not decrease the risk of postoperative vomiting in a collective assessment of all nine trials (RR 0.83, 95% CI 0.63–1.09, p = 0.18). Subgroup analysis of continuous-infusion naloxone found further reductions in nausea and vomiting, but these findings were limited to 186 of the 946 patients. Three studies recorded antiemetic doses and found an overall dose reduction (RR 0.64, 95% CI 0.42–0.96, p = 0.03). Compared with controls, naloxone prophylaxis of PONV did not significantly change cumulative postoperative opioid needs (mean difference 0.29 mg, 95% CI −3.55 to 4.13 mg, p = 0.88) among five trials, nor visual analog scale pain scores (mean difference −0.11, 95% CI −0.26 to 0.05, p = 0.18) in six studies.” (R. W. Barrons, rbarrons@wingate.edu)
Benzalkonium Chloride in Albuterol Nebulizer Solutions: Authors advise against use of a bronchoconstricting preservative in pharmacy-prepared continuous albuterol nebulizer solutions (10.1002/phar.1929): “For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.” (L. Hendeles, lhendeles@gmail.com)
Drug Polymorphisms in Renal Transplant Recipients: Single nucleotide polymorphisms (SNPs) affect genes for metabolizing enzymes and transporters, a 148-patient study from Brazil shows, and this affects dose and dose-adjusted trough blood concentrations (CLaugh ratio) (10.1002/phar.1928): “ABCC2 c.−24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.−76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus CLaugh values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus CLaugh values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.−76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49–18.79, p <0.05).” (F. D. V. Genvigir, fdallavecchia@yahoo.com.br)
>>>PNN NewsWatch
* The
U.S. Senate Committee on Health, Education, Labor & Pensions this morning continues its consideration of S. 934, the Food and Drug Administration Reauthorization Act. The legislation is being fast-tracked by Congressional leadership and has become a vehicle for other health-related bills, including one that would create a category of OTC hearing aids for use in patients with mild or moderate deficits. Biosimilars, generic drugs, complex nonbiologic bioequivalence, and orphan drugs are other topics in the bill, according to RAPS and National Law Review reports.
PNN Pharmacotherapy Line
May 12, 2017 * Vol. 24, No. 92
Providing news and information about medications and their proper use
>>>Chest Highlights
Source: May issue of Chest (2017; 151).
Combination Therapy of H3N2 Influenza: Among adult patients hospitalized for influenza A(H3N2) infections in early 2015, treatment with a clarithromycin–naproxen–oseltamivir combination reduced 30- and 90-day mortality rates and hospital length of stay, investigators from Hong Kong write of a phase 2b/3 trial (pp. 1069–80). Compared with oseltamivir without placebo for 5 days in the open-label trial, 2 days of the drug combination followed by 3 days of oseltamivir produced these results: “Among the 217 patients with influenza A(H3N2) enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years, and 53.5% were men. Adverse events were uncommon. Ten patients died during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P = .01), less frequent high dependency unit admission (P = .009), and shorter hospital stay (P < .0001). The virus titer and [pneumonia severity index] (days 1–3; P < .01) and the [serial nasopharyngeal aspirate] specimens with [percentage of neuraminidase-inhibitor-resistant A(H3N2) virus] quasispecies ≥ 5% (days 1–2; P < .01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (OR, 0.06; 95% CI, 0.004–0.94; P = .04).” (K-Y Yuen)
Prophylactic Corticosteroids Before Elective Extubation: In critical care settings, postextubation airway events and reintubation were reduced by administration of prophylactic corticosteroids before elective extubations in mechanically ventilated patients (pp. 1002–10). A systematic review and meta-analysis found these outcomes in 11 trials of 2,472 patients: “Use of prophylactic corticosteroids was associated with a reduced incidence of postextubation airway events (risk ratio [RR], 0.43; 95% CI, 0.29–0.66) and reintubation (RR, 0.42; 95% CI, 0.25–0.71) compared with placebo or no treatment. This association was prominent in participants at high risk for the development of postextubation airway complications, defined using the cuff-leak test, with a reduced incidence of postextubation airway events (RR, 0.34; 95% CI, 0.24–0.48) and reintubation (RR, 0.35; 95% CI, 0.20–0.64). This association was not found in trials with unselected participants. Adverse events were rare.” (A. Kuriyama)
>>>Cardiology Report
Source: May issue of the Journal of the American College of Cardiology (2017; 69).
Ambulatory Hemodynamic Monitoring in Heart Failure: “Real-world” effectiveness of ambulatory hemodynamic monitoring of patients with heart failure (HF) is supported by CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in New York Heart Association Functional Class III Heart Failure Patients) trial data (10.1016/j.jacc.2017.03.009). The retrospective cohort analysis of U.S. Medicare data shows a reduction in heart failure hospitalization (HFH) and HF costs with monitoring of patients undergoing pulmonary artery pressure sensor implantation in 2014–15: “Among 1,114 patients receiving implants, there were 1,020 HFHs in the 6 months before, compared with 381 HFHs, 139 deaths, and 17 ventricular assist device implantations and/or transplants in the 6 months after implantation (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.49 to 0.61; p < 0.001). This lower rate of HFH was associated with a 6-month comprehensive HF cost reduction of $7,433 per patient (IQR: $7,000 to $7,884), and was robust in analyses restricted to 6-month survivors. Similar reductions in HFH and costs were noted in the subset of 480 patients with complete data available for 12 months before and after implantation (HR: 0.66; 95% CI: 0.57 to 0.76; p < 0.001).” (A. S. Desai)
>>>PNN NewsWatch
*
Cholera vaccine recommendations for travelers to areas with active cholera transmission are published in yesterday’s MMWR.
* The number of
new hepatitis C virus infections reported to the CDC has tripled over the past 5 years, the agency reported yesterday. While many baby boomers continue to harbor undetected, asymptomatic virus, new infections are more common among those 20–29 years of age and are the result of the U.S. opioid epidemic.

PNN Pharmacotherapy Line
May 15, 2017 * Vol. 24, No. 93
Providing news and information about medications and their proper use
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Acute Myocardial Infarction With NSAIDs in Real-World Use: Patients taking any traditional or selective NSAID, including celecoxib and naproxen, are at increased risk of acute myocardial infarction, according to a systematic review and meta-analysis (j1909). “Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDs and was lower than for rofecoxib,” the authors conclude. “Risk was greatest during the first month of NSAID use and with higher doses.” (M. Bally, michele.bally.chum@ssss.gouv.qc.ca)
Diet & Risk of Gout in Men: Compared with a Western diet (high intake of red and processed meats, French fries, refined grains, sweets, and desserts), the DASH (Dietary Approaches to Stop Hypertension) diet is associated with a lower risk of gout in men, researchers report (j1794). Data for 44,444 men in the Health Professionals Follow-up Study show these benefits for those with high intake of fruits, vegetables, nuts and legumes, low fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats: “During 26 years of follow-up, 1,731 confirmed cases of incident gout were documented. A higher DASH dietary pattern score was associated with a lower risk for gout (adjusted relative risk for extreme fifths 0.68, 95% confidence interval 0.57 to 0.80, P value for trend <0.001). In contrast, a higher Western dietary pattern score was associated with an increased risk for gout (1.42, 1.16 to 1.74, P = 0.005).” (H. K. Choi, hchoi@partners.org)
Genetic Risks of Early-Onset Hypertension: Heritable factors appear important when parents had early-onset hypertension, according to an analysis of data from the Framingham Heart Study (j1949). Patients with parental onset of hypertension before age 55 years had twice the risk of hypertension, leading to this conclusion: “Early onset and not late onset hypertension in parents was strongly associated with hypertension in offspring. In turn, early onset compared with late onset hypertension was associated with greater odds of cardiovascular, and particularly coronary, death. These findings suggest it may be important to distinguish between early onset and late onset hypertension as a familial trait when assessing an individual’s risk for hypertension, and as a specific type of blood pressure trait when estimating risk for cardiovascular outcomes in adults with established hypertension.” (T. J. Niiranen, teemu.niiranen@thl.fi)
>>>Lancet Highlights
Source:
 May 13 issue of Lancet (2017; 389).
Extrafine Triple Therapy in COPD: Single-inhaler extrafine therapy using three drugs was more effective for relieving symptoms of chronic obstructive pulmonary disease than tiotropium alone, the TRINITY study shows (pp. 1919–29). Participants received either tiotropium alone, fixed triple therapy with beclomethasone, formoterol fumarate, and glycopyrronium bromide as a single-dose, extrafine inhaler (fixed) or as individual inhalers (open), with these results: “Between Jan 21, 2014, and March 18, 2016, 2,691 patients received fixed triple (n = 1,078), tiotropium (n = 1,075), or open triple (n = 538). Moderate-to-severe exacerbation rates were 0.46 (95% CI 0.41–0.51) for fixed triple, 0.57 (0.52–0.63) for tiotropium, and 0.45 (0.39–0.52) for open triple; fixed triple was superior to tiotropium (rate ratio 0.80 [95% CI 0.69–0.92]; p = 0.0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0.061 L [0.037 to 0.086]; p <0.0001) and non-inferior to open triple (−0.003L [–0.033 to 0.027]; p = 0.85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple.” (J. Vestbo, jorgen.vestbo@manchester.ac.uk)
>>>PNN JournalWatch
* Mortality From Different Causes Associated With Meat, Heme Iron, Nitrates, and Nitrites in the NIH–AARP Diet And Health Study: Population Based Cohort Study, in BMJ, 2017; 357: j1957. (A. Etemadi, arash.etemadi@nih.gov
* Biologics in Patients With Skin Diseases, in 
Journal of Allergy and Clinical Immunology, 2017; 139: 1423–30. (N. H. Shear, neil.shear@sunnybrook.ca
* Charting the Future of Infectious Disease: Anticipating and Addressing the Supply and Demand Mismatch , in 
Clinical Infectious Diseases, 2017; 64: 1299–301. (R. P. Walensky, rwalensky@partners.org)

PNN Pharmacotherapy Line
May 16, 2017 * Vol. 24, No. 94
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 May 16 issue of the Annals of Internal Medicine (2017; 166).
Prevention and Treatment of Substance Use Disorders: In a position paper, the American College of Physicians advocates for management of substance use disorder involving illicit or prescription drugs as a chronic medical condition and supports “removing or reducing criminal penalties for nonviolent offenses involving illicit drugs” (pp. 733–6): “Substance use disorders have been regarded as a moral failing for centuries, a mindset that has helped establish a harmful and persistent stigma that affects how the medical community confronts addiction. We now know more about the nature of addiction and its effects on brain function, which has led to broader acceptance of the concept that substance use disorder is a disease, like diabetes, that can be treated. Communities across the country are confronting an opioid epidemic that has taken tens of thousands of lives, leading physicians to take a more active role in managing the condition and spurring policymakers to reassess the nation’s drug control policy. Physicians can help guide their patients toward recovery by becoming educated about substance use disorders, proper prescribing practices, consulting prescription drug monitoring programs to reduce opioid misuse, and assisting patients in their treatment. Policymakers can mitigate the effects of drug use by permitting harm reduction strategies, such as syringe exchange programs, supporting initiatives to increase the behavioral health workforce, testing evidence-based prevention and stigma-reduction programs, and encouraging treatment of substance use disorders among incarcerated persons and diversion programs for those with nonviolent drug arrests.” (R. A. Crowley, RCrowley@mail.acponline.org)
HEART Score for ED Chest Pain: Use of the HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score in patients presenting to emergency departments with chest pain is safe for identification of short-term risks of major adverse cardiac events (MACEs), Dutch researchers report, but clinicians often are reluctant to follow its management recommendations (pp. 689–97). At nine hospitals in the Netherlands, unselected patients with chest pain presenting in 2013–14 were managed with either usual care or, in one hospital every 6 weeks, with “HEART care,” producing these results in a stepped-wedge, cluster randomized trial: “A total of 3,648 patients were included (1,827 receiving usual care and 1,821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed.” (J. M. Poldervaart, j.poldervaart@umcutrecht.nl)
Cardiac Troponin T for Rapid Rule-out of AMI: Combined with a nonischemic electrocardiogram (ECG), a single high-sensitivity cardiac troponin T assay below detectable limits can be used to quickly rule out acute myocardial infarction (AMI), according to a collaborative meta-analysis (pp. 715–24). Investigators of studies provided data on the number of low-risk patients and the number who had AMI during hospitalization. Results were as follows: “Of 9,241 patients in 11 cohort studies, 2,825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day major adverse cardiac events ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died.” (M. Than, martinthan@xtra.co.nz)
>>>PNN NewsWatch
ASHP yesterday urged the U.S. Senate to “safeguard public health through the provision of robust coverage including access to health care services, affordable medications, and pharmacist patient care services” as it drafts health care reform legislation. As part of a six-point listing of its top priorities, the Society called for preserving the integrity of 340B drug pricing programs and recognizing pharmacists as full providers of care in team-based delivery models.

PNN Pharmacotherapy Line
May 17, 2017 * Vol. 24, No. 95
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 May 16 issue of JAMA (2017; 317).
Oral Iron Repletion in Heart Failure: In patients with heart failure with reduced left ventricular ejection fraction (HFrEF), exercise capacity was unchanged after 16 weeks of high doses of oral iron polysaccharide, researchers report (pp. 1958–66). Iron deficiency occurs in about 50% of these patients. Based on a primary end point of change in peak oxygen uptake (Vo2), effects of oral iron polysaccharide 150 mg twice daily or placebo were as follows: “Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak Vo2 was 1196 mL/min (interquartile range [IQR], 887–1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887–1449 mL/min) in the placebo group. The primary end point … did not significantly differ between the oral iron and placebo groups (+23 mL/min vs −2 mL/min; difference, 21 mL/min [95% CI, −34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), [plasma N-terminal pro-B-type natriuretic peptide] levels (159; 95% CI, −280 to 599 pg/mL), or [Kansas City Cardiomyopathy Questionnaire] score (1; 95% CI, −2.4 to 4.4), all P >.05.” (G. D. Lewis, glewis@partners.org)
Intra-articular Triamcinolone in Knee Osteoarthritis: Two years of steroid injections into the knees of patients with osteoarthritis produced significantly worse outcomes than saline injections, a study shows (pp. 1967–75). Intra-articular triamcinolone or saline every 12 weeks produced these changes in cartilage volume measured with annual magnetic resonance imaging: “Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm (between-group difference, −0.11 mm; 95% CI, −0.20 to −0.03 mm); and no significant difference in pain (−1.2 vs −1.9; between-group difference, −0.6; 95% CI, −1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels (between-group difference, −0.2%; 95% CI, −0.5% to −0.007%).” (T. E. McAlindon, tmcalindon@tuftsmedicalcenter.org)
Intravitreous Fluocinolone Implants in Uveitis: A common cause of noninfectious intraocular inflammation leading to visual impairment, uveitis is better treated with systemic therapy than implants of fluocinolone acetonide, according to 7-year follow-up results of participants in a randomized trial (pp. 1993–2005). Based on minimal clinically important differences of 7 letters in visual acuity testing, results for surgically placed implants and systemic corticosteroids supplemented by immunosuppression were as follows for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy): “Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1–12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).” (J. H. Kempen, john_kempen@meei.harvard.edu)
Postoperative Opioid Prescribing & Pain Scores: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) pain scores in Michigan hospitals did not correlate with opioid prescribing after surgery, a study shows, supporting less opioid use in these patients (pp. 2013–5; J. F. Waljee, filip@med.umich.edu).
>>>PNN NewsWatch
FDA has added a boxed warning to the labeling of canagliflozin (Invokana, Invokamet, Invokamet XR; Janssen) cautioning of an increased risk of leg and foot amputations with the antidiabetic drug.

PNN Pharmacotherapy Line
May 18, 2017 * Vol. 24, No. 96
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 May 18 issue of the New England Journal of Medicine (2017; 376).
Imatinib in Severe Refractory Asthma: A 24-week trial of imatinib in patients with poorly controlled severe asthma indicates involvement of KIT-dependent processes and mast cells in the pathophysiology of the disease, researchers report (pp. 1911–20). Participants had airway hyperresponsiveness despite maximal medical therapy when imatinib or placebo produced these results: “Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (± SD) of 1.73 ± 0.60 doubling doses in the imatinib group, as compared with 1.07 ± 0.60 doubling doses in the placebo group (P = 0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02 ± 2.32 vs. 0.56 ± 1.39 ng per milliliter, P = 0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group.” (E. Israel, eisrael@partners.org)
“In those unfortunate people in whom the functions of mast cells can be strongly implicated as contributing to disease, suppressing their function or reducing their numbers may indeed confer more benefit than harm, particularly if these cells can be targeted locally at sites of disease,” an editorialist writes (
pp. 1983–4). “It should go without saying that if agents were to be devised that can more specifically target mast cells than do drugs such as imatinib, and can do so safely, then testing such agents in the clinic will be of particular interest.” (S. J. Galli)
Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: The anti–interleukin-5 monoclonal antibody mepolizumab produced significantly more weeks in remission among patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis and enabled less use of glucorticoids, a study shows, but only about one-half of patients benefited from the intervention (pp. 1921–32). Subcutaneous mepolizumab or placebo every 4 weeks over 52 weeks yielded these outcomes in 136 participants: “Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P <0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P <0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P <0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P <0.001). The safety profile of mepolizumab was similar to that observed in previous studies.” (M. E. Wechsler, mikewechsler@gmail.com)
“After this proof-of-concept study, additional research is needed to identify biomarkers that inform success and failure of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis and to elucidate the fate of tissue eosinophils, especially in vasculitic lesions,” according to editorialists (
pp. 1985–6). “Further studies may discover previously unknown pro-eosinophilic mechanisms or identify eosinophil-independent mechanisms in eosinophilic granulomatosis with polyangiitis. Future trials will also need not only to establish the appropriate dosing of mepolizumab but also to include participants with life-threatening eosinophilic granulomatosis with polyangiitis who were not included in this trial and possibly to evaluate synergy with immunosuppressants such as azathioprine and cyclophosphamide.” (R. Djukanovic)
>>>PNN NewsWatch
FDA yesterday expanded the approved use of ivacaftor (Kalydeco, Vertex Pharmaceuticals) for treating cystic fibrosis, tripling the number of rare gene mutations that the drug can now treat and expanding the indication from the treatment of 10 to 33 mutations.

PNN Pharmacotherapy Line
May 19, 2017 * Vol. 24, No. 97
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 (2017; 64).
Repeated Influenza Vaccinations & Hospitalizations: A study provides supportive data for people receiving annual influenza vaccinations, with higher vaccine effectiveness (VE) against hospitalization for influenza in those immunized during both current and prior seasons, compared with those immunized only in a single season (pp. 1564–72). Some studies have shown lower VE after multiple influenza vaccinations. In this study, data from the Australian Influenza Complications Alert Network (FluCAN) provide more reassuring data: “Over 2010–2015, 6,223 cases and 6,505 controls were hospitalized with confirmed influenza and influenza test–negative acute respiratory illness, respectively. Following stratification by quintile of propensity score, site, and year, VE was estimated to be 43% (95% confidence interval [CI], 37%–49%) overall. VE was estimated to be 51% (95% CI, 45%–57%) in those vaccinated in both the current and previous season, compared with 33% (95% CI, 17%–47%) vaccinated in the current season only and 35% (95% CI, 21%–46%) in the previous season only. Similar results were observed for influenza A/H1N1, influenza A/H3N2, and influenza B strains.” (A. C. Cheng)
Phage Lysis for Pathogenic E. coli: In an in vitro microscope study, therapeutically relevant bacteriophages were noninferior to beta-lactams in their cidal effects on pathogenic Escherichia coli, researchers report (pp. 1582–8). Comparing two phages and four antibiotics in two bacterial strains, investigators assessed kill rates and levels of associated endotoxin release (ER): “While beta-lactams have a relatively slow effect, both tested phages, as well as amikacin, were able to rapidly abolish the bacterial growth. Even when considering the fastest phage (cell lysis in 9 minutes), the concentrations of phage-induced ER never reached the highest values, which were recorded with antibiotic treatments. Cumulative concentrations of endotoxin over time in phage-treated conditions were lower than those observed with beta-lactams and close to those observed with amikacin. Whereas beta-lactams were responsible for strong cell morphology changes (spheroplast with imipenem, filamentous cells with cefoxitin and ceftriaxone), amikacin and phages did not modify cell shape but produced intracellular inclusion bodies.” (L. Debarbieux, laurent.debarbieux@pasteur.fr)
>>>Oncology Highlights
Source:
 May 10 issue of the Journal of Clinical Oncology (2017; 35).
Pravastatin in Small-Cell Lung Cancer: Combined with standard therapy for small-cell lung cancer (SCLC), pravastatin was safe but failed to demonstrate benefits among 846 patients (pp. 1506–14). Observational studies have shown possible statin benefits, but this randomized, placebo-controlled trial of pravastatin 40 mg daily during six chemotherapy cycles produced these results: “The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 [progression-free survival (PFS)] events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year [overall survival (OS)] rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups.” (M. J. Seckl, m.seckl@imperial.ac.uk)
“On the basis of these and other prospective trial data and given the resources required, additional prospective trials of statins to improve survival in other cancers are likely not justified,” an editorialist writes (
pp. 1497–8). “These data also fire another loud warning shot for cancer therapy repurposing, given the negative outcomes for thalidomide, topical nitroglycerin, and dalteparin. Moreover, for SCLC, where multiple trials have previously failed to deliver new systemic therapies despite encouraging retrospective or preclinical evidence, the systemic therapeutics future now eagerly anticipates late-phase development of immune-checkpoint inhibitors and antibody drug conjugates….” (S. Popat, sanjay.popat@rmh.nhs.uk)

PNN Pharmacotherapy Line
May 22, 2017 * Vol. 24, No. 98
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 May 20 issue of Lancet (2017; 389).
Rituximab & Short-Term Prednisone in Pemphigus: Compared with prednisone alone, first-line rituximab plus short-term prednisone proved more effective for patients with pemiphigus and produced fewer adverse events, researchers report (pp. 2031–40). At 25 French dermatology hospital departments, 90 adults newly diagnosed with pemphigus had these treatment responses: “At month 24, 41 (89%) of 46 patients assigned to rituximab plus short-term prednisone were in complete remission off-therapy versus 15 (34%) of 44 assigned to prednisone alone (absolute difference 55 percentage points, 95% CI 38.4–71.7; p <0.0001. This difference corresponded to a relative risk of success of 2.61 (95% CI 1.71–3.99, p <0.0001), corresponding to 1.82 patients (95% CI 1.39–2.60) who would need to be treated with rituximab plus prednisone (rather than prednisone alone) for one additional success. No patient died during the study. More severe adverse events of grade 3–4 were reported in the prednisone-alone group (53 events in 29 patients; mean 1.20 [SD 1.25]) than in the rituximab plus prednisone group (27 events in 16 patients; mean 0.59 [1.15]; p = 0.0021). The most common of these events in both groups were diabetes and endocrine disorder (11 [21%] with prednisone alone vs six [22%] with rituximab plus prednisone), myopathy (ten [19%] vs three [11%]), and bone disorders (five [9%] vs five [19%]).” (J. Pascal, Pascal.Joly@chu-rouen.fr)
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Medical Abortion & Online Telemedicine: Self-sourced medical abortion supported by online telemedicine services produces outcomes similar to those obtained in clinics, a study from Ireland and Northern Ireland shows (j2011). “Women are able to self identify the symptoms of potentially serious complications, and most report seeking medical attention when advised,” the authors conclude based on these results: “In 2010-12, abortion medications (mifepristone and misoprostol) were sent to 1,636 women and follow-up information was obtained for 1,158 (71%). Among these, 1,023 women confirmed use of the medications, and follow-up information was available for 1,000. At the time women requested help from [Women on Web], 781 (78%) were <7 weeks pregnant and 219 (22%) were 7–9 weeks pregnant. Overall, 94.7% (95% confidence interval 93.1% to 96.0%) reported successfully ending their pregnancy without surgical intervention. Seven women (0.7%, 0.3% to 1.5%) reported receiving a blood transfusion, and 26 (2.6%, 1.7% to 3.8%) reported receiving antibiotics (route of administration (IV or oral) could not be determined). No deaths resulting from the intervention were reported by family, friends, the authorities, or the media. Ninety three women (9.3%, 7.6% to 11.3%) reported experiencing any symptom for which they were advised to seek medical advice, and, of these, 87 (95%, 87.8% to 98.2%) sought attention. None of the five women who did not seek medical attention reported experiencing an adverse outcome.” (A. Aiken, araa2@utexas.edu)
Physician Age & Outcomes in Hospitalized Older Americans: Older adults treated in U.S. hospitals have poorer outcomes when treated by older physicians, according to analysis of a 20% sample of Medicare fee-for-service beneficiaries in 2011–14 (j1797): “Patients’ adjusted 30 day mortality rates were 10.8% for physicians aged <40 (95% confidence interval 10.7% to 10.9%), 11.1% for physicians aged 40-49 (11.0% to 11.3%), 11.3% for physicians aged 50–59 (11.1% to 11.5%), and 12.1% for physicians aged ≥60 (11.6% to 12.5%). Among physicians with a high volume of patients, however, there was no association between physician age and patient mortality. ” (Y. Tsugawa, ytsugawa@hsph.harvard.edu)
>>>PNN JournalWatch
* An Appraisal of the Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-analysis of the Age-Stratified Disease Occurrence, in Clinical Infectious Diseases, 2017; 64: 1604–11. (C. Britto, carl.britto@paediatrics.ox.ac.uk)
* Creation of an Interprofessional Teledementia Clinic for Rural Veterans: Preliminary Data, in 
Journal of the American Geriatrics Society, 2017; 65: 1092–9. (B. B. Powers, powersb3@uthscsa.edu
* Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups, in 
J. Gerontology, Series A, 2017; 72: 838–45. (M. A. Espeland, mespelan@wakehealth.edu)

PNN Pharmacotherapy Line
May 23, 2017 * Vol. 24, No. 99
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Rheumatology Report
Source:
 May issue of Arthritis & Rheumatology (2017; 69).
Risk Stratification Needed for Rheumatoid Arthritis Prevention: Among 110 participants in the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial, methotrexate administered for 1 year delayed and prevented development of rheumatoid arthritis (RA) in those at high risk who had undifferentiated arthritis (UA), researchers report (pp. 926–31). Reinvestigation of the methotrexate’s effects during 5 years of follow-up showed these results: “Twenty-two of the 110 patients in the PROMPT trial had a high risk of RA at baseline. In the MTX arm, 6 of 11 patients (55%) developed RA, compared to 11 of 11 patients (100%) in the placebo arm (P = 0.011). Time to RA development was longer in the MTX arm than in the placebo arm (median 22.5 months versus 3 months; P <0.001). Drug-free remission was achieved by 4 of 11 patients (36%) in the MTX arm compared to 0 of 11 patients (0%) in the placebo arm (P = 0.031). These beneficial effects of MTX were observed both in anti–citrullinated protein antibody (ACPA)–positive and in ACPA-negative UA patients with a high risk of RA, but not in UA patients without a high risk of RA. In retrospect, 43 of 110 patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. In addition, beneficial effects were observed only in patients with a high prediction score.” (L. E. Burgers, l.e.burgers@lumc.nl)
>>>Neurology Highlights
Source:
 May issue of Neurology (2017; 88).
Alcohol & ICH Risk: In the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study, rare and moderate use of alcohol decreased participants’ risk of intracranial hemorrhage (ICH), while heavy alcohol consumption was linked to increased risk, particularly in black and Hispanic patients (pp. 2043–51). The case–control study recruited 1,000 patients with ICH in each of three racial-ethnic groupings and determined their risk based on alcohol use. With no-alcohol as the reference group, results showed: “Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p <0.0001), moderate (OR 0.65, p <0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p < 0.0001). A similar association was not found in white participants.” (S. Koch, skoch@med.miami.edu)
>>>PNN NewsWatch
FDA approval of an additional indication for subcutaneous tocilizumab (Actemra, Roche) provides the first therapy specific for giant cell arteritis. The agent was previously approved for subcutaneous treatment of moderate to severely active rheumatoid arthritis and intravenous treatment of moderate to severely active rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis.
* Consumers should stop using the dietary supplement product 
Tri-Ton immediately and discard it in accordance in state and local ordinances, FDA said yesterday. Analysis of Tri-Ton indicated the presence of the selective anabolic androgen receptor modulators andarine and ostarine, the agency explained. All lots of the products are being recalled.
FDA announced yesterday that its review to date has identified no adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. While GBCAs may be associated with some gadolinium retention in the brain and other body tissues, lack of evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time, the agency said. FDA will continue to assess the safety of GBCAs and plans to have a public meeting to discuss this issue.

PNN Pharmacotherapy Line
May 24, 2017 * Vol. 24, No. 100
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 May 23/30 issue of JAMA (2017; 317).
Bevacizumab in Macular Edema: Among 362 patients with macular edema caused by central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept based on visual acuity after 6 months of treatment, SCORE2 researchers report (pp. 2072–87). Every-4-week injections of the drugs produced these outcomes with a noninferiority margin of 5 letters on visual acuity tests: “At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, −0.14; 97.5% CI, −3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure.” (P. C. VanVeldhuisen, score2@emmes.com)
“These results are welcome news for the treatment of common global eye care problems like retinal vein occlusions, given the priority that people place on avoiding blindness,” an editorialist writes (
pp. 2067–9). “The noninferior efficacy findings for visual acuity, the comparable rates of adverse ocular events, and the lower cost for bevacizumab from the 6-month primary outcome from SCORE2 are an excellent start. However, given the long-term need for anti-VEGF therapy in many eyes with macular edema from a central retinal or hemiretinal vein occlusion, additional data will be needed to guide further therapy. Continued follow-up results from SCORE2 are anticipated to compare outcomes between these anti-VEGF agents when other than fixed-monthly dosing schedules are used after 6 months. The primary outcome and subsequent results then can be weighed by patients with physician guidance in deciding which anti-VEGF agent to consider when treating macular edema from a central retinal or hemiretinal vein occlusion.” (N. M. Bressler, nbressler@jhmi.edu)
“The effort to compare efficacy and safety of treatments is increasingly critical when therapeutic options differ in cost, either to the individual consumer or to society as a whole,” writes the author of an invited 
JAMA Ophthalmology commentary (10.1001/jamaophthalmol.2017.1142). “Although studies including SCORE2 and Protocol T have been successful at collaborating with industry partners to provide partial support, the availability of resources independent of these companies through federal funding is essential for such endeavors. Both real and perceived conflicts of interest must be carefully managed with respect to industry involvement in studies. Future leveraging of available clinical trial infrastructure through existing networks and collaborations also would promote efficient implementation of such efforts.” (J. K. Sun, jennifer.sun@joslin.harvard.edu)
Antibiotics for Uncomplicated Cellulitis: “Among [496]patients with uncomplicated cellulitis, the use of cephalexin plus trimethoprim–sulfamethoxazole compared to cephalexin alone did not result in higher rates of clinical resolution of cellulitis in the per-protocol analysis,” investigators conclude based on findings of a multicenter U.S. trial (pp. 2088–96). Relying on a primary outcome of clinical cure as evidenced by absence of signs of clinical failure, the group adds: “However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.” (G. J. Moran, idnet@ucla.edu)
>>>PNN NewsWatch
FDA yesterday granted accelerated approval to pembrolizumab (Keytruda, Merck) for treatment of adult and pediatric patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic solid tumors. This is the first agent approved for use in patients with a specific genetic biomarker without regard to location of the tumor.

PNN Pharmacotherapy Line
May 25, 2017 * Vol. 24, No. 101
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 Early-release article from and the May 25 New England Journal of Medicine (2017; 376).
Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome: Among 120 children and young adults with the Dravet syndrome and drug-resistant seizures, cannabidiol reduced convulsive-seizure frequency more than placebo but was associated with higher rates of adverse events (pp. 2011–20). Dosed as an oral solution, cannabidiol 20 mg/kg/d produced these results in combination with standard antiepileptic therapy: “The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P = 0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P = 0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P = 0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P = 0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P = 0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.” (O. Devinsky, od4@nyu.edu)
While requiring replication, “this trial represents the beginning of solid evidence for the use of cannabinoids in epilepsy,” an editorialist writes (
pp. 2075–6). “Future trials may answer further questions about the applicability of cannabinoids to the many other syndromes of childhood epilepsy and to treatment in adults. After an era dominated by anecdote and obfuscated by medicolegal issues and emotionally infused debate, more scientific studies are under way. Much more research is needed to understand the basic science, benefits, and risks of cannabinoids in epilepsy.” (S. F. Berkovic)
Benralizumab in Severe Asthma: The interleukin-5-alpha receptor inhibitor benralizumab performed significantly better than placebo in a 28-week trial of 220 patients with severe asthma (10.1056/NEJMoa1703501). As presented at an American Thoracic Society meeting, the study showed reduced glucocorticoid use and exacerbation rates with the agent, as evident in these results: “The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P <0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P = 0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P <0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.” (P. Nair, parames@mcmaster.ca)
>>>PNN NewsWatch
* Pharmacies with substantial numbers of patients on Medicaid would be affected by the large decrease in enrollments under the American Health Care Act, if yesterday’s figures from the Congressional Budget Office prove accurate. Decreases in numbers of Medicaid beneficiaries would be 4.2 million by 2018, and this would climb to 14.4 million in 2026.

PNN Pharmacotherapy Line
May 26, 2017 * Vol. 24, No. 102
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Geriatrics Report
Source:
 May issue of the Journal of the American Geriatrics Society (2017; 65).
B12 Levels & Long-term Metformin Therapy: Among veterans in 2002–12, long-term use of metformin was associated with reduced serum levels of vitamin B12, researchers report, and these should be monitored and replaced based on clinical guidelines (pp. 1061–6). At a single Veterans Affairs Medical Center (VAMC), those aged 50 years or older with type 2 diabetes and taking long-term metformin showed these associations: “Only 37% of older adults with diabetes receiving metformin were tested for vitamin B12 status after long-term metformin prescription. The mean B12 concentration was significantly lower in the metformin-exposed group (439.2 pg/dL) compared to those without diabetes (522.4 pg/dL) (P = .0015). About 7% of persons with diabetes receiving metformin were vitamin B12 deficient (<170 pg/dL) compared to 3% of persons without diabetes or metformin use (P = .0001). Depending on their age, metformin users were two to three times more likely not to receive vitamin B12 testing compared to those without metformin exposure, after adjusting for sex, race and ethnicity, body mass index, and number of years treated at the VAMC.” (C. P. Vaughan, camille.vaughan@emory.edu)
Outcomes in Treated Hypertension at Age 80 or Older: Unplanned dips in systolic blood pressure (SBP) to levels below 135 mm Hg were associated with the highest levels of mortality in a study of patients aged 80 years or older who were being treated for hypertension at U.K. primary practices (pp. 995–1003). This could be a useful clinical sign of poor prognosis, the authors conclude, “perhaps requiring clinical review of overall care.” Assessment of SBPs in increments of 10 mm Hg from 125 to 185 mm Hg yielded these findings: “Myocardial infarction hazards increased linearly with increasing SBP, and stroke hazards increased for SBP of 145 mmHg or greater, although lowest mortality was in individuals with SBP of 135 to 154 mmHg. Mortality of the 13.1% of patients with SBP less than 135 mm Hg was higher than that of the reference group (Cox hazard ratio = 1.25, 95% confidence interval = 1.19–1.31; equating to one extra death per 12.6 participants). This difference in mortality was consistent over short- and long-term follow-up; adjusting for diastolic [blood pressure] did not change the risk. Incident heart failure rates were higher in those with SBP less than 125 mm Hg than in the reference group.” (D. Melzer, d.melzer@exeter.ac.uk)
>>>Diabetes Highlights
Source:
 June issue of Diabetes Care (2017; 40).
Renal Handling of Ketones With SGLT-2 Inhibitors: Glycosuria and other metabolic effects of sodium–glucose cotransporter 2 (SGLT-2) inhibitors lead to increased excretion of beta-hydroxybutyrate (beta-HB) and sodium, according to a study of 66 patients with type 2 diabetes and preserved renal function (pp. 771–6). These changes were positively related to glycosuria, the authors report, with smaller changes in those without diabetes than among controls. The group adds: “We conclude that the [SGLT-2] inhibitor–induced increase in beta-HB is not because of reduced renal clearance but because of overproduction. The increased lactate excretion contributes to lower plasma lactate levels, whereas the increased natriuresis may help in normalizing the exchangeable sodium pool. Taken together, glucose loss through joint inhibition of glucose and sodium reabsorption in the proximal tubule induces multiple changes in renal metabolism.” (E. Ferrannini, ferranni@ifc.cnr.it)
>>>PNN NewsWatch
* Older age, obesity, and lower socioeconomic status are among the factors believed involved in a higher incidence of arthritis among rural U.S. residents. In this week’s MMWR, investigators report that 1 in 3 adults has arthritis, and about one-half of affected patients report arthritis-attributable activity limitations (2017; 66(20): 527–32; M. A. Boring, MBoring@cdc.gov): “Health care providers can help their patients manage their arthritis by recommending physical activity and self-management education programs. Adults with arthritis are more likely to attend a self-management education program when it is recommended by a health care provider.”
PNN will not be published on Mon., May 29, Memorial Day.

PNN Pharmacotherapy Line
May 30, 2017 * Vol. 24, No. 103
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 May 27 issue of Lancet (2017; 389).
Early Tranexamic Acid in Postpartum Hemorrhage: In the WOMAN trial, early administration of tranexamic acid reduced death from bleeding in women with postpartum hemorrhage, researchers report, with no adverse effects (pp. 2105–16). “When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset,” the authors conclude, based on these results at 193 hospitals in 21 countries: “Between March, 2010, and April, 2016, 20,060 women were enrolled and randomly assigned to receive tranexamic acid (n = 10,051) or placebo (n = 10,009), of whom 10,036 and 9,985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1.5%] of 10,036 patients vs 191 [1.9%] of 9,985 in the placebo group, risk ratio [RR] 0.81, 95% CI 0.65–1.00; p = 0.045), especially in women given treatment within 3 h of giving birth (89 [1.2%] in the tranexamic acid group vs 127 [1.7%] in the placebo group, RR 0.69, 95% CI 0.52–0.91; p = 0.008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3.6%] patients in the tranexamic acid group vs 351 [3.5%] in the placebo group, RR 1.02, 95% CI 0.88–1.07; p = 0.84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5.3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5.5%] in the placebo group, RR 0.97, 95% CI 0.87-1.09; p = 0.65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.” (Clinical Trials Unit, thewomantrial@LSHTM.AC.UK)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 356).
Antibiotic Rx Strategies in Lower Respiratory Tract Infections: In a prospective study of adolescents and adults with lower respiratory tract infections at U.K. general practices, delayed antibiotic prescriptions appeared preferable over immediate treatment, producing statistically similar numbers of hospitalizations and fewer subsequent consultations for worsening illness within 30 days (j2148). Multivariate analysis based on primary outcomes of reconsultations, hospital admissions, or death showed these results: “Of the 28,883 participants, 104 (0.4%) were referred to hospital for radiographic investigation or admission, or both on the day of the index consultation, or were admitted with cancer. Of the remaining 28,779, subsequent hospital admission or death occurred in 26/7,332 (0.3%) after no antibiotic prescription, 156/17,628 (0.9%) after prescription for immediate antibiotics, and 14/3,819 (0.4%) after a prescription for delayed antibiotics. Multivariable analysis documented no reduction in hospital admission and death after immediate antibiotics (multivariable risk ratio 1.06, 95% confidence interval 0.63 to 1.81, P = 0.84) and a non-significant reduction with delayed antibiotics (0.81, 0.41 to 1.64, P = 0.61). Reconsultation for new, worsening, or non-resolving symptoms was common (1,443/7,332 (19.7%), 4,455/17,628 (25.3%), and 538/3,819 (14.1%), respectively) and was significantly reduced by delayed antibiotics (multivariable risk ratio 0.64, 0.57 to 0.72, P <0.001) but not by immediate antibiotics (0.98, 0.90 to 1.07, P = 0.66).” (P. Little, p.little@soton.ac.uk)
>>>PNN NewsWatch
AstraZeneca is recalling one lot of professional sample bottles containing eight tablets of Brilinta (ticagrelor) 90 mg tablets (#JB5047) because of a report of one bottle also containing the company’s Zurampic (lesinurad) 200 mg tablets.
* Because of a rotation of blister packaging, 
Lupin Pharmaceuticals Inc. has recalled lot L600518 (exp. 05/18) of Mibelas 24 Fe (norethindrone acetate and ethinyl estradiol 1 mg/0.02 mg chewable and ferrous fumarate 75 mg) tablets to the consumer level.
>>>PNN JournalWatch
* Targeted-Release Budesonide Versus Placebo in Patients With IgA Nephropathy (NEFIGAN): A Double-Blind, Randomised, Placebo-Controlled Phase 2b Trial, in Lancet, 2017; 389: 2117–27. (B. C. Fellström, bengt.fellstrom@medsci.uu.se)
* Considerations and Controversies in Managing Chronic Kidney Disease: An Update, in 
American Journal of Health-System Pharmacy, 2017; 74: 795–810. (L. Prasad-Reddy, lprasad@csu.edu)

PNN Pharmacotherapy Line
May 31, 2017 * Vol. 24, No. 104
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 (2017; 55).
ROI for ADR Surveillance: Pharmacovigilance programs that use active surveillance systems could generate large returns on investment (ROIs), authors conclude after analyzing public health and economic benefits in three case examples during which early signals of safety hazards were not recognized (pp. 545–51). Rofecoxib, cerivastatin, and troglitazone were eventually pulled from the U.S. market, but not until these costs — estimated using individual patient simulation model and the health care system perspective — were incurred: “We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773–$884 million for rofecoxib, $3–$10 million for cerivastatin, and $38–$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present.” (K. F. Huybrechts, khuybrechts@bwh.harvard.edu)
“We all … [bear] the financial return from public investment in a modern surveillance system for adverse drug effects,” an editorialist writes (
pp. 543–4). “Politics, for better or for worse, plays a critical role in public health financing decisions. Sustained public investment in a robust national pharmacovigilance system is warranted economically and because it provides the public health safety-net necessary in an era of faster drug approvals. It should be noted, however, that a robust pharmacovigilance system requires more than data and analytics alone. It requires rapid and transparent risk communication and regulatory decision-making processes. It also requires the ability to monitor the impact of regulatory decisions on health care utilization and health outcomes so that risk management strategies can be modified on the basis of evidence and not conjecture. Only then will we gain from our investment.” (E. H. Morrato, elaine.morrato@ucdenver.edu)
Cost-effectiveness of Antihypertensive Medications: Treatment of hypertension is cost-saving in white and black adults, a study concludes, with particularly marked effects on costs of care among black men and women (pp. 552–60). Using a State Transition Model to assess costs and quality-adjusted life–years (QALYs) and treatment data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study and published literature, researchers report these results in 2012 dollars for cardiovascular disease (CVD) events and health states such as stroke, coronary heart disease, heart failure, chronic kidney disease, and end-stage renal disease: “Antihypertensive medication treatment was cost-saving and increased QALYs compared with no-treatment for white men ($7,387; 1.14 QALYs), white women ($7,796; 0.89 QALYs), black men ($8,400; 1.66 QALYs), and black women ($10,249; 1.79 QALYs).” (G. S. Tajeu, gtajeu@uab.edu)
Quality of Midlevel Practitioner Primary Care: In community health centers in 2006–10, quality of care provided by nurse practitioners (NPs) and physician assistants (PAs) was “largely comparable” to that of primary care physicians (PCMDs), an analysis shows (pp. 615–22). National Ambulatory Medical Care Survey data for 23,704 patient visits to 1,139 practitioners showed these patterns in a multivariate regression analysis based on nine patient-level outcomes (three quality indicators, four service utilization measures, and two referral pattern measures): “On 7 of the 9 outcomes studied, no statistically significant differences were detected in NP or PA care compared with PCMD care. On the remaining outcomes, visits to NPs were more likely to receive recommended smoking cessation counseling and more health education/counseling services than visits to PCMDs (P ≤0.05). Visits to PAs also received more health education/counseling services than visits to PCMDs (P ≤0.01; design-based model only).” (E. T. Kurtzman, etk@gwu.edu)
>>>PNN NewsWatch
* Released early by the Annals of Internal Medicine, an article shows that switching directly to biologic therapy when methotrexate fails in rheumatoid arthritis is not cost-effective. Triple therapy with sulfasalazine, hydroxychloroquine, and methotrexate should be tried first, the results indicate.

PNN Pharmacotherapy Line
June 1, 2017 * Vol. 24, No. 105
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 1 New England Journal of Medicine (2017; 376).
Non–Small-Cell Lung Cancer Evolution: Chromosome instability is an important prognostic predictor in non–small-cell lung cancer (NSCLC), according to a study of intratumor heterogeneity and cancer genome evolution (pp. 2109–21). Multiregion whole-exome sequencing of 100 early-stage NSCLC tumors showed these results in the prospective cohort TRACERx study: “We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P = 4.4×10−4), which remained significant in multivariate analysis.” (C. Swanton, charles.swanton@crick.ac.uk)
“It is hoped that TRACERx is not just a candle at the end of the heterogeneity tunnel but a headlight on a train of similar initiatives that can carry cancer researchers out of the darkness,” editorialists write (
pp. 2190–1). “TRACERx is a proof of concept that longitudinal sampling can uncover novel pathways for tumor evolution, heterogeneity, and resistance to therapy. This report will no doubt be followed by more such efforts that will apply these principles to untangling the phylogenetic complexity of other types of cancers.” (A. I. Robles)
Strategies for Previously Treated HCV: In the POLARIS-1 and POLARIS-4 trials, 12 weeks of sofosbuvir–velpatasvir–voxilaprevir provided high rates of sustained virologic response among patients with several genotypes of hepatitis C virus (HCV) infection for whom treatment with direct-acting antiviral agents had previously failed (pp. 2134–46). POLARIS-1 included 300 patients with HCV genotype 1 infection and 114 patients with other genotypes; 314 patients with HCV genotype 1, 2, or 3 infection and 19 patients with HCV genotype 4 infection participated in POLARIS-4. Sofosbuvir–velpatasvir–voxilaprevir produced these compartative outcomes: “In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.” (M. Bourlière, mbourliere@hopital-saint-joseph.fr)
Adjuvant Capecitabine for Breast Cancer: Among 910 patients with HER2-negative breast cancer who had residual invasive disease, addition of adjuvant capecitabine therapy to standard neoadjuvant chemotherapy was safe and effective, researchers report, prolonging disease-free and overall survival (pp. 2147–59): “The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P = 0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P = 0.01).…” (M. Toi, toi@kuhp.kyoto-u.ac.jp)
>>>PNN NewsWatch
Jeff A. Goad, PharmD, MPH, of Chapman U. School of Pharmacy has received the 2017 Ronald P. Bangasser, MD, Immunization Leadership Award from the California Immunization Coalition. Goad has maintained an active travel health clinic for 15 years and was president of CIC in 2012–14.

PNN Pharmacotherapy Line
June 2, 2017 * Vol. 24, No. 106
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 (2017; 139).
Safety of Cough & Cold Medications: Countering concerns about adverse events (AEs) with cough and cold medication (CCM) use in pediatric patients, a study shows low rates of reactions and no deaths with therapeutic doses among cases with experiences recorded in five data sources (10.1542/peds.2016-3070). Reports with AEs following ingestion of at least one CCM (brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, guaifenesin, phenylephrine, pseudoephedrine) in children younger than 12 years of age were assessed by an expert panel, with these results: “Of the 4,202 cases reviewed, 3,251 (77.4%) were determined to be at least potentially related to a CCM, with accidental unsupervised ingestions (67.1%) and medication errors (13.0%) the most common exposure types. Liquid (67.3%), pediatric (75.5%), and single-ingredient (77.5%) formulations were most commonly involved. AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose. The overall reported AE rate was 0.573 cases per 1 million units (ie, tablets, gelatin capsules, or liquid equivalent) sold (95% confidence interval, 0.553–0.593) or 1 case per 1.75 million units.” (J. L. Green)
Aspirin Dose in Kawasaki Disease: Administered concomitantly with intravenous immunoglobulin to children aged 0 to 10 years of age with acute Kawasaki disease (KD), low-dose aspirin was noninferior to higher doses of acetylsalicylic acid (ASA), researchers report (10.1542/peds.2017-0098). At two institutions that routinely used low-dose ASA (3–5 mg/kg/d) and three institutions using high-dose ASA (80 mg/kg/d) in 2004–15, these results were recorded: “There were 1,213 subjects included, 848 in the high-dose and 365 in the low-dose ASA group. There was no difference in the risk of [coronary artery (CA)] abnormalities in the low-dose compared with the high-dose ASA group (22.2% vs 20.5%). The risk difference adjusted for potential confounders was 0.3% (95% confidence interval [CI]: −4.5% to 5.0%). The adjusted risk difference for CA abnormalities persisting at the 6-week follow-up was −1.9% (95% CI: −5.3% to 1.5%). The 95% CI of the risk difference of CA abnormalities adjusted for confounders was within the prespecified 5% margin considered to be noninferior.” (F. Dallaire)
Evidence-Based Asthma Interventions: “Evidence-based interventions can be successfully adapted into primary care settings that serve impoverished, high-risk populations, reducing the morbidity of asthma in these high-need populations,” conclude investigators who studied 590 children aged 5–12 years with moderate to severe asthma (10.1542/peds.2016-4221). In the Community Healthcare for Asthma Management and Prevention of Symptoms (CHAMPS) study, these results were noted at three intervention and three control sites in Arizona, Michigan, and Puerto Rico: “Allergen sensitivity testing (96%) and home environmental assessments (89%) were performed on the majority of intervention children. Overall study activity completion (eg, intervention visits, clinical assessments) was 70%. Overall and individual site participant symptom days in the previous 4 weeks were significantly reduced compared with control findings (control, change of −2.28; intervention, change of −3.27; difference, −0.99; P < .001), and this result was consistent with changes found in the rigorous evidence-based interventions.” (S. Kennedy)
Disparities in ADHD Treatment Quality: Care of Medicaid-enrolled youth with attention-deficit/hyperactivity disorder (ADHD) is poor overall, with minorities having higher rates of medication discontinuation, a study shows (10.1542/peds.2016-2444). Based on data from nine state programs, the authors conclude that these disparities “translate into higher rates of treatment disengagement because most youth discontinuing medication receive no psychotherapy.” (J. R. Cummings)
>>>PNN NewsWatch
FDA yesterday approved the first generic versions of Strattera (atomoxetine) to treat attention-deficit/hyperactivity disorder in pediatric and adult patients.

PNN Pharmacotherapy Line
June 5, 2017 * Vol. 24, No. 107
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 357).
ADHD Risk & Prenatal Antidepressant Use: Data from Hong Kong indicate that if there is a causal association between maternal use of antidepressants during pregnancy and offspring development of attention-deficit/hyperactivity disorder (ADHD), a confounding factor related to drug indication partially explains the relationship and “the size of the effect is probably smaller than that reported previously” (j2350). Analysis of 190,618 children and 1,252 mothers who used prenatal antidepressants yielded these results: “5,659 children (3.0%) were given a diagnosis of ADHD or received treatment for ADHD. The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P <0.01) compared with non-use. After adjustment for potential confounding factors, including maternal psychiatric disorders and use of other psychiatric drugs, the adjusted hazard ratio was reduced to 1.39 (95% confidence interval 1.07 to 1.82, P = 0.01). Likewise, similar results were observed when comparing children of mothers who had used antidepressants before pregnancy with those who were never users (1.76, 1.36 to 2.30, P <0.01). The risk of ADHD in the children of mothers with psychiatric disorders was higher compared with the children of mothers without psychiatric disorders even if the mothers had never used antidepressants (1.84, 1.54 to 2.18, P <0.01). All sensitivity analyses yielded similar results. Sibling matched analysis identified no significant difference in risk of ADHD in siblings exposed to antidepressants during gestation and those not exposed during gestation (0.54, 0.17 to 1.74, P = 0.30).” (I. C. K. Wong, i.wong@ucl.ac.uk)
“Decision models that incorporate the risks of maternal depression and drugs and also take into account individual factors, including genetic traits, would be helpful,” an editorialist writes, adding, “Such models will require more research on the importance of these factors, and greater collaboration to reach sample sizes big enough to generate answers to these important questions.” (
j2544). The author adds this advice for clinicians: “Future care of pregnant women with depression should ideally consider detailed clinical and background information, including type of treatment and pharmacogenetic traits. Importantly, the nature and severity of maternal mental illness must be taken into account. Because the uncertainties around many of the risks statistically associated with antidepressants cannot be disregarded, pregnant women with mild depression may benefit from non-drug treatment. However, pregnant women with severe depression need effective treatment that will in most cases include antidepressants.” (L. H. Pedersen, LHP@clin.au.dk)
>>>PNN NewsWatch
ASHP’s House of Delegates yesterday adopted a policy of “studied neutrality” on the issue of pharmacist participation in medical aid in dying, leaving the choice to individual pharmacists based on their own conscience. The policy is similar to that of APhA, which avoids “a particular moral stance on the issue of physician-assisted suicide.” Other policy topics adopted by the ASHP House during its first meeting at the Society’s Summer Meetings in Minneapolis included expansion of federal and state laws and regulations on collaborative drug therapy management by pharmacists, multimodal pain therapy, increased competition among generic and biosimilar products, transgender care, and controlled substance diversion prevention programs. The ASHP election slate was also announced; presidential candidates are Philip J. Schneider of Kansas and Kelly M. Smith of Kentucky.
>>>PNN JournalWatch
* The Impact of Pediatric-Specific Vancomycin Dosing Guidelines: A Quality Improvement Initiative, in Pediatrics, 2017; 139: 10.1542/peds.2016-2423. (M. Miloslavsky) 
* Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review, in 
Pediatrics, 2017; 139: 10.1542/peds.2016-4131. (J. N. Lind) 
* Nutritional and Dietary Interventions for Autism Spectrum Disorder: A Systematic Review, in 
Pediatrics, 2017; 139: 10.1542/peds.2017-0346. (N. Sathe) 
* Irritability in Youths: A Translational Model, in 
American Journal of Psychiatry, 2017; 174: 520–32. (M. A. Brotman)
* Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD, in 
American Journal of Kidney Diseases, 2017; 69: 815–26. (J. B. Wish, jaywish@earthlink.net)

PNN Pharmacotherapy Line
June 6, 2017 * Vol. 24, No. 108
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June 6 issue of the Annals of Internal Medicine (2017; 166).
Antibiotics for Nonbacterial AURIs in Older Adults: Physician descriptors can be used to identify likely prescribers of antibiotics for older adults with nonbacterial acute upper respiratory infections (AURIs), a study shows (pp. 765–74). Among primary care practices in Ontario in 2012, mid- or late-career physicians with high patient volumes were more likely to give antibiotic prescriptions for nonbacterial AURIs, as were physicians trained outside of Canada or the U.S. The low-risk patient population, all aged 66 years or older, had these outcomes during encounters for nonbacterial AURIs: “The cohort included 8,990 primary care physicians and 185,014 patients who presented with a nonbacterial AURI, including the common cold (53.4%), acute bronchitis (31.3%), acute sinusitis (13.6%), or acute laryngitis (1.6%). Forty-six percent of patients received an antibiotic prescription; most prescriptions were for broad-spectrum agents (69.9% [95% CI, 69.6% to 70.2%]). Patients were more likely to receive prescriptions from mid- and late-career physicians than early-career physicians (rate difference, 5.1 percentage points [CI, 3.9 to 6.4 percentage points] and 4.6 percentage points [CI, 3.3 to 5.8 percentage points], respectively), from physicians trained outside of Canada or the United States (3.6 percentage points [CI, 2.5 to 4.6 percentage points]), and from physicians who saw 25 to 44 patients per day or 45 or more patients per day than those who saw fewer than 25 patients per day (3.1 percentage points [CI, 2.1 to 4.0 percentage points] and 4.1 percentage points [CI, 2.7 to 5.5 percentage points], respectively).” (M. F. Silverman, michael.silverman@sjhc.london.on.ca)
“We should be optimistic that the current state of affairs is amenable to large-scale improvement,” an editorialist writes (
pp. 844–5). “Durable reductions in antibiotic prescribing have been observed in countries where rigorous local and national campaigns were launched. In the United States, we have substantially decreased antibiotic use in young children. Outpatient stewardship is an expanding feature of antibiotic stewardship programs associated with health systems, which heretofore focused on the inpatient setting. Further research will improve our understanding of the cognitive and motivational processes that drive clinical behaviors and how clinicians share information, attitudes, and practice norms to shape prescribing patterns. Studies of behavioral interventions that target modifiable risk factors, can be integrated into clinician workflow, and promote sustainable change are needed. The tipping point to a culture of judicious antibiotic use is within reach, with clinicians at the forefront of change. Preservation of the benefits of the ‘wonder drugs’ depends on us.” (B. E. Jones, barbara.jones@hsc.utah.edu)
HBV Reactivation During HCV Therapy: In patients being treated with direct-acting agents for hepatitis C virus (HCV) infection, reactivation of hepatitis B virus (HBV) is “a newly identified safety concern” (pp. 792–8). Clinical monitoring is needed in patients with a history of HBV infection, researchers conclude, based on these cases reported in the FDA Adverse Event Reporting System: “The FDA identified 29 unique reports of HBV-R in patients receiving DAAs from 22 November 2013 to 15 October 2016. Two cases resulted in death and 1 case in liver transplantation. Patients in whom [HBV reactivation (HBV-R)] developed were heterogeneous regarding HCV genotype, DAAs received, and baseline HBV characteristics. At baseline, 9 patients had a detectable HBV viral load, 7 had positive results on hepatitis B surface antigen (HBsAg) testing and had an undetectable HBV viral load, and 3 had negative results on HBsAg testing and had an undetectable HBV viral load. For the remaining 10 patients, data points were not reported or the data were uninterpretable. Despite provider knowledge of baseline HBV, HBV-R diagnosis and treatment were delayed in 7 cases and possibly 7 others.” (S. Bersoff-Matcha, Susan.Bersoff-Matcha@fda.hhs.gov)
Osteoporosis Guideline: A practice guideline from the American College of Physicians recommends treatment of women with osteoporosis for 5 years with alendronate, risedronate, zoledronic acid, or denosumab (pp. 818–39). Men with clinically recognized osteoporosis should be treated with bisphosphonates, the guideline states, but no duration of therapy is specified. (A. Qaseem, aqaseem@acponline.org)

PNN Pharmacotherapy Line
June 7, 2017 * Vol. 24, No. 109
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 6 issue of JAMA (2017; 317).
Obstacles to Biosimilar Adoption: Noting the need for pharmacists to be able to substitute biosimilars, authors of a Viewpoint article outlined obstacles to the agents’ adoption for chronic diseases (pp. 2163–4): “Several policy solutions may help ensure that savings from biosimilars can be realized, assuming that biosimilars are less expensive and are priced lower than branded biologics. The US biosimilars pathway allows the FDA to designate biosimilar products as ‘interchangeable,’ a higher standard than ‘biosimilarity.’ However, since 2013, only 21 states have passed laws allowing substitution by a pharmacist based on interchangeability. Moreover, the FDA released draft regulatory guidance in January 2017 outlining a case-by-case approach for determining whether a biosimilar could be designated as interchangeable, considering biocharacterization, analytical similarity, switching studies, and postmarketing data. With this guidance in place, automatic substitution laws in all states based on interchangeability could bolster competition, lower prices, and increase biosimilar availability for patients.” (J. S. Ross, joseph.ross@yale.edu)
Trends in Medicare Annual Wellness Visits: Use of annual wellness visits (AWVs) by Medicare beneficiaries has remained “modest” since their introduction as part of the Affordable Care Act in 2010, researchers report (pp. 2233–5). A 20% sample of Medicare claims indicated these patterns among nearly 6 million eligible patients for each year from 2011 to 2014, which showed an increase from 7.5% of beneficiaries in 2011 to 15.6% in 2014: “White individuals, urban residents, and those from higher-income areas and with 1 or 2 comorbidities were more likely to receive an AWV, as were beneficiaries who received an AWV in the previous year (53.4% receiving an AWV in the previous year vs 10.4% not receiving an AWV in the previous year; P <.001) or belonged to an [accountable care organization (ACO)] (25.9% belonged to an ACO vs 17.6% did not belong to an ACO; P <.001). Among all AWVs, 44.4% (95% CI, 44.3%–44.5%) had a concurrent problem-based visit.
“Regional AWV rates in 2014 varied from 3.0% (95% CI, 2.5%–3.5%) in San Angelo, Texas, to 34.3% (95% CI, 33.0%–35.8%) in Appleton, Wisconsin. Rates were not correlated with Medicare spending (Pearson coefficient, 0.01; P = .85).” (I. Ganguli, 
iganguli@partners.org)
>>>PNN NewsWatch
* Three quarters of patients with Legionnaire’s disease acquired the pathogen from health care facilities, CDC said yesterday. Referring to data from 21 U.S. juridictions, CDC Acting Director Anne Schuchat said, “Legionnaires’ disease in hospitals is widespread, deadly, and preventable. These data are especially important for health care facility leaders, doctors, and facility managers because it reminds them to think about the risks of Legionella in their facility and to take action. Controlling these bacteria in water systems can be challenging, but it is essential to protect patients.”
Max L. (Mick) Hunt last night received the 2017 Harvey A. K. Whitney Award at the ASHP Summer Meetings in Minneapolis. Hunt, associate professor emeritus at the Northeast Ohio Medical U. College practiced during his career at Novation (now Vizient), U. Kentucky Hosp., Lutheran General Hosp. in Park Ridge, IL, and St. Marys Hosp. in Rochester, MN.
* Reporting yesterday to the ASHP House of Delegates at its second meeting, 
Lisa M. Gersema of St. Paul, MN, reviewed her year as the Society’s president by reviewing the components of “Pharmacy’s True North,” the theme of her presidential year: Accountability, Collaboration, Excellence, and Leadership. The new ASHP president is Paul W. Bush of Durham, NC.
* Attendance at the ASHP Midyear Clinical Meeting last year in Las Vegas reached a record 25,483, said 
ASHP CEO Paul W. Abramowitz. Former First Lady Michelle Obama will keynote this year’s Midyear, scheduled for Dec. 3–7 in Orlando. The ASHP budget continues to grow, from $40.5 million in 2012 to a projected $50.7 million in 2018, he added. ASHP — celebrating its 75th anniversary this year — recently sold its building as part of transportation and redevelopment activities in downtown Bethesda, MD, and has now settled into a state-of-the-art facility a few blocks away. The new facility was dedicated last month as the Joseph A. Oddis Global Headquarters of ASHP.

PNN Pharmacotherapy Line
June 8, 2017 * Vol. 24, No. 110
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 8 issue of the New England Journal of Medicine (2017; 376).
Cardiac Malformations With Lithium Use in Pregnancy: A study supports previous observations of a link between heart defects and maternal use of lithium in the first trimester of pregnancy but finds a smaller magnitude of effect than “previously postulated” (pp. 2245–54). In a cohort study of 1.3 million pregnancies in Medicaid-enrolled women, infants born alive between 2000 and 2010 had these heart problems: “Cardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1,945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group.” (E. Patorno, epatorno@bwh.harvard.edu)
Early, Goal-Directed Therapy for Septic Shock: A patient-level meta-analysis shows lack of better mortality outcomes and higher costs with early, goal-directed therapy (EGDT) in those with septic shock (pp. 2223–34). PRISM investigators report these results when data from the ProCESS, ARISE, and ProMISe trials were pooled: “We studied 3,723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1,852 patients [24.9%]) and usual care (475 of 1,871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P = 0.68). EGDT was associated with greater mean (± SD) use of intensive care (5.3 ± 7.1 vs. 4.9 ± 7.0 days, P = 0.04) and cardiovascular support (1.9 ± 3.7 vs. 1.6 ± 2.9 days, P = 0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation.” (PRISM Investigators, kathy.rowan@icnarc.org)
Mortality With Mandated Emergency Care for Sepsis: The times to treatment for sepsis care and antibiotic initiation — but not the time to initiation of intravenous fluids — are associated with lower risk-adjusted in-hospital mortality, a study shows (pp. 2235–44). Based on data reported to the New York State Department of Health from Apr. 1, 2014, to June 30, 2016, investigators found these outcomes among patients who had a sepsis protocol initiated within 6 hours of arrival in the emergency department and had all items in a 3-hour bundle of care completed within 12 hours: “Among 49,331 patients at 149 hospitals, 40,696 (82.5%) had the 3-hour bundle completed within 3 hours. The median time to completion of the 3-hour bundle was 1.30 hours (interquartile range, 0.65 to 2.35), the median time to the administration of antibiotics was 0.95 hours (interquartile range, 0.35 to 1.95), and the median time to completion of the fluid bolus was 2.56 hours (interquartile range, 1.33 to 4.20). Among patients who had the 3-hour bundle completed within 12 hours, a longer time to the completion of the bundle was associated with higher risk-adjusted in-hospital mortality (odds ratio, 1.04 per hour; 95% confidence interval [CI], 1.02 to 1.05; P <0.001), as was a longer time to the administration of antibiotics (odds ratio, 1.04 per hour; 95% CI, 1.03 to 1.06; P <0.001) but not a longer time to the completion of a bolus of intravenous fluids (odds ratio, 1.01 per hour; 95% CI, 0.99 to 1.02; P = 0.21).” (C. W. Seymour, seymourcw@upmc.edu)
>>>PNN NewsWatch
Brad Tice, PharmD, MBA, FAPhA, of Thompsons Station, TN, is the 2018–19 APhA president-elect, the Association announced this week. Elected to 3-year terms as trustees were Magaly Rodriguez de Bittner, PharmD, FAPhA, of U. Maryland and Theresa Tolle, BPharm, FAPhA, of Sebastian, FL.

PNN Pharmacotherapy Line
June 9, 2017 * Vol. 24, No. 111
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Chest Highlights
Source:
 June issue of Chest (2017; 151).
Hydrocortisone, Vitamin C, & Thiamine for Severe Sepsis: In a retrospective before–after clinical study of patients with severe sepsis and septic shock, intravenous vitamin C, given with corticosteroids and thiamine, prevented progressive organ dysfunction — including acute kidney injury — and reduced mortality, researchers report (pp. 1229–38). Compared with a control group of 47 patients treated in an intensive care unit during the previous 7 months, 47 patients given the triple therapy during the ensuing 7-month period had these outcomes: “The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P <.001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04–0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P <.001).” (P. E. Marik)
“The pathophysiology of sepsis reminds us that high-dose IV vitamin C should probably be limited to the very early phase of severe sepsis or septic shock because in the long run, low levels of [reactive oxygen species] are crucial for intracellular signaling,” editorialists write (
pp. 1199–200). “To avoid the Linus Pauling trap [considering megadoses of vitamin C a panacea for cancer], pragmatic multicenter trials are needed to confirm this benefit and to exclude unforeseen harm as was seen in previous sepsis trials using promising drugs. Studies should also determine optimal dose and treatment duration, whether normal or temporarily supernormal plasma concentrations should be obtained, whether intermittent (high peak concentrations) or continuous dosing (less renal excretion of vitamin C and oxalate) performs better, whether coadministration of thiamine reduces oxalate excretion, and finally whether the combination with hydrocortisone acts synergistically.” (H. M. Oudemans–van Straaten)
>>>Cardiology Report
Source:
 June 13 issue of the Journal of the American College of Cardiology (2017; 69).
Non–Vitamin K Antagonist Oral Anticoagulant Dosing in AF With Renal Dysfunction: Non–vitamin K antagonist oral anticoagulants (NOACs) are often dosed outside product labeling, a study shows, compromising safety without greater effectiveness of the drugs in patients with atrial fibrillation (AF) (10.1016/j.jacc.2017.03.600). Analysis of a large U.S. administrative database identified 14,865 patients with AF who were taking apixaban, dabigatran, or rivaroxaban in 2010–15 showed these outcomes with standard doses in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication was not present (potential underdosing): “Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.” (X. Yao)
>>>PNN NewsWatch
FDA yesterday requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market. In a statement, FDA said, “After careful consideration, the agency is seeking removal based on its concern that the benefits of the drug may no longer outweigh its risks. This is the first time the agency has taken steps to remove a currently marketed opioid pain medication from sale due to the public health consequences of abuse.”

PNN Pharmacotherapy Line
June 12, 2017 * Vol. 24, No. 112
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>BMJ Highlights
Source:
 Early-release articles from BMJ (2017; 356).
Incretin-Based Treatments & Mortality: Claims that incretin-based treatment of patients with type 2 diabetes is associated with increased mortality are not supported in a systematic review and meta-analysis (j2499). The authors conclude that further study of the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is needed, based on these findings: “189 randomised controlled trials (n = 155,145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3,888 deaths among 151,614 patients. Meta-analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1,925/84,136 v 1,963/67,478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2 = 0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1,000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.” (X. Sun, sunx26@gmail.com)
Alcohol Intake & Cognition: Britain’s cancer-based recommendations for lower alcohol intake are supported by results of an observational cohort study of 550 men and women who had adverse brain outcomes with moderate consumption, researchers conclude (j2353). Screening questionnaires and magnetic resonance imaging showed the following: “Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P ≤0.001), even those drinking moderately (14–21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P = 0.007). There was no protective effect of light drinking (1–<7 units/week) over abstinence. Higher alcohol use was also associated with differences in corpus callosum microstructure and faster decline in lexical fluency. No association was found with cross sectional cognitive performance or longitudinal changes in semantic fluency or word recall.” (A. Topiwala, anya.topiwala@psych.ox.ac.uk)
>>>Lancet Highlights
Source:
 June 10 issue of Lancet (2017; 389).
Infliximab-to-Biosimilar Switches: In the Norwegian noninferiority NOR-SWITCH trial, efficacy, safety, and immunogenicity outcomes were similar among patients treated with the infliximab originator product and a biosimilar, CT-P13 (pp. 2304–16). The phase 4 trial was conducted in 2014–15, and the adult patients had one of several diseases for which the agent is used. Based on a primary end point of disease worsening during 52-week follow-up and a noninferiority margin of 15% (assuming 30% disease worsening), results showed: “155 (32%) patients in the full analysis set had Crohn’s disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4.4%, 95% CI −12.7 to 3.9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively).” (T. K. Kvien, t.k.kvien@medisin.uio.no)
>>>PNN JournalWatch
* LOX-1 in Atherosclerosis and Myocardial Ischemia : Biology, Genetics, and Modulation, in Journal of the American College of Cardiology, 2017; 69: 2759–68. (N. V. K. Pothineni) 
* Sleep and Neurodegeneration: A Critical Appraisal, in 
Chest, 2017; 151: 1375–86. (J. A. Pillai) 
* A Randomized Clinical Trial Comparing the Effects of Antitussive Agents on Respiratory Center Output in Patients With Chronic Cough, in 
Chest, 2017; 151: 1288–94. (G. Fontana) 
* Composite End Points in Clinical Research: A Time for Reappraisal, in 
Circulation, 2017; 135: 2299–307. (P. W. Armstrong)
PNN Pharmacotherapy Line
June 13, 2017 * Vol. 24, No. 113
Providing news and information about medications and their proper use

Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June issue of JAMA Internal Medicine (2017; 177).
Preventing CMV Reactivation in Critically Ill Patients: Reactivation of cytomegalovirus (CMV) during critical illness can be blocked through prophylaxis with valacyclovir or low-dose valganciclovir, researchers report (pp. 774–83). Occurring in up to one third of critically ill patients, reactivation of latent CMV infections is associated with a 2-fold increase in mortality. In 124 CMV-seropositive patients who had mechanical ventilation for at least 24 hours in a British intensive care unit, these outcomes were noted in a 28-day, proof-of-principle study: “Among the 124 patients in the study (46 women and 78 men; mean [SD] age, 56.9 [16.9] years), viral reactivation in the blood occurred in 12 patients in the control group, compared with 1 patient in the valganciclovir group and 2 patients in the valacyclovir group (combined treatment groups vs control: hazard ratio, 0.14; 95% CI 0.04–0.50). Although this trial was not powered to assess clinical end points, the valacyclovir arm was halted prematurely because of higher mortality; 14 of 34 patients (41.2%) had died by 28 days, compared with 5 of 37 (13.5%) patients in the control arm at the point of the decision to halt this arm.” (N. J Cowley, nicholascowley@nhs.net)
Acid Suppression & Recurrent Clostridium difficile Infection: Patients on long-term proton pump inhibitors or histamine-2 blockers may be at greater risk of recurrent primary Clostridium difficile infection (CDI), according to a systematic review and meta-analysis (pp. 784–91). “These data should be interpreted with caution because they may be confounded owing to the observational design of the individual studies,” the authors conclude. “It may be reasonable to re-evaluate the need for these medications in patients with CDI.” In 16 observational studies of 7,703 patients with CDI, including 1,525 individuals with recurrent cases, these associations were evident: “The rate of recurrent CDI in patients with gastric acid suppression was 22.1% (892 of 4,038 patients) compared with 17.3% (633 of 3,665) in patients without gastric acid suppression, which indicated an increased risk by meta-analysis (odds ratio [OR], 1.52; 95% CI, 1.20–1.94; P < .001). There was significant heterogeneity among the studies, with an I2 value of 64%. Subgroup analyses of studies adjusting for age and potential confounders confirmed an increased risk of recurrent CDI with use of gastric acid suppressants (OR, 1.38; 95% CI, 1.08–1.76; P = .02).” (S. Khanna, khanna.sahil@mayo.edu)
“An unbiased assessment without the risk of unmeasured confounding would require randomized clinical trials of gastric acid suppressant continuation vs withdrawal among patients with 
C difficile colitis who are also using chronic gastric acid suppressants,” editorialists write (p. 791). “In the meantime, these findings support a strategy of withholding gastric acid suppression therapy in the setting of active or recent C difficile infection.” (S. R. Bauer)
Reducing Antipsychotic Use Through Communication Training: In 93 Massachusetts nursing homes, antipsychotic use declined during implementation of an OASIS train-the-trainer communication intervention (pp. 846–53). Decreases did not continue during the maintenance phase of the intervention, but the authors concluded that their “study adds evidence for nonpharmacological programs to treat behavioral and psychological symptoms of dementia.” (J. Tjia, jennifer.tjia@umassmed.edu)
Polypharmacy Among Older Adults: In a “Teachable Moment” contribution, authors use the case of an 83-year-old woman on unnecessary digoxin and atorvastatin to examine principles of polypharmacy and utility of the Beers and STOPP criteria (p. 871): “Optimizing an individual’s medication takes into account more than just practice guidelines but also patient preferences. Correctly assessing the unique preferences of the patient allows for tailoring medication regimens to each patient’s individual circumstances, including affordability, tolerability, and goals of care. In this case, the patient’s priorities were to minimize pill burden, improve affordability, and avoid hospitalization if at all possible.” (C. Carroll, casey.carroll@ucdenver.edu)
>>>PNN NewsWatch
* The 2018 print and online editions of the CDC’s travel-health Yellow Book are now available.

PNN Pharmacotherapy Line
June 14, 2017 * Vol. 24, No. 114
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 13 issue of JAMA (2017; 317).
Iron Products for Nutritional Iron-Deficiency Anemia: In a study of infants and young children with nutritional iron-deficiency anemia (IDA), ferrous sulfate produced a greater increase in hemoglobin concentration at 12 weeks than iron polysaccharide complex, researchers report (pp. 2297–304). Doses of elemental iron 3 mg/kg using products with the two iron sources produced these results at a U.S. tertiary care hospital among participants aged 9–48 months: “Of 80 randomized infants and children (median age, 22 months; 55% male; 61% Hispanic white; 40 per group), 59 completed the trial (28 [70%] in ferrous sulfate group; 31 [78%] in iron polysaccharide complex group). From baseline to 12 weeks, mean hemoglobin increased from 7.9 to 11.9 g/dL (ferrous sulfate group) vs 7.7 to 11.1 g/dL (iron complex group), a greater difference of 1.0 g/dL (95% CI, 0.4 to 1.6 g/dL; P <.001) with ferrous sulfate (based on a linear mixed model). Proportion with a complete resolution of IDA was higher in the ferrous sulfate group (29% vs 6%; P = .04). Median serum ferritin level increased from 3.0 to 15.6 ng/mL (ferrous sulfate) vs 2.0 to 7.5 ng/mL (iron complex) over 12 weeks, a greater difference of 10.2 ng/mL (95% CI, 6.2 to 14.1 ng/mL; P <.001) with ferrous sulfate. Mean total iron-binding capacity decreased from 501 to 389 μg/dL (ferrous sulfate) vs 506 to 417 μg/dL (iron complex) (a greater difference of −50 μg/dL [95% CI, −86 to −14 μg/dL] with ferrous sulfate; P <.001). There were more reports of diarrhea in the iron complex group than in the ferrous sulfate group (58% vs 35%, respectively; P = .04).” (J. M. Powers, jacquelyn.powers@bcm.edu)
NSAIDs for Chronic Low Back Pain: NSAIDs are of limited value in treatment of patients with chronic low back pain, according to authors of a JAMA Clinical Evidence Synopsis (pp. 2327–8). Results of 13 randomized clinical trials that included 4,807 participants led to this bottom line: “Compared with placebo, NSAIDs are associated with a small but significant improvement in pain and disability in patients with chronic low back pain, although this difference became nonsignificant when studies with high risk for bias were excluded. The associated benefits were smaller than the minimal clinically important difference.” (W. T. M. Enthoven, w.enthoven@erasmusmc.nl)
Brain Amyloid & Cognitive Function: Elevated brain amyloid levels in cognitively normal people are a troublesome prognostic indicator, a study shows (pp. 2305–16). Over a median follow-up period of 3.1 years in 445 study participants, those with elevated amyloid levels had a higher likelihood of cognitive decline than did those with normal levels. (M. C. Donohue, mdonohue@usc.edu)
“Together with the findings reported from other independent cohorts, [this study] clearly indicates that amyloid pathology in cognitively normal older persons is not a benign phenomenon of normal aging but part of a progressive neurodegenerative disease,” editorialists write (
pp. 2285–7). “These findings pave the way for the development of preventive strategies that ultimately may enable persons with [Alzheimer disease] to live without dementia.” (P. J. Visser, pj.visser@maastrichtuniversity.nl)
>>>PNN NewsWatch
* Announcing plans for a July 10–11 meeting to assess opioid formulations with abuse-deterrent properties, FDA Commissioner Scott Gottlieb, MD, said in a statement posted on the FDA website, “Opioid formulations with properties designed to deter abuse are not abuse-proof or addiction-proof. These drugs can still be abused, particularly orally, and their use can still lead to new addiction. Nonetheless, these new formulations may hold promise as one part of a broad effort to reduce the rates of misuse and abuse. One thing is clear: we need better scientific information to understand how to optimize our assessment of abuse deterrent formulations; and I look forward to a productive discussion on how to best tackle this challenge.” FDA released an issues paper outlining existing regulatory and public health challenges regarding these products.
* Bristol-Myers Squibb is voluntarily recalling one lot (HN0063) of 
Eliquis (apixaban) 5 mg tablets to the consumer level because of a consumer complaint of a bottle labeled as 5 mg that contained 2.5 mg tablets, FDA said yesterday.

PNN Pharmacotherapy Line
June 15, 2017 * Vol. 24, No. 115
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 15 issue of the New England Journal of Medicine (2017; 376).
Buprenorphine for Neonatal Abstinence Syndrome: Compared with oral morphine, sublingual doses of buprenorphine produced better efficacy and equivalent safety outcomes in 63 term infants with neonatal abstinence syndrome, a study shows (pp. 2341–8). Infants exposed to opioids in utero and with signs of the syndrome were randomized to one of the treatments, with these results based on a primary end point of duration of treatment for symptoms of neonatal opioid withdrawal: “The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P <0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P = 0.36). Rates of adverse events were similar in the two groups.” (W. K. Kraft, walter.kraft@jefferson.edu)
Treatment of HIV-Associated Talaromycosis: Amphotericin produced significantly better outcomes in treating infections of the dimorphic fungus Talaromyces (previously Penicilliummarneffei in patients with HIV infections than the oral agent itraconazole, researchers report (pp. 2329–40). The infections are a major source of mortality in patients with HIV in South and Southeast Asia. Based a primary outcome of all-cause mortality at week 24, investigators report the following results in 440 adult patients with HIV and talaromycosis at five Vietnamese hospitals: “The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], −3.9 to 5.6; P <0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P = 0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and [immune reconstitution inflammatory syndrome] than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.” (T. Le, thuyl@oucru.org)
Effects of Hospital Value-Based Purchasing on Quality: In the 4 years since being mandated under provisions of the Affordable Care Act, hospital value-based purchasing (HVBP) “has resulted in little tangible benefit,” authors conclude, adding, “It may be useful for the Centers for Medicare and Medicaid Services to continue to experiment with other value-based payment models, including the [Hospital Readmissions Reduction Program], accountable care organization programs, and bundled payment programs, in an effort to improve the value of hospital spending” (pp. 2358–66). The HVBP program incentivizes acute-care hospitals for quality performance-based adjustments of up to 1% of Medicare reimbursements. Comparing acute-care hospitals with a control group of critical access hospitals, which were not exposed to HVBP, the authors found that “HVBP was not associated with improvements in measures of clinical process or patient experience and was not associated with significant reductions in two of three mortality measures” (mortality among patients admitted for acute myocardial infarction or heart failure was unchanged, while mortality among those admitted for pneumonia declined). (A. M. Ryan, amryan@umich.edu)
>>>PNN NewsWatch
Biosimilars scored a victory in the U.S. Supreme Court this week when Sandoz prevailed in a case against Amgen. The result should be accelerated marketing of biosimilars, as the Court ruled that a required 180-day notification need not begin after FDA approval; the biosimilars company can notify the originator company of its intent at the time of application submission to FDA, according to SCOTUSblog.
* Consumers, distributors, and retailers with any lot of several 
Phillips Company products should stop using and return unused, unexpired products to the manufacturer, FDA said yesterday. This recall affects Tetrastem, Diabecline, Tetracycline-ABC, VenomX, Acneen, StaphWash, StringMed, NoPain, and LidoMed.

PNN Pharmacotherapy Line
June 16, 2017 * Vol. 24, No. 116
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Infectious Diseases Report
Source:
 June 15 issue of Clinical Infectious Diseases (2017; 64).
Hospitalization & Pediatric Pneumococcal Vaccine: At eight U.S. children’s hospitals, pneumococcal pneumonia (PP) requiring hospitalization declined after introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 (pp. 1699–704). In 2006–14, these annual pneumococcal pneumonia hospitalization rates per 100,000 admissions were identified: “A total of 377 patients with PP requiring hospitalization were identified. Hospitalization rates of PP decreased from 53.6 to 23.3 per 100,000 admissions post PCV13 (P <.0001). Complicated PP rates also decreased (P <.0001). Need for intensive care, mechanical ventilation, and invasive procedure remained unchanged after the introduction of PCV13. Comorbidities were more common among children with uncomplicated than complicated pneumonia (52.2% vs. 22.5%, P <.001). Overall, PCV13 serotypes 19A, 3, 7F, and 1 caused 80% of PP. Hospitalization rates of PCV13 serotype pneumonia decreased from 47.2 to 15.7 per 100,000 admissions post PCV13. In 2014, the most common serotypes were 3, 19A and 35B.” (L. Olarte)
Efficacy of All-Oral HCV/HIV Regimens: Oral treatment of patients coinfected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) produced high sustained virologic response (SVR) rates in those with genotype-1 (GT1) HCV, researchers report (pp. 1711–20). An observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry led to this conclusion for 12 weeks of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV: “African American race or [proton pump inhibitor] use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with [tenofovir disoproxil fumarate].” (D. Bhattacharya)
Short-Course Adjunctive Gentamicin in Severe Sepsis: In two Dutch intensive care units, short courses of empirical gentamicin “in patients with sepsis was associated with an increased incidence of renal failure but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance,” a study of 648 patients shows (pp. 1731–6). One of the units used a protocol that recommended empirical gentamicin as add-on therapy; logistic regression analysis of outcomes showed the following: “The adjusted odds ratios associated with gentamicin use were 1.39 (95% confidence interval [CI], 1.00–1.94) for renal failure, 1.34 (95% CI, 0.96–1.86) for shock duration, and 1.41 (95% CI, 0.94–2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (P = .62).” (D. S. Y. Ong)
>>>Oncology Highlights
Source:
 June issue of the Journal of Clinical Oncology (2017; 35).
Adjuvant Bisphosphonates in Breast Cancer: Zolendrate or clodronate are preferred agents in adjuvant therapy of postmenopausal women with breast cancer, according to a guideline from Cancer Care Ontario and the American Society of Clinical Oncology (pp. 2062–81): “Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations.” (S. Dhesy-Thind)
>>>PNN NewsWatch
* Advanced Pharma, Inc. (Avella of Houston) is voluntarily recalling all unexpired lots of nitroglycerin admixtures produced between Mar. 3 and May 31 to the hospital/user level, FDA said yesterday. The agency also said Teva is recalling to the consumer/user level Actavis-labeled paliperidone extended-release tablets, 3 mg, 90 count bottles, lot 1160682A, because of failure of the dissolution test.

PNN Pharmacotherapy Line
June 19, 2017 * Vol. 24, No. 117
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 June 17 issue of Lancet (2017; 389).
NSAID Selection in Patients with CVD, GI Risks: In the CONCERN trial of patients at high risk of both cardiovascular and gastrointestinal events who require concomitant aspirin and NSAID, celecoxib was safer than naproxen for reducing the risk of recurrent upper gastrointestinal bleeding, researchers report (pp. 2375–82). Both drugs were administered in combination with PPIs, and study participants all were taking aspirin for cardiovascular prophylaxis. The cyclooxygenase-2–selective NSAID celecoxib, administered in doses of 100 mg twice daily, produced these outcomes in comparison with naproxen 500 mg twice daily: “Between May 24, 2005, and Nov. 28, 2012, we enrolled 514 patients, assigning 257 patients to each study group, all of whom were included in the intention-to-treat population. Recurrent upper gastrointestinal bleeding occurred in 14 patients in the celecoxib group (nine gastric ulcers and five duodenal ulcers) and 31 patients in the naproxen group (25 gastric ulcers, three duodenal ulcers, one gastric ulcer and duodenal ulcer, and two bleeding erosions). The cumulative incidence of recurrent bleeding in 18 months was 5.6% (95% CI 3.3–9.2) in the celecoxib group and 12.3% (8.8–17.1) in the naproxen group (p = 0.008; crude hazard ratio 0.44, 95% CI 0.23–0.82; p = 0.010). Excluding patients who reached study endpoints, 21 (8%) patients in the celecoxib group and 17 (7%) patients in the naproxen group had adverse events leading to discontinuation of treatment. No treatment-related deaths occurred during the study.” (F. K. L. Chan, fklchan@cuhk.edu.hk)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 356).
Congenital Malformations With Maternal Overweight, Obesity: Women with body mass indices (BMIs) above the normal range should attempt to lose weight before becoming pregnant, based on results of a study of major congenital malformations among 1.2 million singletons (j2563). Assessing data from Swedish national registries in 2001–14, investigators found these relationships in a cohort study: “A total of 43,550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20,074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.” (M. Persson, Martina.Persson@ki.se)
>>>PNN NewsWatch
* Alvogen is voluntarily recalling seven lots of Hospira’s Clindamycin Injection USP ADD-Vantage Vials to the hospital/retail level due to microbial growth detected during a routine simulation of the manufacturing process, FDA said on Friday.
FDA also announced that Hospira is voluntarily recalling 42 lots of 8.4% Sodium Bicarbonate Injection, USP, 50 mL vials, 5 lots of Neut (sodium bicarbonate 4% additive solution) 5 mL vials, 5 lots of Quelicin (Succinylcholine Chloride Injection, USP) 200 mg/10 mL vials and 7 lots of Potassium Phosphates Injection, USP, 45 mM vials to the hospital/retail level, also because of microbial growth detected during a routine simulation of the manufacturing process.
>>>PNN JournalWatch
* Phenotypic and Genetic Aspects of Epithelial Barrier Function in Asthmatic Patients, in Journal of Allergy and Clinical Immunology, 2017; 139: 1736–51. (Donna E. Davies, donnad@soton.ac.uk
* Benefits, Pitfalls, and Future Design of Population-Based Registers in Neurodegenerative Disease, in 
Neurology, 2017; 88: 2321–9. (J. P .K. Rooney, jrooney@rcsi.ie)

PNN Pharmacotherapy Line
June 20, 2017 * Vol. 24, No. 118
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Internal Medicine Report
Source:
 June 20 issue of the Annals of Internal Medicine (2017; 166).
Lipid Screening & Cardiovascular Risks in Young Adults: Among American adults aged 30–49 years, prevalence of increased atherosclerotic cardiovascular disease (ASCVD) was low among women younger than 50 and men younger than 40 if they had no ASCVD risk factors, researchers report (pp. 876–82). Data from the National Health and Nutrition Examination Survey 1999 to 2000 through 2011 to 2012 for those without known ASCVD or diabetes showed the following: “Overall, 9,608 NHANES participants representing 67.9 million adults were included, with approximately half (47.12%, representing 32 million adults) in low-prevalence subgroups. In the absence of smoking or hypertension, 0.09% (95% CI, 0.02% to 0.35%) of adult men younger than 40 years and 0.04% (CI, 0.0% to 0.26%) of adult women younger than 50 years had an elevated risk. Among other subgroups, 0% to 75.9% of participants had an increased risk. Overall, 2.9% (CI, 2.3% to 3.5%) had an LDL-C level of 4.92 mmol/L (190 mg/dL) or greater.” (K. K. Patel, patelkris@umkc.edu)
This analysis excluded those already on statins and those with known hypercholesterolemia in youth, editorialists point out (
pp. 901–2). These and other limitations of the study led editorialists to this conclusion: “Absence of evidence is not evidence of absence. We disagree with the [U.S Preventive Services Task Force] recommendation to delay lipid screening until mid-adulthood simply because clinical trial evidence is not available in younger persons. Rather, we believe that at least 1-time LDL-C screening should be universally recommended for all patients in their late teen or early adult years. If anything, we support the principled biologic approach promoted by the American Academy of Pediatrics, which recommends that all children be screened for high cholesterol levels at least once between the ages of 9 and 11 years, and again between ages 17 and 21 years.” (P. M. Ridker, pridker@partners.org)
>>>Allergy/Immunology Report
Source:
 June issue of the Journal of Allergy and Clinical Immunology (2017; 139).
Intradermal Grass Pollen Immunotherapy: While “intradermal allergen immunotherapy suppressed skin late-phase responses,” investigators conclude that the intervention “was not clinically effective and resulted in worsening of respiratory allergic symptoms” in 93 adult participants with grass pollen–induced allergic rhinitis (pp. 1830–9.e13). Seven preseason intradermal allergen injections or a histamine control produced these outcomes based on a primary end point of daily combined symptom–medication scores during the 2013 pollen season: “There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, −172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, −11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense–specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03).” (S. J. Till, stephen.till@kcl.ac.uk)
>>>PNN NewsWatch
* FDA yesterday approved the fluoroquinolone delafloxacin (Baxdela, Melinta Therapeutics) for treatment of adults with acute bacterial skin and skin-structure infections caused by susceptible bacteria. The agent has activity against both gram-positive and gram-negative pathogens, including methicillin-resistant Staphylococcus aureus. It will be available in intravenous and oral formulations. As with other fluoroquinolones, delafloxacin labeling includes a boxed warning of serious adverse reactions, including tendinitis, tendon rupture, peripheral neuropathy, CNS effects, and exacerbation of myasthenia gravis.

PNN Pharmacotherapy Line
June 21, 2017 * Vol. 24, No. 119
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 20 issue of JAMA (2017; 317).
Combination Regimens for Advanced Colorectal Cancer: For treating patients with KRAS wild-type (wt) untreated advanced or metastatic colorectal cancer, addition of cetuximab or bevacizumab to the mFOLFOX6 or FOLFIRI chemotherapy regimen produced statistically similar outcomes, a study shows (pp. 2392–401). In 2005–12, adults at National Clinical Trials Network centers in the U.S. and Canada had these outcomes: “Among 1,137 patients (median age, 59 years; 440 [39%] women), 1,074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0–110.7 months), and 82% of patients (938 of 1,137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab–chemotherapy group and 29.0 months in the bevacizumab–chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77–1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab–chemotherapy group and 10.6 months in the bevacizumab–chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84–1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%–9.0%, P = .13).” (A. Venook, alan.venook@ucsf.edu)
“No difference” does not mean “not the same,” editorialists counter (
pp. 2376–8): “Taking the results at face value, it may appear that it would be reasonable to treat advanced, unresectable RAS wt colorectal cancer with either FOLFOX or FOLFIRI in combination with either cetuximab or bevacizumab given that there were no significant differences between the regimens for overall survival or progression-free survival. However, with emerging data from several trials regarding right- vs left-sided colon cancer, the most recent National Comprehensive Cancer Network Guidelines for colon cancer now recommend consideration of [epidermal growth factor-receptor (EGFR)] therapy [cetuximab] for patients with RAS wt and left-sided tumors only in the first-line therapy setting. What cannot be determined from the study by Venook et al is the effect of subsequent therapy or if EGFR inhibitors can be effectively used in RAS wt right-sided colon cancer for second-line treatment and beyond.” (W. A. Messersmith, wells.messersmith@ucdenver.edu)
Screening for Pediatric Obesity: Updating its 2010 recommendation, the U.S. Preventive Services Task Force (USPSTF) advises clinicians to “screen for obesity in children and adolescents 6 years and older and offer or refer them to comprehensive, intensive behavioral interventions to promote improvements in weight status” (pp. 2417–26). The “B” recommendation is based on these findings from an evidence review: “Comprehensive, intensive behavioral interventions (≥26 contact hours) in children and adolescents 6 years and older who have obesity can result in improvements in weight status for up to 12 months; there is inadequate evidence regarding the effectiveness of less intensive interventions. The harms of behavioral interventions can be bounded as small to none, and the harms of screening are minimal. Therefore, the USPSTF concluded with moderate certainty that screening for obesity in children and adolescents 6 years and older is of moderate net benefit.” (D. C. Grossman, chair@uspstf.net)
“The USPSTF recommendation should provide an impetus to redouble efforts to invest in practice, community, policy, and multilevel intervention research focused on achieving primary prevention and sustained improvements in health and health trajectories for children and adolescents and their families,” editorialists write (
pp. 2378–80). “Such a focus is critical for reversing the obesity epidemic.” (R. L. J. Thornton, rjohns21@jhmi.edu)
Chronic Pain Therapies: “The primary change in approach to the treatment of chronic pain is the use of nonpharmacological therapies,” write Viewpoint authors (pp. 2367–8). “A wide range of psychological, self-management, educational, and complementary and alternative therapies are available but are often underutilized.” These include structured educational programs, cognitive behavioral and other psychologic therapies, mindfulness meditation, and increased activity through structured exercise programs (usually walking). (T. L. Schwenk, tschwenk@med.unr.edu)

PNN Pharmacotherapy Line
June 22, 2017 * Vol. 24, No. 120
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 22 issue of the New England Journal of Medicine (2017; 376).
First-Line Nivolumab in Non–Small-Cell Lung Cancer: In an open-label phase 3 trial of 423 patients with previously untreated stage IV or recurrent non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) expression level of 5% or more, overall survival was similar with first-line nivolumab or platinum-based chemotherapy (pp. 2415–26). With crossover to nivolumab allowed in patients with disease progression, the trial investigators found these results: “The median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P = 0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.” (D. P. Carbone, david.carbone@osumc.edu)
“In light of these data, the presence of PD-L1 expression in at least 50% of tumor cells versus in less than 50% of tumor cells should be determined in patients with newly diagnosed, advanced NSCLC with the use of the assay associated with pembrolizumab efficacy until a prospectively evaluated alternative biomarker shows similar predictive value,” an editorialist writes (
pp. 2483–5). “The exploratory biomarker of the tumor-mutation burden that is proposed by Carbone et al. is intriguing, but it is akin to an algorithm developed today that predicts last season’s World Series victory by the Cubs. Although potentially meritorious, its ability to pick this season’s champion is unclear. If subtly different PD-L1–enhancement strategies can distinguish a strongly positive study from a clearly negative one, it will be important to evaluate consistency among pathologists. If the strategies for the selection of patients in clinical practice differ significantly from proven approaches, the data suggest that our patients may not derive the same benefits as have been seen in clinical trials.” (E. B. Garon)
Recombinant Influenza Vaccine in Adults Aged 50 Years or More: In 8,855 adults aged 50 years or older, a quadrivalent, recombinant influenza vaccine (RIV4) provided better protection than a standard-dose, egg-grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2-predominant 2014–15 influenza season, researchers report (pp. 2427–36). The RIV4 formulation had 3 times as much hemagglutinin (HA) per strain (45 mcg versus 15 mcg of HA per strain in the IIV4 product). Based on occurrence of reverse-transcriptase polymerase-chain-reaction (RT-PCR)–confirmed, protocol-defined, influenza-like illness, results showed the following: “Among RIV4 recipients, the RT-PCR–confirmed influenza attack rate was 2.2% (96 cases among 4,303 participants) in the modified per-protocol population and 2.2% (96 cases among 4,427 participants) in the modified intention-to-treat population. Among IIV4 recipients, the attack rate was 3.2% (138 cases among 4,301 participants) in the modified per-protocol population and 3.1% (138 cases among 4,428 participants) in the modified intention-to-treat population. A total of 181 cases of influenza A/H3N2, 47 cases of influenza B, and 6 cases of nonsubtypeable influenza A were detected. The probability of influenza-like illness was 30% lower with RIV4 than with IIV4 (95% confidence interval, 10 to 47; P = 0.006) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4. The safety profiles of the vaccines were similar.” (L. M. Dunkle, ldunkle@proteinsciences.com)
Benralizumab in Severe Asthma: The interleukin-5-alpha receptor inhibitor benralizumab was oral glucocorticoid–sparing in a trial of 220 patients with severe asthma (pp. 2448–58). Over 28 weeks of randomized treatment, exacerbation rates were lower with the monoclonal antibody than with placebo, and median steroid doses were 75% lower. (P. Nair, parames@mcmaster.ca)

PNN Pharmacotherapy Line
June 23, 2017 * Vol. 24, No. 121
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Health Affairs Report
Source:
 June issue of Health Affairs, a theme issue on Pursuing Health Equity (2017; 36).
Impacts of Obamacare: As the U.S. Senate takes up a bill to repeal and replace the Affordable Care Act (ACA), researchers report the 3-year impacts of ACA in two expansion (AR and KY) states and one nonexpansion (TX) state (pp. 1119–28): “By the end of 2016 the uninsurance rate in the two expansion states had dropped by more than 20 percentage points relative to the nonexpansion state. For uninsured people gaining coverage, this change was associated with a 41-percentage-point increase in having a usual source of care, a $337 reduction in annual out-of-pocket spending, significant increases in preventive health visits and glucose testing, and a 23-percentage-point increase in ‘excellent’ self-reported health. Among adults with chronic conditions, we found improvements in affordability of care, regular care for those conditions, medication adherence, and self-reported health.” (B. D. Sommers, bsommers@hsph.harvard.edu)
U.S. Trends That Could Exacerbate Health Inequities: Trends in U.S. health care that could worsen health inequities are reviewed (pp. 992–8): “Health inequities among people of different races and ethnicities, geographical locations, and social classes are not a new phenomenon, although the size of the inequities has changed since researchers first began documenting them. While interventions to improve the health of targeted disadvantaged groups may help combat disparities, broader trends that disproportionately benefit privileged groups or harm vulnerable populations can eclipse the progress made through isolated interventions. These trends threaten equity in health and health care in the United States either through direct effects on health or through impacts on the distribution of resources, risks, and power. We highlight trends in four domains: health care technologies, health reform policies, widening socioeconomic inequality, and environmental hazards. We suggest ways of countering the effects of these trends to promote health equity, focusing on strategies that promise co-benefits across multiple sectors.” (M. C. Arcaya, marcaya@mit.edu)
Income-Related Differences in Perception About Health Care: Large differences in the ways Americans view health care relate to income, a study shows, and the gaps are much larger than in other countries (pp. 1032–40). In 32 middle- and high-income countries, income gaps and perceptions in 2011–13 showed these trends: “While high-income respondents were generally more positive about their health and health care in most countries, the gap between them and low-income respondents was much bigger in some than in others. The United States has among the largest income-related differences in each of the measures we studied, which assessed both respondents’ past experiences and their confidence about accessing needed health care in the future. Relatively low levels of moral discomfort over income-based health care disparities despite broad awareness of unmet need indicate more public tolerance for health care inequalities in the United States than elsewhere. Nonetheless, over half of Americans felt that income-based health care inequalities are unfair, and these respondents were significantly more likely than their compatriots to support major health system reform—differences that reflect the country’s political divisions. Given the many provisions in the Affordable Care Act that seek to reduce disparities, any replacement would also require attention to disparities or risk taking a step backward in an area where the United States is in sore need of improvement.” (J. O. Hero, hero@fas.harvard.edu)
>>>PNN NewsWatch
FDA has approved Haegarda, the first C1 esterase inhibitor (human) for subcutaneous administration to prevent attacks of the orphan disease hereditary angioedema (HAE) in adolescent and adult patients. The CSL Behring product is a human plasma–derived, purified, pasteurized, lyophilized concentrate prepared from large pools of human plasma from U.S. donors. It is indicated for routine prophylaxis to prevent but not treat acute HAE attacks.
* Following Hospira’s recent recall (
see PNN, June 19), Advanced Pharma, Inc. d/b/a Avella of Houston, is conducting a limited recall of specific lots of repackaged or compounded potassium phosphate and succinylcholine chloride.

PNN Pharmacotherapy Line
June 26, 2017 * Vol. 24, No. 122
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Lancet Highlights
Source:
 June 24 issue of Lancet (2017; 389).
Nocebo Effect With Statins: In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, reports of adverse reactions to statins were higher during nonblinded periods, researchers report, illustrating the “so-called nocebo effect” (pp. 2473–81). The study of adults ages 40–79 years was blinded in 1998–2002 and nonblinded in 2002–05. Differences in reports of adverse effects (AEs) during these periods were as follows: “During the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not…. We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders … and blood and lymphatic system disorders.
“These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects.” (P. Sever, 
p.sever@imperial.ac.uk)
Nivolumab in Advanced Hepatocellular Carcinoma: Used for treating patients with advanced hepatocellular carcinoma in the phase 1/2 CheckMate 040 study, nivolumab had a “manageable safety profile” and produced “no new signals” (pp. 2492–502). In dose-escalation and dose-expansion phases of the study, these results were recorded: “Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase.” (A. B. El-Khoueiry, elkhouei@med.usc.edu)
>>>BMJ Highlights
Source:
 Early-release article from BMJ (2017; 356).
Life Expectancy & CVD/Cancer Mortality: As cardiovascular diseases (CVDs) were controlled in the decades since 1980, inequalities developed in longevity related to differences in declining cancer mortality rates, according to an analysis of national data of member states of the World Health Organization (j2765). Declining lung cancer mortality rates were an important factor in better outcomes for men, the authors note in reaching this conclusion: “The inequality in improvement in longevity attributed to declining cancer mortality rates reflects inequities in implementation of cancer control, particularly in less resourced populations and in women. Global actions are needed to revitalize efforts for cancer control, with a specific focus on less resourced countries.” (B. Cao, CaoB@fellows.iarc.fr)
>>>PNN NewsWatch
* Another recall resulting from the Hospira sterility problems involves three lots of Fagron Sterile Services’ Succinylcholine Chloride 20 mg/mL 5 mL syringe to the hospital/clinic level, FDA said.
>>>PNN JournalWatch
* Metabolic Syndrome, Its Components, and Knee Osteoarthritis: The Framingham Osteoarthritis Study, in Arthritis & Rheumatology, 2017; 69: 1194–203. (D. T. Felson, dfelson@bu.edu
* Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update, in 
Journal of Clinical Oncology, 2017; 35: 2082–94. (L. Sung, lillian.sung@sickkids.ca
* Surgical Guidelines for Perioperative Management of Older Adults: What Geriatricians Need to Know, in 
Journal of the American Geriatrics Society, 2017; 65: 1339–46. (J. L. Colburn, jcolbur1@jhmi.edu)

PNN Pharmacotherapy Line
June 27, 2017 * Vol. 24, No. 123
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Geriatrics Highlights
Source:
 June issue of the Journal of the American Geriatrics Society (2017; 65).
CNS Medication Burden & Nursing Home Falls: Among older adults residing in nursing homes, a CNS medication burden equivalent to 3 or more standardized daily doses was associated with a significantly increased risk of serious falls, researchers report (pp. 1183–9). A nested case–control study of 5,556 residents aged 65 years or older had these outcomes based on Medicare Parts A and B codes and use of psychoactive Part D medications (specific antidepressants, antiepileptics, antipsychotics, benzodiazepines, and opioid receptor agonists): “Those taking 3+ CNS standardized daily doses were more likely to have a serious fall than those not taking any CNS medications (adjusted odds ratio 1.83; 95% confidence interval 1.35–2.48). There was no significant difference in fall risk for residents taking >0 to <3 CNS standardized daily doses compared to residents taking no CNS medications (adjusted odds ratio 0.85; 95% CI 0.63–1.15).” The authors conclude, “Clinicians should be vigilant for opportunities to discontinue or decrease the doses of individual CNS medications and/or consider non-pharmacological alternatives. Such interventions that reduce use of CNS medications in nursing homes could reduce fall rates but further research is needed to confirm this.” (J. T. Hanlon, jth14@pitt.edu)
Antipsychotic Use After Cardiac Surgery: First- and second-generation antipsychotic agents are associated with similar risks of adverse events, according to a study of patients undergoing coronary artery bypass grafting or valve surgery (pp. 1229–37). Among 3,706 inpatients with an average age of 70 years, results for those receiving antipsychotic medications (APMs) were as follows: “In the propensity score–matched cohort, median treatment duration was 3 days (interquartile range (IQR) 1–6 days) for atypical APMs and 2 days (IQR 1–3 days) for typical APMs. There were no large differences in in-hospital mortality (atypical 5.4%, typical 5.3%; risk difference (RD) = 0.1%, 95% confidence interval (CI) = −2.1 to 2.3%), arrhythmia (2.0% vs 2.2%; RD = 0.0%; 95% CI = −1.4 to 1.4%), pneumonia (16.1% vs 14.5%; RD = 1.6%, 95% CI = −1.9 to 5.0%), and length of stay (9.9 days vs 9.3 days; mean difference = 0.5 days, 95% CI = −1.2 to 2.2). Use of brain imaging was more common after initiating atypical APMs (17.3%) than after typical APMs (12.4%; RD = 4.9%, 95% CI = 1.4–8.4).” (D. H. Kim, dkim12@partners.org)
Statins & Vitamin D Responses: Older adults have lower responses to vitamin D doses when they are taking statins, according to a pooled analysis of three clinical trials (pp. 1267–73). Among 646 participants with a mean age of 76.3 years, 25(OH)D serum levels for statin users and nonusers showed these patterns: “At baseline, 17.5% were statin users, and 65% were vitamin D deficient (25(OH)D < 20 ng/mL). Baseline 25(OH)D levels did not differ significantly between groups (18.8 for statin users, 17.2 ng/mL for nonusers, P = .07), but according to the longitudinal analyses, the total increase over 12 months in 25(OH)D concentration was significantly lower in statin users (13.1 ng/L) than nonusers (15.9 ng/mL; 21.4% difference; P = .009).” (H. A. Bischoff-Ferrari, Heike.Bischoff@usz.ch)
>>>Rheumatology Report
Source:
 June issue of Arthritis & Rheumatology (2017; 69).
Cardiovascular Safety of Tocilizumab: Among patients with rheumatoid arthritis (RA) whose therapy was changed from tumor necrosis factor inhibitors (TNFi) or tofacitinib to tocilizumab (TCZ), cardiovascular risks were unchanged, according to a multi-database population-based cohort study (pp. 1154–64): “We included 9,218 TCZ initiators propensity score matched to 18,810 TNFi initiators across all 3 databases. The mean age was 72 years in Medicare, 51 in PharMetrics, and 53 in MarketScan. Cardiovascular disease was present at baseline in 14.3% of TCZ initiators and 13.5% of TNFi initiators. During the study period (mean ± SD 0.9 ± 0.7 years; maximum 4.5 years), 125 composite cardiovascular events occurred, resulting in an incidence rate of 0.52 per 100 person–years for TCZ initiators and 0.59 per 100 person–years for TNFi initiators. The risk of cardiovascular events associated with TCZ use versus TNFi use was similar across all 3 databases, with a combined HR of 0.84 (95% confidence interval 0.56–1.26).” (S. C. Kim, skim62@partners.org)

PNN Pharmacotherapy Line
June 28, 2017 * Vol. 24, No. 124
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>JAMA Report
Source:
 June 27 issue of JAMA (2017; 317).
Clinical Applications of Acupuncture: Two studies and an editorial explore the possibilities of using acupuncture for conditions often treated with medications.
Compared with sham electroacupuncture in 482 women with stress urinary incontinence (SUI), electroacupuncture involving the lumbosacral region reduced urine leakage after 6 weeks, a study shows (
pp. 2493–501). “Mean urine leakage at baseline was 18.4 g for the electroacupuncture group and 19.1 g for the sham electroacupuncture group. Mean 72-hour incontinence episodes were 7.9 for the electroacupuncture group and 7.7 for the sham electroacupuncture group. At week 6, the electroacupuncture group had greater decrease in mean urine leakage (−9.9 g) than the sham electroacupuncture group (−2.6 g) with a mean difference of 7.4 g (95% CI, 4.8 to 10.0; P <.001). During some time periods, the change in the mean 72-hour incontinence episodes from baseline was greater with electroacupuncture than sham electroacupuncture with between-group differences of 1.0 episode in weeks 1 to 6 (95% CI, 0.2-1.7; P = .01), 2.0 episodes in weeks 15 to 18 (95% CI, 1.3-2.7; P <.001), and 2.1 episodes in weeks 27 to 30 (95% CI, 1.3-2.8; P <.001). The incidence of treatment-related adverse events was 1.6% in the electroacupuncture group and 2.0% in the sham electroacupuncture group, and all events were classified as mild.” (B. Liu, baoyanjournal@163.com)
Live births were not increased through use of acupuncture with or without clomiphene in 1,000 Chinese women with polycystic ovary syndrome, researchers report (
pp. 2502–14): “Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, −0.6%; 95% CI, −5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%).” (X-K Wu, xiaokewu2002@vip.sina.com)
“[These] 2 clinical trials … add to the evidence base involving potential clinical applications of acupuncture,” editorialists write (
pp. 2489–90). “The trial by Wu et al indicates that for infertility associated with polycystic ovary syndrome, acupuncture is no substitute for clomiphene. The trial by Liu et al suggests that for women with stress urinary incontinence, acupuncture, like behavioral interventions such as pelvic floor muscle training, may be a reasonable option to explore before considering surgical intervention. These studies shed new light on when and when not to consider using acupuncture, although why and how this procedure may work require further study. Clearly these ancient practices are helping reveal the complexity of the links between the mind and the body.” (J. P. Briggs, briggsj@mail.nih.gov)
>>>PNN NewsWatch
* While the world watched yesterday’s drama on Capitol Hill regarding Senate debate on Obamacare, FDA took what it described as “important steps under the new Drug Competition Action Plan” announced in late May. The agency published a list of off-patent, off-exclusivity branded drugs without approved generics, and also implemented, for the first time, a new policy to expedite the review of generic drug applications where competition is limited. “No patient should be priced out of the medicines they need,” FDA Commissioner Scott Gottlieb, MD, said in a news release. “Getting safe and effective generic products to market in an efficient way, being risk-based in our own work, and making sure our rules aren’t used to create obstacles to new competition can all help make sure that patients have access to more lower-cost options.”

PNN Pharmacotherapy Line
June 29, 2017 * Vol. 24, No. 125
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>NEJM Report
Source:
 June 29 New England Journal of Medicine (2017; 376).
Levothyroxine in Geriatric Subclinical Hypothyroidism: Among 737 older adults with subclinical hypothyroidism, thyroid hormone therapy provided no apparent benefits, researchers report (pp. 2534–44). Participants received titrated doses of levothyroxine or placebo, with these results based on change in 1-year Hypothyroid Symptoms and Tiredness scores on a thyroid-related quality-of-life questionnaire: “The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (± SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P <0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2 ± 15.3 in the placebo group and 0.2 ± 14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], −2.0 to 2.1) or the Tiredness score (3.2 ± 17.7 and 3.8 ± 18.4, respectively; between-group difference, 0.4; 95% CI, −2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest.” (D. J. Stott, david.j.stott@glasgow.ac.uk)
Antibiotics for Small Skin Abscesses: Short-term outcomes in patients with simple abscesses were better when antibiotics were used than with incision and drainage alone, a study of 786 adults and children shows (pp. 2545–55). Skin abscesses were 5 cm or less in diameter; two thirds of lesions grew Staphylococcus aureus, with many methicillin-resistant strains. Randomization to clindamycin, trimethoprim–sulfamethoxazole (TMP-SMX), or placebo for 10 days yielded these outcomes based on clinical cure rates: “Ten days after therapy in the intention-to-treat population, the cure rate among participants in the clindamycin group was similar to that in the TMP-SMX group (221 of 266 participants [83.1%] and 215 of 263 participants [81.7%], respectively; P = 0.73), and the cure rate in each active-treatment group was higher than that in the placebo group (177 of 257 participants [68.9%], P <0.001 for both comparisons). The results in the population of patients who could be evaluated were similar. This beneficial effect was restricted to participants with S. aureus infection. Among the participants who were initially cured, new infections at 1 month of follow-up were less common in the clindamycin group (15 of 221, 6.8%) than in the TMP-SMX group (29 of 215 [13.5%], P = 0.03) or the placebo group (22 of 177 [12.4%], P = 0.06). Adverse events were more frequent with clindamycin (58 of 265 [21.9%]) than with TMP-SMX (29 of 261 [11.1%]) or placebo (32 of 255 [12.5%]); all adverse events resolved without sequelae. One participant who received TMP-SMX had a hypersensitivity reaction.” (R. S. Daum, rsdaum@gmail.com)
Air Pollution & Mortality: A study of more than 60 million Medicare beneficiaries shows “significant evidence of adverse effects related to exposure to [particulate matter] and ozone at concentrations below current national standards” (pp. 2513–22, F. Dominici, fdominic@hsph.harvard.edu). A related editorial is critical of the U.S. decision to withdraw from the Paris climate agreement, asking, “Do we really want to breathe air that kills us?” (pp. 2591–2; R. E. Berger)
>>>PNN NewsWatch
* With 27 charts and 114 tables, the 40th annual report on the health of the nation illustrates the marked changes in longevity and indicators of morbidity and mortality since 1975. CDC notes that the number of Americans 65 years of age or older more than doubled, from 22.6 million to 47.8 million. The population grew more diverse, with 38.4% of people now identifying as racial or ethnic minorities, up from 20.1%. Between 1978 and September 2016 (preliminary data), the percentage of children under age 18 who were uninsured decreased from 12.0% to 5.0%; the percentage with Medicaid coverage increased from 11.3% to 39.2%; and the percentage with private coverage decreased from 75.1% to 53.5%.
* Specific lots of PharMEDium 
potassium phosphate and succinylcholine chloride admixtures distributed to health systems are being recalled, FDA said; they were compounded with the Hospira lines that lacked sterility assurance.

PNN Pharmacotherapy Line
June 30, 2017 * Vol. 24, No. 126
Providing news and information about medications and their proper use
Click here for a PDF of this issue.
>>>Diabetes Care Report
Source:
 July issue of Diabetes Care (2017; 40).
Cardiovascular Benefits of Antidiabetic Drugs — New Era? Authors of two Perspectives in Care articles examine the mechanisms responsible for cardiovascular benefits of antidiabetic medications.
“Since liraglutide, semaglutide, pioglitazone, and empagliflozin … lower the plasma glucose concentration but appear to reduce [cardiovascular disease (CVD)] risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit,” authors write (
pp. 813–20). Noting the most deaths of people with type 2 diabetes (T2D) are caused by CVD but that lowering A1C levels does not affect CVD risk, the group notes: “The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone. However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events.” (R. A. DeFronzo, albarado@uthscsa.edu)
Since FDA began requiring new antidiabetic agents to rule out excess cardiovascular (CV) risk, trials show a “favorable benefit-risk balance … in mitigating CV risk in patients with type 2 diabetes,” authors of the second article conclude (
pp. 821–31). “The results of seven trials have been presented so far—three with dipeptidyl peptidase 4 inhibitors, one with a sodium–glucose cotransporter 2 (SGLT2) inhibitor, and three with glucagon-like peptide 1 receptor agonists (GLP-1 RA). While all seven trials showed noninferiority in the rate of MACE with the use of these agents compared with placebo, three of them revealed CV benefits. Treatment with empagliflozin (an SGLT2 inhibitor) and treatment with liraglutide (a GLP-1 RA) both significantly reduced the risk of MACE, mortality from CV causes, and mortality from any cause when compared with placebo. Treatment with semaglutide, another GLP-1 RA, showed a significantly lower rate of MACE but not mortality from CV or any cause compared with placebo. In all of the trials, the effects of treatment on outcomes were out of proportion to the small differences in glycemic control levels, suggesting that the effects observed were likely unrelated to differences in the glucose-lowering efficacy.” (S. Kaul, sanjay.kaul@cshs.org)
>>>PNN NewsWatch
* A week after FDA Commissioner Scott Gottlieb committed to eliminating a backlog of orphan drug applications within 90 days, the agency has unveiled its Orphan Drug Modernization Plan. Following a steady increase in orphan drug applications over the past 5 years, FDA has about 200 requests pending review. To ensure all future requests receive a response within 90 days of receipt, the agency will take this multifaceted approach: Reorganize review staff to maximize expertise and improve workload efficiencies; better leverage the expertise across the FDA’s medical product centers; and establish a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.
FDA yesterday allowed marketing of ClearLLab Reagents (T1, T2, B1, B2, M), the first agency authorized test for use with flow cytometry to aid in the detection of several leukemias and lymphomas, including chronic leukemia, acute leukemia, non-Hodgkin lymphoma, myeloma, myelodysplastic syndrome, and myeloproliferative neoplasms.
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