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.
PNN will not be published on Mon. and Tues., July 3–4, Independence Day.
PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN January–March 2017

PNN Pharmacotherapy Line
Jan. 3, 2017 * Vol. 24, No. 1
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Jan. 3 issue of the Annals of Internal Medicine (2017; 166).
Oral Treatment of Type 2 Diabetes: In an update to a 2012 clinical practice guideline, the American College of Physicians recommends first-line use of metformin for oral pharmacologic treatment of type 2 diabetes in adults (10.7326/M16-1860). The guideline, endorsed by the American Academy of Family Physicians, cites the safety advantages of metformin over other oral agents, particularly its weight loss effect. Based on a systematic review and meta-analysis of monotherapy and metformin-based combination therapy (2016;164:740–51; N. M. Maruthur, maruthur@jhmi.edu), ACP makes these recommendations (A. Qaseem, aqaseem@acponline.org):
* ACP recommends that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)
* ACP recommends that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing benefits, adverse effects, and costs.
Evidence Supporting Increased Metformin Use: Describing evidence that supports recent changes in recent FDA-approved labeling of metformin-containing products, authors of a systematic review conclude that “metformin use in patients with moderate [chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD)] with hepatic impairment is associated with improvements in key clinical outcomes” (10.7326/M16-1901). Studies selected for inclusion in the review assessed metformin’s effects in adults with type 2 diabetes and CKD, defined as estimated glomerular filtration rate less than 60 mL/min/1.73 sq m, and reported all-cause mortality, major adverse cardiovascular events, and other outcomes. The data showed: “On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.” (M. J. Crowley, matthew.crowley@dm.duke.edu)
Treatment of Gout: One of several articles in this issue on treatment of gout (pp. 26–36, S. J. Newberry, sydnen@rand.org; pp. 37–51, P. G. Shekelle, shekelle@rand.org; pp. 73–4, R. M. McLean, robert.mclean@ynhh.org; pp. 1–16, A. Qaseem), an editorial concludes that “although some approaches have not yet been formally tested in trials, a clear understanding of the pathophysiology of gout provides a strong foundation for rational recommendations while we await clarity on these important clinical issues” (pp. 71–2): “We acknowledge that the existing literature only indirectly addresses what the optimal serum urate target is. However, it is a disservice to our patients and primary care colleagues to suggest that treating to avoid symptoms is acceptable with [urate-lowering therapy (ULT)] in the absence of evidence. At the very least, based on the biochemistry of urate, a treatment target below the physiologic threshold of urate crystallization (<6.8 mg/dL) would be appropriate, even if a lower target is not yet supported by randomized trials. A target of less than 6.8 mg/dL (or <357 µmol/L [<6 mg/dL] with assay variation taken into account) seems reasonable, based on the authors’ own admission that serum urate levels exceeding this threshold are the cause of gout.” (T. Neogi)

>>>PNN JournalWatch
* 2017 Standards of Medical Care in Diabetes, in
Diabetes Care, 2017; 40 (suppl 1). (American Diabetes Association) 
* Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA, in
American Journal of Psychiatry, 2017; 174: 18–25. (W. V. McCall) 
* Risk Stratification for Opioid Misuse in Children, Adolescents, and Young Adults: A Quality Improvement Project, in
Pediatrics, 2017; 139: 10.1542/peds.2016-0258. (R. Thienprayoon) 
* Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-0955. (D. Harrison) 

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 4, 2017 * Vol. 24, No. 2
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 3 issue of JAMA (2017; 317).
Trastuzumab Biosimilar in Metastatic Breast Cancer: In a randomized comparison, a proposed trastuzumab biosimilar performed similarly to the originator product in women with ERBB2 (HER2)–positive metastatic breast cancer, researchers report (pp. 37–47). The phase 3 trial included 500 women treated with a taxane plus either the biosimilar or trastuzumab, with these results: “Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The [overall response rate (ORR)] was 69.6% (95% CI, 63.62%–75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%–70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974–1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%).” (H. S. Rugo, hope.rugo@ucsf.edu)
In addition to exploring the impact of a biosimilar on treatment in developing countries, editorialists delve into the effect on prices in the U.S. (
pp. 30–2): “The trastuzumab biosimilar will probably reduce prices, although this will not take full effect until the patent on trastuzumab expires in 2019. Under the prevailing ‘buy and bill’ system of Medicare Part B, oncology practices are reimbursed for chemotherapy based on a drug’s average sales price plus a 6% margin intended to cover overhead and inventory management. To mitigate the financial disincentive to prescribe inexpensive alternatives, the Centers for Medicare & Medicaid Services has wisely pegged reimbursement for biosimilar products to the average sales price of the biosimilar plus 6% of the branded version, that is, the 6% is based on the cost of the more expensive drug.” (D. Schrag, deb_schrag@dfci.harvard.edu)
JAMA editors explain their decision to publish this article in light of trial sponsorship by the biosimilar developers, including Mylan, which has been under scrutiny for its pricing of EpiPen (pp. 33–4): “Ultimately, the decision to publish this article was based on the determination that the scientific merit and potential to contribute meaningful clinical information for care of patients with breast cancer outweighed other considerations. The controversy over the pricing of drugs in the United States and around the world is an ongoing debate, and not unique to 1 company or 1 product. The authors have provided assurance to the editors that the study was conducted ethically and appropriately. The lead academic author indicates that she had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The data from this study will also be subject to additional scrutiny by regulatory agencies in making determinations about approval of the proposed trastuzumab biosimilar product.” (H. Bauchner, howard.bauchner@jamanetwork.org)
Longer Dosing Interval for Zoledronic Acid: Administration of zoledronic acid in patients with cancer every 12 weeks was noninferior to every-4-week dosing in a randomized open-label trial (pp. 48–58): “Among 1,822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of −0.3% [1-sided 95% CI, −4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma.…” (A. L. Himelstein, ahimelstein@cbg.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 5, 2017 * Vol. 24, No. 3
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 5 issue of the New England Journal of Medicine (2017; 376).
Inclisiran for PCSK9–Mediated Cholesterol Lowering: A long-acting RNA interference therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), inclisiran significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months without serious adverse events, researchers report (pp. 41–51). Tested in ascending and multiple doses in a phase 1 trial, inclisiran produced these results in small numbers of healthy volunteers: “The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the gamma-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84).” (K. Fitzgerald, kfitzgerald@alnylam.com)
Entry of inclisiran into clinical testing brings attention to the new field of oligonucleotide therapeutics, according to the author of a Perspective article (
pp. 4–7): “The [small interfering RNAs (siRNAs)] consist of two strands, guide and passenger. The guide strand carries the sequence information necessary for target-gene recognition, while the passenger strand serves as a prodrug that supports the geometry required for loading into the RNA-induced silencing complex (RISC). When siRNAs are introduced into the cells, the guide strand enters the RISC and reprograms the powerful natural mechanism RNA interference (RNAi), silencing genes on demand. The loaded RISC has a long half-life, and as few as 100 to 200 loaded RISC complexes per cell are sufficient to eliminate expression of the targeted gene. The importance of this fundamental mechanism is well recognized — indeed, the two scientists who discovered it, Craig Mello and Andrew Fire, were awarded the Nobel Prize in 2006.” (A. Khvorova)
Oligonucleotide technology is also being tested with antisense agents, writes the author of a Clinical Implications of Basic Research article (
pp. 86–8). “The advantages of the targeted delivery strategy are … demonstrated by comparing the results of a pair of phase 2 studies in which the activity of two antisense oligonucleotides against apolipoprotein(a), which is expressed in the liver, were compared,” the author explains. “One of the antisense oligonucleotides was nontargeted, and the second was targeted to hepatocytes with the use of triantennary [N-acetylgalactosamine]. On the basis of the reductions in the mean change in circulating levels of apolipoprotein(a) according to dose, targeted delivery was determined to result in a median effective dose that was one thirtieth of that associated with nontargeted delivery, which clearly underscored the potential advantage of the approach.” (A. A. Levin)
Ticagrelor in Symptomatic Peripheral Artery Disease: In 13,885 patients with symptomatic peripheral artery disease, ticagrelor was not superior to clopidogrel for reduction of cardiovascular events, and major bleeding rates were similar (pp. 32–40). A primary efficacy composite end point of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke occurred in 751 of 6,930 patients (10.8%) receiving ticagrelor and in 740 of 6,955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P = 0.65), the investigators report. (M. R. Patel, manesh.patel@duke.edu)

>>>PNN NewsWatch
*
FDA, now classifying an October recall as Class I, yesterday issued an alert about a potential link between us of Nurse Assist I.V. Flush Syringes with Burkholderia cepacia bloodstream infections.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 6, 2017 * Vol. 24, No. 4
Providing news and information about medications and their proper use

>>>Diabetes Report
Source: Jan. issue and annual standards supplement of Diabetes Care (2017; 40).
2017 Standards of Medical Care in Diabetes: Psychosocial issues have been added to the ADA’s Standards of Care for 2017, including self-management, mental health, communication, complications, comorbidities, and life-stage considerations (supplement 1). Several tweaks were made to the pharmacotherapy recommendations, including the following (Am. Diabetes Assoc.):
* Patients on long-term metformin therapy should have periodic B12 measurements and supplementation as needed.
* A new section describes newly available biosimilar insulins.
* Empagliflozin or liraglutide are recommended in patients with established cardiovascular disease to reduce the risk of mortality.
* A figure illustrating antihyperglycemic therapy in type 2 diabetes is updated to acknowledge the high cost of insulin.
* An algorithm for the use of combination injectable therapy in patients with type 2 diabetes is changed to reflect studies demonstrating the noninferiority of basal insulin plus glucagon-like peptide 1 receptor agonist versus basal insulin plus rapid-acting insulin versus two daily injections of premixed insulin, as well as studies demonstrating the noninferiority of multiple-dose premixed insulin regimens versus basal-bolus therapy.
* New tables show the median costs of noninsulin agents.
Metformin & Gut Microbiome: Clinical data support an emerging hypothesis that use of metformin “shifts gut microbiota composition through the enrichment of mucin-degrading Akkermansia muciniphila as well as several [short-chain fatty acid (SCFA)]–producing microbiota,” researchers report (pp. 54–62). Among 28 patients with type 2 diabetes, half of whom were taking metformin, and 84 participants without diabetes, these results were found in clinical tests and gene sequencing of fecal samples: “We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus.” (J. S. Escobar, jsescobar@serviciosnutresa.com)
Saxagliptin & Renal Outcomes: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, saxagliptin significantly improved albumin/creatinine ratios (ACRs) among patients with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, an effect that could not be explained by the drug’s glycemic actions (pp. 69–76). “Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively),” the authors wrote of the 16,492 study participants. “At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was −19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA.…” (I. Raz, ntv502@netvision.net.il)

>>>PNN NewsWatch
* After a very quiet beginning of the
2016–17 influenza season, the bug produced its annual holiday bump in surveillance data during the week before Christmas as Americans shared a viral gift with other travelers and loved ones. Nationally, 10.4% of respiratory specimens tested positive for influenza that week, and 9 of the 10 regions in the U.S. had elevated activity. Remind patients that it’s not too late to get vaccinated and that peak activity last season was in March.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 9, 2017 * Vol. 24, No. 5
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 7 issue of Lancet (2017; 389).
Regorafenib in Hepatocellular Carcinoma: In a phase 3 trial of 567 patients with sorafenib-resistant hepatocellular carcinoma (HCC), regorafenib significantly improved overall and median survival, researchers report (pp. 56–66). “Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment,” the group concludes based on these study results: “Regorafenib improved overall survival with a hazard ratio of 0.63 (95% CI 0.50–0.79; one-sided p <0.0001); median survival was 10.6 months (95% CI 9.1–12.1) for regorafenib versus 7.8 months (6.3–8.8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand–foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.” (J. Bruix, jbruix@clinic.ub.es)
Atezolizumab in Urothelial Carcinoma: Results of a single-arm, phase 2 trial of the anti-programmed death-ligand 1 (PD-L1) atezolizumab show improved durable response rates, survival, and tolerability in 119 previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible (pp. 67–76): “At 17.2 months’ median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n = 11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.” (A. V. Balar, arjun.balar@nyumc.org)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
“Screen & Treat” in Type 2 Diabetes Prevention: Identification of prediabetes using the two available screening tests is often inaccurate, a systematic review and meta-analysis shows, indicating “‘screen and treat’ policies alone are unlikely to have substantial impact on the worsening epidemic of type 2 diabetes” (i6538). Results indicated that “fasting glucose is specific but not sensitive and HbA1c is neither sensitive nor specific,” the authors conclude based on these findings: “The final analysis included 49 studies of screening tests (five of which were prevalence studies) and 50 intervention trials. HbA1c had a mean sensitivity of 0.49 (95% confidence interval 0.40 to 0.58) and specificity of 0.79 (0.73 to 0.84), for identification of pre-diabetes, though different studies used different cut-off values. Fasting plasma glucose had a mean sensitivity of 0.25 (0.19 to 0.32) and specificity of 0.94 (0.92 to 0.96). Different measures of glycaemic abnormality identified different subpopulations (for example, 47%of people with abnormal HbA1c had no other glycaemic abnormality). Lifestyle interventions were associated with a 36% (28% to 43%) reduction in relative risk of type 2 diabetes over six months to six years, attenuating to 20% (8% to 31%) at follow-up in the period after the trials.” (E. Barry, Eleanor.barry@phc.ox.ac.uk)

>>>PNN JournalWatch
* Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack, in
Circulation, 2017; 135: 21–33. (Y. Wang, yilong528@gmail.com
* Treatment of ARDS With Prone Positioning, in
Chest, 2017; 151: 215–24. (E. L. Scholten) 

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 10, 2017 * Vol. 24, No. 6
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. issue of JAMA Internal Medicine (2017; 177).
Treating Delirium in Palliative Care: In 247 patients at 11 Australian inpatient hospice or hospital palliative care units in 2008–14, individualized management and supportive strategies were significantly better than antipsychotic agents for reducing delirium symptoms, a study shows (pp. 34–42). Participants, all of whom had life-limiting illness, received oral risperidone, haloperidol, or placebo solution every 12 hours for 72 hours, based on symptoms of delirium as measured using the sum of Nursing Delirium Screening Scale behavioral, communication, and perceptual items, with these results: “In the primary intention-to-treat analysis, participants in the risperidone arm had delirium symptom scores that were significantly higher than those among participants in the placebo arm (on average 0.48 Units higher; 95% CI, 0.09–0.86; P = .02) at study end. Similarly, for those in the haloperidol arm, delirium symptom scores were on average 0.24 Units higher (95% CI, 0.06–0.42; P = .009) than in the placebo arm. Compared with placebo, patients in both active arms had more extrapyramidal effects (risperidone, 0.73; 95% CI, 0.09–1.37; P = .03; and haloperidol, 0.79; 95% CI, 0.17–1.41; P = .01). Participants in the placebo group had better overall survival than those receiving haloperidol (hazard ratio, 1.73; 95% CI, 1.20–2.50; P = .003), but this was not significant for placebo vs risperidone (hazard ratio, 1.29; 95% CI, 0.91–1.84; P = .14).” (M. R. Agar)
Experiences with use of antipsychotic agents in patients with dementia may be instructive for use of the agents in delirium, editorialists write, noting a history of harms with use of antipsychotic agents for medicating distress (
pp. 42–3): “The advertisement for Thorazine with the white-haired gentleman wielding a cane illustrates that, since their development, antipsychotic drugs have been seen as useful to treat the distressing behavioral and psychological symptoms of dementia (BPSD). However, as manufacturers sought approval to use the newer atypical antipsychotic drugs specifically for distressing BPSD, it became clear that their use caused an increased risk of death relative to placebo. In 2005, the US Food and Drug Administration issued a black box warning regarding the increased risk of mortality associated with the use atypical antipsychotic drugs to treat BPSD.” (D. T. Maust)
Antihypertensive Medications & Fracture Risk: Compared with other antihypertensive medications, a thiazide diuretic lowered the risk of hip or pelvic fracture among 16,622 participants swith mild to moderate hypertension in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (pp. 67–76). Intention-to-treat analysis of data from 1994 through 2006 show these results: “During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63–0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58–0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63–1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74–1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up.” (J. I. Barzilay, joshua.barzilay@kp.org)
These results provide an excellent opportunity for “dodging complexity,” editorialists write (
pp. 77–8). “The large sample size and randomized, masked nature of ALLHAT greatly mitigate … concerns because … confounders are likely to be balanced between the groups,” the authors explain. “This is good news for those of us wanting to avoid complexity because thiazides are also a preferred class for first-line treatment of hypertension based on lower rates of cardiovascular events observed in ALLHAT and other trials, as described in American Heart Association/American College of Cardiology and Joint National Committee 8 guidelines.” (C. S. Colón-Emeric)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 11, 2017 * Vol. 24, No. 7
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 10 issue of JAMA (2017; 317).
Etelcalcetide in Secondary Hyperparathyroidism: The intravenous calcimimetic etelcalcetide was more effective for reducing serum parathyroid hormone (PTH) concentrations than placebo or orally administered cinacalcet in two trials of patients on hemodialysis (pp. 146–55, pp. 156–64, G M. Chertow, gchertow@stanford.edu). Commenting on the trials, editorialists write of “second chances” for improving outcomes in those with end-stage renal disease (ESRD) (pp. 139–41): “Can nephrologists soon expect a randomized trial of etelcalcetide with hard clinical end points? Demonstration of the efficacy of etelcalcetide for improving biochemical end points like PTH and serum phosphate is the low bar that must be overcome to secure regulatory approval for new treatments of disordered mineral metabolism in ESRD. This low-cost regulatory pathway enables more rapid introduction of new agents into ESRD practice but also serves as a powerful disincentive to conduct costly outcomes trials that are rightfully required in other therapeutic areas and thereby perpetuates the outcomes trial–deprived culture that permeates and stifles nephrology. Regulatory authorities should reconsider their approval processes to incentivize hard end-point trials in ESRD, and the manufacturer of etelcalcetide should conduct a rigorous second-generation trial to evaluate the effects of this promising second-generation calcimimetic for reducing mortality and major cardiovascular events and improving quality of life for patients with ESRD.” (M. Wolf, myles.wolf@duke.edu)
Folic Acid for PreventingNeural Tube Defects: Given the mandatory fortification of foods with folic acid, do women of child-bearing age still need folic acid supplements? Yes, says the U.S. Preventive Services Task Force (USPSTF) in a recommendation statement that updates its 2009 conclusion that benefits far outweigh risks (pp. 183–9): “The USPSTF assessed the balance of the benefits and harms of folic acid supplementation in women of childbearing age and determined that the net benefit is substantial. Evidence is adequate that the harms to the mother or infant from folic acid supplementation taken at the usual doses are no greater than small. Therefore, the USPSTF reaffirms its 2009 recommendation.” (K. Bibbins-Domingo, chair@uspstf.net)
Studies conducted before the 1998 initiation of food fortification demonstrate the effectiveness of the practice, according to authors of USPSTF’s evidence report (pp. 190–203). “Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.” (M. Viswanathan, viswanathan@rti.org)
“While identification of the causal link between folic acid and neural tube defects and the subsequent reduction in the prevalence of these conditions via folic acid fortification are remarkable public health successes, the current USPSTF recommendation provides an important reminder that we have yet to achieve the full benefit of these successes,” a
JAMA Pediatrics writer notes (10.1001/jamapediatrics.2016.4983). “The current recommendation statement should serve as a catalyst for renewed efforts to develop and deliver folic acid messages that will translate into further reductions in the population prevalence of neural tube defects.” (L. E. Mitchell, Laura.E.Mitchell@uth.tmc.edu)
A
JAMA editorialist agrees (pp. 144–5): “The USPSTF recommendation that all women of childbearing age take folic acid supplements is a prudent one. Ideally, it will educate all women who are planning or capable of pregnancy to follow this recommendation and thereby reduce the risk of these severe birth defects in their infants.” (J. L. Mills, jamesmills@nih.gov)
Marijuana Risks in Pregnancy: “Pregnant women and those considering becoming pregnant should be advised to avoid using marijuana or other cannabinoids either recreationally or to treat their nausea,” according to Viewpoint authors who note that 29 states and the District of Columbia now allow some form of legal cannabis. (pp. 129–30). “Physicians and other health care providers in a position to recommend medical marijuana must be mindful of the possible risks and err on the side of caution by not recommending this drug for patients who are pregnant.” (E. M. Wargo, wargoem@nida.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 13, 2017 * Vol. 24, No. 9
Providing news and information about medications and their proper use

>>>Cardiology Report
Source: Jan. 17 Journal of the Am. College of Cardiology (2017; 69).
Dual Antiplatelet Therapy After CABG: In patients with diabetes after coronary artery bypass grafting (CABG), routine dual antiplatelet therapy (DAPT) may not be needed, according to a post-hoc analysis of data from the FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial (pp. 119–27). Comparing patients on aspirin plus thienopyridine or aspirin monotherapy after CABG, results show: “At 30 days post-CABG, 544 (68.4%) patients received DAPT and 251 (31.6%) patients received aspirin alone. The median (25th, 75th percentile) duration of clopidogrel therapy was 0.98 (0.23 to 1.91) years. There was no significant difference in the 5-year primary composite outcome between DAPT- and aspirin-treated patients (12.6% vs. 16.0%; adjusted hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.54 to 1.27; p = 0.39). The 5-year primary composite outcomes were similar for patients receiving DAPT versus aspirin monotherapy respectively, in subgroups with pre-CABG ACSs (15.2% vs. 16.5%; HR: 1.06; 95% CI: 0.53 to 2.10; p = 0.88) and those with stable angina (11.6% vs. 15.8%; HR: 0.82; 95% CI: 0.50 to 1.343; p = 0.42).… No treatment-related differences in major bleeding (5.6% vs. 5.7%; HR: 1.00; 95% CI: 0.50 to 1.99; p = 0.99), blood transfusions (4.8% vs. 4.5%; HR: 1.09; 95% CI: 0.51 to 2.34; p = 0.82), or hospitalization for bleeding (2.6% vs. 3.3%; HR: 0.85; 95% CI: 0.34 to 2.17; p = 0.74) were observed between aspirin- and DAPT-treated patients, respectively.” (S. van Diepen, sv9@ualberta.ca)
“Addition, intensification, or prolongation of antiplatelet therapy, although decreasing ischemic events, increases bleeding complications,” editorialists write (
pp. 128–30). “It is thus not surprising that many surgeons are not prescribing such therapy. Whether findings from this current study lead to modifications of future guideline recommendations or impact practice patterns remains to be determined.” (G. N. Levine, glevine@bcm.tmc.edu)
Cangrelor in PCI: For reducing ischemic complications after percutaneous coronary interventions (PCI), cangrelor is effective with or without concomitant glycoprotein IIb/IIIa inhibitors, CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) investigators report (pp. 176–85). Patient-level analysis of 24,902 participants showed the following based on a primary composite endpoint of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization: “Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%).… Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
“Further investigation is needed to better contextualize the role of cangrelor in the setting of other medications used during PCI,” writes an editorialist (
pp. 186–8). “Whether there is added benefit to using cangrelor with newer antiplatelet agents, such as ticagrelor and prasugrel, remains unknown. Also, decision making at the point of care may be challenging without a better accounting of the prognostic significance of the endpoints of interest.” (S. S. Brar, sbrar@cvri.org)

>>>PNN NewsWatch
* The
Biosimilars Forum is critical of an FDA decision to use nonsensical suffixes to differentiate biosimilars from innovator biologics. In a statement issued yesterday, the Forum wrote, “Nonmeaningful suffixes will certainly be more difficult for physicians and patients to recall than meaningful suffixes. Additionally, they will likely lessen the ability to carefully track the identity of the biologic drug administered to patients, thereby contrary to the stated purpose of having a suffix to enhance pharmacovigilance.”
*
PNN will not be published on Mon., Jan. 16, King Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 17, 2017 * Vol. 24, No. 10
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Jan. 17 issue of and early-online articles from the Annals of Internal Medicine (2017; 166).
Medication Adherence in Medical Homes: Adherence to medications for common, high-cost, chronic diseases is higher among patients receiving care in a patient-centered medical home than in other primary-care settings, a case–control study shows (pp. 81–8). Retrospective analysis of Aetna claims show these patterns of prescription refills for patients initiating therapy in 2011–13 for diabetes, hypertension, or hyperlipidemia: “Of 313,765 patients meeting study criteria, 18,611 (5.9%) received care in patient-centered medical homes. Mean rates of adherence were 64% among medical home patients and 59% among control patients. Among 4,660 matched control and medical home practices, medication adherence was significantly higher in medical homes (2.2% [95% CI, 1.5% to 2.9%]). The association between medical homes and better adherence did not differ significantly by disease state (diabetes, 3.0% [CI, 1.5% to 4.6%]; hypertension, 3.2% [CI, 2.2% to 4.2%]; hyperlipidemia, 1.5% [CI, 0.6% to 2.5%]).” (N. K. Choudhry, nkchoudhry@bwh.harvard.edu)
Figuring out what about medical homes helps people take their long-term medications is the next step in the research process, an editorialist writes (
pp. 146–7): “Success in 4 domains will likely be essential for overall success: 1) fostering sustained, trusting, and collaborative relationships between providers and patients; 2) systems to systematically monitor patients’ levels of adherence to medications from all prescribers and to identify barriers to adherence and appropriate strategies to address them; 3) proactive identification of patients who require higher levels of adherence support; and 4) provision of necessary support between face-to-face visits.” (M. Heisler)
Managing Osteoarthritis in Primary Care: Among 537 outpatients with symptomatic hip or knee osteoarthritis, a combined patient/provider intervention at a VA medical center did not result in statistically significant improvement in disease markers, compared with usual care, researchers report (10.7326/M16-1245). The patient intervention, which used telephone communications to focus on weight management, physical activity, and cognitive behavioral pain management, was combined with electronic delivery of patient-specific recommendations to providers. Results showed: “No difference was observed in [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)] score changes from baseline to 12 months in the patient (−1.5 [95% CI, −5.1 to 2.0]; P = 0.40), provider (2.5 [CI, −0.9 to 5.9]; P = 0.152), or patient–provider (−0.7 [CI, −4.2 to 2.8]; P = 0.69) intervention groups compared with usual care. All groups had improvements in WOMAC scores at 12 months (range, −3.7 to −7.7). In addition, no differences were seen in objective physical function or depressive symptoms at 12 months in any of the intervention groups compared with usual care.” (K. D. Allen, kdallen@email.unc.edu)

>>>Lancet Highlights
Source: Jan. 14 issue of Lancet (2017; 389).
Inhaled Corticosteroids in Mild Asthma: Results of the 3-year inhaled Steroid Treatment As Regular Therapy (START) study show benefits of once-daily, low-dose budesonide in patients with mild recent-onset asthma, countering assumptions that corticosteroids should be restricted to those with symptoms on more than 2 days per week (pp. 157–66). Findings for the 7,138 pediatric and adult study participants suggest that “treatment recommendations for mild asthma should consider both risk reduction and symptoms,” the authors conclude. (H. K. Reddel, helen.reddel@sydney.edu.au)

>>>PNN JournalWatch
* An Evidence-Based Medicine Approach to Antihyperglycemic Therapy in Diabetes Mellitus to Overcome Overtreatment, in
Circulation, 2017; 135: 180–95. (A. N. Makam, anil.makam@utsouthwestern.edu
* Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians, in
Annals of Internal Medicine, 2017; 166: 10.7326/M16-1785. (A. Qaseem, aqaseem@acponline.org)
* Migraine and Risk of Perioperative Ischemic Stroke and Hospital Readmission: Hospital Based Registry Study, in
BMJ, 2017; 356: i6635. (M. Eikermann, meikermann@partners.org

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 18, 2017 * Vol. 24, No. 11
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 17 issue of JAMA (2017; 317).
Fungal Infections After Empiric Antifungals in Critical Care: Among critically ill patients, use of antifungal agents before a definitive diagnosis of invasive fungal infection (IFI) is associated with lower rates of IFIs but no significant changes in mortality, according to a JAMA Clinical Evidence Synopsis (pp. 311–2). Noting the low quality of the evidence in a Cochrane review, the authors conclude: “Clinical practice guidelines from Infectious Diseases Society of America and European Society of Clinical Microbiology and Infectious Diseases support the use of antifungal treatment in critically ill patients administered before definitive diagnosis of IFI in certain circumstances (eg, patients at risk of IFI). Evidence from this Cochrane review is only partly consistent with these guidelines because although no association with reduced mortality was found, there was an association with lower incidence of [IFIs].” (A. Cortegiani, andrea.cortegiani@unipa.it)
Revisiting Asthma Diagnoses in Adults: In a study of adults diagnosed with asthma within the prior 5 years, one-third of participants had no symptoms after medications were stopped (pp. 269–79). In Canada in 2012–16, a cohort study found these results after daily asthma medications were weaned and stopped over 4 study visits: “Of 701 participants (mean [SD] age, 51 [16] years; 467 women [67%]), 613 completed the study and could be conclusively evaluated for a diagnosis of current asthma. Current asthma was ruled out in 203 of 613 study participants (33.1%; 95% CI, 29.4%–36.8%). Twelve participants (2.0%) were found to have serious cardiorespiratory conditions that had been previously misdiagnosed as asthma in the community. After an additional 12 months of follow-up, 181 participants (29.5%; 95% CI, 25.9%–33.1%) continued to exhibit no clinical or laboratory evidence of asthma. Participants in whom current asthma was ruled out, compared with those in whom it was confirmed, were less likely to have undergone testing for airflow limitation in the community at the time of initial diagnosis (43.8% vs 55.6%, respectively; absolute difference, 11.8%; 95% CI, 2.1%–21.5%).” (S. D. Aaron, saaron@ohri.ca)
Urban Diabetes in China: Over a 7-year period, a prospective nationwide study of 512,869 adults in China found a higher prevalence of diabetes in urban areas but a greater excess mortality rate from the disease in rural sections (pp. 280–9). With recruitment into the study in 2004–08 and follow-up through Jan. 2014, authors gathered these results for 30,380 adults with diabetes (4.1% of those in rural areas, 8.1% in urban areas): “During 3.64 million person–years of follow-up, there were 24,909 deaths, including 3,384 among individuals with diabetes. Compared with adults without diabetes, individuals with diabetes had a significantly increased risk of all-cause mortality (1,373 vs 646 deaths per 100,000; adjusted RR, 2.00 [95% CI, 1.93–2.08]), which was higher in rural areas than in urban areas (rural RR, 2.17 [95% CI, 2.07–2.29]; urban RR, 1.83 [95% CI, 1.73–1.94]). Presence of diabetes was associated with increased mortality from ischemic heart disease (3,287 deaths; RR, 2.40 [95% CI, 2.19–2.63]), stroke (4,444 deaths; RR, 1.98 [95% CI, 1.81–2.17]), chronic liver disease (481 deaths; RR, 2.32 [95% CI, 1.76–3.06]), infections (425 deaths; RR, 2.29 [95% CI, 1.76–2.99]), and cancer of the liver (1,325 deaths; RR, 1.54 [95% CI, 1.28–1.86]), pancreas (357 deaths; RR, 1.84 [95% CI, 1.35–2.51]), female breast (217 deaths; RR, 1.84 [95% CI, 1.24–2.74]), and female reproductive system (210 deaths; RR, 1.81 [95% CI, 1.20–2.74]). For chronic kidney disease (365 deaths), the RR was higher in rural areas (18.69 [95% CI, 14.22–24.57]) than in urban areas (6.83 [95% CI, 4.73–9.88]). Among those with diabetes, 10% of all deaths (16% rural; 4% urban) were due to definite or probable diabetic ketoacidosis or coma (408 deaths).” (Z. Chen, lmlee@vip.163.com)
“In public health, what gets measured gets done,” writes the WHO director-general (
pp. 264–6). “The quality of [these] precise measurement[s] … provides confidence that Chinese authorities will continue to move the country’s health reforms in the right direction, with results that also improve the prevention and control of diabetes. The World Health Organization has identified a number of best-buy interventions for diabetes and other noncommunicable diseases to help countries do so.” (M. Chan, chanm@who.int)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 19, 2017 * Vol. 24, No. 12
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 19 New England Journal of Medicine (2017; 376).
B-Cell Depletion in Relapsing Multiple Sclerosis: Articles report and discuss results of phase 3 trials of ocrelizumab, which selectively depletes CD20-expressing B cells.
Among 732 patients with primary progressive multiple sclerosis, ocrelizumab produced lower rates of clinical and MRI progression than placebo (
pp. 209–20). The phase 3 trial compared I.V. ocrelizumab 600 mg and placebo given every 24 weeks for at least 120 weeks or until progression of disability. Rates of progression were 32.9% and 39.3% in the two respective groups. Adverse effects were more common with active therapy, including neoplasms in 2.3% and 0.8% of those receiving ocrelizumab and placebo, respectively. (X. Montalban, xavier.montalban@cem-cat.org)
The second article finds lower rates of disease activity and progression with ocrelizumab in two identical, 96-week, phase 3, head-to-head comparisons with interferon beta-1a (
pp. 221–34): “The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P <0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P <0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P <0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P = 0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P <0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P <0.001). The change in the Multiple Sclerosis Functional Composite score … significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P = 0.004) but not in trial 1 (0.21 vs. 0.17, P = 0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.” (S. L. Hauser, stephen.hauser@ucsf.edu)
While “patients with primary progressive multiple sclerosis … are desperately in need of a therapy, side effects must also be considered,” an editorialist writes (
pp. 280–2). “Although the dreaded complication of other drugs for multiple sclerosis, infection with JC virus causing progressive multifocal leukoencephalopathy, has not been seen with B-cell depletion in multiple sclerosis to date, there does appear to be a higher-than-normal risk of herpes reactivation and of neoplasms, especially breast cancer.” (P. A. Calabresi)
Extensively Drug-Resistant Tuberculosis in South Africa: In a tuberculosis-plagued region of South Africa, extensively drug-resistant (XDR) organisms are spreading through transmission rather than acquisition secondary to failed treatment, researchers report (pp. 243–53). This reinforces the importance of efforts to control the epidemic of drug-resistant tuberculosis through “an increased focus on interrupting transmission,” the authors conclude. Differentiating between acquired multidrug-resistant (MDR) tuberculosis strains and the transmitted XDR ones, the investigators report these results of data gathered in 2011–14 from interviews, medical records, and genetic analysis of XDR Mycobacterium tuberculosis isolates: “Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%).” (N. R. Gandhi, neel.r.gandhi@emory.edu)

>>>PNN NewsWatch
*
FDA has released draft guidances on drug/device manufacturers’ communications with formulary committees and payers.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 20, 2017 * Vol. 24, No. 13
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Feb. 1 issue of Clinical Infectious Diseases (2017; 64).
Vancomycin Taper v. Fecal Transplantation in CDI: In a phase 2/3, open-label trial, 30 patients with single acute episodes of recurrent Clostridium difficile infection (CDI), fecal transplantation (FT) was not significantly different from oral vancomycin taper, researchers report (pp. 265–71). In Ontario, 14 days of oral vancomycin therapy followed by either FT or a 6-week taper of vancomycin produced these results: “The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon.” (S. S. Hota, susy.hota@uhn.ca)
While more evidence is needed to determine whether a “fecal fixation” is justified in those who see the intervention as “the holy grail for treatment of recurrent CDI,” this study adds to the evidence supporting vancomycin taper for this condition, editorialists write (
pp. 272–4): “Refinement of [fecal microbiota transplantation (FMT)] to make it a more acceptable, safe, and more defined product is an area of active research, with at least 2 products in phase 2/3 clinical trials.… As we go forward, it is clear that well- designed [randomized controlled trials] of FMT and related products with appropriate comparator groups conducted in patients with recently identified episodes of multiply recurrent CDI are required to assess the efficacy of this potentially highly effective strategy for prevention of CDI recurrence. In the meantime, we have additional evidence of the efficacy of vancomycin taper/pulse administration as an effective treatment.” (S. Johnson, stuart.johnson2@va.gov)

>>>Oncology Highlights
Source: Jan. issue of the Journal of Clinical Oncology (2017; 35).
Basket Trials in Oncology: Testing of targeted therapies that may be present in tumors of different subtypes or sites — “basket trials” — have “scientific goals [that] are typically more complex and frequently not specified with the precision conventionally used for clinical trials,” authors write in a Comments and Controversies article (pp. 271–3): “Most investigators view a basket trial as a series of independent phase II clinical trials. In fact, the simplest type of basket trial, the evaluation of a single drug targeting a single mutation in multiple disease sites, presents a much more complex framework than a conventional evaluation of a single drug in a single disease. We believe that creative investigation into design options offers the potential to meet the study goals faster, with fewer patients. Such investigation must recognize the fact that most basket trials typically aim to answer multiple questions simultaneously. Most importantly, in this period of transition to precision medicine, our clinical research tools must maintain the scientific rigor embedded in the traditional clinical trials paradigm, in which hypotheses are specified precisely and the clinical trial is designed to address these hypotheses.” (A. Iasonos, iasonosa@mskcc.org)

>>>PNN NewsWatch
*
Plecanatide (Trulance, Synergy Pharmaceuticals) was approved yesterday for treatment of chronic idiopathic constipation in adult patients. This is the first drug designed to replicate the function of uroguanylin, a naturally occurring and endogenous human gastrointestinal peptide that is thought to stimulate fluid secretion, the company said in a news release. The result of treatment is a stool consistency associated with more regular bowel function.
* Just in time for Inauguration Day,
FDA Commissioner Robert Califf, MD, has announced formation of the Oncology Center of Excellence, with Richard Pazdur, MD, as director. Creation of the center makes oncology the first disease area with a coordinated clinical review of drugs, biologics, and devices across the agency’s three medical product centers. Talk of a Trump appointment to head the FDA has centered around nontraditional picks from Silicon Valley. The president-elect has hinted at relaxed FDA standards for drug approval but has also attacked the pharmaceutical industry regarding pricing of drug products.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 23, 2017 * Vol. 24, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 21 issue of Lancet (2017; 389).
Atezolizumab in Previously Treated Non-Small-Cell Lung Cancer: In the first randomized phase 3 study to report results of a programmed death-1 (PD-1)–targeted therapy, atezolizumab treatment was significantly more effective than docetaxel for improving overall survival in previously treated patients with squamous or nonsquamous non-small-cell lung cancer (pp. 255–65). OAK investigators in 31 countries randomized patients with squamous or nonsquamous non-small-cell lung cancer to atezolizumab or docetaxel every 3 weeks, with these intention-to-treat (ITT) results in the first 850 of 1,225 enrolled patients: “Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13.8 months [95% CI 11.8–15.7] vs 9.6 months [8.6–11.2]; hazard ratio [HR] 0.73 [95% CI 0.62–0.87], p = 0.0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n = 241) compared with docetaxel (n = 222; median overall survival was 15.7 months [95% CI 12.6–18.0] with atezolizumab vs 10.3 months [8.8–12.0] with docetaxel; HR 0.74 [95% CI 0.58–0.93]; p = 0.0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12.6 months vs 8.9 months; HR 0.75 [95% CI 0.59–0.96]). Overall survival improvement was similar in patients with squamous (HR 0.73 [95% CI 0.54–0.98]; n = 112 in the atezolizumab group and n = 110 in the docetaxel group) or non-squamous (0.73 [0.60–0.89]; n = 313 and n = 315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 [15%] of 609 patients) versus docetaxel (247 [43%] of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group.” (D. R. Gandara, drgandara@ucdavis.edu)
Filgotinib in Crohn Disease: In a phase 2 trial of 174 adults with moderate-to-active Crohn disease, the Janus kinase 1 (JAK1)-selective inhibitor filgotinib induced remission significantly more often than placebo, researchers report (pp. 266–75). The safety profile of the new drug was acceptable as well, the study shows, with these results based on primary endpoint was clinical remission, defined as Crohn’s Disease Activity Index (CDAI) less than 150 at week 10: “In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9–39], p = 0.0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.” (S. Vermeire, severine.vermeire@uzleuven.be)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
RAS Inhibitors in Stable Coronary Artery Disease: For treating patients with stable coronary artery disease without heart failure, available evidence does not support a “preferred status” for agents that inhibit the renin–angiotensin system (RASi), authors of a meta-analysis of 24 trials of 198,275 patients conclude (j4): “RASi reduced cardiovascular events and death only when compared with placebo but not when compared with active controls. Even among placebo controlled trials in this study, the benefit of RASi was mainly seen in trials with higher control event rates but not in those with lower control event rates.” (S. Bangalore, sripalbangalore@gmail.com)

>>>PNN JournalWatch
* Early Oral Immunotherapy in Peanut-Allergic Preschool Children Is Safe and Highly Effective, in
Journal of Allergy and Clinical Immunology, 2017; 139: 173–81.e8. (A. W. Burks, wesley.burks@unc.edu
* Increased Antiviral Treatment Among Hospitalized Children and Adults With Laboratory-Confirmed Influenza, 2010–2015, in
Clinical Infectious Diseases, 2017; 64: 364–7. (A. P. Campbell, app4@cdc.gov
* Hormone-Related Migraine Headaches and Mood Disorders: Treatment with Estrogen Stabilization, in
Pharmacotherapy, 2017; 37: 120–8. (L. J. Cohen, lawrence.cohen@unthsc.edu

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 24, 2017 * Vol. 24, No. 15
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Jan. issue of the Journal of the American Geriatrics Society (2017; 65).
Hospitalizations & Pharmacists’ Medication Management: In Hawaii, provision of medication management services by specially trained community and hospital pharmacists reduced rehospitalizations of high-risk older adults by 38%, yielding a 2.6:1 return on investment, a study shows (pp. 212–9). Working with high-risk individuals from hospitalization through transition to home and for up to 1 year after discharge, Pharm2Pharm pharmacists produced these results at six study and five control Hawaiian hospitals with more than 50 beds: “The predicted, case mix–adjusted medication-related hospitalization rate of individuals aged 65 and older was 36.5% lower in the Pharm2Pharm hospitals after implementation than in the nonintervention hospitals (P = .01). The estimated annualized cost of avoided admissions was $6.6 million. The annual cost of the pharmacist services for all Pharm2Pharm participants was $1.8 million.” (K. L. Pellegrin, karen3@hawaii.edu)
Expected Benefit of Warfarin in Atrial Fibrillation: Over time, “competing death events” diminish the expected benefits of warfarin among patients with atrial fibrillation (AF), according to community-based cohort results from the Anticoagulation and Risk Factors in Atrial Fibrillation Study (pp. 35–41). Adults diagnosed with nonvalvular AF in 1996–2003—four-fifths of them aged 65 years or older—had these outcomes based on longitudinal warfarin exposure and rates of thromboembolism and all-cause deaths: “The rate of death was much higher in the group not taking warfarin (8.1 deaths/100 person–years (PY)) than in the group taking warfarin (5.5 deaths/100 PY). The cause-specific HR indicated a large reduction in thromboembolism with warfarin use (adjusted HR = 0.57, 95% confidence interval (CI) = 0.50–0.65), although this association was substantially attenuated after accounting for competing death events (adjusted HR = 0.87, 95% CI = 0.77–0.99). In analyses limited to 1 year of follow-up, with fewer competing death events, the results for models that did and did not account for competing risks were similar.” (J. M. Ashburner, jashburner@mgh.harvard.edu)
“These results reinforce the growing understanding that, when treating older adults, providers can no longer consider any disease or condition in isolation from the individual’s complete profile of health concerns,” editorialists write (
pp. 25–6): “There is general consensus that use of warfarin is effective in preventing stroke among older adults with AF. At the same time, there is research suggesting that, even in individuals at high risk of stroke, oral anticoagulants are widely underused. A plausible explanation for such underuse appears to be that long-term practitioners prioritize concern about the risk of bleeding over stroke prevention in some older adults with AF. There is also agreement that use of anticoagulants such as warfarin is most effective in individuals with high risk of stroke, whereas treatment with aspirin appears to suffice for persons at lower risk. The marked attenuation of the protective effect of warfarin reported here provides a new perspective on the decision-making process that providers and older adults must navigate. In addition to the older adult’s individual likelihood of stroke, the decision to prescribe anticoagulants must also consider chronic conditions and the overall risk of death from nonstroke causes.” (T. E. Murphy)
Medication Use After Dementia Diagnosis: In patients with type 2 diabetes, “use of cardiometabolic medications fell after a diagnosis of dementia, as recommended in national guidelines,” researchers report (pp. 77–82). The case–control study population included Kaiser patients in northern California, who had these outcomes following a new diagnosis of dementia: “After adjustment, the number of chronic medications and the subset of cardiovascular medications declined after a dementia diagnosis in the overall cohort and in age-, sex-, and time-matched reference individuals, but the decline was significantly greater in the group with dementia (0.71 medications fewer than the reference group, P = .02). The number of diabetes mellitus medications declined in both groups, but the declines were not statistically different (0.18 medications fewer than the reference group, P = .008).” (U. Sarkar, urmimala.sarkar@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 25, 2017 * Vol. 24, No. 16
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Jan. 24/31 issue of JAMA (2017; 317).
Continuous Glucose Monitoring in Type 1 Diabetes: Two articles and an editorial examine utility of continuous glucose monitoring (CGM) in adults with type 1 diabetes.
In the DIAMOND randomized clinical trial, adults using multiple daily insulin injections had significantly better outcomes when they used continuous glucose monitoring (CGM), compared with usual care (
pp. 371–8). Investigators established a primary endpoint of decreased glycated hemoglobin levels for the 24-week trial, as noted in these results: “Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10–31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was –0.6% (95% CI, –0.8% to –0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27–69) in the CGM group vs 80 min/d (IQR, 36–111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group.” (R. W. Beck, rbeck@jaeb.org)
Similar results come from the GOLD randomized clinical trial, a 26-week comparison of CGM with usual care (
pp. 379–87): “Among 161 randomized participants, mean age was 43.7 years, 45.3% were women, and mean HbA1c was 8.6% (70 mmol/mol). A total of 142 participants had follow-up data in both treatment periods. Mean HbA1c was 7.92% (63 mmol/mol) during continuous glucose monitoring use and 8.35% (68 mmol/mol) during conventional treatment (mean difference, −0.43% [95% CI, −0.57% to −0.29%] or −4.7 [−6.3 to −3.1 mmol/mol]; P < .001). Of 19 secondary end points comprising psychosocial and various glycemic measures, 6 met the hierarchical testing criteria of statistical significance, favoring continuous glucose monitoring compared with conventional treatment. Five patients in the conventional treatment group and 1 patient in the continuous glucose monitoring group had severe hypoglycemia. During washout when patients used conventional therapy, 7 patients had severe hypoglycemia.” (M. Lind, lind.marcus@telia.com)
These trials show benefits from CGM and that adult patients with type 1 diabetes like this approach, editorialists write (
pp. 363–4): “CGM limits hyperglycemia and hypoglycemia, improves diabetes control, and reduces glucose variability. These studies also show that selected patients favored this method of monitoring. Additional clinical trials are needed to determine the long-term effect of CGM and whether this approach translates to improved health outcomes and to determine the potential utility of real-time CGM for patients with type 1 diabetes encountered in usual clinical practice and in patients with type 2 diabetes who require insulin injections.” (M. B. Davidson, mayerdavidson@cdrewu.edu)
Gut Bacteria, Obesity & Diabetes: “It is plausible that the human microbiome may affect the risk of obesity and type 2 diabetes and other diseases such as atherosclerosis, and that manipulations of the microbiome might reduce that risk,” writes authors of a Commentary article (pp. 355–6): “However, biomedical science is a long way from proving either proposition. Dissecting the possible role of the microbiome in these and other diseases will be a great challenge, because (1) human genes influence the composition of the gut microbiota, (2) microbial genes influence the expression of human genes, (3) the metabolism of some gut microbes influences the metabolism of other gut microbes, and (4) diet influences both the microbiota and (possibly) the expression of human genes. In short, human genes, microbial genes, and diet share a complicated set of interdependencies.” (A. L. Komaroff, anthony_komaroff@hms.harvard.edu)

>>>PNN NewsWatch
* Hospira is voluntarily recalling one lot of
Vancomycin Hydrochloride for Injection, USP (Lot 591053A, Exp. 11/1/17), to the hospital/retail level due to confirmed presence of particulate matter, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 26, 2017 * Vol. 24, No. 17
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Jan. 26 issue of the New England Journal of Medicine (2017; 376).
Bezlotoxumab for Recurrent Clostridium difficile Infection: In the phase 3 MODIFY I and MODIFY II trials, the antitoxin monoclonal antibody bezlotoxumab was associated with a substantially lower rate of recurrent Clostridium difficile infection than placebo without producing additional adverse effects, researchers report (pp. 305–17). Addition of a second monoclonal, actoxumab, had no added effect, as shown in these results: “In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P <0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P <0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P <0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P <0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea.” (M. H. Wilcox, mark.wilcox@nhs.net)
“Bezlotoxumab is a new, now-FDA-approved anti–
C. difficile agent that has proved effective in reducing the rate of first post-treatment relapses of C. difficile infection,” writes an editorialist (pp. 381–2). “However, uptake by clinicians will vary on the basis of cost and assessments of relapse risk in association with this drug as compared with the alternative options.” (J. G. Bartlett)
Recombinant Vesicular Stomatitis Virus Ebola Vaccine: Phase 1 trials of an Ebola vaccine candidate support further evaluation “for preexposure prophylaxis and suggest that a second dose may boost antibody responses,” rVSV∆G-ZEBOV-GP investigators conclude (pp. 330–41). The attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)–based vaccine candidate was tested in 39 adults at each of two sites received one of three doses of the vaccine; volunteers at one site received a second dose at day 28. Results showed: “The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months.” (J. A. Regules, jason.a.regules.mil@mail.mil)
Treating Metastatic Renal-Cell Carcinoma: Additional progress against metastatic renal cell carcinoma will require “new drugs with new targets and mechanisms of action,” review authors conclude (pp. 354–66). “Although more than 14,000 patients die from kidney cancer each year, we have seen considerable progress in the systemic treatment of metastatic renal-cell carcinoma in the past 20 years. Researchers have achieved a better understanding of the pathogenesis of the most common type of renal-cell carcinoma, clear-cell renal-cell carcinoma. This understanding has led to new agents, expanded treatment options, and increased rates of survival.” (T. K. Choueiri, toni_choueiri@dfci.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 27, 2017 * Vol. 24, No. 18
Providing news and information about medications and their proper use

>>>Diabetes Care Report
Source: Feb. issue of Diabetes Care (2017; 40).
Adverse Pancreatic Reactions to Gliptins: Two studies and a commentary examine the link between gliptin use and adverse pancreatic outcomes.
In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), rates of pancreatitis and pancreatic cancer were statistically similar between sitagliptin and placebo groups, researchers report (
pp. 164–70). Prospective data on 14,671 participants followed for 3 years showed these patterns: “Baseline differences were minimal between participants confirmed to have no pancreatic events, acute pancreatitis, or pancreatic cancer. Among those participants randomized to receive sitagliptin, 23 (0.3%) (vs. 12 randomized to receive placebo [0.2%]) had pancreatitis (hazard ratio 1.93 [95% CI 0.96–3.88], P = 0.065; 0.107 vs. 0.056/100 patient–years), with 25 versus 17 events, respectively. Severe pancreatitis (two fatal) occurred in four individuals allocated to receive sitagliptin. Cases of pancreatic cancer were numerically fewer with sitagliptin (9 [0.1%]) versus placebo (14 [0.2%]) (hazard ratio 0.66 [95% CI 0.28–1.51], P = 0.32; 0.042 vs. 0.066 events/100 patient–years). Meta-analysis with two other DPP-4i cardiovascular outcome studies showed an increased risk for acute pancreatitis (risk ratio 1.78 [95% CI 1.13–2.81], P = 0.01) and no significant effect for pancreatic cancer (risk ratio 0.54 [95% CI 0.28–1.04], P = 0.07).” (J. B. Buse, jbuse@med.unc.edu)
Combining TECOS data with those from the SAVOR-TIMI 53 (saxagliptin) and EXAMINE (alogliptin) trials, a significant risk of pancreatitis is evident, a second study shows (
pp. 284–6). A random-effects model meta-analysis of data on 18,238 gliptin-treated and 18,157 placebo-treated patients showed these results: “The incidence of acute pancreatitis was significantly increased in the gliptin-treated patients when compared with the control groups (odds ratio 1.79 [95% CI 1.13–2.82], P = 0.013). The difference in the absolute risk was small (0.13%).” (I. Tkác, ivan.tkac@upjs.sk)
“DPP-4 inhibitors are well-established agents, and their benefits clearly outweigh the risks,” Commentary authors conclude (
pp. 161–3). “Acute pancreatitis is real, but its frequency is very low to impede the generalized use of DPP-4 inhibitors unless more efficacious agents are preferred. Can we identify people at increased risk for developing DPP-4 inhibitor–related pancreatitis? For those with a history of pancreatitis, avoiding these drugs is a sensible recommendation. However, avoiding its use in subjects with risk factors for pancreatitis may sound justified but solid data supporting such a strategy is lacking. Amylase and lipase levels can be mildly elevated with incretin-based therapies, but the levels fluctuate to a large extent and therefore the positive predictive value of an increased level seems so low that this cannot be used to identify people at risk. Thus, we can conclude that pancreatitis is an established but rare side effect of DPP-4 inhibitors that occurs at a very low frequency. We should inform patients on this potential side effect, and in people on DPP-4 inhibitors having even mild gastrointestinal symptoms suggestive of pancreatitis, it would be justified to measure pancreatic enzymes and appropriate to perform an abdominal ultrasound to exclude gallstones. On the basis of the evidence so far, perhaps in some patients when gallstones are present (even if asymptomatic) and/or when lipase levels are >3 times normal (even if fluctuating), there may be enough basis to consider replacing an incretin-based agent used and consider an alternative therapy.” (J. H. DeVries, j.h.devries@amc.uva.nl)
Oral Diabetic Medications & HIV Infections: While a longitudinal cohort study shows that effectiveness of oral antidiabetic medications is similar in patients with and without HIV infection, data indicate a poorer response among the black and Hispanic patients who make up a large portion of those with the virus (pp. 218–25). The study included 2,454 HIV-infected and 8,892 HIV-uninfected veterans who initiated oral diabetes medications (metformin in half of patients, sulfonylurea in 49%, thiazolidinediones in 1%) between 1999 and 2010. Results showed: “Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA1c level of 0.16% (95% CI 0.08, 0.24) [1.7 mmol/mol (0.9, 2.6)] (P <0.001) and 0.25% (0.11, 0.39) [2.7 mmol/mol (1.2, 4.3)] (P = 0.001), respectively.” (J. H. Han, jennifer.han@uphs.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 30, 2017 * Vol. 24, No. 19
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Jan. 28 issue of Lancet (2017; 389).
Bionic Pancreas in Type 1 Diabetes: Compared with conventional and sensor-augmented insulin pump therapy in 43 patients, a bihormonal bionic pancreas provided superior glycemic regulation using only the person’s weight, a study shows (pp. 369–80). At four U.S. sites, adult volunteers with type 1 diabetes were randomized to the bionic device or pump therapy for 11 days and then crossed over to the alternative therapy. Participants continued all normal activities, and the bionic pancreas provided both insulin and glucagon. Results for 39 participants completing the study showed the following: “The mean [continuous glucose monitoring (CGM)] glucose concentration was 7.8 mmol/L (SD 0.6) in the bionic pancreas period versus 9.0 mmol/L (1.6) in the comparator period (difference 1.1 mmol/L, 95% CI 0.7–1.6; p <0.0001), and the mean time with CGM glucose concentration less than 3.3 mmol/L was 0.6% (0.6) in the bionic pancreas period versus 1.9% (1.7) in the comparator period (difference 1.3%, 95% CI 0.8–1.8; p <0.0001). The mean nausea score on the Visual Analogue Scale (score 0–10) was greater during the bionic pancreas period (0.52 [SD 0.83]) than in the comparator period (0.05 [0.17]; difference 0.47, 95% CI 0.21–0.73; p = 0.0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study.” (S. J. Russell, sjrussell@mgh.harvard.edu)

>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 354).
Thyroid in Subclinical Hypothyroidism of Pregnancy: Among 5,405 pregnant women with subclinical hypothyroidism whose experiences were recorded in a large U.S. administrative database, thyroid hormone treatment reduced the risk of pregnancy loss, a study shows, particularly in those with pretreatment levels of thyroid stimulating hormone (TSH) in the 4.1–10 mIU/L range (i6865). However, the authors add, other pregnancy-related adverse outcomes were more common among those receiving treatment, including preterm delivery, gestational diabetes, and pre-eclampsia. (R. G. McCoy, mccoy.rozalina@mayo.edu)
Atosiban v. Fenoterol as Uterine Relaxant: In 830 pregnant women undergoing external cephalic version (ECV) for breech presentation, the beta-mimetic fenoterol was more effective 30 minutes after the procedure than the oxytocin receptor antagonist atosiban, but neither agent yielded significant improvements at delivery, researchers report (i6773): “Cephalic position 30 minutes after ECV occurred significantly less in the atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95% confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n = 139) of the atosiban group and 40% (n = 166) of the fenoterol group (0.86, 0.72 to 1.03), and caesarean delivery was performed in 60% (n = 240) of women in the atosiban group and 55% (n = 218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were found in neonatal outcomes or drug related adverse events.” (J. Velzel, j.velzel@amc.nl)

>>>PNN NewsWatch
*
Homeopathic teething tablets contain inconsistent and sometimes much-higher-than-labeled amounts of belladonna, FDA said on Friday. The manufacturer of Hyland’s homeopathic teething products, Standard Homeopathic Company, has not agreed to conduct a recall, but FDA said it recommends that consumers stop using the products. “The body’s response to belladonna in children under 2 years of age is unpredictable and puts them at unnecessary risk,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research. ”We recommend that parents and caregivers not give these homeopathic teething tablets to children and seek advice from their health care professional for safe alternatives.” The announcement expands on a Sept. FDA alert and a Nov. recall by another manufacturer.

>>>PNN JournalWatch
* Review: Frontiers of Antifibrotic Therapy in Systemic Sclerosis, in
Arthritis & Rheumatology, 2017; 69: 257–67. (J. H. W. Distler, joerg.distler@uk-erlangen.de
* Gout and Risk of Fracture in Women: A Prospective Cohort Study, in
Arthritis & Rheumatology, 2017; 69: 422–8. (J. Paik, jmpaik@partners.org

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Jan. 31, 2017 * Vol. 24, No. 20
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source: Jan. issue of Health Affairs, a theme issue on Coverage Expansion, Accountable Care, and More, and online blogs (2017; 36).
ACA Replacement Bill: An Affordable Care Act (ACA) repeal-and-replace bill introduced recently by Republican Senators is built around maintaining popular ACA features, shifting decisions to the states, and pushing use of Roth HSAs as a subsidy mechanism (Jan. 24 blog). The Patient Freedom Act of 2017 (PFA) would selectively repeal most of the ACA that dealt with insurance reform and affordability but would give states the options of maintaining the ACA in their states, adopt a different approach based on subsidized Roth HSAs, or reject reform altogether. Noting that PFA is even more complex than ACA, the blog author concludes: “It has become increasingly clear in recent days that Republicans are trying to find a way to couple ACA repeal with ACA replacement. The PFA is an attempt to build a replacement plan on Republican principles of devolution of responsibility to the states and deregulation, but in a way that might appeal to some Democrats. The bill, however, appears to have been rushed into legislative language without adequate consideration of how it would actually work and what it would cost. It may form a basis for discussion, but it is not ready for enactment.” (T. Jost)
People Newly Insured In 2014: More than one-half of those gaining health insurance in 2014 were long-term uninsured individuals who had been without coverage for 3 years or more, researchers report (pp. 16–20). Examining the effects of the Affordable Care Act as reflected in data for 2013–14 from the National Health Interview Survey (NHIS), the investigators found “that 18.0 percent of nonelderly adults were uninsured in 2013, with over half of them (9.4 percent) uninsured for more than three years. The uninsurance rate fell 4.2 percentage points (from 18.0 percent to 13.9 percent) between 2013 and 2014. The percentage of adults uninsured for more than three years fell 2.2 percentage points (from 9.4 percent to 7.1 percent), compared to declines of 0.7 percentage point and 1.1 percentage points among the short- and medium-term uninsured, respectively.” The authors conclude, “Since those who have been uninsured for a long time might not be in the habit of using health care, it will be important to examine the impacts of premium and cost-sharing subsidies on those eligible for subsidized coverage under the ACA, and the extent to which members of this population are able to access appropriate health care providers.” (S. L. Decker, Sandra.decker@ahrq.hhs.gov)
Opioid Withdrawal Without Help: “The medical system is organized in a way that makes it quite difficult for physicians to live up to their withdrawal care responsibility,” writes an author who went through a difficult withdrawal after using opioid analgesics during the aftermath of a major motorcycle accident (pp. 182–5). “The plastic surgeon who had been managing my prescriptions eventually apologized and admitted that he simply had not known how to deal with opioid dependence. I hope that he committed to learning more after this experience.
“My goal is not, however, to change one doctor’s view about what he owes his patients. Instead, I want to start a broader conversation about physician responsibility for opioid-related harms, as well as the systemic forces that make it easier or harder for physicians to recognize and discharge their responsibilities. Opioid withdrawal isn’t minor. It’s not ‘just temporary’ or ‘the price to be paid’ for pain relief. It’s not morally innocuous. The moments that I was in withdrawal—all of the thousands of moments of genuine suffering—were the worst of my life. That kind of suffering matters, and its seriousness needs to be reflected in the way we deal with prescription opioids.” (T. N. Rieder,
trieder@jhu.edu)
ACA Repeal & the Opioid Epidemic: “As our country grapples with an ‘unprecedented opioid epidemic,’ Congress is taking steps to take away an important tool to fight it — the Affordable Care Act (ACA),” blog authors write (Jan. 30 blog). “Millions of people will lose health coverage, including comprehensive behavioral health and [substance use disorder (SUD)] benefits through Medicaid. People remaining covered in the individual and small group markets will lose benefits for SUD related services such as behavioral health services, preventive screenings, and prescription drugs.” (L. Clemans-Cope)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 1, 2017 * Vol. 24, No. 21
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Online-first articles from JAMA Internal Medicine (2017; 177).
Language Barriers & Antidiabetic Medication Adherence: Among Latinos with limited–English proficiency (LEP), control of diabetes improved when they changed to language-concordant primary care providers (PCPs), researchers report (10.1001/jamainternmed.2016.8648). The Kaiser study tracked 1,605 LEP Latino patients who preferred language Spanish and compared outcomes among those who changed PCPs in 2007–13: “There was a significant net improvement in glycemic and LDL control among patients who switched from language-discordant PCPs to concordant PCPs relative to those who switched from one discordant PCP to another discordant PCP. After adjustment and accounting for secular trends, the prevalence of glycemic control increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control decreased by 4% (95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95% CI, 1% to 17%; P = .03). No significant changes were observed in [systolic blood pressure] control. Prevalence of LDL control increased 15% (95% CI, 7% to 24%; P <.001) among LEP Latinos who switched from concordant to discordant PCPs. Risk factor control did not worsen following a PCP switch in any group.” (A. J. Karter, andy.j.karter@kp.org)
A second study shows that factors beyond language concordance are reducing adherence among Latino patients with diabetes (
10.1001/jamainternmed.2016.8653). Observational data from 2006 to 2012 in a large integrated health care delivery system led investigators to this conclusion: “Nonadherence to newly prescribed diabetes medications is substantially greater among Latino than white patients, even among English-speaking Latino patients. Limited English proficiency Latino patients are more likely to be nonadherent than English-speaking Latino patients independent of the Spanish-language fluency of their physicians. Interventions beyond access to interpreters or patient–physician language concordance will be required to improve medication adherence among Latino patients with diabetes.” (A. Fernández, alicia.fernandez@ucsf.edu)
“As the US health care system evolves to more accountable care organizations with integrated health systems, care of the most vulnerable must be prioritized,” editorialists write (
10.1001/jamainternmed.2016.8661). “Latinos with LEP who have diabetes represent such a population, as evidenced not only by their language status but by their socioeconomic disadvantage. There is a need to integrate greater granularity on social determinants into the medical record to provide more precision patient–clinician interactions. Metrics for our health care system need to include an equity outcome that sets a high bar for the most vulnerable patients. Healthcare outcomes of LEP Latinos with diabetes would be an excellent system measure of health equity.” (E. J. Pérez-Stable, eliseo.perez-stable@nih.gov)
High Drug Prices Despite Generic Competition: The case of Duexis — an ibuprofen–famotidine combination whose monthly wholesale price increased from $158 to $2061 in 2012–16 — provides lessons learned about high prices despite generic competition (10.1001/jamainternmed.2016.8423): “First, the states and the federal government should consider banning specialty pharmacies or other third parties from preparing or submitting prior authorization forms or other medical necessity paperwork; this is the responsibility of the physician who prescribes the medication. This practice undermines the intent of utilization controls and raises concerns about patient privacy. Second, states should consider markedly restricting the use of copay assistance programs, particularly since the majority of drug coupons are for brand-name medications for which lower-cost therapeutics are available. Third, better federal regulation and oversight of charity organizations that provide financial assistance to patients is needed. For example, contributions to such organizations from manufacturers should not be allowed for diseases treated by a single drug, because manufacturers can effectively ensure that donations will be spent only on copay assistance for their products. To preserve the long-term financial stability of the health care system, the use of medications that provide high value to patients should be the priority, not high-priced drugs with generic alternatives.” (J. S. Ross, joseph.ross@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 2, 2017 * Vol. 24, No. 22
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 2 New England Journal of Medicine (2017; 376).
Radiation & Antiandrogen Therapy in Recurrent Prostate Cancer: Patients with prostate cancer lived longer and had fewer metastases when antiandrogen therapy was provided for 24 months following salvage radiation therapy, a study shows (pp. 417–28). Among 760 men with T2- or T3-stage tumors in 1998–2003, radiation plus bicalutamide 150 mg daily or placebo for 24 months yielded these results following prostatectomy with lymphadenectomy: “The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P = 0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P <0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P = 0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P <0.001).” (W. U. Shipley, wshipley@partners.org)
“This remarkable contribution by the National Clinical Trials Network of the National Cancer Institute shows the importance of randomized clinical trials with very long follow-up,” writes an editorialist (
pp. 484–5). “Studies that incorporate interventions without proprietary intellectual property (e.g., surgery or radiation therapy) or pharmaceutical agents whose patents often expire before the study is completed can be achieved only with the use of this invaluable national resource.” (I. M. Thompson, Jr.)
Crizanlizumab in Sickle Cell Disease: Pain episodes and adverse events occurred less frequently in patients with sickle cell disease who received crizanlizumab, compared with placebo, researchers report (pp. 429–39). The drug, an antibody against the adhesion molecule P-selectin, was given in low and high doses in a phase 2 trial of 198 patients. Results of 14 intravenous infusions over a 52-week period were as follows: “The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P = 0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P = 0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P = 0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P = 0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.” (K. I. Ataga, kataga@med.unc.edu)
An editorialist supports use of crizanlizumab along with hydroxyurea in management of sickle cell disease (
pp. 485–7): “Lacking a magical ‘silver bullet’ that would increase fetal hemoglobin in each sickle erythrocyte sufficiently to stop the polymerization of sickle hemoglobin or one that would completely normalize blood flow and prevent sickle vaso-occlusion, a polypharmaceutical approach that is focused on different aspects of the pathophysiology of sickle cell disease seems to be the most practical near-term approach. Most experts agree that hydroxyurea should be given to nearly all patients, starting very early in life. Added to this treatment might be an antiadhesive therapy that also should be taken for life and ideally started in childhood.” (M. H. Steinberg)

>>>PNN NewsWatch
* Does the pharmaceutical industry want a
deregulated FDA as Pres. Trump seems to be proposing? Not necessarily, according to an article on the STAT News website. “In a world where the FDA approved medications on scant data, pharma’s wealthiest giants could litter the market with dubious new drugs — and flood the airwaves with ads touting them,” reporter Mike Reddy writes. “That would crowd out upstart competitors and kill a whole industry’s incentive to try new things.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 3, 2017 * Vol. 24, No. 23
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source: Feb. issue of Pediatrics (2017; 139).
Protection From Single-Dose Meningococcal Vaccine: Effectiveness of the meningococcal (groups A, C, W, and Y) polysaccharide diphtheria toxoid conjugate vaccine (MenACWY-D) wanes 3 to <8 years following a single dose, according to a study that led the Advisory Committee on Immunization Practices to recommend a booster dose (10.1542/peds.2016-2193). In a case–control study conducted in 2006–13, these patterns of vaccine effectiveness (VE) and duration of protection were identified: “Serogroup C accounted for 88 (49%), serogroup Y 80 (44%), and serogroup W 13 (7%) of enrolled cases. Thirty-six (20%) cases and 87 (44%) controls received MenACWY-D. The overall VE estimate 0 to 8 years postvaccination was 69% (51% to 80%); VE was 79% (49% to 91%) at <1 year, 69% (44% to 83%) at 1 to <3 years, and 61% (25% to 79%) at 3 to <8 years. VE was 77% (57% to 88%) against serogroup C and 51% (1% to 76%) against serogroup Y.” (A. C. Cohn)
E-cigarette Use by Adolescents: In the first of two studies of electronic cigarettes and other electronic vapor products (EVPs), researchers report other risky behaviors by adolescents who use EVP alone or with cigarette smoking (10.1542/peds.2016-2450). Among 15,624 students in the 2015 national Youth Risk Behavior Survey, health risk behaviors based on nonuse, cigarette smoking only, EVP use only, and dual use were as follows: “In 2015, 73.5% of high school students did not smoke cigarettes or use EVPs, 3.2% smoked cigarettes only, 15.8% used EVPs only, and 7.5% were dual users. Frequency of cigarette smoking and EVP use was greater among dual users than cigarette-only smokers and EVP-only users. Cigarette-only smokers, EVP-only users, and dual users were more likely than nonusers to engage in several injury, violence, and substance use behaviors; have ≥4 lifetime sexual partners; be currently sexually active; and drink soda ≥3 times/day. Only dual users were more likely than nonusers not to use a condom at last sexual intercourse.” (Z. Demissie)
Adolescents using e-cigarettes would not likely have smoked regular cigarettes, an analysis of the 2004–2014 National Youth Tobacco Surveys shows (
10.1542/peds.2016-2193): “Youth cigarette smoking decreased linearly between 2004 and 2014 (P = .009 for ever smoking and P = .05 for current smoking), with no significant change in this trend after 2009 (P = .57 and .23). Based on the psychosocial model of smoking, including demographic characteristics, willingness to wear clothing with a tobacco logo, living with a smoker, likelihood of smoking in the next year, likelihood of smoking cigarettes from a friend, and use of tobacco products other than cigarettes or e-cigarettes, the model categorized <25% of current e-cigarette–only users (between 11.0% in 2012 and 23.1% in 2013) as current smokers.” (L. M. Dutra)
Dietary Supplements & Young Teens: Creatine and testosterone products are being pushed to boy high school athletes by health food store employees, a study shows (10.1542/peds.2016-1257). Contacted by telephone by research personnel posing as 15-year-olds, staff at 244 U.S. health food stores made these recommendations when asked about supplements: “A total of 67.2% (164/244) of sales attendants recommended creatine: 38.5% (94/244) recommended creatine without prompting, and an additional 28.7% (70/244) recommended creatine after being asked specifically about it. A total of 9.8% (24/244) of sales attendants recommended a testosterone booster. Regarding availability for sale, 74.2% (181/244) of sales attendants stated a 15-year-old was allowed to purchase creatine, whereas 41.4% (101/244) stated one could purchase a testosterone booster.” The authors conclude, “In response to these findings, pediatricians should inform their teenage patients, especially athletes, about safe, healthy methods to improve athletic performance and discourage them from using creatine or testosterone boosters. Retailers and state legislatures should also consider banning the sale of these products to minors.” (R. Milanaik, rmilanai@northwell.edu)

>>>PNN NewsWatch
* FDA yesterday warned consumers about two dietary supplements containing undeclared drugs:
Lean Extreme Max, which contains sibutramine (pulled from the market in 2010 for safety reasons), and Goldreallas XXX, a sexual enhancement product containing sildenafil.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 6, 2017 * Vol. 24, No. 24
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 4 issue of Lancet (2017; 389).
Treatment of Newly Diagnosed Myeloma Without Intent for Stem-Cell Transplant: Addition of bortezomib to lenalidomide and dexamethasone significantly improved progression-free and overall survival of patients with newly diagnosed myeloma and no intent for immediate autologous stem-cell transplant, researchers report (pp. 519–27). In the phase 3 SWOG S0777 trial, open-label bortezomib with lenalidomide and dexamethasone (VRd group) or lenalidomide and dexamethasone alone (Rd group) produced these outcomes in 473 randomly assigned patients: “Median progression-free survival was significantly improved in the VRd group (43 months vs 30 months in the Rd group; stratified hazard ratio [HR] 0.712, 96% CI 0.56–0.906; one-sided p value 0.0018). The median overall survival was also significantly improved in the VRd group (75 months vs 64 months in the Rd group, HR 0.709, 95% CI 0.524–0.959; two-sided p value 0.025). The rates of overall response (partial response or better) were 82% (176/216) in the VRd group and 72% (153/214) in the Rd group, and 16% (34/216) and 8% (18/214) of patients who were assessable for response in these respective groups had a complete response or better. Adverse events of grade 3 or higher were reported in 198 (82%) of 241 patients in the VRd group and 169 (75%) of 226 patients in the Rd group; 55 (23%) and 22 (10%) patients discontinued induction treatment because of adverse events, respectively. There were no treatment-related deaths in the Rd group, and two in the VRd group.” (B. G. M. Durie, bdurie@myeloma.org)
Intensified Methotrexate in Plaque-Type Psoriasis: Compared with placebo, an intensified subcutaneous methotrexate dosing schedule produced a favorable 52-week risk–benefit profile in 120 patients with moderate-to-severe plaque-type psoriasis, the METOP trial shows (pp. 528–37). The phase 3 trial included patients who had been diagnosed at least 6 months and were methotrexate-naive. Starting doses of 17.5 mg/week with escalation to 22.5 mg/week permitted after 8 weeks of therapy produced these findings: “At week 16, a [Psoriasis Area and Severity Index] 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3.93, 95% CI 1.31–11.81; p = 0.0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period.” (K. Reich, kreich@dermatologikum.de)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Treatment of WHO Group II Anovulation: For first-line treatment of women with WHO group II anovulation who wish to conceive, clomiphene plus metformin are superior to clomiphene alone in terms of ovulation and pregnancy, according to a systematic review and meta-analysis of 57 trials of 8,082 women (j138): “All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively).” (R. Wang, r.wang@adelaide.edu.au)

>>>PNN NewsWatch
*
FDA warned last week of rare but serious allergic reactions with skin antiseptic products containing chlorhexidine gluconate. The agency is requesting that manufacturers add a warning about this risk to products’ Drug Facts labels.

>>>PNN JournalWatch
* Atrial Fibrillation and Ventricular Arrhythmias: Sex Differences in Electrophysiology, Epidemiology, Clinical Presentation, and Clinical Outcomes, in
Circulation, 2017; 135: 593–608. (A. M. Gillis, amgillis@ucalgary.ca
* Bleeding Disorders in Congenital Syndromes, in
Pediatrics, 2017; 139: e20154360. (S. N. Sarangi) 

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 7, 2017 * Vol. 24, No. 25
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. 7 issue of the Annals of Internal Medicine (2017; 166).
High-Risk Prescribing & Dual Health System Use: As reported in PNN when the this research was first released (Dec. 6), U.S. veterans with dementia who have access to both VA and outside services are at high risk of potentially unsafe medication (PUM) prescribing (pp. 157–63). A retrospective cohort study of VA and Medicare Part D data shows these patterns of prescribing among 75,829 veterans with dementia based on HEDIS high-risk medication in older adults (PUM-HEDIS), any daily exposure to prescriptions with a cumulative Anticholinergic Cognitive Burden (ACB) score of 3 or higher (PUM-ACB), any antipsychotic prescription (PUM-antipsychotic), and any PUM exposure (any-PUM): “Compared with VA-only users, dual users had more than double the odds of exposure to any-PUM (odds ratio [OR], 2.2 [95% CI, 2.2 to 2.3]), PUM-HEDIS (OR, 2.4 [CI, 2.2 to 2.8]), and PUM-ACB (OR, 2.1 [CI, 2.0 to 2.2]). The odds of PUM-antipsychotic exposure were also greater in dual users (OR, 1.5 [CI, 1.4 to 1.6]). Dual users had an adjusted average of 44.1 additional days of any-PUM exposure (CI, 37.2 to 45.0 days).” (J. M. Thorpe, Joshua.Thorpe@va.gov)
Noting that the VA pharmacy system is “perfectly designed to achieve the outcomes it gets,” an editorialist writes (
pp. 221–2): “Thorpe and colleagues note that the VA system has a robust integrated pharmacy and medical record system available in all of the VA health care settings—a system clearly built to achieve better outcomes. Yet when using 3 indicators of unsafe medications among veterans with dementia, the researchers found that approximately 4 of every 10 VA-only users still received potentially harmful medications. Anticholinergic medications were the most commonly prescribed drugs but have long been known to be potentially harmful for elderly persons. The Office of Inspector General of the U.S. Department of Health and Human Services has shown that the leading cause of adverse events in hospitals and skilled nursing facilities is related to medications, many of which induce delirium due to their anticholinergic properties. Yet we as a profession continue to prescribe these medications for our elderly patients. Again, the prioritization of choice holds us back from building a better system.” (D. R. Gifford, dgifford@ahca.org)
Discharge Thresholds in Acute Decompensated Heart Failure: Reacting to a systematic review of discharge natriuretic peptides (NPs) thresholds in hospitalized patients with acute decompensated heart failure (HF) (pp. 180–90; C. A. Umscheid, craig.umscheid@uphs.upenn.edu), editorialists describe the difficulty in generating sufficient evidence to determine the utility of these biomarkers in real-world practice (pp. 223–4): “For one, it is not clear whether patients who do not achieve target NP levels during hospitalization fail to do so due to inadequate treatment (in either intensity or duration) or because their underlying HF is too severe to respond adequately to standard interventions. The former suggests that a strategy focused on intensifying therapy with a ‘discharge goal’ of achieving a specific NP target would likely be beneficial. In the latter case, such efforts are unlikely to be fruitful, other than simply identifying patients at the highest risk. It is unclear whether all admitted patients with HF would be risk-stratified in a similar manner by NP levels. Inclusion of admitted patients with de novo HF reduces the overall risk of the cohort. In addition, it is not clear what ‘intensified treatment’ in the face of failure to achieve NP goals should entail—more diuretics? Higher doses of neurohormonal drugs or vasodilators? Longer length of stay or intensified postdischarge follow-up? At present, our limited options for treating hospitalized patients with HF significantly limit our ability to intensify therapy even in patients identified as being at higher risk.” (D. J. Whellan, david.whellan@jefferson.edu)
Metformin in Chronic Diseases: Metformin use in patients with diabetes plus moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment improves outcomes, a systematic review shows (pp. 191–200): “Metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.” (M. J. Crowley, matthew.crowley@dm.duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 8, 2017 * Vol. 24, No. 26
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 7 issue of JAMA (2017; 317).
Treatment of Pituitary Adenomas: Dopamine agonists are first-line therapy for prolactinomas, review authors conclude (pp. 516–24). Other pituitary adenomas initially require surgery followed by medical therapy only when not cured, they write, adding these details: “Prolactinomas account for 32% to 66% of adenomas and present with amenorrhea, loss of libido, galactorrhea, and infertility in women and loss of libido, erectile dysfunction, and infertility in men; they are generally treated with the dopamine agonists cabergoline and bromocriptine. Growth hormone–secreting tumors account for 8% to 16% of tumors and usually present with enlargement of the lips, tongue, nose, hands, and feet and are diagnosed by elevated insulin-like growth factor 1 levels and growth hormone levels; initial treatment is surgical. Medical therapy with somatostatin analogues, cabergoline, and pegvisomant is often also needed. Adrenocorticotropic hormone (ACTH)–secreting tumors account for 2% to 6% of adenomas and are associated with obesity, hypertension, diabetes, and other morbidity. Measurement of a late-night salivary cortisol level is the best screening test but petrosal sinus sampling for ACTH may be necessary to distinguish a pituitary from an ectopic source. The primary treatment of Cushing disease (hypercortisolism due to ACTH-producing adenomas, which is the cause in approximately 65% of the cases of hypercortisolism) is adenoma resection and medical therapies including ketoconazole, mifepristone, and pasireotide. Hyperthyroidism due to thyroid-stimulating hormone–secreting tumors accounts for 1% of tumors and is treated with surgery and somatostatin analogues if not surgically cured. Clinically nonfunctioning adenomas account for 15% to 54% of adenomas and present with mass effects; surgery is generally required, although incidentally found tumors can be followed if they are asymptomatic.” (M. E. Molitch, molitch@northwestern.edu)
e-Discontinuation: “Prescribers need to be able to e-discontinue prescriptions, just as easily as they can e-prescribe them,” Viewpoint authors write (pp. 469–70): “ CancelRx was first defined by the National Council for Prescription Drug Programs and was published as part of the SCRIPT standard for e-prescribing in the Federal Register by the Centers for Medicare & Medicaid Services in 2010. However, this approach was not incorporated into the ‘meaningful use’ program for electronic health record (EHR) incentive payments, which might have encouraged uptake. Changes to meaningful use under the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) included rules that required EHRs to include the ability to cancel prescriptions and other features of the SCRIPT 10.6 standard.…
“Adding e-discontinuation functionality has the potential to help reduce medication errors and take fuller advantage of e-prescribing technology.” (S. Fischer,
sfischer@rand.org)
Global Vaccine Injury Compensation: “Establishing a global compensation system could build confidence in the processes that lead to the development of vaccines deployed in low-resource settings, relieve vaccine manufacturers of liability concerns that impede vaccine investments, and facilitate effective responses to global public health threats like Ebola and Zika,” according to authors of a Viewpoint article that reviews three models for addressing vaccine injury (pp. 471–2). After discussing approaches in which patients or manufacturers bear the costs of injuries, the authors write: “The third approach, a no-fault compensation system for adverse events attributed to vaccination, balances these competing principles. Under a no-fault vaccine injury compensation system, governments compensate individuals who are harmed by properly manufactured vaccines instead of requiring them to use legal or other processes against manufacturers. A no-fault system acknowledges that a community that promotes immunization, knowing individuals will be injured, must share the burden of the cost of injuries. This approach also acknowledges that manufacturers are a critical part of vaccine access and that they must have a basic level of economic certainty. It fulfills the utilitarian and communitarian expectations of a democratic society. Yet no-fault compensation systems for vaccine injury prevail in only 19 jurisdictions worldwide including the United States.” (S. F. Halabi, sfh9@georgetown.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 9, 2017 * Vol. 24, No. 27
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 9 issue of the New England Journal of Medicine (2017; 376).
Thromboprophylaxis After Knee Arthroscopy/Casting: Use of low-molecular-weight heparins for a few days after knee arthroscopy or for the full duration of lower-leg casting is not supported by results of the POT-KAST and POT-CAST trials (pp. 515–25). Compared with no anticoagulation, prophylactic doses of low-molecular-weight heparin for 8 days after arthroscopy in the POT-KAST trial or during the full period of casting immobilization in the POT-CAST trial produced these results: “In the POT-KAST trial, 1,543 patients underwent randomization, of whom 1,451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, −0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, −0.6 to 0.7). In the POT-CAST trial, 1,519 patients underwent randomization, of whom 1,435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, −0.4 percentage points; 95% CI, −1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection.” (S. C. Cannegieter, s.c.cannegieter@lumc.nl)
Despite these findings, clinicians will likely consider it prudent to anticoagulate some higher-risk patients during and following knee arthroscopy, an editorialist writes, adding that the real question could be whether the patient really needs the procedure (
pp. 576–7): “There is no indication to routinely treat all patients undergoing knee arthroscopy or lower-leg casting with prophylactic anticoagulation. For patients at increased risk for venous thromboembolism, the use of some prophylactic treatment makes intuitive sense but is not evidence-based. The appropriate prevention strategy to consider for these patients — including the type of drug, dose, and duration of treatment — is unknown. Given the large number of arthroscopic knee surgeries and the reported overall limited benefit of these procedures in diminishing pain and improving physical function, another effective strategy to consider in the prevention of venous thromboembolism is a critical reevaluation as to which patients truly need arthroscopic knee surgery.” (S. Moll)
Red-State Medicaid Expansions & ACA Repeal/Reform: Even in GOP-leaning “red states,” the benefits of Medicaid expansion of benefits under the Affordable Care Act (ACA) are associated with overall support for the controversial law, results of a four-state survey show (e7). Compared with Texas — where Medicaid was not expanded — low-income individuals residing in Arkansas, Kentucky, and Louisiana felt that overall the law helped rather than hurt them personally. “Of course, a person’s sense of whether he or she has been helped by the law is inherently subjective and may be influenced by social desirability bias, political partisanship, and numerous other factors,” the authors write. “So what lessons can be drawn from subjective evaluations such as these? In part, the results are useful evidence that even in the most conservative region in the country, many people report substantial benefits from the law and are willing to directly credit the ACA for those changes. These subjective valuations are consistent with the findings of multiple other studies that used more traditional evaluative approaches and have shown large gains in access to care and affordability from Medicaid expansion.” (B. D. Sommers)

>>>PNN NewsWatch
* Citing presence of particulate matter, Exela Pharma Sciences, in association with marketer X-Gen Pharmaceuticals, is voluntarily recalling lot number PLND1613 of
Ibuprofen Lysine Injection, 20 mg /2 mL (10 mg/mL), vials to the hospital or user level, FDA said yesterday.
*
FDA also notes on its website the recall of Kingsway Trading’s Well Balance Xanthium & Siler Combo (Bi Yan Pian) batches 130401 and 150201 because they contain ephedra alkaloids.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 10, 2017 * Vol. 24, No. 28
Providing news and information about medications and their proper use

>>>Cardiology Report
Source: Feb. issue of the Journal of the American College of Cardiology (2017; 69).
Aspirin Formulation & Resistance in Type 2 Diabetes: Aspirin resistance in patients with type 2 diabetes is frequently the result of incomplete bioavailability of enteric formulations, according to a 40-patient, triple-crossover study (doi 10.1016/j.jacc.2016.11.050). Participants received plain aspirin 325 mg, delayed-release, enteric-coated (EC) aspirin, and a modified-release lipid-based aspirin (PL2200) in separate phases of the trial. Antiplatelet activity as measured by the rate and extent of inhibition of serum thromboxane B2 (TXB2) generation showed these patterns: “The rate of aspirin nonresponsiveness was 15.8%, 8.1%, and 52.8% for plain aspirin, PL2200, and EC aspirin, respectively (p < 0.001 for both comparisons vs. EC aspirin; p = 0.30 for comparison between plain aspirin and PL2200). Similarly, 56% of EC aspirin–treated subjects had serum TXB2 levels >3.1 ng/ml, compared with 18% and 11% of subjects after administration of plain aspirin and PL2200 (p < 0.0001). Compared with findings for plain aspirin and PL2200, this high rate of nonresponsiveness with EC aspirin was associated with lower exposure to acetylsalicylic acid (63% and 70% lower geometric mean maximum plasma concentration [Cmax] and 77% and 82% lower AUC0–t [area under the curve from time 0 to the last time measured]) and 66% and 72% lower maximum decrease of TXB2, with marked interindividual variability.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
In patients without diabetes, high patient weight can also contribute to aspirin nonresponsiveness, an editorialist adds (
doi 10.1016/j.jacc.2016.11.049). “Together, these data suggest that diabetes and obesity are independent and possibly additive determinants of poor aspirin responsiveness, limiting the duration and/or degree of platelet COX-1 suppression, and possibly requiring different dosing strategies, well beyond the uncertain effects of aspirin formulations.” (C. Patrono, carlo.patrono@rm.unicatt.it)

>>>Chest Highlights
Source: Feb. issue of Chest (2017; 151).
Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD: In two phase 3 trials, a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-µg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology was superior to placebo and the components administered separately in a total of 3,718 patients with moderate-to-very severe COPD, PINNACLE-1 and -2 researchers report (pp. 340–57): “At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms).” (F. J. Martinez)

>>>PNN NewsWatch

*
FDA yesterday approved the corticosteroid deflazacort (Emflaza, Marathon Pharmaceuticals) to treat patients age 5 years and older with the rare genetic disorder Duchenne muscular dystrophy. This is the first FDA approval of any corticosteroid to treat patients with this condition, which causes progressive muscle deterioration and weakness, and the first approval of deflazacort for any use in the United States, the agency said.
* CareFusion is recalling the
Alaris Syringe Pump because of a faulty Air-In-Line (AIL) sensor, which may generate a false alarm and cause the syringe pump to stop supplying the infusion to the patient, FDA said.
*
Tom Price, MD, congressman from Georgia, was approved early this morning as Pres. Trump’s Secretary of Health and Human Services in a 52–47 party-line vote, STAT news reports. As a former practicing orthopedic surgeon, Price brings a unique outlook on Medicare and Medicaid policies to the position. He has been a staunch opponent of the Affordable Care Act, which the GOP plans to repeal or modify. Price is a member of a “conservative, fringe medical group,” the Washington Post reports. The article said the Association of American Physicians and Surgeons is opposed to Medicare and mandatory vaccinations; the article has a link to a Price video from the group’s 2011 annual meeting in which he said quality is a “buzzword” used by “Washington bureaucrats and the left … to disrupt [the] patient–family–physician relationship.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 13, 2017 * Vol. 24, No. 29
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 11 issue of Lancet (2017; 389).
Thrombolytic Removal of Intraventricular Hemorrhage: In 500 patients with severe stroke caused by intraventricular hemorrhage and with a routine extraventricular drain, irrigation with alteplase did not improve functional outcomes but appeared to be safe, a study shows (pp. 603–11). Based on results obtained in 2009–15, the investigators conclude, “Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.” (D. F. Hanley, dhanley@jhmi.edu)
Masitinib for Severely Symptomatic Indolent Systemic Mastocytosis: In a phase 3 trial of adults with severely symptomatic indolent or smouldering systemic mastocytosis, a myeloid neoplasm, masitinib is an effective and well tolerated (pp. 612–20). The KIT and LYN kinase inhibitor was compared with placebo using a dose-minimization design based on severe symptoms of the lifelong disorder, with these results: “Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n = 71) or placebo (n = 64). By 24 weeks, masitinib was associated with a cumulative response of 18.7% in the primary endpoint (122.6 responses of 656.5 possible responses [weighted generalised estimating equation]) compared with 7.4% for placebo (48.9 of 656.5; difference 11.3%; odds ratio 3.6; 95% CI 1.2–10.8; p = 0.0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).” (O. Hermine, hermine@gmail.com">ohermine@gmail.com)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 354).
Reduced-Dose Anticoagulants in Atrial Fibrillation: In a study of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin, a nonsignificant statistical trend showed possible poorer efficacy with apixaban and better safety results with dabigatran, researchers report (j510). Using individual data from three Danish nationwide registries, the investigators determined: “Among 55,644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n = 4,400; dabigatran n = 8,875; rivaroxaban n = 3,476; warfarin n = 38,893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.” (T. B. Larsen, tobl@rn.dk)

>>>PNN JournalWatch
* Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension, in
Chest, 2017; 151: 468–80. (H-A Ghofrani) 
* Intrathecal Amphotericin B: A 60-Year Experience in Treating Coccidioidal Meningitis, in
Clinical Infectious Diseases, 2017; 64: 519–24. (E. J. C. Goldstein) 
* Antineoplastic Treatment of Advanced-Stage Non–Small-Cell Lung Cancer: Treatment, Survival, and Spending (2000 to 2011), in
Journal of Clinical Oncology, 2017; 35: 529–35. (C. J. Bradley, cathy.bradley@ucdenver.edu
* Acute Asthma, Prognosis, and Treatment, in
Journal of Allergy and Clinical Immunology, 2017; 139: 438–47. (J. E. Fergeson, jfergeso@health.usf.edu
* Don’t Pass the Salt: Evidence to Support Avoidance of High Salt Intake in CKD, in
American Journal of Kidney Diseases, 2017; 69: 175–8. (A. K. Leonberg-Yoo, Amanda.Leonberg-Yoo@uphs.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 14, 2017 * Vol. 24, No. 30
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. issue of JAMA Internal Medicine (2017; 177).
Beta-Blockers After AMI in Older Nursing Home Residents: Among a cohort of nursing home residents in 2007–10, use of beta-blockers after acute myocardial infarction (AMI) was associated with “considerable mortality benefit” but also declines in functional status, particularly in those with poor cognitive and functional status at baseline, researchers report (pp. 254–62). Minimum Data Set 2.0 figures and data from Medicare Parts A and D show these associations based on beta-blocker use in long-stay residents of nursing homes aged 65 years or older: “The initial cohort of 15,720 patients (11,140 women [70.9%] and 4,580 men [29.1%]; mean [SD] age, 83 [8] years) included 8,953 new beta-blocker users and 6,767 nonusers. The propensity-matched cohort included 5,496 new users of beta-blockers and an equal number of nonusers for a total cohort of 10,992 participants (7,788 women [70.9%]; 3,204 men [29.1%]; mean [SD] age, 84 [8] years). Users of beta-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02–1.28), with a number needed to harm of 52 (95% CI, 32–141). Conversely, beta-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67–0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98–1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from beta-blockers (OR, 1.34; 95% CI, 1.11–1.61 and OR, 1.32; 95% CI, 1.10–1.59, respectively). In contrast, little evidence of functional decline due to beta-blockers was found in participants with intact cognition or mild dementia (OR, 1.03; 95% CI, 0.89–1.20; P = .03 for effect modification) or in those in the best (OR, 0.99; 95% CI, 0.77–1.26) and intermediate (OR, 1.05; 95% CI, 0.86–1.27) tertiles of functional independence (P = .06 for effect modification). Mortality benefits of beta-blockers were similar across all subgroups.” (M. A. Steinman, mike.steinman@ucsf.edu)
After listing limitations of data analyses in an area where higher-quality evidence is needed, an editorialist writes, “A randomized clinical trial for frail older adults with cognitive and functional impairment to examine guideline-recommended medications for AMI is needed to address biases inherent in observational studies” (
pp. 262–3). “Furthermore, a trial for discontinuation of beta-blocker therapy in the population of elders with life-limiting illness would be prudent given the changing benefits and risks of treatment across levels of cognitive and functional impairment. The Palliative Care Research Cooperative Group’s discontinuation trial for statin therapy among adults with life-limiting illness provides a useful model for such a study. Regardless of the state of the science, all clinicians should consider improving their approach to communication regarding initiating (and discontinuing) therapy for those in the last quarter of their life.” (J. Tjia, jennifer.tjia@umassmed.edu)
Trust but Verify: Commenting on two randomized controlled trials (RCTs) that show no effects of programs designed to enhance care of high-use veterans through interdisciplinary efforts (pp. 166–75; D. M. Zulman, dzulman@stanford.edu) and improve antibiotic prescribing patterns (pp. 176–83; H. C. Bucher, heiner.bucher@usb.ch), an editorialist reiterates the need for randomized controlled trials in assessment of quality improvement efforts (pp. 162–3). “These 2 RCTs demonstrate the importance of rigorous study design. Common sense doesn’t always prove to be right. Preintervention–postintervention observational designs can be mistaken, especially when there is no concurrent control. Just as we would not accept a drug as efficacious without a randomized clinical design, quality improvement interventions benefit from rigorous evaluation methodology. As the Russian proverb says: trust but verify.” (M. H. Katz, mkatz@dhs.lacounty.gov)
Fish Oil or Aspirin in Arteriovenous Fistula Failure: In the randomized Omega-3 Fatty Acids (Fish Oils) and Aspirin in Vascular Access Outcomes in Renal Disease (FAVOURED) study, neither aspirin nor fish oil supplementation significantly reduced failure rates of new arteriovenous fistulae within 12 months of surgery in patients requiring hemodialysis (pp. 184–93; A. B. Irish, ashley.irish@health.wa.gov.au)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 15, 2017 * Vol. 24, No. 31
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 14 issue of JAMA (2017; 317).
Scalp Cooling After Breast Cancer Chemotherapy: Women who used a scalp-cooling device kept more of their hair during chemotherapy for breast cancer, according to two studies and a related editorial.
During chemotherapy with a taxane and/or anthracycline, 142 women with stage 1 or 2 breast cancer “were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling,” researchers conclude (
pp. 596–605). Adding that longer-term efficacy and safety data are needed, the group adds these details regarding results: “Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%–60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%–7.6%) (success rate difference, 50.5%; 95% CI, 40.5%–60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events.” (J. Nangia, nangia@bcm.edu)
Scalp cooling during nonanthracycline adjuvant chemotherapy was hair sparing among 122 women with stage 1 or 2 breast cancer, a second study shows (
pp. 606–14): “Hair loss of 50% or less (Dean score of 0–2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%–75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P < .001). Three of 5 quality-of-life measures were significantly better 1 month after the end of chemotherapy in the scalp cooling group. Of patients who underwent scalp cooling, 27.3% (95% CI, 18.0%–36.6%) reported feeling less physically attractive compared with 56.3% (95% CI, 31.9%–80.6%) of patients in the control group (P = .02). Of the 106 patients in the scalp cooling group, 4 (3.8%) experienced the adverse event of mild headache and 3 (2.8%) discontinued scalp cooling due to feeling cold.” (H. S. Rugo, hope.rugo@ucsf.edu)
With mortality benefits of adjuvant chemotherapy well established in breast cancer, “the time has come” to address adverse effects of the drugs, writes an editorialist (
pp. 587–8): “Chemotherapy has been a mainstay of adjuvant therapy for breast cancer and has contributed to a reduction in breast cancer–related mortality. However, with the introduction of targeted therapies, it is appealing to imagine a future in which chemotherapy is no longer necessary and some of the distressing adverse effects of cancer treatments can be avoided. Until that time, identifying interventions, such as scalp cooling for the prevention of chemotherapy-induced alopecia, that reduce or eliminate treatment-associated toxic effects will help ease the distress associated with chemotherapy and may, as a result, improve outcomes for patients with breast cancer.” (D. L. Hershman, dlh23@cumc.columbia.edu)
Sublingual Grass Pollen Immunotherapy: Two years of sublingual grass pollen immunotherapy failed to improve nasal responses to allergen challenge at a 3-year follow-up, report researchers who studied 92 adult patients with moderate to severe seasonal allergic rhinitis (pp. 615–25). Comparing the major allergen Phleum p 5 with placebo controls, participants received daily sublingual tablets and monthly injections, with these results: “In the intent-to-treat population, mean [total nasal symptom] score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]).” (S. R. Durham, s.durham@imperial.ac.uk)

>>>PNN NewsWatch
* Synergy Rx Pharmacy is voluntarily recalling all lots of
Human Chorionic Gonadotropin 5,000 units/vial and 11,000 units/vial to the retail level due to a lack of sterility assurance, according to an announcement posted on the FDA website.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 16, 2017 * Vol. 24, No. 32
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 16 New England Journal of Medicine (2017; 376).
Baricitinib in Rheumatoid Arthritis: An oral reversible inhibitor of Janus kinases JAK1 and JAK2, baricitinib was more effective than placebo or adalimumab in treating 1,307 patients with active rheumatoid arthritis, a phase 3 trial shows (pp. 652–62). In the 52-week study, results based on 20% improvement in the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), Disease Activity Score for 28 joints (DAS28), Health Assessment Questionnaire–Disability Index, and Simplified Disease Activity Index at week 12 were as follows: “More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P <0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the [modified Sharp score] at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P <0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P = 0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol.” (P. C. Taylor, peter.taylor@kennedy.ox.ac.uk)
ED Opioid Prescribing & Risk of Long-Term Use: In the nation’s emergency departments, physicians vary widely in their rates of prescribing of opioid analgesics, report researchers, who also found increased risks of long-term opioid use among opioid-naive patients who were seen by high-intensity opioid prescribers (pp. 663–73). A retrospective analysis of Medicare beneficiaries with index emergency department visits in 2008–11 showed these rates of prescribing and long-term opioid use: “Our sample consisted of 215,678 patients who received treatment from low-intensity prescribers and 161,951 patients who received treatment from high-intensity prescribers. Patient characteristics, including diagnoses in the emergency department, were similar in the two treatment groups. Within individual hospitals, rates of opioid prescribing varied widely between low-intensity and high-intensity prescribers (7.3% vs. 24.1%). Long-term opioid use was significantly higher among patients treated by high-intensity prescribers than among patients treated by low-intensity prescribers (adjusted odds ratio, 1.30; 95% confidence interval, 1.23 to 1.37; P <0.001); these findings were consistent across multiple sensitivity analyses.” (M. L. Barnett, mbarnett@hsph.harvard.edu)
FDA Regulation of Prescription Drugs: FDA officials review the current regulatory operations of the agency, reaching this conclusion (pp. 674–82): “Many of the FDA’s benefit–risk assessments and decisions are straightforward, but sometimes the FDA is confronted with a difficult set of benefits, risks, and uncertainties. Particularly in these situations, the FDA and the drug company may reach different conclusions based on the same facts, or there may be differences of opinion among the members of the FDA’s review team. The FDA encourages transparent, robust scientific discussions among its staff and has processes for handling differences of opinion. There is also a process for drug companies to appeal an FDA decision. Such situations can be highly charged and can elicit strong public reactions, with some people criticizing the FDA for being too conservative and delaying access to new drugs, and others criticizing the FDA for being too lenient and approving drugs on the basis of limited data. We believe that the new structured framework for benefit–risk assessment will facilitate a better understanding of the data and uncertainties underlying drug approvals and will make this information more transparent to the public.” (H. V. Joffe, hylton.joffe@fda.hhs.gov)

>>>PNN NewsWatch
*
FDA yesterday approved the injectable agent brodalumab (Siliq, Valeant Pharmaceuticals) for treatment of adults with moderate-to-severe plaque psoriasis.
* Bird flu is spreading in China, according to an article in the
Sydney Morning Herald. Some 79 people died of H7N9 influenza last month, Chinese government sources say.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 17, 2017 * Vol. 24, No. 33
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Feb. 15 issue of Clinical Infectious Diseases (2017; 64).
Mumps Outbreak in Highly Vaccinated University Community: Illustrating how outbreaks can occur in a highly vaccinated population, investigators report 56 cases of mumps from New York City, all linked back to a university community (pp. 408–12). “On 14 January 2014, a vaccinated student presented with parotitis. Mumps immunoglobulin M (IgM) testing was negative and reverse-transcription polymerase chain reaction (RT-PCR) testing was not performed, resulting in a missed diagnosis and the start of an outbreak at a New York City (NYC) university,” the group writes. “Fifty-six NYC residents with mumps were identified with onset between 12 January and 30 April 2014. Fifty-three cases (95%) were university students, 1 (2%) was a staff member, and 2 (4%) had epidemiologic links to the university. The median age was 20 years (range 18–37 years). All cases had parotitis. Three cases were hospitalized, including 1 of 2 cases with orchitis. Fifty-four (96%) cases had received ≥1 mumps-containing vaccine, 1 (2%) was unvaccinated due to religious exemption, and 1 (2%) had unknown vaccination status. Two of the 44 (5%) cases tested by serology were mumps IgM positive, and 27 of the 40 (68%) tested by RT-PCR were positive.” (L. N. Patel)
Diabetes, Insulin Therapy, Hospitalization for Infection & 28-Day Mortality Risk: In the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, community-dwelling adults aged 45 years or older had increased risk of hospitalization for infection when they had been diagnosed with diabetes, and the odds were increased further if they were on insulin therapy (pp. 435–42). The prospective cohort study followed 30,239 participants from 2003 to 2012, identifying these patterns: “Among 29,683 patients from the REGARDS study with complete follow-up, 7,375 had diabetes. Over a median follow-up period of 6.5 years, we identified 2,593 first and 3,411 total infection hospitalizations. In adjusted analyses, participants with diabetes had an increased hazard of infection (hazard ratio, 1.50; 95% confidence interval [CI], 1.37–1.64) compared with those without diabetes. Participants with diabetes hospitalized for infection did not have an increased odds of death within 28 days (odds ratio, 0.94; 95% CI, .67–1.32). Participants receiving insulin therapy had greater hazard of infection (hazard ratio, 2.18; 95% CI, 1.90–2.51) but no increased odds of mortality (odd ratio, 1.07; 95% CI, .67–1.71).” (J. P. Donnelly)

>>>Oncology Highlights
Source: Feb. 20 issue of the Journal of Clinical Oncology (2017; 35).
Viral Status & Sorafenib Effects in Advanced Hepatocellular Cancer: The overall survival (OS) benefit of sorafenib varies depending on patients’ hepatitis status, according to results from the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial (pp. 622–8). Among 1,643 patients who received sorafenib, hazard ratios based on hepatitis C virus (HCV) or hepatitis B virus (HBV) status were as follows: “Hazard ratios show improved OS for sorafenib in patients who are both HBV negative and HCV positive (log [hazard ratio], −0.27; 95% CI, −0.46 to −0.06). Median unadjusted survival is 12.6 (11.15 to 13.8) months for sorafenib and 10.2 (8.88 to 12.2) months for ‘other’ treatments in this subgroup. There was no evidence of improvement in OS for any other patient subgroups defined by HBV and HCV. Results were consistent across all trials with heterogeneity assessed using Cochran’s Q statistic.” (P. Johnson, Philip.Johnson@liverpool.ac.uk)
Personal Genomic Testing for Cancer Risk: When patients learn through genomic testing that they have elevated cancer risks, they do not change their health-related behaviors, a study shows (pp. 636–44; S. W. Gray, stagray@coh.org).

>>>PNN NewsWatch
* A reasonably good match between circulating influenza viruses and strains in the 2016–17 vaccine is reported in yesterday’s
MMWR. Overall vaccine effectiveness is preliminarily estimated at 48% against medically attended acute respiratory infection and 43% overall. As of early Nov. 2016, vaccination rates were 37% in pediatric patients, 37% in adults aged 18–64 years, 57% among older adults, and 47% among pregnant women.
*
PNN will not be published on Mon., Feb. 20, Presidents Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 21, 2017 * Vol. 24, No. 34
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Feb. 21 issue of the Annals of Internal Medicine (2017; 166).
Primary Care–Based Opioid Use Disorder Therapy: “Greater integration of medication-assisted treatment (MAT) for opioid use disorder (OUD) in U.S. primary care settings would expand access to treatment for this condition,” write authors of a review article on this topic (pp. 268–78): “Models for integrating MAT into primary care vary in structure. This article summarizes findings of a technical report for the Agency for Healthcare Research and Quality describing MAT models of care for OUD, based on a literature review and interviews with key informants in the field. The report describes 12 representative models of care for integrating MAT into primary care settings that could be considered for adaptation across diverse health care settings. Common components of existing care models include pharmacotherapy with buprenorphine or naltrexone, provider and community education, coordination and integration of OUD treatment with other medical and psychological needs, and psychosocial services and interventions. Models vary in how each component is implemented. Decisions about adopting MAT models of care should be individualized to address the unique milieu of each implementation setting.” (P. T. Korthuis, korthuis@ohsu.edu)
Editorialists write that primary care clinicians will need training in three areas to improve care of patients with OUD: biology of opioid use disorder, rationale for and efficacy of treatment options, and identification of the spectrum of patients for whom their practice can provide effective treatment (
pp. 307–8). “Federally funded services, such as the Providers’ Clinical Support System for Medication-Assisted Treatment, can provide education, mentoring, and support,” the article continues. “Internists have had a profound effect on developing, researching, disseminating, and implementing the most effective treatments for opioid use disorder. Primary care practices now have a road map to follow to help address the pressing health crisis presented by the current epidemic.” (E. J. Edelman, ejennifer.edelman@yale.edu)
Oral Treatment of Type 2 Diabetes: As reported earlier in PNN (see Jan. 3), the American College of Physicians recommends first-line use of metformin for oral pharmacologic treatment of adults with type 2 diabetes in an update to its 2012 guideline (pp. 279–90). ACP recommends that clinicians (A. Qaseem, aqaseem@acponline.org):
* Prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence)
* Consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered (Grade: weak recommendation; moderate-quality evidence), and select with patients among medications after discussing benefits, adverse effects, and costs.

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Vitamin D Prevention of Respiratory Infections: Supplements of vitamin D protect against acute respiratory tract infections, according to results of a systematic review and meta-analysis (i6583). A 12% reduction in risk was found overall, with greater protective effects in those with lower baseline vitamin D levels (<12 nmol/L) and in those who did not receive bolus supplements of the nutrient. (A. R. Martineau, a.martineau@qmul.ac.uk)

>>>PNN JournalWatch
* Risk of Heart Failure After Community Acquired Pneumonia: Prospective Controlled Study With 10 Years of Follow-up, in
BMJ, 2017; 356: j413. (D. T. Eurich, deurich@ualberta.ca
* The Scientific Basis of Guideline Recommendations on Sugar Intake: A Systematic Review, in
Annals of Internal Medicine, 2017; 166: 257–67. (B. C. Johnston, bradley.johnston@sickkids.ca
* Systematic Review of the Prevalence of Medication Errors Resulting in Hospitalization and Death of Nursing Home Residents, in
Journal of the American Geriatrics Society, 2017; 65: 433–42. (J. E. Ibrahim, joseph.ibrahim@monash.edu
* Pharmacotherapeutic Considerations for Individuals with Down Syndrome, in
Pharmacotherapy, 2017; 37: 214–20. (E. Hefti, erikheft@buffalo.edu
* Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know, in
Pharmacotherapy, 2017; 37: 236–48. (S. E. Conway, susan-conway@ouhsc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 22, 2017 * Vol. 24, No. 35
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 21 issue of JAMA (2017; 317).
Effects of Testosterone Replacement in Older Men: Clinical benefits of testosterone replacement in older men with low levels of the hormone are examined.
Rather than a decrease in noncalcified coronary artery plaque volume, researchers found increases in this cardiovascular risk indicator in older men using testosterone gel for 1 year (
pp. 708–16). In the Testosterone Trials (TTrials), conducted in 2010–14, coronary computed tomographic angiography yielded these results for 138 men with low serum testosterone levels and symptoms suggestive of hypogonadism: “At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis.… Testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003).” (P. J. Snyder, pjs@mail.med.upenn.edu)
In the same study, 492 older men with low testosterone and age-associated memory impairment (AAMI) had no improvements in memory or cognitive function during 1 year of testosterone gel, compared with placebo (
pp. 717–27). “There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88),” the authors write. “Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89).” (P. J. Snyder, pjs@mail.med.upenn.edu)
“It is unlikely that the limited efficacy shown by the TTrials meets the mandate of the 2004 Institute of Medicine report to warrant public funding for a powerful, long-term, large randomized clinical trial for evaluating testosterone,” editorialists write (
pp. 699–701). “In September 2015 the FDA mandated that testosterone manufacturers undertake longer-term safety and efficacy trials for off-label use of testosterone for aging men. If such a study proceeds, it could provide a valuable extension to the short-term safety of the TTrials supported by the manufacturers who have reaped large financial benefit from the boom in testosterone sales. In any case, with the results of [these] studies …, the hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed.” (D. J. Handelsman, djh@anzac.edu.au)
Fibrinogen Concentrate in High-Risk Cardiac Surgery: Intraoperative blood loss was unchanged in 120 patients receiving fibrinogen concentrate during high-risk cardiac surgery, a placebo-controlled study shows (pp. 738–47). In the Netherlands, those undergoing elective, high-risk procedures received fibrinogen concentrate targeted to a postinfusion plasma fibrinogen level of 2.5 g/L or placebo, with these results: “Median blood loss in the fibrinogen group was 50 mL (interquartile range [IQR], 29–100 mL) compared with 70 mL (IQR, 33–145 mL) in the control group (P = .19), the absolute difference 20 mL (95% CI, −13 to 35 mL). There were 6 cases of stroke or transient ischemic attack (4 in the fibrinogen group); 4 myocardial infarctions (3 in the fibrinogen group); 2 deaths (both in the fibrinogen group); 5 cases with renal insufficiency or failure (3 in the fibrinogen group); and 9 cases with reoperative thoracotomy (4 in the fibrinogen group).” (S. Bilecen, s.bilecen@umcutrecht.nl)

>>>PNN NewsWatch
* On Friday, a U.S. district court judge entered a consent decree of permanent injunction against
Pick and Pay Inc./Cili Minerals, a manufacturer and distributor of drugs and dietary supplements, and its owner, Anton S. Botha, requiring the business to immediately cease operations until it comes into compliance with federal laws, FDA said yesterday in a news release. Products were sold online, FDA said, and also at a retail location in Lafayette, LA.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 23, 2017 * Vol. 24, No. 36
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Feb. 23 issue of the New England Journal of Medicine (2017; 376).
Lanadelumab in Hereditary Angioedema Prophylaxis: In a phase 1b, ascending-dose trial, the kallikrein inhibitor lanadelumab reduced cleavage of high-molecular-weight kininogen and attacks of angioedema in 37 patients with hereditary angioedema with C1 inhibitor deficiency (pp. 717–28). Investigators describe the following pharmacodynamic profile of the new drug based on two administration periods 14 days apart: “No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.” (A. Banerji, abanerji@partners.org)
“Kallikrein inhibition with lanadelumab given by fortnightly subcutaneous injection would be convenient and widely accessible,” writes an editorialist (
pp. 788–9). “Early safety indications are encouraging, with no indication of antibody formation or the anaphylactoid events associated with short-term inhibition of kallikrein; therefore, self-administration could be feasible. Most exciting, [this] preliminary study … suggests an unprecedented level of protection against angioedema. If this proves reproducible in larger studies currently under way, and if the treatment will be affordable, lanadelumab could herald a transformation in the way that we manage hereditary angioedema and in the life prospects for families affected by this devastating disorder.” (H. J. Longhurst)
Tight Glycemic Control in Critically Ill Children: Tight glycemic control was not beneficial in a 35-center trial of 713 patients, researchers report (pp. 729–41). Comparing target blood glucose ranges of 80–100 versus 150–180 mg/dL, results showed: “The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm.… In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P = 0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P <0.001). Patients in the lower-target group also had higher rates of health care–associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P = 0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days.” (M. S. D. Agus, michael.agus@childrens.harvard.edu)
Minimizing Health Risks of Recreational Cannabis: “We should be skeptical of people who claim to know what the net effect of cannabis legalization on public health will be,” the author of a Perspective article concludes (pp. 705–7). “Much will depend on implementation decisions, but jurisdictions’ ability to minimize health risks will also depend on how they respond to new information and other sources of uncertainty.” (B. Kilmer)

>>>PNN NewsWatch
* Organic Herbal Supply, Inc. has voluntarily recalled of all lots of
XtraHRD Natural Male Enhancement capsules after an FDA analysis showed the product contains tadalafil, the agency said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 24, 2017 * Vol. 24, No. 37
Providing news and information about medications and their proper use

>>>Medical Care Report
Source: Mar. issue of Medical Care (2017; 55).
Readmissions in Safety-Net Hospitals: Safety-net hospitals (SNHs) have more barriers to reduction of readmissions, according to a national survey, yet are less likely to use readmission-reduction strategies (pp. 229–35). Responses from a survey of 980 of 1,600 U.S. acute care hospitals in 2013–14 showed these results: “SNHs were more likely to report patient-related barriers, including lack of transportation, homelessness, and language barriers compared with non-SNHs (P-values <0.001). Despite reporting more barriers, SNHs were less likely to use e-tools to share discharge summaries (70.1% vs. 73.7%, P <0.04) or verbally communicate (31.5% vs. 39.8%, P <0.001) with outpatient providers, track readmissions by race/ethnicity (23.9% vs. 28.6%, P <0.001), or enroll patients in postdischarge programs (13.3% vs. 17.2%, P <0.001). SNHs were also less likely to use discharge coordinators, pharmacists, and postdischarge programs. When we examined the use of strategies within SNHs, we found trends to suggest that high-performing SNHs were more likely to use several readmission strategies.” (J. F. Figueroa, jfigueroa@hsph.harvard.edu)
Predictors of Overdose Among Medicaid Beneficiaries: A study demonstrates how claims data can be used to identify Medicare patients at risk for opioid overdoses (pp. 291–8). Such findings could be used to restrict opioid prescribing or dispensing or make referrals to treatment, the authors conclude based on these data for adults in the Pennsylvania Medicaid program in 2007–12: “A total of 372,347 Medicaid enrollees with 583,013 new opioid treatment episodes were included in the cohort. Opioid overdose was higher among those with abuse (1.5%) compared with those without (0.2%, P <0.001). Overdose was higher among those with probable (1.8%) and possible (0.9%) misuse compared with those without (0.2%, P <0.001). Abuse [adjusted rate ratio (ARR), 1.52; 95% confidence interval (CI), 1.10–2.10), probable misuse (ARR, 1.98; 95% CI, 1.46–2.67), and possible misuse (ARR, 1.76; 95% CI, 1.48–2.09) were associated with significantly more events of opioid medication overdose compared with those without.” (G. Cochran, gcochran@pitt.edu)
Patient Perceptions of Deprescribing: The Patient Perceptions of Deprescribing questionnaire provides “a novel, multidimensional instrument to measure patients’ attitudes and experiences related to medication discontinuation that can be used to determine how to best involve patients in deprescribing decisions,” researchers report (pp. 306–13). The instrument includes dimensions of “Medication Concerns,” “Provider Knowledge,” “Interest in Stopping Medicines,” “Unimportance of Medicines,” and “Patient Involvement in Decision-Making.” (A. Linsky, amy.linsky@va.gov)

>>>Health Affairs Highlights
Source: Feb. issue of Health Affairs (2017; 36).
End-of-Life Spending & Length of Hospice Service: Seeking to better define the impact of hospice care on end-of-life spending, investigators assessed costs in Medicare regions with high expenditures (pp. 328–36). Results for 2004–11 demonstrated both the potential of cost savings and the limitations of the intervention: “Longer periods of hospice service were associated with decreased end-of-life expenditures for patients residing in regions with high average expenditures but not for those in regions with low average expenditures. Hospice use accounted for 8 percent of the expenditure variation between the highest and the lowest spending quintiles, which demonstrates the powers and limitations of hospice use for saving on costs.” (S. Wang, shiyi.wang@yale.edu)

>>>PNN NewsWatch
* Don’t look for Medimmune’s
live attenuated influenza virus vaccine to return soon -- and maybe never, based on discussions this week at a CDC Advisory Committee on Immunization Practices meeting. Problems with effectiveness of the H1N1 component of the vaccine began after the 2009 pandemic, STAT reports based on a company presentation. While solutions are under study, ACIP won’t likely be willing to reinstate recommendations to use of the product until data are available from one or more H1N1-dominated influenza seasons. Panel members wondered aloud how long the company will stick with the product given that uncertainty.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 27, 2017 * Vol. 24, No. 38
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Feb. 25 issue of Lancet (2017; 389).
Terminal Room Disinfection & Pathogen Control: Enhanced disinfection of the last hospital room occupied by discharged patients who had infections or colonizations with certain pathogens is an effective means of decreasing infection risk in hospitals, researchers report (pp. 805–14). At nine hospitals in the southeastern U.S., 21,395 patients with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Clostridium difficile, or multidrug-resistant Acinetobacter were studied. The rooms from which the patients were discharged were disinfected using one of four strategies, and patients admitted into those rooms were considered infected. Results showed that the incidence of target organisms was lower when ultraviolet (UV) light was added to standard cleaning regimens (quaternary ammonium disinfectant except for C. difficile, for which bleach was used). Addition of bleach or disinfecting UV light to these cleaning strategies did not significantly lower the incidence of infection or colonization of exposed patients. (D. J Anderson, deverick.anderson@duke.edu)
Risk Information & Taster Sessions in Smoking Cessation: Delivery of personalized risk information and an invitation to a no-commitment “come and try it” taster session increased cessation rates among smokers in the U.K., a study shows (pp. 823–33). The letter used information from a screening questionnaire and the patient’s medical record to personalize their risks of smoking; at the taster sessions, information was provided about the National Health Service Stop Smoking Services (SSSs), address participant concerns, and encourage signing up for cessation services. Results showed: “Recruitment, collection of baseline data, delivery of the intervention, and follow up of participants took place between Jan 31, 2011, and July 12, 2014. We randomly assigned 4,384 smokers to the intervention group (n = 2,636) or the control group (n = 1,748); 4,383 participants comprised the intention-to-treat population. Attendance at the first session of an SSS course was significantly higher in the intervention group than in the control group (458 [17.4%] vs 158 [9.0%] participants; unadjusted odds ratio 2.12 [95% CI 1.75–2.57]; p <0.0001).” (H. Gilbert, hazel.gilbert@ucl.ac.uk)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Off-Label Antidepressant Use: At primary practices in Quebec, use of prescribed antidepressants for off-label indications were often not supported by “strong scientific evidence,” according to analysis of records from 2003 to 2015 (j603). Results showed: “106,850 antidepressant prescriptions were written by 174 physicians for 20,920 adults. By class, tricyclic antidepressants had the highest prevalence of off-label indications (81.4%, 95% confidence interval, 77.3% to 85.5%), largely due to a high off-label prescribing rate for amitriptyline (93%, 89.6% to 95.7%). Trazodone use for insomnia was the most common off-label use for antidepressants, accounting for 26.2% (21.9% to 30.4%) of all off-label prescriptions. For only 15.9% (13.0% to 19.3%) of all off-label prescriptions, the prescribed drug had strong scientific evidence for the respective indication. For 39.6% (35.7% to 43.2%) of off-label prescriptions, the prescribed drug did not have strong evidence but another antidepressant in the same class had strong evidence for the respective indication. For the remaining 44.6% (40.2% to 49.0%) of off-label prescriptions, neither the prescribed drug nor any other drugs in the class had strong evidence for the indication.” (J. Wong, jenna.wong@mail.mcgill.ca)

>>>PNN NewsWatch
*
Advanced Pharma, doing business as Avella of Houston, is conducting a voluntary recall of all unexpired sterile injectable products labeled “latex free” produced at its Houston location between Sept. 2016 and mid-February. The recall, extending to the user level (hospitals and institutions), results from possible synthetic latex and/or natural latex in the products.

>>>PNN JournalWatch
* Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action, in
Diabetes Care, 2017; 40: 419–30. (K. Cusi, kenneth.cusi@medicine.ufl.edu)
* Women in Leadership and the Bewildering Glass Ceiling, in
American Journal of Health-System Pharmacy, 2017; 74: 312–24. (M. A. Chisholm-Burns, mchisho3@uthsc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Feb. 28, 2017 * Vol. 24, No. 39
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Feb. issue of the Journal of the American Geriatrics Society (2017; 65).
Improving Warfarin Use in Older Adults: Two studies and an editorial show benefits of using warfarin in older adults, but risks always weight on clinicians’ decisions. 
In older adults with atrial fibrillation (AF), more than 40% were not placed on oral anticoagulants (OACs) at discharge despite a very high stroke risk, researchers report (
pp. 241–8). Based on findings from two large community cohorts of patients with AF, the group concludes, “Dominant reasons [for not using OACs] included fall risk, poor prognosis, older age, and dementia. These individuals’ high 1-year mortality rate confirmed their high level of comorbidity. To improve anticoagulation decisions and outcomes in this population, future research should focus on strategies to mitigate fall risk, improve assessment of risks and benefits of anticoagulation in individuals with AF, and determine whether newer anticoagulants are safer in complex elderly and frail individuals.” (A. S. Go, alan.s.go@kp.org)
Among veterans aged 65 years or older, discontinuance of warfarin after diagnosis of dementia was followed by a significant increase in stroke and mortality, a study shows (
pp. 249–56). Based on new diagnoses of dementia in 2007 or 2008, patients with at least a 6-month history of warfarin therapy for nonvalvular atrial fibrillation had these outcomes: “After a diagnosis of dementia, 405 individuals (16%) persisted on warfarin therapy. Unadjusted Cox proportional hazards analysis demonstrated a protective effect of warfarin in prevention of ischemic stroke (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.46–0.89, P = .008), major bleeding (HR = 0.72, 95% CI = 0.55–0.94, P = .02), and all-cause mortality (HR = 0.66, 95% CI = 0.55–0.79, P < .001). Using propensity score matching, the protective effect of continuing warfarin persisted in prevention of stroke (HR = 0.74, 95% CI = 0.54–0.996, P = .047) and mortality (HR = 0.72, 95% CI = 0.60–0.87, P < .001), with no statistically significant decrease in risk of major bleeding (HR = 0.78, 95% CI = 0.61–1.01, P = .06).” (A. R. Orkaby, aorkaby@partners.org)
“Even under the most ideal circumstances of care, there will continue to be large numbers of older adults with atrial fibrillation who are not treated with warfarin or for whom therapy will be discontinued once started,” writes an editorialist (
pp. 236–7). “The opportunity to provide safer and highly effective oral anticoagulant therapy is an extremely attractive prospect for both providers and the complex older patients under their care. Unfortunately, this will never be the case for warfarin.” (J. H. Gurwitz)

>>>Diabetes Highlights
Source: Mar. issue of the Diabetes Care (2017; 40).
Tackling the Prandial Problem: A review article author “proposes that a greater proportion of available resources be directed to basic and clinical research on the prandial problem” (pp. 291–300): “Both basal and postprandial elevations contribute to the hyperglycemic exposure of diabetes, but current therapies are mainly effective in controlling the basal component. Inability to control postprandial hyperglycemia limits success in maintaining overall glycemic control beyond the first 5 to 10 years after diagnosis, and it is also related to the weight gain that is common during insulin therapy. The ‘prandial problem’—comprising abnormalities of glucose and other metabolites, weight gain, and risk of hypoglycemia—deserves more attention. Several approaches to prandial abnormalities have recently been studied, but the patient populations for which they are best suited and the best ways of using them remain incompletely defined. Encouragingly, several proof-of-concept studies suggest that short-acting glucagon-like peptide 1 agonists or the amylin agonist pramlintide can be very effective in controlling postprandial hyperglycemia in type 2 diabetes in specific settings.” (M. C. Riddle, riddlem@ohsu.edu)

>>>PNN NewsWatch
*
Endo Pharmaceuticals is recalling one lot of Edex (alprostadil for injection) 10 mcg to the consumer level because of a defect in the crimp caps used in the manufacture of the product lot. This defect has the potential to lead to a loss of container closure integrity and thereby result in loss of sterility assurance.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 1, 2017 * Vol. 24, No. 40
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Feb. 28 issue of JAMA (2017; 317).
Antithrombotic Drug Use & Subdural Hematoma: Use of low-dose aspirin, vitamin K antagonists (VKAs), direct oral anticoagulants, and combined antithrombotic drug treatment is associated with increased risk of subdural hematoma, according to analysis of regional and national data from Denmark (pp. 836–46). “The highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug,” the authors conclude. “The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.” Among 5.2 million people in Denmark, 10,010 patients with first-ever subdural hematomas had these implicating factors compared with matched controls: “Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15–1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57–2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31–2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38–4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40–4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49–14.02]).… The largest increase [in incidence] was among older patients (>75 years; n = 4,441) who experienced an increase from 55.1 per 100,000 person–years to 99.7 per 100,000 person–years (P < .001 for trend).” (D. Gaist, dgaist@health.sdu.dk)
Subsequent Neoplasm Risk in Childhood Cancer Survivors: Lower rates of subsequent neoplasms among 23,603 childhood cancer survivors from the 1990s are associated with radiation exposure reduced from 1970s levels, researchers report (pp. 814–24). Analysis of data from pediatric tertiary hospitals in the U.S. and Canada showed these patterns for 1970 through 1999, with follow-up through the end of 2015: “Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for 1990s), as did median dose (30 Gy [interquartile range, 24–44] for 1970s vs 26 Gy [interquartile range, 18–45] for 1990s). Fifteen-year cumulative incidence of subsequent malignancies decreased by decade of diagnosis (2.1% [95% CI, 1.7%–2.4%] for 1970s, 1.7% [95% CI, 1.5%–2.0%] for 1980s, 1.3% [95% CI, 1.1%–1.5%] for 1990s). Reference absolute rates per 1,000 person–years were 1.12 (95% CI, 0.84–1.57) for subsequent malignancies, 0.16 (95% CI, 0.06–0.41) for meningiomas, and 1.71 (95% CI, 0.88–3.33) for nonmelanoma skin cancers for survivors with reference characteristics (no chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years).” (L. M. Turcotte, turc0023@umn.edu)
Early Complications of Type 1 vs. Type 2 Diabetes: In patients diagnosed with diabetes before age 20, those with type 1 conditions have fewer early complications and comorbidities than those with type 2 diabetes, but such problems are common in both patient types, a study shows (pp. 825–35). In 2,018 participants followed from diagnosis in 2002 to 2015, these outcomes were observed in 2011–15: “After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease (odds ratio [OR], 2.58; 95% CI, 1.39–4.81; P=.003), retinopathy (OR, 2.24; 95% CI, 1.11–4.50; P = .02), and peripheral neuropathy (OR, 2.52; 95% CI, 1.43–4.43; P = .001), but no significant difference in the odds of arterial stiffness (OR, 1.07; 95% CI, 0.63–1.84; P = .80) and hypertension (OR, 0.85; 95% CI, 0.50–1.45; P = .55).” (D. Dabelea, dana.dabelea@ucdenver.edu)

>>>PNN NewsWatch
*
FDA on Tuesday approved elotristat ethyl (Xermelo, Lexicon Pharmaceuticals) as the first and only orally administered therapy for treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. The new drug targets overproduction of serotonin by metastatic neuroendocrine tumors. It will be distributed by specialty pharmacies beginning Mar. 6.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 2, 2017 * Vol. 24, No. 41
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 2 issue of the New England Journal of Medicine (2017; 376).
Treatment of Thyroid Deficiency in Pregnancy: Levothyroxine therapy was ineffective for improving offspring cognitive function when administered during pregnancy to mothers with subclinical hypothyroidism or hypothyroxinemia, researchers report (pp. 815–25). Compared with placebo, levothyroxine administered at 8–20 weeks’ gestation produced these outcomes based on children’s IQ at 3–5 years of age or at death in those younger than 3 years: “A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P = 0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P = 0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.” (B. M. Casey, brian.casey@utsouthwestern.edu)
While these findings “indicate that screening and treatment for subclinical hypothyroidism, if performed well into the second trimester of pregnancy, are unlikely to be beneficial,” drug administration at an earlier point in pregnancy remains a reasonable option, editorialists write (
pp. 876–7): “Because more than 75% of women in the United States have their first prenatal visit before 12 weeks of gestation, earlier treatment appears to be feasible. We continue to endorse the recent guidelines of the American Thyroid Association, since the early initiation of low-dose levothyroxine therapy for subclinical hypothyroidism may be of benefit, is inexpensive, and is unlikely to be harmful.” (D. S. Cooper)
Anti–Interleukin-31 Receptor A Antibody for Atopic Dermatitis: Targeting of the interleukin-31 receptor A was effective for reducing pruritus symptoms in 264 patients with moderate-to-severe atopic dermatitis, a phase 2 study shows (pp. 826–35). Based on a primary end point of percentage improved (lowered) scores on the pruritus visual-analogue scale at week 12, subcutaneous nemolizumab every 4–8 weeks showed these results: “At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were −43.7% in the 0.1-mg group, −59.8% in the 0.5-mg group, and −63.1% in the 2.0-mg group, versus −20.9% in the placebo group (P <0.01 for all comparisons). Changes on the [Eczema Area and Severity Index] were −23.0%, −42.3%, and −40.9%, respectively, in the nemolizumab groups, versus −26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were −7.5%, −20.0%, and −19.4% with nemolizumab, versus −15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group.” (T. Ruzicka, thomas.ruzicka@med.uni-muenchen.de)
“New therapies [such as nemolizumab] should be included as part of a comprehensive approach that includes education on skin care and trigger avoidance, psychological support to enhance adherence and reduce itching, and treatment of the already established mental health and sleep disorders,” writes an editorialist (
pp. 878–9). “Data from larger long-term studies and pediatric trials are needed to fully understand how these new agents will fit into the management of atopic dermatitis. It will be important to evaluate how quickly patients have disease flares after stopping the agents and whether the addition of topical agents may provide more effective or longer remission.” (L. C. Schneider)

>>>PNN NewsWatch
*
FDA yesterday approved Odactra (Merck, Sharp & Dohme; Catalent Pharma), the first sublingually administered allergen extract for treatment of house dust mite–induced allergic rhinitis, with or without conjunctivitis, in people 18 through 65 years of age.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 3, 2017 * Vol. 24, No. 42
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source: Mar. issue of Pediatrics (2017; 139).
Improving Adolescent Immunization Rates: Practical approaches for optimizing adolescent immunizations are offered in a clinical report from the American Academy of Pediatrics (AAP; 10.1542/peds.2016-4187): “With the expansion of the adolescent immunization schedule during the past decade, immunization rates notably vary by vaccine and by state. Addressing barriers to improving adolescent vaccination rates is a priority. Every visit can be viewed as an opportunity to update and complete an adolescent’s immunizations. It is essential to continue to focus and refine the appropriate techniques in approaching the adolescent patient and parent in the office setting. Health care providers must continuously strive to educate their patients and develop skills that can help parents and adolescents overcome vaccine hesitancy. Research on strategies to achieve higher vaccination rates is ongoing, and it is important to increase the knowledge and implementation of these strategies. This clinical report focuses on increasing adherence to the universally recommended vaccines in the annual adolescent immunization schedule of the American Academy of Pediatrics, the American Academy of Family Physicians, the Centers for Disease Control and Prevention, and the American Congress of Obstetricians and Gynecologists. This will be accomplished by (1) examining strategies that heighten confidence in immunizations and address patient and parental concerns to promote adolescent immunization and (2) exploring how best to approach the adolescent and family to improve immunization rates.” (H. H. Bernstein)
In an accompanying clinical report, AAP reviews vaccines recommended for administration during the adolescent years and discusses evidence supporting the need for immunization (
10.1542/peds.2016-4186): “The adolescent period heralds the pediatric patient’s transition into adulthood. It is a time of dynamic development during which effective preventive care measures can promote safe behaviors and the development of lifelong health habits. One of the foundations of preventive adolescent health care is timely vaccination, and every visit can be viewed as an opportunity to update and complete an adolescent’s immunizations.” (H. H. Bernstein)
Overdoses Among Children of Mothers Prescribed Opioids: Based on a study showing a “markedly increased risk of overdose” among young children whose mothers are prescribed opioids, researchers conclude, “Physicians, pharmacists, and parents should take measures to mitigate the risk of opioid-related harm to children, such as prescribing smaller quantities, emphasizing the importance of secure medication storage, and the prompt disposal of unused opioids” (10.1542/peds.2016-2887). The study compared 103 children with opioid overdose with 412 matched controls. Results showed: “Children with an opioid overdose were far more likely to have a mother who received a prescription opioid (unadjusted odds ratio, 2.41; 95% confidence interval, 1.68–3.45) and who was prescribed antidepressants. The most commonly implicated overdose opioids were codeine (53.4%), oxycodone (32.0%), and methadone (15.5%).” (Y. Finkelstein)

>>>Psychiatry Highlights
Source: Mar. issue of the American Journal of Psychiatry (2017; 174).
Mood Switch Rates During Acute Bipolar Treatment: Mood switches among patients with bipolar II depression were similar for two commonly used medications in a 16-week study of 142 participants, and combination therapy produced higher discontinuance rates without improvement in responses (pp. 266–76). Random assignment to lithium, sertraline, or both produced these changes in mood at patient visits: “Twenty participants (14%) experienced a switch during the study period (hypomania, N = 17; severe hypomania, N = 3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N = 89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response.” (L. L. Altshuler)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 6, 2017 * Vol. 24, No. 43
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source: Early-release articles from BMJ (2017; 356).
Congenital Heart Defects With SSRI Use During Pregnancy: Use of SSRIs by pregnant women during the cardiogenesis phase of fetal development can lead to congenital heart defects when the mother or child has certain variants in folate, homocysteine, or transsulfuration pathways, a study shows (j832). Using data from the U.S. National Birth Defects Prevention Study on 1,180 liveborn infants with congenital heart defects and 1,644 controls born in 1997–2008, investigators found these correlations of outcomes with single nucleotide polymorphism panels: “For women who reported taking SSRIs periconceptionally, maternal SHMT1 (rs9909104) GG and AG genotypes were associated with a 5.9 and 2.4 increased risk of select congenital heart defects in offspring, respectively, versus the AA genotype ([Bayesian false discovery probabilities (BFDP)] = 0.69). Compared with the AA genotype, BHMT (rs492842 and rs542852) GG and AG genotypes were associated with twice the risk of congenital heart defects (BFDP = 0.74 and 0.79, respectively). MGST1 (rs2075237) CC and AC genotypes were associated with an increased risk compared with the GG genotype (8.0 and 2.8, respectively; BFDP = 0.79). Single nucleotide polymorphism in infant genes in the folate (MTHFS rs12438477), homocysteine (TRDMT1 rs6602178 and GNMT rs11752813) and transsulfuration (GSTP1 rs7941395 and MGST1 rs7294985) pathways were also associated with an increased risk of congenital heart defects.” (W. Nembhard, wnnembhard@uams.edu)
Immunosuppression & Serious Infections During Pregnancy: Among 4,961 pregnant women with systemic inflammatory conditions, use of high-dose steroids is associated with an increased risk of serious infections, while risks are similar among those on steroids, nonbiologic agents, or TNF inhibitors, researchers report (j895). In an observational cohort study based on public and private insurance program data, the authors found: “The crude incidence rates of serious infections per 100 person years among 2,598 steroid users, 1,587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose–response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose = 0.019, P = 0.02).” (R. J. Desai, rdesai@bwh.harvard.edu)
>>>PNN NewsWatch
* In the first
FDA approval of a product for nocturnal polyuria, the agency has OK’d desmopressin acetate (Noctiva; Renaissance Lakewood, Serenity Pharmaceuticals) nasal spray for adults who awaken at least two times per night to urinate. The product carries a boxed warning about severe hyponatremia risk, and a Medication Guide must be dispensed with prescriptions.

>>>PNN JournalWatch
* Neuraminidase Inhibitors During Pregnancy and Risk of Adverse Neonatal Outcomes and Congenital Malformations: Population Based European Register Study, in
BMJ, 2017; 356: j629. (S. Graner, Sofie.graner@ki.se)
* Intra-articular Corticosteroids Versus Intra-articular Corticosteroids Plus Methotrexate in Oligoarticular Juvenile Idiopathic Arthritis: A Multicentre, Prospective, Randomised, Open-Label Trial, in
Lancet, 2017; 389: 909–16. (A. Ravelli, angeloravelli@gaslini.org)
* Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology, in
American Journal of Psychiatry, 2017; 174: 216–29. (O. D. Howes) 
* Treatment of Prescription Opioid Use Disorder in Pregnant Women, in
American Journal of Psychiatry, 2017; 174: 208–14. (C. Guille) 
* Inhaled Corticosteroids and Respiratory Infections in Children With Asthma: A Meta-analysis, in
Pediatrics, 2017; 139: 10.1542/peds.2016-3271. (C. Cazeiro) 
* Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors, in
Pediatrics, 2017; 139: 10.1542/peds.2016-1450. (C. Unegbu) 

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 7, 2017 * Vol. 24, No. 44
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Mar. 7 issue of the Annals of Internal Medicine (2017; 166).
Anakinra in Chronic Fatigue Syndrome: Symptoms of chronic fatigue syndrome (CFS) were not improved by 4 weeks of subcutaneous anakinra therapy, researchers report (10.7326/M16-2391). 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)
Moving Health Care to a Single-Payer System: With the process of repealing and replacing Obamacare under way, authors of an opinion article advocate moving toward a single-payer system as a solution to the high overhead associated with billing and payment under current processes (10.7326/M17-0302): “The president has promised universal coverage and reduced deductibles and copayments, all within tight budgetary constraints. That is a tall order and unlikely to be filled by proposals that Republicans have offered thus far.…
“The economic case for single-payer reform is compelling. Private insurers’ overhead currently averages 12.4% versus 2.2% in traditional Medicare. Reducing overhead to Medicare’s level would save approximately $220 billion this year. Single-payer reform could also sharply reduce billing and paperwork costs for physicians, hospitals, and other providers. For example, by paying hospitals lump-sum operating budgets rather than forcing them to bill per patient, Scotland and Canada have held hospital administrative costs to approximately 12% of their revenue versus 25.3% in the United States. Simplified, uniform billing procedures could reduce the money and time that physicians spend on billing-related documentation.” (S. Woolhandler,
swoolhan@hunter.cuny.edu)
Pay-for-Performance Programs: Paying for performance in health care leads to improved processes but not to better health outcomes, authors of a systematic review conclude (pp. 341–53). Data from 69 studies of pay-for-performance (P4P) programs show the following: “Low-strength evidence suggested that P4P programs in ambulatory settings may improve process-of-care outcomes over the short term (2 to 3 years), whereas data on longer-term effects were limited. Many of the positive studies were conducted in the United Kingdom, where incentives were larger than in the United States. The largest improvements were seen in areas where baseline performance was poor. There was no consistent effect of P4P on intermediate health outcomes (low-strength evidence) and insufficient evidence to characterize any effect on patient health outcomes. In the hospital setting, there was low-strength evidence that P4P had little or no effect on patient health outcomes and a positive effect on reducing hospital readmissions.” (D. Kansagara, kansagar@ohsu.edu)

>>>Health Affairs Highlights
Source: Mar. issue of Health Affairs, a theme issue on Delivery System Innovation (2017; 36).
Value-Based Insurance Design & Med Adherence: Patients with high-deductible health plans require value-based insurance designs to avoid reduced medication adherence, an analysis indicates (pp. 516–23): “We found that the value-based plan offset reductions in medication adherence associated with switching to a deductible plan. The value-based plan appeared particularly beneficial for patients who started with low levels of medication adherence. Patients with additional clinical complexity or vulnerable populations living in neighborhoods with lower socioeconomic status, however, did not show adherence improvements and might not be taking advantage of value-based insurance design provisions.…” (M. E. Reed, mary.e.reed@kp.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 8, 2017 * Vol. 24, No. 45
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 7 issue of JAMA (2017; 317).
Opioid Agonist for Dependence Treatment: Long-term maintenance therapy with methadone or buprenorphine is more effective in patients with dependence than opioid taper or psychological treatments alone, according to a summary of a Cochrane review (pp. 967–8): “For patients who are dependent on prescription opioids, long-term maintenance of opioid agonists is associated with less prescription opioid use and better adherence to medication and psychological therapies for opioid dependence compared with opioid taper or psychological treatments alone. Methadone maintenance was not associated with differences in therapeutic efficacy compared with buprenorphine maintenance treatment. Evidence quality was low to moderate.” (S. Nielsen, suzanne.nielsen@unsw.edu.au)
Diet & Mortality: Many U.S. deaths attributed to heart disease, stroke, or type 2 diabetes are associated with poor diet, according to data from the National Health and Nutrition Examination Surveys for 1999–2002 and 2009–12 (pp. 912–24). Overall, 48.6% of deaths of men from cardiometabolic disease and 41.8% of deaths of women from these causes were associated with suboptimal dietary factors. The pattern held in various age, race/ethnicity, and education subgroups. These patterns were noted for consumption of 10 foods or nutrients that have been associated with cardiometabolic diseases: “The largest numbers of estimated diet-related cardiometabolic deaths were related to high sodium (66,508 deaths in 2012; 9.5% of all cardiometabolic deaths), low nuts/seeds (59,374; 8.5%), high processed meats (57,766; 8.2%), low seafood omega-3 fats (54,626; 7.8%), low vegetables (53,410; 7.6%), low fruits (52,547; 7.5%), and high [sugar-sweetened beverages (SSBs)] (51,694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (−20.8% relative change [95% UI, −18.5% to −22.8%]), nuts/seeds (−18.0% [95% UI, −14.6% to −21.0%]), and excess SSBs (−14.5% [95% UI, −12.0% to −16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]).” (R. Micha, renata.micha@tufts.edu)
“The findings reported by Micha et al appear correct—a substantial proportion of [cardiometabolic disease (CMD)] deaths are associated with suboptimal diet, and improving diet quality could help prevent a large fraction of CMD deaths and reduce health disparities,” conclude editorialists (
pp. 908–9). “There is some precedence, such as from trials of the Mediterranean diet plus supplemental foods, that modification of diet can reduce cardiovascular disease risk by 30% to 70%. Yet estimation of downstream benefits is complex and imprecise. Whether the authors overestimated or underestimated the potential effects of improved diet, the likely benefits are substantial and justify policies designed to improve diet quality.” (N. T. Mueller, noeltmueller@jhu.edu)
Lipoprotein Lipase Gene Variants & Coronary Artery Disease: People with rare, damaging mutations in the gene for lipoprotein lipase (LPL) have an increased risk of higher triglyceride levels and early-onset coronary artery disease (CAD), a study shows (pp. 937–46). Case–control genomic and clinical cohorts showed these associations: “Among 46,891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%–0.46%) carried a damaging mutation in LPL, including 105 of 32,646 control participants (0.32%) and 83 of 14,245 participants with early-onset CAD (0.58%). Compared with 46,703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6–34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35–2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39–1.64; P = 1.1 × 10−22) per 1-SD increase in triglycerides.” (S. Kathiresan, skathiresan1@mgh.harvard.edu)

>>>PNN NewsWatch
*
A&H Focal Inc. is voluntarily recalling all lots marketed as dietary supplements for male sexual enhancement since January 2014 because FDA tests show they contain phosphodiesterase-5 inhibitors.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 9, 2017 * Vol. 24, No. 46
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 9 issue of the New England Journal of Medicine (2017; 376).
Long-Term Imatinib Outcomes in CML: Among patients with newly diagnosed chronic myeloid leukemia (CML), the selective BCR-ABL1 kinase inhibitor imatinib was effective and had no unacceptable cumulative or late toxic effects over 11 years of follow-up, a Novartis-funded study shows (pp. 917–27). The trial, an open-label multicenter crossover study, compared imatinib and interferon alfa plus cytarabine, with these outcomes based on overall survival, response to treatment, and serious adverse events: “The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment.” (A. Hochhaus, andreas.hochhaus@med.uni-jena.de)
“Although the journey to cancer cure has just begun, the use of imatinib to treat CML has pointed oncology in a new direction,” concludes an editorialist (
pp. 982–3). “The development of imatinib fundamentally altered the field of oncology. Priorities shifted from agents that were active on dividing cells to understanding the biology of individual types of cancer. Once genetic analysis of tumors began, nearly all the cancer types had more complex genetic abnormalities than did CML, but the complexity gave rise to a revolution in cancer nosology. We now recognize that the grouping of tumors on the basis of the appearance of a hematoxylin and eosin–stained tissue fragment examined under a light microscope lumps together entities that are distinct both genetically and clinically. Lung cancer is now considered to be at least eight or nine entities, and the number of variants is continuing to expand. That is the good news. The bad news is that the inherent genetic instability of many cancers also facilitates the development of resistance to these interventions. In some instances, new genetic abnormalities create vulnerabilities that can be attacked by new agents.” (D. L. Longo)
Access Problems With Medicaid Expansion: While increased insurance coverage was evident in the second year after 29 states and the District of Columbia expanded Medicaid programs under the Affordable Care Act, wait times for appointments also climbed, researchers report, suggesting persistence of access problems (pp. 947–56). Among 60,766 U.S. adults ages 18–64 years with low incomes, uninsurance rates fell by 8.2 percentage points in expansion states in the second year of increased coverage, compared with nonexpansion states. Rates of Medicaid coverage increased by 15.6 percentage points. Expansion states showed fewer reports of inability to afford needed follow-up care (3.4 percentage points less than nonexpansion states), and reports of worrying about how to pay medical bills dropped by 7.9 percentage points. However, reports of longer wait times climbed by 2.6 percentage points in expansion states, compared with nonexpansion jurisdictions. (S. Miller, amille@umich.edu)

>>>PNN NewsWatch
* Only about one-third of
smokers hospitalized for myocardial infarction and other serious heart conditions received proven smoking-cessation therapy while they were in the hospital, according to research scheduled for presentation at next week’s American College of Cardiology’s 66th Annual Scientific Session. The findings come from a study of 282 U.S. hospitals and 36,675 patients in 2004–14. Of patients who received smoking-cessation therapy, about 20% were given the nicotine patch, which was the most commonly given treatment, and about 10% received professionally delivered smoking-cessation counseling. Few patients received medication or other forms of nicotine replacement therapy such as nicotine gum or lozenges.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 10, 2017 * Vol. 24, No. 47
Providing news and information about medications and their proper use

>>>Chest Highlights
Source: Mar. issue of Chest (2017; 151).
Asthma—Catching Up With the Evidence? In a retrospective cohort study of adolescents and adults with asthma in British Columbia, inappropriate use of short-acting beta-agonists (SABAs) declined over time but increased over the course of the disease, researchers report (pp. 612–8). Examination of the administrative health database for the province showed these trends between 2002 and 2013 for those between ages 15 and 67 years: “Three hundred fifty-six thousand, one hundred twelve patients (56.5% female sex; mean age, 30.5 years) contributed 2.6 million patient-years. In 7.3% of the patient-years, SABAs were prescribed inappropriately. This proportion dropped by a relative rate of 5.3% per year (P <.001). In the first year of asthma, 6.3% of patients had indicators of inappropriate SABA use, which dropped within the first 3 years but increased thereafter. Excessive prescription of SABAs increased rapidly during the time course of asthma (change of 23.3% per year; P <.001) and by age (change of 5.1% per year; P <.001).” (M. Sadatsafavi)
Management of Chronic Hypersensitivity Pneumonitis: Assessed retrospectively for effectiveness in patients with chronic hypersensitivity pneumonitis (cHP), use of either mycophenolate mofetil (MMF) or azathioprine (AZA) was associated with improvements in lung function, a study shows (pp. 619–25). Experiences at four interstitial lung disease centers showed these patterns: “Seventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (Dlco) % predicted were declining at a mean rate of 0.12% (P <.001) and 0.10% (P <.001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in Dlco of 4.2% (P <.001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% (P = .103) and Dlco increased by 3.9% (P < .001).” (J. Morisset)

>>>Cardiology Report
Source: Mar. 14 issue of the Journal of the American College of Cardiology (2017; 69).
Rheumatoid Arthritis & Heart Failure: Patients diagnosed with rheumatoid arthritis (RA) are at increased risk of developing heart failure (HF), a Swedish study shows, with symptoms developing quickly that were not explainable by increased risk of ischemic heart disease (pp. 1275–85). Implicating inflammatory factors associated with RA, investigators found a 25% increased risk of HF that was evident quickly after RA onset. (Ä. Mantel, angla.mantel@ki.se)
“Although effective treatments for heart failure targeting inflammation are at least years away, an immediate clinical implication of the association of rheumatoid arthritis and heart failure is the potential for improved diagnosis of left ventricular dysfunction,” writes an editorialist (
pp. 1286–7; P. Heidenreich).

>>>PNN NewsWatch
* A study of 43,145 men followed for a mean of 3.3 years shows beneficial effects of
phosphodiesterase-5 inhibitors following myocardial infarction (MI). In research scheduled for next week’s American College of Cardiology’s 66th Annual Scientific Session, Andersson et al. found that Swedish men who had prescriptions filled for the erectile dysfunction drugs had a 30% lower all-cause mortality rate and a 36% reduced risk of hospitalization for heart failure after an incident MI.
* Another
ACC presentation reports increased risk of stroke and heart failure among U.S. marijuana users. Kalla et al. studied adults aged 18–55 years with records in the Nationwide Inpatient Sample 2009–10, finding a 10% increased risk of heart failure and 24% increased risk of cerebrovascular accident among cannabis users after correcting for potentially confounding factors.
*
Regeneca Worldwide, division of VivaCeuticals, is conducting a nationwide recall of all of its herbal and dietary supplement products pursuant to a consent decree entered by the federal court for the Central District of California, FDA announced yesterday. This recall applies to all lot numbers produced from June 1, 2011, to Feb. 8, 2017.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 13, 2017 * Vol. 24, No. 48
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Mar. 11 issue of Lancet (2017; 389).
Quarter-Dose Quadpills for Hypertension: In a small trial, quarter-doses of four antihypertensive agents combined in one tablet showed promise for additive effects in the control of high blood pressure, researchers report (pp. 1035–42). Testing irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg, the group found these effects among 21 patients with hypertension: “The placebo-corrected reduction in systolic 24-h blood pressure with the quadpill was 19 mm Hg (95% CI 14–23), and office blood pressure was reduced by 22/13 mm Hg (p <0.0001). During quadpill treatment, 18 (100%) of 18 participants achieved office blood pressure less than 140/90 mm Hg, compared with six (33%) of 18 during placebo treatment (p = 0.0013). There were no serious adverse events and all patients reported that the quadpill was easy to swallow. Our systematic review identified 36 trials (n = 4,721 participants) of one drug at quarter-dose and six trials (n = 312) of two drugs at quarter-dose, against placebo. The pooled placebo-corrected blood pressure-lowering effects were 5/2 mm Hg and 7/5 mm Hg, respectively (both p <0.0001), and there were no side-effects from either regimen.” (C. K. Chow, cchow@georgeinstitute.org.au)
“Obtaining the full public health benefit of polypills will require education, advocacy, endorsement, and implementation by key global agencies such as WHO and national clinical bodies, as well as endorsement from governments,” authors of a related article write (
pp. 1066–74). “The evidence clearly shows polypills improve adherence and cardiovascular disease risk factors for patients with indications for use of polypill components—ie, those with established cardiovascular disease or at high risk. However, the implementation of polypills into clinical practice has many challenges. The clinical trials literature provides insights into the clinical impact of a polypill strategy, including cost-effectiveness, safety of use, substantial improvement in adherence, and better risk factor control than usual care. Despite the clear need for such a strategy and the available clinical data backing up the use of the polypill in different patient populations, challenges to widespread implementation, such as an absence of government reimbursement and poor physician uptake (identified from on the ground experience in countries following commercial rollout), have greatly obstructed real-world implementation.” (R. Webster, rwebster@georgeinstitute.org.au)

>>>BMJ Highlights
Source: Early-release article from BMJ (2017; 356).
Insulin Initiation in Primary Care: A novel, nurse-centered model of care improved insulin initiation rates among patients with type 2 diabetes in a cluster-randomized trial in Australia (j783). The Stepping Up model involved a practice nurse leading insulin initiation and mentoring by registered nurses with diabetes educator credentials, with these results in 266 patients at 74 practices: “HbA1c improved in both arms, with a clinically significant between arm difference (mean difference −0.6%, 95% confidence interval −0.9% to −0.3%), favouring the intervention. At 12 months, in intervention practices, 105/151 (70%) of participants had started insulin, compared with 25/115 (22%) in control practices (odds ratio 8.3, 95% confidence interval 4.5 to 15.4, P <0.001). Target HbA1c (≤7% (53 mmol/mol)) was achieved by 54 (36%) intervention participants and 22 (19%) control participants (odds ratio 2.2, 1.2 to 4.3, P = 0.02). Depressive symptoms did not worsen at 12 months (PHQ-9: −1.1 (3.5) v −0.1 (2.9), P = 0.05).” (J. Furler, j.furler@unimelb.edu.au)

>>>PNN JournalWatch
* 2017 Infectious Diseases Society of America’s Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis, in
Clinical Infectious Diseases, 2017; 64: 701–6. (A. R. Tunkel) 
* The Role of Stewardship in Addressing Antibacterial Resistance: Stewardship and Infection Control Committee of the Antibacterial Resistance Leadership Group, in a special supplement to
Clinical Infectious Diseases, 2017; 64(suppl 1): S36–40. (D. J. Anderson) 
* Improving the Management of COPD in Women, in
Chest, 2017; 151: 686–96. (C. R. Jenkins) 
* Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association, in
Circulation, 2017; 135: e604–33. (A. N. Raval) 

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 14, 2017 * Vol. 24, No. 49
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Mar. issue of JAMA Internal Medicine (2017; 177).
Language & Diabetes Care: Researchers and editorialists examine antidiabetic medication adherence and glycemic control based on language discordance between patients and providers. 
Limited English proficiency (LEP) Latino patients with diabetes were significantly less likely to adhere to newly prescribed antidiabetic agents than other groups, a study shows, including English-speaking Latinos (
pp. 371–9). Observational data from 2006 through 2012 at a large integrated health care delivery system showed that Spanish fluency of the physician and availability of interpreters were insufficient to improve LEP’s primary medication adherence (never dispensed), early-stage persistence (dispensed only once), late-stage persistence (two or more cycles dispensed, but discontinued within 24 months), or inadequate overall medication supply (more than 20% of time with insufficient medication supply during first 24 months). (A. Fernández, alicia.fernandez@ucsf.edu)
A second study, using a pre–post, difference-in-differences design, found that switching LEP Latino patients from language-discordant primary-care providers (PCPs) to language-concordant care improved clinical outcomes (
pp. 380–7). In 2007–13, Kaiser Northern California adult patients with diabetes who identified as Latino had these clinical outcomes based on patient–PCP language concordance: “Overall, 1,605 LEP Latino adults with diabetes (mean [SD] age, 60.5 [13.1] years) were included in this study, and there was a significant net improvement in glycemic and LDL control among patients who switched from language-discordant PCPs to concordant PCPs relative to those who switched from one discordant PCP to another discordant PCP. After adjustment and accounting for secular trends, the prevalence of glycemic control increased by 10% (95% CI, 2% to 17%; P = .01), poor glycemic control decreased by 4% (95% CI, −10% to 2%; P = .16) and LDL control increased by 9% (95% CI, 1% to 17%; P = .03). No significant changes were observed in SBP control. Prevalence of LDL control increased 15% (95% CI, 7% to 24%; P < .001) among LEP Latinos who switched from concordant to discordant PCPs. Risk factor control did not worsen following a PCP switch in any group.” (A. J. Karter, andy.j.karter@kp.org)
“As the US health care system evolves to more accountable care organizations with integrated health systems, care of the most vulnerable must be prioritized,” editorialists write (
pp. 313–5). “Latinos with LEP who have diabetes represent such a population, as evidenced not only by their language status but by their socioeconomic disadvantage. There is a need to integrate greater granularity on social determinants into the medical record to provide more precision patient–clinician interactions. Metrics for our health care system need to include an equity outcome that sets a high bar for the most vulnerable patients. Healthcare outcomes of LEP Latinos with diabetes would be an excellent system measure of health equity.” (E. J. Pérez-Stable, eliseo.perez-stable@nih.gov)
Outcomes Data Imbalance Among Antidiabetic Drugs: FDA requirements for randomized controlled trial data on adverse cardiovascular events for new antidiabetic drugs have created an imbalance in available information, a Viewpoint author writes, such that “there is no longer more evidence for the cardiovascular benefit of metformin than there is for some of the newer second-line drugs” (pp. 301–2): “At what point can newer drugs be used instead of metformin as first-line agents? Although direct comparisons between metformin and newer agents in randomized clinical trials with primary cardiovascular outcomes are the best way to address this question, no such studies are under way, as evidenced by studies that have been registered at clinicaltrials.gov as of November 2016.” (J. Flory, jaf9052@med.cornell.edu)
Better Adult Pneumococcal Vaccine Needed: “A new [pneumococcal] vaccine exclusively for older adults and those who are immunocompromised is needed,” Viewpoint authors suggest (pp. 303–4). “Simply creating a new vaccine with additional serotypes and administering it to both children and adults is unlikely to solve this problem. A compelling solution is to develop a conjugate vaccine for exclusive use in adults while continuing to use PCV13 and PPV23 in children.” (D. M. Weinberger, daniel.weinberger@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 15, 2017 * Vol. 24, No. 50
Providing news and information about medications and their proper use

>>>JAMA Report
Source: Mar. 14 issue of JAMA (2017; 317).
Adequacy of Anticoagulation & Stroke: When ischemic stroke occurs, patients with atrial fibrillation who are adequately anticoagulated have lower odds of developing moderate or severe symptoms and of dying during hospitalization for the event, a study shows (pp. 1057–67). In the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study, retrospective analysis of data from 1,622 hospitals in 2012–15 showed these patterns based on participation in the Get With the Guidelines–Stroke program: “Of 94,474 patients (mean [SD] age, 79.9 [11.0] years; 57.0% women), 7,176 (7.6%) were receiving therapeutic warfarin (international normalized ratio [INR] ≥2) and 8,290 (8.8%) were receiving non–vitamin K antagonist oral anticoagulants (NOACs) preceding the stroke. A total of 79,008 patients (83.6%) were not receiving therapeutic anticoagulation; 12,751 (13.5%) had subtherapeutic warfarin anticoagulation (INR <2) at the time of stroke, 37,674 (39.9%) were receiving antiplatelet therapy only, and 28,583 (30.3%) were not receiving any antithrombotic treatment. Among 91,155 high-risk patients (prestroke CHA2DS2-VASc score ≥2), 76,071 (83.5%) were not receiving therapeutic warfarin or NOACs before stroke. The unadjusted rates of moderate or severe stroke were lower among patients receiving therapeutic warfarin (15.8% [95% CI, 14.8%–16.7%]) and NOACs (17.5% [95% CI, 16.6%–18.4%]) than among those receiving no antithrombotic therapy (27.1% [95% CI, 26.6%–27.7%]), antiplatelet therapy only (24.8% [95% CI, 24.3%–25.3%]), or subtherapeutic warfarin (25.8% [95% CI, 25.0%–26.6%]); unadjusted rates of in-hospital mortality also were lower for those receiving therapeutic warfarin (6.4% [95% CI, 5.8%–7.0%]) and NOACs (6.3% [95% CI, 5.7%–6.8%]) compared with those receiving no antithrombotic therapy (9.3% [95% CI, 8.9%–9.6%]), antiplatelet therapy only (8.1% [95% CI, 7.8%–8.3%]), or subtherapeutic warfarin (8.8% [95% CI, 8.3%–9.3%]). After adjusting for potential confounders, compared with no antithrombotic treatment, preceding use of therapeutic warfarin, NOACs, or antiplatelet therapy was associated with lower odds of moderate or severe stroke (adjusted odds ratio [95% CI], 0.56 [0.51–0.60], 0.65 [0.61–0.71], and 0.88 [0.84–0.92], respectively) and in-hospital mortality (adjusted odds ratio [95% CI], 0.75 [0.67–0.85], 0.79 [0.72–0.88], and 0.83 [0.78–0.88], respectively).” (Y. Xian, ying.xian@duke.edu)
Getting to Goal in Type 2 Diabetes: “Patient-centered diabetes management can be accomplished with lifestyle modification and combination therapy,” write the authors of a Viewpoint on managing type 2 diabetes in 2017 (pp. 1015–6). “Metformin is an optimal first-line agent; newer GLP1 and SGLT2 agents have efficacy for glucose lowering coupled with weight loss and potential cardiovascular risk reduction; and insulin therapy is generally safe and effective for patients not controlled with noninsulin agents. In younger, healthy, newly diagnosed patients, a hemoglobin A1c level less than 7% should be the goal; in older individuals with comorbidities, less stringent goals with a focus on safety and avoidance of hypoglycemia are critical. Antihyperglycemic therapy should be combined with evidence-based treatment of cholesterol and blood pressure for cardiovascular risk reduction. Although the cardiovascular benefits of SGLT2 and GLP1 agents merit consideration, these medications are not replacements for statin therapy or blood pressure management for reducing the risk of cardiovascular disease.” (J. E. Manson, jmanson@rics.bwh.harvard.edu)
Efficacy Endpoints in Diabetes Studies: Achieving glycemic control in patients with type 2 diabetes is not a valid predictor of reduced risk of complications of the disease, according to Viewpoint authors who argue for use of heart disease and mortality outcomes in studies of the disease (pp. 1017–8; H. M. Krumholz, harlan.krumholz@yale.edu).

>>>PNN NewsWatch
* A U.S. district judge yesterday entered a consent decree of permanent injunction against
EonNutra LLC, CDSM LLC and HABW LLC, manufacturers and distributors of unapproved drugs and dietary supplements, and their owner, Michael Floren, requiring Floren’s businesses to immediately cease operations until they come into compliance with federal laws, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, 3100 1st St. N., Arlington, VA 22201; 571/970-5533 or 844/270-0717 (fax). Copyright © 2017, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Mar. 16, 2017 * Vol. 24, No. 51
Providing news and information about medications and their proper use

>>>NEJM Report
Source: Mar. 16 issue of the New England Journal of Medicine (2017; 376).
Pembrolizumab in Advanced Urothelial Carcinoma: Used as second-line therapy in 542 patients with platinum-refractory advanced urothelial carcinoma, pembrolizumab extended overall survival by approximately 3 months with a lower rate of treatment-related adverse events, compared with chemotherapy, the KEYNOTE-045 trial shows (p