Jun 2014

PNN April–June 2014

PNN Pharmacotherapy Line
Apr. 1, 2014 * Vol. 21, No. 62
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 1 issue of the Annals of Internal Medicine (2014; 160).
Medication Nonadherence in Primary Care: Lower drug costs and copayments and increased prescriber follow-up could help reduce primary nonadherence (not filling a prescription within 9 months) to chronic medications, researchers conclude based on a study of 15,961 patients in Quebec (pp. 441–50). Analysis of electronic health records in primary care network of 131 physicians showed the following: “Overall, 31.3% of the 37,506 incident prescriptions written for the 15,961 patients were not filled. Drugs in the upper quartile of cost were least likely to be filled (odds ratio [OR], 1.11 [95% CI, 1.07 to 1.17]), as were skin agents, gastrointestinal drugs, and autonomic drugs, compared with anti-infectives. Reduced odds of nonadherence were associated with increasing patient age (OR per 10 years, 0.89 [CI, 0.85 to 0.92]), elimination of prescription copayments for low-income groups (OR, 0.37 [CI, 0.32 to 0.41]), and a greater proportion of all physician visits with the prescribing physician (OR per 0.5 increase, 0.77 [CI, 0.70 to 0.85]).” (R. Tamblyn, robyn.tamblyn@mcgill.ca)
Intensified Lipid-Lowering Choices: In high-risk patients with elevated lipids for whom high-dose statins are effective or acceptable, a lower-dose statin regimen plus bile acid sequestrant is a reasonable alternative, according to authors of a systematic review previously reported in PNN (see Feb. 25; pp. 468–76). This approach should be used with caution since long-term evidence of benefits and harms is lacking, the group writes based on a review of 36 trials: “Low-intensity statin plus bile acid sequestrant decreases LDL cholesterol 0% to 14% more than does mid-intensity monotherapy among high-risk hyperlipidemic patients. Mid-intensity statin plus ezetimibe decreases LDL cholesterol 5% to 15% and 3% to 21% more than does high-intensity monotherapy among patients with [atherosclerotic cardiovascular disease] and diabetes mellitus, respectively. Evidence was insufficient to evaluate LDL cholesterol for fibrates, niacin, and omega-3 fatty acids. Evidence was insufficient for long-term clinical outcomes, adherence, and harms for all regimens.” (K. Gudzune, gudzune@jhu.edu)
Research Priorities in Adolescent/Young Adult Bipolar Disorder: Three areas are identified for research into bipolar disorder in adolescent and young adult patients (pp. 492–8): “Despite a paucity of high-quality evidence about benefits and harms, antipsychotic medication use among adolescents and young adults with bipolar disorder is increasing. The Patient-Centered Outcomes Research Institute tasked the Duke Evidence Synthesis Group with creating a prioritized agenda for research in this area that would incorporate the perspectives of relevant stakeholders. We identified a list of potential evidence gaps by reviewing existing literature and engaged a diverse group of 9 stakeholders to expand and refine this list. Using a forced-ranking prioritization method, stakeholders prioritized 10 of 23 potential evidence gaps as the most pressing for future research. These evidence gaps relate to 3 areas: the comparative effectiveness of intervention strategies, the effect of antipsychotics on patient-centered outcomes, and the influence of various patient characteristics on antipsychotic effectiveness. In addition to presenting these findings, we suggest appropriate study designs for addressing the stakeholder-prioritized research questions.” (G. D. Sanders, gillian.sanders@duke.edu)

>>>PNN NewsWatch
* FDA yesterday clarified its previous recommendation related to prescribing sildenafil (Revatio, Pfizer) for children with pulmonary arterial hypertension (the product is approved for use in adults but not children): “FDA revised the Revatio drug label in August 2012, adding a warning stating that ‘use of Revatio, particularly chronic use, is not recommended in children.’ This recommendation was based on an observation of increasing mortality with increasing Revatio doses in a long-term clinical trial in pediatric patients with [pulmonary arterial hypertension]. FDA issued a Drug Safety Communication at that time. There may be situations in which the benefit–risk profile of Revatio may be acceptable in individual children, for example, when other treatment options are limited and Revatio can be used with close monitoring.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 2, 2014 * Vol. 21, No. 63
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 2 issue of JAMA (2014; 311).
Tadalafil for Erectile Dysfunction Prevention After Prostate Cancer Radiotherapy: Compared with placebo, tadalafil had no effect on development of erectile dysfunction in 242 men undergoing radiotherapy for prostate cancer, researchers report (pp. 1300–7). At 76 sites in the U.S. and Canada, tadalafil 5 mg daily or placebo produced these outcomes based on participant and partner ratings of sexual function: “Among 221 evaluable participants, 80 (79%; 95% CI, 70%–88%) assigned to receive tadalafil retained erectile function between weeks 28 and 30 compared with 61 (74%; 95% CI, 63%–85%) assigned to receive placebo (P = .49); an absolute difference of 5% (95% CI, −9% to 19%). A significant difference was also not observed at 1 year (72%; 95% CI, 60%–84% vs 71%; 95% CI, 59%–84%; P = .93). Tadalafil was not associated with significantly improved overall sexual function or satisfaction; a significant difference was not observed in any domain subscale. Partners of men assigned tadalafil noted no significant effect on sexual satisfaction, and marital adjustment was not significantly improved in participants or partners.” (T. M. Pisansky, pisansky.thomas@mayo.edu)
Sepsis-Related Mortality in Critically Ill Patients: While the factors driving the change are unclear, mortality decreased from 2000 to 2012 among critically ill patients who had severe sepsis with or without shock in Australia and New Zealand, according to findings of a retrospective, observational study (pp. 1308–16). “Although no single explanation can be offered for our findings, they challenge the view that little progress has been made in the management of severe sepsis,” the authors conclude. “They also suggest that outcomes for severe sepsis should be interpreted according to the year of data collection and that, on average, a yearly 1% improvement in crude mortality can be expected.” Analysis of the records of 101,064 patients in 171 intensive-care units (ICUs) yielded these results: “Absolute mortality in severe sepsis decreased from 35.0% (95% CI, 33.2%–36.8%; 949/2708) to 18.4% (95% CI, 17.8%–19.0%; 2300/12 512; P < .001), representing an overall decrease of 16.7% (95% CI, 14.8%–18.6%), an annual rate of absolute decrease of 1.3%, and a relative risk reduction of 47.5% (95% CI, 44.1%–50.8%). After adjusted analysis, mortality decreased throughout the study period with an odds ratio (OR) of 0.49 (95% CI, 0.46–0.52) in 2012, using the year 2000 as the reference (P < .001). The annual decline in mortality did not differ significantly between patients with severe sepsis and those with all other diagnoses (OR, 0.94 [95% CI, 0.94–0.95] vs 0.94 [95% CI, 0.94–0.94]; P = .37). The annual increase in rates of discharge to home was significantly greater in patients with severe sepsis compared with all other diagnoses (OR, 1.03 [95% CI, 1.02–1.03] vs 1.01 [95% CI, 1.01–1.01]; P < .001). Conversely, the annual increase in the rate of patients discharged to rehabilitation facilities was significantly less in severe sepsis compared with all other diagnoses (OR, 1.08 [95% CI, 1.07–1.09] vs 1.09 [95% CI, 1.09–1.10]; P < .001). In the absence of comorbidities and older age, mortality was less than 5%.” (R. Bellomo, rinaldo.bellomo@austin.org.au)
While these findings are not solely the result of “stage migration” (also known as the Will Rogers phenomenon), editorialists note that “short-term mortality has declined to a level at which it no longer reflects the entire story of outcomes for patients with severe sepsis” (
pp. 1295–7): “Although the reduction in sepsis-related mortality is welcome, it makes the need for data on morbidity and longer-term outcomes all the more pressing.… Critical care is improving for patients with severe sepsis and throughout the ICU, and clinicians and researchers must raise the standards and broaden measurement to continue such progress.” (T. J. Iwashyna, tiwashyn@umich.edu)

>>>PNN NewsWatch
* Provider status was the talk of APhA2014, according to numerous news reports about the conference posted on pharmacist.com. One article, describing the keynote address of APhA’s Executive Vice President/CEO Tom Menighan, notes: “Pharmacy is united, Menighan said. The Patient Access to Pharmacists’ Care Coalition, of which APhA is a member, ‘is growing, and very focused on the federal ask.’”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 3, 2014 * Vol. 21, No. 64
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 3 issue of the New England Journal of Medicine (2014; 370).
Postpartum Thrombosis Events: Women have higher risks of thrombosis between 7 and 12 weeks after delivery, but the absolute risk is low, according to a study of claims data from California (pp. 1307–15). Between 2005 and 2010, women hospitalized for labor and delivery had these outcomes: “Among the 1,687,930 women with a first recorded delivery, 1,015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery.” (H. Kamel, hok9010@med.cornell.edu)
Hyperimmune Globulin for Congenital CMV Prophylaxis: In a Phase II trial, hyperimmune globulin administered to 124 pregnant women did not affect the rate of congenital cytomegalovirus (CMV) infection in offspring as diagnosed at birth or by amniocentesis, researchers report (pp. 1316–26). Study participants had primary CMV infection at 5–26 weeks’ gestation. Hyperimmune globulin or placebo was administered every 4 weeks until 36 weeks’ gestation or detection of CMV in amniotic fluid, with these results: “A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, −3 to 31; P = 0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell–mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%).” (M. G. Revello, mg.revello@smatteo.pv.it)
Lessons From the 2009 Influenza Pandemic: “Influenza outbreaks and pandemics will continue to challenge policymakers and public health leaders to make decisions under conditions of stress and uncertainty,” conclude authors who review pandemic preparedness and response during the spike in H1N1 influenza infections during 2009 (pp. 1335–42). Here is their assessment of pharmacotherapeutic options: “In addition to superior surveillance and agreements on virus and vaccine sharing, the world needs better antiviral agents and more effective influenza vaccines, greater production capacity, and faster throughput. One comprehensive assessment showed that the effectiveness of current influenza vaccines in practice is lower than is typically asserted, especially among elderly persons. The traditional methods of influenza-vaccine production, which rely on egg cultures, are often too slow to keep up with a first wave of pandemic spread, and in total, the annual capacity of influenza-vaccine production covers less than one third of the global population.
“In early 2013, the Food and Drug Administration approved the first trivalent influenza vaccine produced with the use of recombinant technology, and other production methods are under active research and development. At least four lower-income countries have their own influenza-vaccine manufacturing facilities, and more are on the way. Most important, if research could yield a universal (non–strain-specific), long-lasting, safe, and effective vaccine against influenza, the annual frenzy of action against influenza would be transformed into a proactive, long-term prevention program.” (H. V. Fineberg,
fineberg@nas.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 4, 2014 * Vol. 21, No. 65
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Vancomycin-Associated Nephrotoxicity: Among adult internal medicine patients, vancomycin-associated nephrotoxicity (VAN) is common, and risks are elevated significantly with concomitant piperacillin–tazobactam, a study shows (10.1002/phar.1423). In this retrospective cohort analysis, 125 patients with mean baseline creatinine clearance of 84.6 mL/min had these outcomes after receiving vancomycin for 72 hours or more: “Nephrotoxicity, defined as an increase in serum creatinine of 0.5 mg/dl or 50% above baseline (whichever was larger), occurred in 17 (13.6%) of 125 patients. No patients with VAN progressed to Loss or End stage as defined by the RIFLE criteria. The incidence rate of VAN was 0.02 cases/day of vancomycin treatment. Nephrotoxicity developed at a median of 4.5 days (interquartile range [IQR] 2.2–4.9) peaked at 5.7 days (IQR: 3.8–9.6), and resolved in 70.6% of the cases within 16.5 days (IQR: 6.0–17.8) after onset. On multivariable logistic regression analysis, after controlling for hypotensive episodes, Charlson Comorbidity Index, and baseline creatinine clearance, concomitant use of piperacillin–tazobactam was associated with increased VAN (adjusted odds ratio 5.36, 95% confidence interval 1.41–20.5).” (L. Hynicka, lhynicka@rx.umaryland.edu)
Tacrolimus Absorption With Topical Administration: Used topically for treatment of cutaneous manifestations of graft-versus-host disease (GVHD) for rapid, symptomatic relief of pruritus and erythema, tacrolimus was absorbed extensively in two patients when occlusive dressings were used, authors report, leading to toxic levels of the macrolide immunosuppressant (10.1002/phar.1418): “The first patient was a 62-year-old woman with a history of acute myelogenous leukemia (AML) who underwent allogeneic bone marrow transplantation and developed chronic GVHD involving 70% of her body surface area. Her GVHD treatment plan consisted of oral corticosteroids, oral tacrolimus, topical corticosteroids, topical tacrolimus 0.1% ointment twice/day, emollient creams, intravenous rituximab, and photopheresis. The patient’s tacrolimus trough levels rose rapidly over the course of 6 days from less than 2 ng/ml to 23 ng/ml, despite oral tacrolimus dosage adjustments. The second patient was a 25-year-old man who developed severe, chronic skin GVHD after undergoing allogeneic sibling bone marrow transplantation for AML. In addition to intravenous corticosteroids, corticosteroid creams, and oral tacrolimus, the patient also received topical tacrolimus twice/day with occlusive dressings. Over the course of 2 days, his tacrolimus trough levels increased from 7.10 ng/ml to 22.10 ng/ml. Although improvement was noted in both patients’ skin GVHD with application of the occlusive dressings, the practice was discontinued due to increased and erratic systemic tacrolimus absorption.… Based on the findings from our two patients as well as published case reports, systemic absorption appears to increase with greater skin permeability, skin barrier dysfunction, amount of body surface area applied, and use of occlusive dressings. When one or more of these factors are present, it may be prudent to monitor tacrolimus levels.” (K. West, Kathleen.west@roswellpark.org)

>>>PNN NewsWatch
* FDA yesterday approved a new handheld naloxone autoinjector (Evzio, kaléo) that can be used by family members or caregivers to treat a person known or suspected to have had an opioid overdose. The device can be used for intramuscular or subcutaneous administration of naloxone, and repeat doses may be needed. Once turned on, Evzio provides oral instructions about how to deliver the medication.
*
FDA also yesterday allowed marketing of an expandable, multisponge wound dressing to control the bleeding from certain types of wounds received in battle. For military use only, the XSTAT (RevMedX) is a temporary dressing for wounds in areas that a tourniquet cannot be placed, such as the groin or armpit. The dressing can be used up to 4 hours, which could allow time for the patient to receive surgical care, FDA said. The device consists of three, syringe-style applicators containing 92 compressed, cellulose sponges with absorbent coatings. After 20 seconds of contact with water from blood or body fluids, the sponges expand and swell to fill the wound cavity.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 7, 2014 * Vol. 21, No. 66
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Vitamin D & Mortality, Health Outcomes: A pair of systematic reviews/meta-analyses examine clinical benefits of dietary and supplemental vitamin D in observational studies and randomized trials.
Reduced mortality is evident with higher levels of circulating 25-hydroxyvitamin D, one study shows, but the optimal dose and duration of supplementation is not yet clear (
g1903). Based on 73 cohort studies with 849,412 participants and 22 randomized controlled trials with 30,716 participants, the investigators found these effects on mortality outcomes: “In the primary prevention observational studies, comparing bottom versus top thirds of baseline circulating 25-hydroxyvitamin D distribution, pooled relative risks were 1.35 (95% confidence interval 1.13 to 1.61) for death from cardiovascular disease, 1.14 (1.01 to 1.29) for death from cancer, 1.30 (1.07 to 1.59) for non-vascular, non-cancer death, and 1.35 (1.22 to 1.49) for all cause mortality. Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements. In randomised controlled trials, relative risks for all cause mortality were 0.89 (0.80 to 0.99) for vitamin D3 supplementation and 1.04 (0.97 to 1.11) for vitamin D2 supplementation. The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics. However, for vitamin D2 supplementation, increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods.” (R. Chowdhury, rajiv.chowdhury@phpc.cam.ac.uk)
While “associations with a selection of outcomes are probable,” authors of an umbrella review find that “highly convincing evidence of a clear role of vitamin D does not exist for any outcome” (
g2035). The researchers examined 107 systematic reviews and 74 meta-analyses of observational studies that looked for associations between vitamin D concentrations and health outcomes and 87 randomized controlled trials of vitamin D supplementation, with these results: “The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people.” (E. Theodoratou, e.theodoratou@ed.ac.uk)

>>>PNN JournalWatch
* Antidepressant-Induced Liver Injury: A Review for Clinicians, in
American Journal of Psychiatry, 2014; 171: 404–15. (G. Perlemuter, gabriel.perlemuter@abc.aphp.fr)
* Toward Personalized Medicine in the Pharmacotherapy of Alcohol Use Disorder: Targeting Patient Genes and Patient Goals, in
American Journal of Psychiatry, 2014; 171: 391–4. (S. L. Batki, steven.batki@ucsf.edu)
* Improving Immunization Rates in a Hospital-Based Primary Care Practice, in
Pediatrics, 2014; 133: e1047–e1054. (C. J. Bottino)
* Proposal for a Functional Classification System of Heart Failure in Patients With End-Stage Renal Disease: Proceedings of the Acute Dialysis Quality Initiative (ADQI) XI Workgroup, in
Journal of the American College of Cardiology, 2014; 63: 1246–52. (L. S. Chawla)
* National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation, in
Circulation, 2014; 129: 1407–14. (J. S. Dlott, Jeffrey.S.Dlott@QuestDiagnostics.com)
* The Intelligent Use of Digital Tools and Social Media in Practice Management, in
Chest, 2014; 145: 896–902. (C. L. Carroll, ccarrol@connecticutchildrens.org)
* Review of Tolvaptan for Autosomal Dominant Polycystic Kidney Disease, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1421. (C. J. Meaney, cjmeaney@buffalo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 8, 2014 * Vol. 21, No. 67
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. issue of JAMA Internal Medicine (2014; 174).
Acid Blockers & Infectious Complications in ICU: In mechanically ventilated patients in intensive-care units (ICUs), use of proton-pump inhibitors (PPIs) is associated with greater risk of gastrointestinal (GI) hemorrhage, pneumonia, and Clostridium difficile infection (CDI) than is use of histamine-2 receptor antagonists (H2RAs), researchers report (pp. 564–74). In 71 hospitals in 2003–08, patients who required mechanical ventilation for 24 hours or more and who received PPIs or H2RAs had these outcomes in a pharmacoepidemiologic cohort study: “Of 35,312 patients, 13,439 (38.1%) received H2RAs and 21,873 (61.9%) received PPIs. Gastrointestinal hemorrhage (2.1% vs 5.9%; P < .001), pneumonia (27% vs 38.6%; P < .001), and CDI (2.2% vs 3.8%; P < .001) occurred less frequently in the H2RA group. After adjusting for propensity score and covariates, odds ratios of GI hemorrhage (2.24; 95% CI, 1.81–2.76), pneumonia (1.2; 95% CI, 1.03–1.41), and CDI (1.29; 95% CI, 1.04–1.64) were greater with PPIs. Similar results were obtained in the propensity-matched models of 8,799 patients in each cohort.” (R. MacLaren, rob.maclaren@ucdenver.edu)
These conclusions are the opposite of those reached in a recent systematic review and meta-analysis, editorialists note in reaching the following conclusion (
pp. 574–6): “While well-designed randomized clinical trials remain the gold standard for determining efficacy, observational cohort studies provide key insights into clinical effectiveness in real-world settings. The primary challenges to interpreting the results of MacLaren and colleagues is the absence of a clear biologic model to explain the results and the potential for persistent indication bias away from the null hypothesis. Additional studies will be needed to determine if the increased risk of pneumonia, CDI, and acute GI hemorrhage in mechanically ventilated patients in this study is due to the administration of a PPI instead of an H2RA or a result of residual indication bias.” (C. H. Goss, goss@u.washington.edu)
Antihypertensive Medications & Falls in Older Adults: Continuation of antihypertensive medications in older adults, particularly those who have been injured in the past from falls, should be re-evaluated with attention to potential harms versus benefits, a study concludes (pp. 588–95). In a competing risk analysis of a nationally representative Medicare Current Beneficiary Cohort during 3-year follow-up through 2009, these outcomes were noted for community-living adults older than 70 years with hypertension: “Of the 4,961 participants, 14.1% received no antihypertensive medications; 54.6% were in the moderate-intensity and 31.3% in the high-intensity antihypertensive groups. During follow-up, 446 participants (9.0%) experienced serious fall injuries, and 837 (16.9%) died. The adjusted hazard ratios for serious fall injury were 1.40 (95% CI, 1.03–1.90) in the moderate-intensity and 1.28 (95% CI, 0.91–1.80) in the high-intensity antihypertensive groups compared with nonusers. Although the difference in adjusted hazard ratios across the groups did not reach statistical significance, results were similar in the propensity score–matched subcohort. Among 503 participants with a previous fall injury, the adjusted hazard ratios were 2.17 (95% CI, 0.98–4.80) for the moderate-intensity and 2.31 (95% CI, 1.01–5.29) for the high-intensity antihypertensive groups.” (M. E. Tinetti, mary.tinetti@yale.edu)
Risks of Compounded Drugs: Reacting to a research letter that reports a hospital system’s response to discovery of mold contamination in an intravenous magnesium sulfate infusion prepared by a compounding pharmacy (pp. 630–1; J. M. Boyce, John.Boyce@ynhh.org), an editorialist summarizes the recently enacted Drug Quality and Secuity Act and describes what measures FDA, USP, institutions, and health professionals can take to “contribute to the success of the new category of FDA-approved outsourcing facilities” (pp. 613–4; A. Coukell, ACoukell@pewtrusts.org).

>>>PNN NewsWatch
* Consumers should immediately stop using Zi Xiu Tang Bee Pollen, marketed as a product for weight loss and body reshaping, FDA said yesterday. Products tested by the agency, including some claiming to be “genuine” and “anti-counterfeit,” have been found to contain sibutramine and/or phenolphthalein.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 9, 2014 * Vol. 21, No. 68
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 9 issue of JAMA (2014; 311).
Validation of Atherosclerotic CVD Risk Equations: Risk equations at the center of the controversy over the recently released cardiovascular disease (CVD) risk equations are “well calibrated in the population for which they were designed to be used,” a study shows (pp. 1406–15). Data collected at enrollment of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study in 2003–07 and at follow up through 2010 were used to test the equations. Among 10,997 participants for whom a statin-initiation discussion would be triggered based on equation-estimated risks of CVD outcomes (nonfatal myocardial infarction, coronary heart disease [CHD] death, nonfatal or fatal stroke) during the observation period: “There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year atherosclerotic CVD incidence per 1,000 person–years for participants with a 10-year predicted atherosclerotic CVD risk of less than 5% was 1.9 (95% CI, 1.3–2.7) and 1.9, respectively, risk of 5% to less than 7.5% was 4.8 (95% CI, 3.4–6.7) and 4.8, risk of 7.5% to less than 10% was 6.1 (95% CI, 4.4–8.6) and 6.9, and risk of 10% or greater was 12.0 (95% CI, 10.6–13.6) and 15.1 (Hosmer–Lemeshow chi square = 19.9, P = .01). The C index was 0.72 (95% CI, 0.70–0.75). There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year atherosclerotic CVD incidence per 1,000 person–years for participants with a predicted risk of less than 7.5% was 5.3 (95% CI, 2.8–10.1) and 4.0, respectively, risk of 7.5% to less than 10% was 7.9 (95% CI, 4.6–13.5) and 6.4, and risk of 10% or greater was 17.4 (95% CI, 15.3–19.8) and 16.4 (Hosmer–Lemeshow chi square = 5.4, P = .71). The C index was 0.67 (95% CI, 0.64–0.71).” (P. Muntner, pmuntner@uab.edu)
American Adults Affected by 2014 Hypertension Guideline: Fewer patients will need antihypertensive therapy and more patients diagnosed with hypertension will be categorized as achieving blood pressure goals under the recently released blood pressure guideline, according to analysis of data from the National Health and Nutrition Examination Survey in 2005–10 (pp. 1424–9). Among 16,372 patients in the nationally representative sample, proportions of patients in various categories under the 2014 and the older Seventh Joint National Committee (JNC 7) guidelines were as follows: “The proportion of younger adults (18–59 years) with treatment-eligible hypertension under the JNC 7 guideline was 20.3% (95% CI, 19.1%–21.4%) and decreased to 19.2% (95% CI, 18.1%–20.4%) under the 2014 BP guideline. Larger declines were observed among older adults (≥60 years), decreasing from 68.9% (95% CI, 66.9%–70.8%) under JNC 7 to 61.2% (95% CI, 59.3%–63.0%) under the 2014 BP guideline. The proportion of adults with treatment-eligible hypertension who met BP goals increased slightly for younger adults, from 41.2% (95% CI, 38.1%–44.3%) under JNC 7 to 47.5% (95% CI, 44.4%–50.6%) under the 2014 BP guideline, and more substantially for older adults, from 40.0% (95% CI, 37.8%–42.3%) under JNC 7 to 65.8% (95% CI, 63.7%–67.9%) under the 2014 BP guideline. Overall, 1.6% (95% CI, 1.3%–1.9%) of US adults aged 18–59 years and 27.6% (95% CI, 25.9%–29.3%) of adults aged 60 years or older were receiving BP-lowering medication and meeting more stringent JNC 7 targets. These patients may be eligible for less stringent or no BP therapy with the 2014 BP guideline.” (A. M. Navar–Boggan, ann.navar@duke.edu)
Reflecting on both of the above studies, an editorialist considers “the path forward” with respect to cholesterol and blood pressure management (
pp. 1403–5): “These guidelines, with their innovations and controversy, have established a new course. Navigating it may be uncomfortable and will perhaps force clinicians to grapple with issues that have been ignored for too long. While it is important to advocate for health and promote healthy environments and behaviors on the broader scale, for medical decision making, it is even more important to ensure informed choice with the full participation of the person who will incur the risks and benefits of the decision. When viewed through this lens, the controversies about the guidelines become less contentious and the focus shifts to refining the evidence and producing better ways to communicate what is known for decision-making purposes.” (H. M. Krumholz, harlan.krumholz@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 10, 2014 * Vol. 21, No. 69
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Articles released early by the New England Journal of Medicine in conjunction with the 49th annual International Liver Congress 2014 in London (2014; 370).
Curative HCV Therapy: In a Phase III trial of patients with hepatitis C virus (HCV) genotype 1 infection whose conditions had not responded to prior therapies, a 12-week, interferon-free regimen of ABT-450 with ritonavir, ombitasvir, dasabuvir, and ribavirin produced responses in more than 95% of patients, according to an article released this morning (10.1056/NEJMoa1401561). Based on a primary end point of rate of sustained virologic response 12 weeks after the end of study treatment, the investigators report these results: “A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P = 0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively.” (S. Zeuzem, zeuzem@em.uni-frankfurt.de)
Given the difficulties in developing an effective HCV vaccine, eradication is the main hope for stopping this virus, authors of a Commentary write (
10.1056/NEJMp1400986). That may be feasible, the writers continue, if three challenges can be overcome: “First, in the absence of effective screening programs, HCV infection is often diagnosed at a late stage (in high-income countries) or seldom diagnosed at all (in low- or middle-income countries). Second, the high cost of [direct-acting antiviral agents (DAAs)] will preclude their use in most infected patients in low- or middle-income countries; in high-income countries, the need for payers to provide major resources for HCV treatment may lead to the selective use of DAAs for certain patient subgroups. Third, reinfection remains possible even after successful curative therapy.” (R. T. Chung)
Other writers note the “onerous charge” that funding agencies are ignoring the availability of “definitive, curative therapies” for an infectious disease while directing large amounts of money to HIV and other infections (
10.1056/NEJMp1400160): “HCV prevalence is five times that of HIV, and a large proportion of infected people remain unaware of their status — one of several challenges to the expansion of access to DAA therapy. It may be necessary to initially target higher-prevalence countries and prioritize higher-risk groups, such as patients with advanced liver fibrosis, cirrhosis, and HIV or hepatitis B coinfection. The greatest challenge, however, may stem from poor global advocacy, perhaps due in part to a false perception of the indolent course of HCV. The global mortality burden of viral hepatitis (A, B, C, and E) is similar to that of HIV and higher than that of tuberculosis or malaria, but the difference in the political and social climate surrounding these infections could not be starker. For example, the Global Fund to Fight AIDS, Tuberculosis, and Malaria received almost $30 billion in pledges between 2002 and 2015, whereas no dedicated international agencies or well-funded, broad-based campaigns exist for eradication of viral hepatitis. In contrast to the groundswell of HIV activism, HIV’s place in the United Nations Millennium Declaration in 2000, and consequent public health ‘exceptionalism’ — which led to impressive gains — there have been few calls to list DAAs as essential medicines, create nimbler fund-raising mechanisms, or engage low- and middle-income countries that stand to benefit from these developments.” (C. R. Jayasekera)

>>>PNN NewsWatch
* Recent blogs on the FDA website recognize the Alzheimer’s Association and “those who strive to vanquish” this disease and a description of efforts by the director of the Center for Tobacco Products to connect with the cancer-research community.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 11, 2014 * Vol. 21, No. 70
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (2014; 145).
ACE Inhibitors & Pulmonary Function Decline in Smokers: In patients who have ever smoked, risks of developing chronic obstructive pulmonary disease (COPD) are higher during periods of rapid decline in lung function, but the decline is attenuated by use of ACE inhibitors, researchers report (pp. 695–703). In the longitudinal Lovelace Smokers Cohort, 1,170 ever smokers were followed over a median of 5.9 years; 809 patients had no spirometric abnormalities at bedtime. Based on postbronchodilator FEV1 measurements over all examinations and annualized as rapid, normal, or no decline, the investigators found: “Approximately 32% of ever smokers exhibited rapid decline. Among ever smokers without a baseline spirometric abnormality, rapid decline was associated with an increased risk for incident COPD (OR, 1.88; P = .003). The use of … ACE inhibitors at baseline examination was protective against rapid decline, particularly among those with comorbid cardiovascular disease, hypertension, or diabetes (ORs 0.48, 0.48, and 0.12, respectively; P ≤ .02 for all analyses).” (H. Petersen, hpeterse@lrri.org)
“The message from this article is that before the development and diagnosis of COPD, there is a period of rapid FEV
1 decline in ever smokers,” editorialists write (pp. 671–2). Describing the beneficial effects of ACE inhibitors as “intriguing,” the authors add, “This suggests that an ACE inhibitor may actually protect against the development of COPD and also alter its natural history. This observation needs to be confirmed, however, in larger representative cohorts. The mechanisms for the observation need to be studied, especially as ACE inhibitors have actions ranging from those local to the lung to systemic actions. As the authors suggest, if this effect is correct, then the likely mechanism is an antiinflammatory action on the airways or some action on vascular endothelial dysfunction.” (J. A. Wedzicha, w.wedzicha@ucl.ac.uk)
Inhaled GM-CSF in Pulmonary Alveolar Proteinosis: In more than one-half of 35 patients with autoimmune pulmonary alveolar proteinosis (aPAP), inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) produced sustained remissions, a study shows (pp. 729–37). Investigators also note that baseline vital capacity “might be a prognostic factor for disease recurrence” in patients with this condition: “During the observation, 23 patients remained free from additional treatments, and 12 patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P < .01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC ≥ 80.5) and the low %VC group was seen by a Kaplan–Meier analysis and a log-rank test (P < .0005).” (K. Nakata, radical@med.niigata-u.ac.jp)

>>>Circulation Report
Source:
Early-release articles from Circulation (2014).
High On-Treatment Platelet Reactivity: “On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization,” conclude authors who analyzed data from the ARCTIC study (10.1161/CIRCULATIONAHA.113.007524). A total of 2,440 patients were randomized to pre-stent platelet-response testing with drug adjustment or no monitoring/drug modifications. Death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization over a 1-year period occurred in similar numbers of patients in each group (8.6% of those monitored and 7.9% in the conventional arm; HR 1.105; 95% CI, 0.835–1.461, p = 0.48). (G. Montalescot, gilles.montalescot@psl.ap-hop-paris.fr)
Should we have “a freeze on tailored antiplatelet therapy?” ask editorialists (
10.1161/CIRCULATIONAHA.114.009930). “Although the question asked is sound and of potential clinical relevance, many unanswered questions remain to better determine in whom and under what conditions a strategy of tailored antiplatelet therapy may improve clinical outcomes.” (D. Voora, deepak.voora@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 14, 2014 * Vol. 21, No. 71
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 12 issue of Lancet (2014; 383).
Efficacy of Combined MMR–Varicella Vaccine: Results of a trial of combined measles–mumps–rubella–varicella vaccine (MMRV) in 10 European countries with endemic varicella support implementation of a two-dose, short-course regimen in young children (pp. 1313–24). Healthy children in the 12–22-month age group were randomized to receive two doses of MMRV 42 days apart (MMRV group, MMR at dose 1 and monovalent varicella vaccine at dose 2 (MMR+V group), or two doses of MMR (control group). Results showed: “Between Sept 1, 2005, and May 10, 2006, 5,803 children (mean age 14.2 months, SD 2.5) were vaccinated. In the efficacy cohort of 5,285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8.8), in the MMR+V group was 36 months (8.5) and in the MMR group was 35 months (8.9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94.9% (97.5% CI 92.4–96.6), and against moderate to severe varicella was 99.5% (97.5–99.9). Efficacy of one-dose varicella vaccine against all varicella was 65.4% (57.2–72.1), and against moderate to severe varicella (post hoc) was 90.7% (85.9–93.9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57.4% (95% CI 53.9–60.9) of participants in the MMRV group reported fever of 38°C or more, by contrast with 44.5% (41.0–48.1) with MMR+V, and 39.8% (33.8–46.1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period.” (O.Nicholson, uzama.n.henry@gsk.com">ouzama.n.henry@gsk.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Oseltamivir for Influenza: Prophylactic and treatment use of oseltamivir for influenza is supported by evidence from a systemtic review of regulatory information, authors write, but the agent produces several adverse effects, especially when used for treatment (g2545): “In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.” (T. Jefferson, jefferson.tom@gmail.com)
Zanamivir for Influenza: In a systematic review of clinical study reports and regulatory comments, efficacy of zanamivir for influenza is assessed (g2547): “Zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.” (C. J. Heneghan, carl.heneghan@phc.ox.ac.uk)

>>>PNN JournalWatch
* The Global Challenge of Carbapenem-Resistant Enterobacteriaceae in Transplant Recipients and Patients With Hematologic Malignancies, in
Clinical Infectious Diseases, 2014; 58: 1274–83. (M. J. Satlin, mjs9012@med.cornell.edu)
* To Treat or Not to Treat, That Is the Question: The Role of Bone-Targeted Therapy in Metastatic Prostate Cancer, in
Journal of Clinical Oncology, 2014; 32: 1107–11. (C. S. Higano, thigano@u.washington.edu)
* Long QT Syndrome, in
Circulation, 2014; 129: 1524–9. (D. J. Abrams, dominic.abrams@cardio.chboston.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 15, 2014 * Vol. 21, No. 72
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-online article and Apr. 15 issue of the Annals of Internal Medicine (2014; 160).
U.S. Diabetes Trends: While the prevalence of diabetes “has increased substantially” over the past two decades, an analysis of trends in the U.S. also finds reduced proportions of undiagnosed diabetes and improved glycemic control among most racial and ethnic groups (pp. 517–25). Data from the National Health and Nutrition Examination Survey (NHANES) in 1988–94 and 1999–2010 show these prevalence and control patterns among Americans: “In 2010, approximately 21 million U.S. adults aged 20 years or older had total confirmed diabetes (self-reported diabetes or diagnostic levels for both fasting glucose and calibrated HbA1c). During 2 decades, the prevalence of total confirmed diabetes increased, but the prevalence of undiagnosed diabetes remained fairly stable, reducing the proportion of total diabetes cases that are undiagnosed to 11% in 2005–2010. The prevalence of prediabetes was lower when defined by calibrated HbA1c levels than when defined by fasting glucose levels but has increased from 5.8% in 1988–1994 to 12.4% in 2005–2010 when defined by HbA1c levels. Glycemic control improved overall, but total diabetes prevalence was greater and diabetes was less controlled among non-Hispanic blacks and Mexican Americans compared with non-Hispanic whites.” (E. Selvin, lselvin@jhsph.edu)
Low-Dose Aspirin in Preeclampsia: Low-dose aspirin administered starting in the second trimester of pregnancy “prevented clinically important health outcomes” without evidence of harms, according to a systematic evidence review conducted by the U.S. Preventive Services Task Force (10.7326/M13-2844). Long-term evidence was limited, the group notes, adding these details on randomized controlled trials (RCTs) and large cohort studies: “Two large, multisite RCTs and 13 smaller RCTs of high-risk women (8 good-quality) were included, in addition to 6 RCTs and 2 observational studies of average-risk women to assess harms (7 good-quality). Depending on baseline risk, aspirin use was associated with absolute risk reductions of 2% to 5% for preeclampsia (relative risk [RR], 0.76 [95% CI, 0.62 to 0.95]), 1% to 5% for intrauterine growth restriction (RR, 0.80 [CI, 0.65 to 0.99]), and 2% to 4% for preterm birth (RR, 0.86 [CI, 0.76 to 0.98]). No significant perinatal or maternal harms were identified, but rare harms could not be ruled out. Evidence on long-term outcomes was sparse, but 18-month follow-up from the largest trial found no developmental harms.” (AHRQ Web site, www.ahrq.gov)

>>>Infectious Disease Report
Source:
May 1 issue of Clinical Infectious Diseases (2014; 58).
Measles Among People With Prior Immunity: Secondary vaccine failure occurred in an index patient in a 2011 outbreak of measles in New York City, researchers report (pp. 1205–10). “The index patient had 2 doses of measles-containing vaccine; of 88 contacts, 4 secondary patients were confirmed who had either 2 doses of measles-containing vaccine or a past positive measles IgG antibody,” the authors write. “All patients had laboratory confirmation of measles infection, clinical symptoms consistent with measles, and high-avidity IgG antibody characteristic of a secondary immune response. Neutralizing antibody titers of secondary patients reached >80,000 mIU/mL 3–4 days after rash onset and that of the index was <500 mIU/mL 9 days after rash onset. No additional cases of measles occurred among 231 contacts of secondary patients.” The investigators conclude that “this is the first report of measles transmission from a twice-vaccinated individual with documented secondary vaccine failure.” (J. Rosen, jrosen4@health.nyc.gov)
Pill Burden & HIV Therapy: In patients with HIV infection, “lower pill burden is associated with both better adherence and virological suppression,” according to authors of a meta-analysis of 19 studies of antiretroviral regimens (pp. 1297–307). “Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens,” the authors add, with a mean increase in adherence of 2.55 percentage points. “Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens…. Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing.” (J. B. Nachega, jbn16@pitt.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 16, 2014 * Vol. 21, No. 73
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 16 issue of JAMA (2014; 311).
Aleglitazar After Acute Coronary Syndrome in Type 2 Diabetes: Aleglitazar—a dual agonist of peroxisome proliferator–activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipids—failed to improve cardiovascular outcomes among patients with type 2 diabetes and recent acute coronary syndrome in the AleCardio study, researchers report (pp. 1515–25). The Phase III trial was under way at 720 hospitals in 26 countries when it was stopped early for futility. Participants received aleglitazar 150 mcg or placebo daily for a median of 104 weeks with these effects on a primary efficacy end point of time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke: “A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83–1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P < .001) were increased.” (A. M. Lincoff, lincofa@ccf.org)
Metformin After STEMI in Patients Without Diabetes: Left ventricular ejection fraction (LVEF) was not improved by 4 months of metformin therapy in patients without diabetes who presented with ST-segment elevation myocardial infarction (STEMI), the GIPS-III trial shows (pp. 1526–35). Metformin has shown favorable effects on ventricular function in other studies. Among 380 patients who underwent primary percutaneous coronary intervention for STEMI in 2011–13, metformin 500 mg or placebo twice daily for 4 months produced these outcomes: “At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%–54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%–56.1%) (P = .10) in the placebo group (n = 136). [N-terminal pro-brain natriuretic peptide] concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65–393 ng/L) and 167 ng/L in the placebo group (IQR, 74–383 ng/L) (P = .66). [Major adverse cardiac events (combined end point of death, reinfarction, or target-lesion revascularization)] were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L [IQR, 70–87 µmol/L] vs 79 µmol/L [IQR, 72–89 µmol/L], P = .61) and glycated hemoglobin (5.9% [IQR, 5.6%–6.1%] vs 5.9% [IQR, 5.7%–6.1%], P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed.” (I. C. C. van der Horst, i.c.c.van.der.horst@umcg.nl)

>>>PNN NewsWatch
* FDA yesterday approved once-weekly albiglutide (Tanzeum, GlaxoSmithKline) subcutaneous injection to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes. In eight clinical trials of the glucagon-like peptide-1 (GLP-1) receptor agonist that included more than 2,000 patients with type 2 diabetes, albiglutide improved glycosylated hemoglobin levels. The most common adverse effects in these Phase III Harmony trials were diarrhea, nausea, and injection site reactions. Albiglutide should not be used in patients with type 1 diabetes, those with diabetic ketoacidosis, or as first-line therapy of patients who cannot be managed with diet and exercise. The product carries a boxed warning about thyroid C-cell tumors that have been observed in rodent studies with some GLP-1 receptor agonists. Albiglutide should not be used in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. FDA approved Tanzeum with a REMS program that includes communications with health professionals about the serious risks associated with the product.
* The New Jersey Providing Access to Healthy Solutions (PATHS) report, developed by Harvard Law School’s Center for Health Law & Policy Innovation, calls for inclusion of pharmacists on
diabetes care teams and supports compensation for the services, pharmacist.com reports.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 17, 2014 * Vol. 21, No. 74
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 17 New England Journal of Medicine (2014; 370).
Ledipasvir/Sofosbuvir for Previously Treated HCV: In patients with HCV genotype 1 infection without sustained virologic responses to interferon-based treatment, once-daily, single-tablet ledipasvir and sofosbuvir produced high rates of sustained virologic response, researchers report (pp. 1483–93). The Phase III, open-label trial of the NS5A/nucleotide polymerase inhibitor combination produced these results in a 12-week trial: “Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir–sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir–sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea.” (N. Afdhal, nafdhal@bidmc.harvard.edu)
New drugs for HCV are effective, editorialists write, but their costs make use prohibitive for many (
pp. 1552–3). A 12-week course of sofosbuvir is $84,000, they note in reaching this conclusion: “The predicted costs of the new oral antiviral agents are as breathtaking as their effectiveness. Chronic hepatitis C is estimated to affect 3.2 million Americans, half of whom may not be aware that they are infected. Public health efforts are now under way to identify persons with HCV infection and to direct them to medical care. With the present estimates of costs, however, treating even half the HCV-infected persons in the United States would add billions of dollars to an already overburdened medical care system. Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a safe and effective therapy for hepatitis C.” (J. H. Hoofnagle)
Perioperative Aspirin in Noncardiac Surgery: Aspirin 200 mg/d before surgery followed by 100 mg/d for 30 days after surgery had no significant effects on death and nonfatal myocardial infarction among 10,010 patients at risk for vascular complications who were undergoing noncardiac surgery, according to results of the POISE-2 trial (pp. 1494–503). Rates of major bleeding were higher among those on aspirin. For the 5,628 participants who had not been on aspirin previously and the 4,382 patients who were continuing the drug, results were as follows: “The primary outcome [of composite of death or nonfatal myocardial infarction at 30 days] occurred in 351 of 4,998 patients (7.0%) in the aspirin group and in 355 of 5,012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P = 0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P = 0.04).” (P. J. Devereaux, philipj@mcmaster.ca)
Perioperative Clonidine in Noncardiac Surgery: In a second arm of the POISE-2 study, low-dose clonidine also increased risks without clinical benefits among at-risk patients undergoing noncardiac surgery (pp. 1504–13). Clonidine 0.2 mg/d or placebo just before surgery and for 72 hours postsurgery had these effects on a primary outcome of composite of death or nonfatal myocardial infarction at 30 days: “Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P = 0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P = 0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P < 0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02).” (P. J. Devereaux, philipj@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 18, 2014 * Vol. 21, No. 75
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Apr. issue of the Journal of Allergy and Clinical Immunology (2014; 133).
Live Vaccines in Immunodeficient Patients: Addressing “the present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations,” the Medical Advisory Committee of the Immune Deficiency Foundation has issued “recommendations based on published literature and the collective experience of the committee members” (pp. 961–6): “These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine–derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.” (W. T. Shearer, wtsheare@TexasChildrensHospital.org)
BCG Vaccination in Severe Combined Immunodeficiency: Until a safer vaccine for tuberculosis is available for use in those with severe combined immunodeficiency, “delay in BCG vaccination should be considered to protect highly vulnerable populations from preventable complications,” conclude authors who used a questionnaire to collect information from 349 BCG-vaccinated patients in 17 countries (pp. 1134–41): “Fifty-one percent of the patients had BCG-associated complications, 34% disseminated and 17% localized (a 33,000- and 400-fold increase, respectively, over the general population). Patients receiving early vaccination (≤1 month) showed an increased prevalence of complications (P = .006) and death caused by BCG-associated complications (P < .0001). The odds of experiencing complications among patients with T-cell numbers of 250/µL or less at diagnosis was 2.1 times higher (95% CI, 1.4-3.4 times higher; P = .001) than among those with T-cell numbers of greater than 250/µL. BCG-associated complications were reported in 2 of 78 patients who received antimycobacterial therapy while asymptomatic, and no deaths caused by BCG-associated complications occurred in this group. In contrast, 46 BCG-associated deaths were reported among 160 patients treated with antimycobacterial therapy for a symptomatic BCG infection (P < .0001).” (S. D. Rosenzweig, srosenzweig@cc.nih.gov)

>>>PNN NewsWatch
* FDA yesterday approved another sublingual allergen-extract product, this one for treatment of patients with short ragweed pollen–induced allergic rhinitis, with or without conjunctivitis, in adults 18 years through 65 years of age. In clinical trials, Ragwitek (Merck, Sharp & Dohme) reduced symptoms and the need for other medications among 760 patients with ragweed allergies by 26%. The most commonly reported adverse reactions in those treated with Ragwitek were itching in the mouth and ears and throat irritation. Treatment with Ragwitek is started 12 weeks before the start of ragweed pollen season and continued throughout the season. The first dose is taken in a health care professional’s office where the patient is to be observed for at least 30 minutes for potential adverse reactions. After the first dose, patients can take Ragwitek at home. A medication guide accompanies the product; it includes information on the possibility of severe allergic reactions.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 21, 2014 * Vol. 21, No. 76
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Antibiotics & Growth: In low- and middle-income countries, antibiotic use in prepubertal children is associated with increased ponderal and linear growth, according to a systematic review and meta-analysis, with greater effects on weight in older populations and height in younger groups (g2267). The antibiotic effect “may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota,” the authors conclude, based on these findings: “Data were pooled from 10 randomised controlled trials representing 4,316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. In random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions.” (A. R. Manges, amee.manges@ubc.ca)
Incretins & Pancreatitis: While “available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis,” authors of a systematic review and meta-analysis reach this conclusion: “Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk” (g2366). Analysis of 55 randomized controlled trials of 33,350 patients and 5 observational studies of 320,289 participants showed the following: “Pooled estimates [at low or moderate risk of bias] … did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1,466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 [0.63 to 1.36] in one study and 0.9 [0.6 to 1.5] in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case–control study at moderate risk of bias (1,003 cases, 4,012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case–control study (1,269 cases, 1,269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13).” (X. Sun, sunx26@gmail.com)
Chronic Hypertension in Pregnancy: Adverse outcomes are common among women with chronic hypertension who become pregnant, researchers report (g2301). A systematic review and meta-analysis of 55 studies of 795,221 pregnancies led the group to the conclusion that “adverse outcomes of pregnancy are common” and “heightened antenatal surveillance [is needed]. A consistent strategy to study women with chronic hypertension is needed, as previous study designs have been diverse. These findings should inform counselling and contribute to optimisation of maternal health, drug treatment, and pre-pregnancy management in women affected by chronic hypertension.” (L. Chappell, lucy.chappell@kcl.ac.uk)

>>>PNN JournalWatch
* Advances in Basic and Clinical Immunology in 2013, in
Journal of Allergy and Clinical Immunology, 2014; 133: 967–76. (W. T. Shearer, wtsheare@texaschildrenshospital.org)
* Brain Glucose Transporters: Implications for Neurologic Disease, in
Neurology, 2014; 82: 1374–9. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
* New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges, in
Gastroenterology, 2014; 146: 1176–92. (J-M Pawlotsky, jean-michel.pawlotsky@hmn.aphp.fr)
* When the Purple Do-Not-Resuscitate Bracelet Was Slipped Onto My Wrist, in
Journal of the American Geriatrics Society, 2014; 62: 770–1. (W. R. Hazzard, whazzard@wakehealth.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 22, 2014 * Vol. 21, No. 77
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2014; 174).
Reducing Inappropriate Benzodiazepine Use Through Pharmacy-Based Patient Education: Compared with usual care, direct-to-consumer education provided to Quebec community pharmacy patients was effective for reducing inappropriate benzodiazepine use in older adults, according to the cluster-randomized EMPOWER (Eliminating Medications Through Patient Ownership of End Results) trial (10.1001/jamainternmed.2014.949). Participants, aged 65–95 years and on long-term benzodiazepines, were recruited at 30 community pharmacies (all from a single chain) located within 200 km of Montreal. Participants in the intervention group received a personalized 8-page booklet by mail 1 week after allocation; participants in the control group received the booklet 6 months later. Results showed: “A total of 261 participants (86%) completed the 6-month follow-up. Of the recipients in the intervention group, 62% initiated conversation about benzodiazepine therapy cessation with a physician and/or pharmacist. At 6 months, 27% of the intervention group had discontinued benzodiazepine use compared with 5% of the control group (risk difference, 23% [95% CI, 14%–32%]; intracluster correlation, 0.008; number needed to treat, 4). Dose reduction occurred in an additional 11% (95% CI, 6%–16%). In multivariate subanalyses, age greater than 80 years, sex, duration of use, indication for use, dose, previous attempt to taper, and concomitant polypharmacy (10 drugs or more per day) did not have a significant interaction effect with benzodiazepine therapy discontinuation.” (C. Tannenbaum, cara.tannenbaum@umontreal.ca)
Bleeding With Anticoagulation Plus NSAIDs or Aspirin: Patients on anticoagulation for venous thromboembolism have significantly higher rates of clinically relevant and major bleeding when they also take NSAIDs or aspirin, report researchers who prospectively analyzed observational data from the EINSTEIN trial (10.1001/jamainternmed.2014.946). The 8,246 study participants were receiving rivaroxaban with enoxaparin–vitamin K antagonist (VKA) for deep-vein thrombosis or pulmonary embolism in 2007–09. Those who used NSAIDs or aspirin had these outcomes: “During NSAID–anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient–years vs 16.6 per 100 patient–years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46–2.14]). Major bleeding during NSAID–anticoagulant treatment occurred with an event rate of 6.5 per 100 patient–years, compared to 2.0 per 100 patient–years during nonuse (HR, 2.37 [95% CI, 1.51–3.75]). For aspirin–anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient–years, compared to 16.9 per 100 patient–years during aspirin nonuse (HR, 1.70 [95% CI, 1.38–2.11]). Major bleeding in aspirin–anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient–years, compared to 2.2 per 100 patient–years during aspirin nonuse (HR, 1.50 [95% CI, 0.86–2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin–VKA anticoagulation regimens.” (B. L. Davidson, brucedavidson@pobox.com)

>>>PNN NewsWatch
* Following expedited review, FDA yesterday approved the orphan drug ramucirumab (Cyramza, Lilly) for treatment of patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma. Ramucirumab is an angiogenesis inhibitor intended for use in patients with unresectable or metastatic cancers who have been treated with a fluoropyrimidine- or platinum-containing therapy. Lilly notes that this is the “first FDA-approved treatment for advanced gastric cancer after prior chemotherapy.” In clinical trials of 355 participants with unresectable or metastatic stomach or gastroesophageal junction cancer, participants treated with ramucirumab had a median overall survival of 5.2 months compared with 3.8 months in those receiving placebo. Additionally, participants on ramucirumab had increased progression-free survival compared with participants given placebo. A second clinical trial that evaluated ramucirumab plus paclitaxel versus paclitaxel alone also showed an improvement in overall survival. Common adverse effects of ramucirumab include diarrhea and high blood pressure.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 23, 2014 * Vol. 21, No. 78
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 23/30 issue of JAMA (2014; 311).
Lorazepam v. Diazepam for Pediatric Status Epilepticus: While recommended by many experts for treatment of status epilepticus in infants and children, lorazepam proved no more effective or safe than diazepam in a study of 273 participants at 11 U.S. academic pediatric emergency departments (pp. 1652–60). Intravenous doses of diazepam 0.2 mg/kg or lorazepam 0.1 mg/kg were given; half doses were repeated after 5 minutes if necessary. Fosphenytoin was administered if status epilepticus was not controlled at 12 minutes. Results showed: “Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, −11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, −9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%).”
The authors noted that the study results have important implications outside the hospital and in emergency department care: “Diazepam can be stored without refrigeration and thus has been used as the treatment of choice in many prehospital systems. The results of this study do not support the superiority of lorazepam over diazepam as a first-line agent for pediatric status epilepticus.” (J. M. Chamberlain,
jchamber@childrensnational.org)
Acetazolamide for Idiopathic Intracranial Hypertension: Visual field function was improved modestly in patients with idiopathic intracranial hypertension and mild visual loss when they received acetazolamide in relatively high doses of up to 4 g/d, Neuro-Ophthalmology Research Disease Investigator Consortium (NORDIC) researchers report (pp. 1641–51). Compared with placebo, the drug plus a low-sodium weight-reduction diet produced these changes in perimetric mean deviation (PMD) and other outcome measures: “The mean improvement in PMD was greater with acetazolamide (1.43 dB, from −3.53 dB at baseline to −2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from −3.53 dB to −2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: −1.31, from 2.76 to 1.45; placebo: −0.61, from 2.76 to 2.15; treatment effect, −0.70; 95% CI, −0.99 to −0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: −7.50 kg, from 107.72 kg to 100.22 kg; placebo: −3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, −4.05 kg, 95% CI, −6.27 to −1.83 kg; P < .001).” (M. Wall, michael-wall@uiowa.edu)
“The main benefit of acetazolamide is achieved by inhibition of carbonic anhydrase in the choroid plexus, but it also may have worked in the NORDIC trial by causing loss of appetite,” an editorialist writes (
pp. 1618–9). “Patients treated with acetazolamide lost a mean of 7.5 kg, twice the amount lost by control participants. Obese patients can reach a tipping point, whereupon a small additional weight gain can push intracranial pressure into the danger zone. Patients with new-onset papilledema often report a history of recent weight gain. Losing just 6% of body weight can lead to marked reduction in papilledema. All patients in the NORDIC trial were counseled regarding weight loss, which unavoidably may have attenuated the treatment effect of acetazolamide. Weight loss is so helpful as a treatment for pseudotumor cerebri that some authors have suggested that bariatric surgery should be considered for patients who do not respond to dietary measures.” (J. C. Horton, hortonj@vision.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 24, 2014 * Vol. 21, No. 79
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Apr. 24 issue of the New England Journal of Medicine (2014; 370).
Blood Pressure Targets in Sepsis: During initial resuscitation of patients in septic shock, targeting a higher-than-recommended mean arterial pressure made no difference in mortality at 28 or 90 days, but other parameters varied, SEPSISPAM researchers report (pp. 1583–93). In the open-label trial, 776 patients with septic shock were assigned to a high-target (80–85 mm Hg) or low-target (65–70 mm Hg) group, with these results: “At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P = 0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P = 0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P = 0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.” (P. Asfar, piasfar@chu-angers.fr)
Identifying the correct mean arterial pressure (MAP) target for each patient is the real goal, an editorialist writes (
pp. 1649–51): “A high MAP target may decrease the risk of renal injury and the need for renal-replacement therapy (number needed to treat of 9.5 to prevent one patient from needing renal- replacement therapy) in patients with hypertension. I make this point because of the well-known risks and costs of renal-replacement therapy. Thus, there are several target MAPs for septic shock, depending on the circumstances of the patient. In some randomized, controlled trials (and in clinical practice), practitioners use more fluid (increasing the risk of acute lung injury), whereas others use more vasopressors (increasing the risk of renal injury). Indeed, methods for targeting a MAP among patients in septic shock are probably critical to the success of the strategy and deserving of greater investigation.” (J. A. Russell)
Zyhydro & Other Opioids: “Pointing the finger at Zohydro is not going to resolve the tension that exists today between chronic pain and addiction,” Perspective authors write (10.1056/NEJMp1404181). “All concerned about the treatment of chronic pain and all responding to the rise in overdose deaths need to come together to promote high-quality and effective prevention and treatment for both conditions. (Y. Olsen)
In a second Perspectives article, authors call for improved medical practices and prescribing in addressing the prescription-opioid epidemic (
10.1056/NEJMp1402780): “Expanding access to [medication-assisted therapies (MATs)] is a crucial component of the effort to help patients recover [from addiction]. It is also necessary, however, to implement primary prevention policies that curb the inappropriate prescribing of opioid analgesics — the key upstream driver of the epidemic — while avoiding jeopardizing critical or even lifesaving opioid treatment when it is needed. Essential steps for physicians will be to reduce unnecessary or excessive opioid prescribing, routinely check data from prescription-drug–monitoring programs to identify patients who may be misusing opioids, and take full advantage of effective MATs for people with opioid addiction.” (N. D. Volkow)

>>>PNN NewsWatch
* FDA has approved siltuximab (Sylvant, Janssen Biotech) to treat patients with multicentric Castleman’s disease (MCD), a rare disorder similar to lymphoma. The injectable chimeric monoclonal antibody, an orphan drug approved following expedited review, blocks the action of interleukin-6. Administered to 79 patients with MCD along with best supportive care, siltuximab produced tumor response in 34% of patients, compared with none of those receiving best supportive care and placebo. Adverse effects include pruritus, weight gain, rash, hyperuricemia, and upper respiratory tract infection.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 25, 2014 * Vol. 21, No. 80
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Apr. issue of Health Affairs, a theme issue on Alzheimer disease (2014; 33).
Training Health Care Workers To Care for Patients With AD: The American health care workforce will be challenged in coming years by the numbers and needs of patients with Alzheimer disease, authors write, with the population aging and the condition present in 1 in 9 patients 65 or older and 1 in 3 of those 85 or older (pp. 633–41). A tripling in number of cases by 2050 to 13.8 million Americans will stress the health care system and workers, the writers note, adding their perspective on “what is likely to be an increasing shortage of physicians, nurses, and social workers with specialized training in geriatrics and, more specifically, in the care of people with dementia. We highlight [in this article] the limited training of health care professionals in best practices of dementia care and chronic disease management. To address these shortfalls, we recommend the dissemination of team-based models of care that integrate health and social services; expansion of education loan forgiveness and faculty development programs to attract students into clinician–educator careers focusing on Alzheimer’s disease; inclusion of curricula specific to the disease in all health professions training; expansion of federal programs to train existing workers; and increased compensation for the direct care workforce.” (G. A. Warshaw, Gregg.Warshaw@uc.edu)
Economic Effects of Healthy Brain Aging: Implemented nationwide, a memory-care model could produce health care cost savings in the billions of dollars, researchers report (pp. 613–8). The collaborative care model within primary care has been used for two decades and “has proved to be effective in improving care quality, efficiency, and outcomes for older adults suffering from dementia and depression. In collaboration with community partners, scientists from Indiana University have implemented this model at the Healthy Aging Brain Center (HABC), a memory care clinic that is part of Eskenazi Health, an integrated safety-net health care system in Indianapolis, Indiana. The HABC generates an annual net cost savings of up to $2,856 per patient, which adds up to millions of dollars for Eskenazi Health’s patients. This article demonstrates the financial sustainability of the care processes implemented in the HABC, as well as the possibility that payers and providers could share savings from the use of the HABC model.” (D. D. French, ustin.French@northwestern.edu">Dustin.French@northwestern.edu)

>>>Medical Care Report
Source:
May issue of Medical Care (2014; 52).
Functional Health/Well-Being Outcomes With Drug Therapy: Tested with the SF-36 Health Survey, drug therapy in clinical drug trials produces “meaningful functional health benefits” about half the time, according to a systematic review of randomized, placebo-controlled studies (pp. 439–45): “Of 805 screened trials, 185 met eligibility criteria. Primary clinical and SF-36 outcomes were concordant in 151 trials (82%). Among clinically efficacious trials, 58% reported net mean SF-36 improvements [greater than or equal to the minimal important difference (MID)] threshold; however, SF-36 changes were often modest ([physical component summary] IQR, 1.6–4.1; [mental component summary] IQR, 0.8–3.5). Variations in treatment impact were apparent across conditions. Clinically efficacious therapies for rheumatoid arthritis, psoriatic arthritis, and psoriasis consistently achieved the largest SF-36 improvements, with 87% exceeding MID, whereas no efficacious therapies for peripheral arterial disease or chronic obstructive pulmonary disease achieved MID threshold.” (D. M. Frendl)
Continuity of Care & Medication Adherence: Among Korean patients with type 2 diabetes, those with better continuity of care were significantly more adherent to their medications, authors of a longitudinal study report (pp. 446–53). The 23,034 adult study participants were first diagnosed with diabetes in 2004. Based on data from the Korea National Health Insurance program, the odds of having a medication possession ratio of 0.8 or more were directly related to the Continuity of Care Index: 0.2≤COCI<0.4, odds ratio (OR) = 2.20; 0.4≤COCI<0.6, OR = 3.46; 0.6≤COCI<0.8, OR = 4.76; 0.8≤COCI<1.0, OR = 4.43; COCI=1.0, OR = 7.24. (J-S Hong)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 28, 2014 * Vol. 21, No. 81
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 26 issue of Lancet (2014; 383).
Alcohol-Related Mortality in Russia: Excessive consumption of vodka is a major cause of premature mortality in Russia, researchers found based on interviews with 200,000 adults in three cities in 1999–2008 (pp. 1465–73). Follow-up continued through 2010. Among 151,000 interviewees with no previous disease and some follow-up at ages 35–74, these patterns were evident: “Among 57,361 male smokers with no previous disease, the estimated 20-year risks of death at ages 35–54 years were 16% (95% CI 15–17) for those who reported consuming less than a bottle of vodka per week at baseline, 20% (18–22) for those consuming 1–2.9 bottles per week, and 35% (31–39) for those consuming three or more bottles per week; trend p < 0.0001. The corresponding risks of death at ages 55–74 years were 50% (48–52) for those who reported consuming less than a bottle of vodka per week at baseline, 54% (51–57) for those consuming 1–2.9 bottles per week, and 64% (59–69) for those consuming three or more bottles per week; trend p < 0.0001. In both age ranges most of the excess mortality in heavier drinkers was from external causes or the eight disease groupings strongly associated with alcohol in the retrospective enquiries. Self-reported drinking fluctuated; of the men who reported drinking three or more bottles of vodka per week who were reinterviewed a few years later, about half (185 of 321) then reported drinking less than one bottle per week. Such fluctuations must have substantially attenuated the apparent hazards of heavy drinking in this study, yet self-reported vodka use at baseline still strongly predicted risk. Among male non-smokers and among females, self-reported heavy drinking was uncommon, but seemed to involve similar absolute excess risks.” (D. Zaridze, dgzaridze@crc.umos.ru)
Reduced Dosing of Efavirenz: In the ENCORE1 trial, reduced dosing with efavirenz (400 mg daily) was noninferior to the standard 600-mg dose among 630 patients with HIV-1 infections (pp. 1474–82): “The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI −2.1 to 5.79). CD4 T-cell counts at week 48 were significantly higher for the 400 mg group than for the 600 mg group (mean difference 25 cells per µL, 95% CI 6–44; p = 0.01). We recorded no difference in grade or number of patients reporting adverse events (efavirenz 400 = 89.1%, efavirenz 600 = 88.4%; difference 0.75%, 95% CI −4.19 to 5.69; p = 0.77). Study drug-related adverse events were significantly more frequent in the 600 mg group than in the 400 mg group (146% [47] vs 118 [37]), difference −10.5%, 95% CI −18.2 to −2.8; p = 0.01) and significantly fewer patients with these events stopped treatment (400 mg = 6 [2%], 600 mg = 18 [6%], difference −3.96%, 95% CI −6.96 to −0.95; p=0.01).” (ENCORE1 Study Group)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Incretins & Acute Pancreatitis: In a population-based cohort study, acute pancreatitis occurred in similar proportions of patients with type 2 diabetes taking incretin-based drugs and sulfonylureas (g2780). Comparing 20,748 new users of incretins with 51,712 patients taking sulfonylureas, the researchers found these patterns in 2012–13: “The crude incidence rate for acute pancreatitis was 1.45 per 1,000 patients per year (95% confidence interval 0.99 to 2.11) for incretin based drug users and 1.47 (1.23 to 1.76) for sulfonylurea users. The rate of acute pancreatitis associated with the use of incretin based drugs was not increased ([high dimensional propensity score] adjusted hazard ratio: 1.00, 95% confidence interval 0.59 to 1.70) relative to sulfonylurea use.” The authors conclude, “While this study is reassuring, it does not preclude a modest increased risk [of pancreatitis with incretins], and thus additional studies are needed to confirm these findings.” (S. Suissa, samy.suissa@mcgill.ca)

>>>PNN JournalWatch
* Review: Treat to Target in Rheumatoid Arthritis: Fact, Fiction, or Hypothesis?, in
Arthritis & Rheumatism, 2014; 66: 775–82. (D. H. Solomon, dsolomon@partners.org)
* Medicare Star Ratings: Stakeholder Proceedings on Community Pharmacy and Managed Care Partnerships in Quality, in
Journal of the American Pharmacists Association, 2014; 54: e238–50. (J. A. Owen, jowen@aphanet.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 29, 2014 * Vol. 21, No. 82
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2014; 160).
Addressing Viral Hepatitis in the U.S.: More action is needed to identify and treat Americans who are at high risk of progressive liver disease, liver failure, and liver cancer because of viral hepatitis, authors of an opinion article write (10.7326/M14-0404): “We need new partners, heightened commitment, and concrete evidence that our efforts are making a difference for the health of Americans. Because the 2011 plan did not outline specific action steps beyond 2013, the HHS has released an updated version of the Viral Hepatitis Action Plan for 2014–2016. The updated plan builds on the goals of its predecessor but is enhanced: It spells out specific actions to be undertaken by federal partners in 2014–2016, emphasizes the need for a comprehensive national response by calling out potential contributions of clinical and other nongovernmental partners, and expands the focus on evaluation with the addition of specific metrics to monitor the plan’s 4 major goals. The framework and vision offered by this updated plan will continue to provide a critical platform for medical, public health, and community actions. In light of its release, we call for further commitments to break the silence, stop this epidemic, and propel our nation toward a healthier future where viral hepatitis no longer exerts such a profound toll in morbidity and mortality.” (R. O. Valdiserri, ron.valdiserri@hhs.gov)

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Antibacterials in Medicaid Outpatients: Antibacterial use among Medi-Cal fee-for-service patients differs based on demographics, a study shows (10.1002/phar.1425). Beneficiaries on systemic antibacterial agents in 2006–11 had these patterns in the cohort study: “Of the 10,018,066 systemic antibacterial claims selected for analysis, antibacterial prescribing rates decreased from 542 claims/1,000 beneficiaries in 2006 to 461 claims/1,000 beneficiaries in 2011 (r = −0.971, p = 0.0012; tau-b = −1.00, p=0.009). Among age groups, children had the highest rate of use (605 claims/1,000 beneficiaries, chi square (2) = 320,000, p <0.001); among racial/ethnic groups, Alaskan Natives and Native Americans had the highest rate of use (1,086/1,000 beneficiaries, chi square (5) = 197,000, p <0.001). Broad-spectrum antibacterial prescribing increased from 28.1% (95% confidence interval [CI] 28.1–28.2%) to 32.7% (95% CI 32.6–32.8%) over the study period. Senior age groups and whites received the highest proportions of broad-spectrum agents (53.4% [95% CI 52.5–54.3%] and 36.6% [95% CI 36.6–36.7%], respectively). Population density was inversely related to both overall antibacterial use (rho = −0.432, p = 0.0018) and broad-spectrum antibacterial prescribing (rho = −0.359, p <0.001). The rate of prescribing decreased over the study period for all antibacterial classes with the exception of macrolides and sulfonamides. Amoxicillin was the most frequently prescribed agent.” (B. J. Guglielmo, guglielmoj@pharmacy.ucsf.edu)
Analgosedation with Fentanyl: Among critically ill patients on mechanical ventilation, analgosedation with fentanyl was safe and effective in a comparison with traditional propofol sedation, researchers report (10.1002/phar.1429). Among 100 patients at a community teaching hospital in 2011–13, those in pain particularly benefited from fentanyl: “Median duration of mechanical ventilation was similar between patients receiving propofol and fentanyl infusions (46.7 hr vs 46.0 hr, p = 0.19). No difference was noted in median intensive care unit length of stay between groups (p = 0.42). A larger percentage of patients receiving propofol required rescue opioids compared with patients receiving fentanyl (56% vs 34%, p = 0.04). Furthermore, patients receiving propofol required significantly more rescue opioid therapy during the course of mechanical ventilation as calculated by fentanyl equivalents (150 µg vs 100 µg, p = 0.03). No difference in the rate of intensive care unit delirium was noted between groups (fentanyl 23% vs propofol 27%, p = 0.80).” (K. M. Tedders, kristen.tedders@stjohn.org)

>>>PNN NewsWatch
* Super Arthgold 500 mg capsules (Nano Well-being Health) have been recalled to the consumer level because they contain undeclared chlorzoxazone, diclofenac, and indomethacin, FDA said yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 30, 2014 * Vol. 21, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care, which contains a theme section on Advances in Artificial Pancreas Development (2014; 37).
Closed-Loop Artificial Pancreas Systems: Two articles provide a bench-to-clinic perspective on closed-loop artificial pancreas (AP) systems. The bench narrative “provides an in-depth understanding of insulin-glucose-glucagon physiology in conditions that mimic the free-living situation to the extent possible in type 1 diabetes that will help refine and improve future closed-loop system algorithms” (pp. 1184–90; A. Basu, basu.ananda@mayo.edu)
The clinic narrative compares and evaluates “AP technology to gain further momentum toward outpatient trials and eventual approval for widespread use,” the authors write (
pp. 1191–7). “We enumerate the design objectives, variables, and challenges involved in AP development, concluding with a discussion of recent clinical advancements. Thanks to the effective integration of engineering and medicine, the dream of automated glucose regulation is nearing reality. Consistent and methodical presentation of results will accelerate this success, allowing head-to-head comparisons that will facilitate adoption of the AP as a standard therapy for type 1 diabetes.” (F. J. Doyle III, doyle@engineering.ucsb.edu)
Second-Line Agents for Type 2 Diabetes: Sulfonylureas are as effective and less expensive than newer second-line agents used in the treatment of type 2 diabetes, a pharmacoeconomic analysis shows (pp. 1338–45). Investigators “developed and validated a new population-based glycemic control Markov model that simulates natural variation in HbA1c progression.” Applying the model to treatment intensification of metformin monotherapy with sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, or insulin, the authors found these changes in life–years (LYs), quality-adjusted life–years (QALYs), and other variables: “All regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens.” (B. T. Denton, btdenton@umich.edu)
Antidiabetic Drug Use in U.S.: Nationally projected data based on IMS figures for community pharmacies led researchers to this conclusion about U.S. antidiabetic drug use in 2003–12 (pp. 1367–74): “The antidiabetic drug market is characterized by steady increases in volume, and newly approved drugs experienced substantial uptake, especially DPP-4 inhibitors. The use of rosiglitazone has been negligible since restrictions were put in place in 2011. Further study is needed to understand why one-third to one-half of other noninsulin antidiabetic drug use was not concomitant with metformin use despite guidelines recommending that metformin be continued when other agents are added to treatment.” (C. Hampp, christian.hampp@fda.hhs.gov)

>>>PNN NewsWatch
* FDA yesterday granted accelerated approval to the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor ceritinib (Zykadia, Novartis) for patients with metastatic ALK-positive non-small cell lung cancer (NSCLC) who were previously treated with crizotinib. Only 2%–7% of patients with NSCLC are ALK-positive. The drug’s safety and effectiveness were established in a clinical trial of 163 participants with metastatic ALK-positive NSCLC. Tumors shrank in about one-half of the patients, all of whom received ceritinib, and this effect lasted a mean of 7 months. Common adverse effects include diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities such as increased liver enzymes, pancreatic enzymes, and increased glucose levels were also observed in the clinical trial. This approval was granted unusually early, 4 months ahead of FDA’s deadline.
*
FDA yesterday recommended that patients stop using GenStrip Blood Glucose Test Strips and that glucose test strips for LifeScan OneTouch glucose meters be substituted. During a recent inspection of Shasta Technologies LLC, FDA said it found extensive violations of federal regulations intended to assure the quality of products in the manufacturing of GenStrip Test Strips. Without assurance of an adequate quality system, FDA said it believes that the strips could report incorrect blood glucose levels.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 1, 2014 * Vol. 21, No. 84
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 1 issue of the New England Journal of Medicine (2014; 370).
Protocol-Based Care in Early Septic Shock: A multicenter trial that replicated early goal-directed therapy (EGDT) in patients diagnosed in the emergency department with septic shock found no differences among the protocol-based placement of a central line, protocol-based care without a central line, and bedside care provided according to the physician’s judgment (pp. 1683–93). In the ProCESS trial, patients with septic shock at 31 U.S. emergency departments were randomized to protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. Based on a primary end point of 60-day in-hospital mortality, the researchers found: “We enrolled 1,341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P = 0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P = 0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.” (D. C. Angus, angusdc@upmc.edu)
“The publication of the ProCESS trial launches the era of early recognition and treatment in the management of sepsis,” an editorialist writes (
pp. 1750–1). “The ProCESS trial also provides transformative insights about the treatments for septic shock that bring generalizable benefits when septic shock is recognized in the first hours after arrival in the emergency department. The use of central hemodynamic and oxygen-saturation monitoring in the protocol-based … EGDT group did not result in better outcomes than those that were achieved with clinical assessment of the adequacy of circulation. The finding that adjusting therapies to surrogate physiological targets measured with invasive catheters was not required to reduce mortality is consistent with the results of a study that showed that serial measurement of blood lactate levels was noninferior to catheter-derived measurements and of analyses that have not found benefits of the use of pulmonary-artery catheters. State legislation and clinical guidelines, including those endorsed by the National Quality Forum, should be updated to remove the requirement for central hemodynamic monitoring and to focus on less costly, lower-risk, and equally effective alternatives.” (C. M. Lilly)
Darapladib in Stable Coronary Heart Disease: A selective oral inhibitor of lipoprotein-associated phospholipase A2, darapladib was not effective for reducing the risk of a primary composite end point of cardiovascular death, myocardial infarction, or stroke, according to results of the STABILITY trial (pp. 1702–11). A total of 15,828 patients with stable coronary heart disease were randomized to once-daily darapladib 160 mg or placebo, with these results: “During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7,924 patients (9.7%) in the darapladib group and 819 of 7,904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P = 0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P = 0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P = 0.02).” (H. D. White, harveyw@adhb.govt.nz)

>>>PNN NewsWatch
* Several unapproved products are being recalled to the retail and consumer level by Flawless Beauty and Skin, FDA said. These include Rx Sterile Water for Injection, Tatiomax Reduced Glutathione + Hydrolyzed Collagen, and TP Drug Laboratories Vitamin C.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 2, 2014 * Vol. 21, No. 85
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
May issue of the American Journal of Psychiatry (2014; 171).
Maternal Influenza & Bipolar Disorder in Adult Offspring: Adding clarity to a potential cause of schizophrenia, a study demonstrates a link between maternal influenza and bipolar disorder with psychotic features in adult offspring (pp. 557–63). Using a nested case–control design to evaluate a Child Health and Development Study birth cohort, investigators found no association between maternal exposure to influenza and development of bipolar disorder in 85 individuals with bipolar disorder and 170 comparison subjects. However, the group notes, “maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features.” They conclude, “Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.” (A. S. Brown, asb11@columbia.edu)
Coaching Healthy Dietary Practices: “Lifestyle interventions like coaching in healthy dietary practices may hold promise as effective, practical, nonstigmatizing interventions for preventing episodes of major depressive disorder in older adults with subsyndromal depressive symptoms,” according to a Treatment in Psychiatry review article (pp. 499–505): “Prevention of major depressive disorder is important because current treatments are only partially adequate in reducing symptom burden and promoting health-related quality of life. Lifestyle interventions may be a desirable prevention strategy for reasons of patient preference, particularly among older patients from minority groups. Using evidence from a randomized depression prevention trial for older adults, the authors found that coaching in healthy dietary practices was potentially effective in protecting at-risk older adults from developing incident episodes of major depression. The authors describe the dietary coaching program (highlighted in a case example) as well as the feasibility and potential efficacy of the program within the context of evidence-based interventions for preventing episodes of major depression and mitigating symptoms of depression. Older adults receiving dietary coaching experienced a low incidence of major depressive episodes and exhibited a 40%−50% decrease in depressive symptoms, as well as enhanced well-being, during the initial 6-week intervention; these gains were sustained over 2 years.” (C. F. Reynolds III, reynoldscf@upmc.edu)

>>>Pediatrics Report
Source:
May issue of Pediatrics (2014; 133).
Pediatric Codeine Prescriptions in Emergency Departments: Emergency department prescriptions for codeine-containing products for cough or upper respiratory infections (URIs) did not decline following release of two 2006 guidelines that recommended against use of the drug for those indications, researchers report (pp. e1139–47). Data for the nationally representative National Hospital Ambulatory Medical Care Survey showed these usage patterns for children ages 3–17 years in 2001–10: “The proportion of visits (N = 189 million) with codeine prescription decreased from 3.7% to 2.9% during the study period (P = .008). Odds of codeine prescription were higher for children ages 8 to 12 years (odds ratio [OR], 1.42; 95% confidence interval [1.21–1.67]) and among providers outside the northeast. Odds were lower for children who were non-Hispanic black (OR, 0.67 [0.56–0.8]) or with Medicaid (OR, 0.84 [0.71–0.98]). The 2006 guidelines were not associated with a decline in codeine prescriptions for cough or URI visits.” (S. V. Kaiser, sunithavemula1@gmail.com)
“We must find novel ways to convince [clinicians] that there is a need to change and that the time to retire this drug is today,” editorialists conclude based on the above findings (
pp. e1354–5; A. D. Woolf, alan.woolf@childrens.harvard.edu)

>>>PNN NewsWatch
* It was 20 years ago today when PNN was first published. Later this month, we’ll publish issue number 5000. It’s been a great ride!
* PNN began as a fax newsletter but transitioned to e-mail delivery within a couple years. By chance, today we’ll be
disconnecting our dedicated fax line in favor of the e-fax number of 844/270-0717. Please change your records as needed.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 5, 2014 * Vol. 21, No. 86
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 3 issue of Lancet (2014; 383).
Preoperative Chemotherapy in NSCLC: In patients with resectable non-small-cell lung cancer (NSCLC), most of which was in stage IIB–IIIA, chemotherapy administered preoperatively significantly improved overall survival, time to distant recurrence, and recurrence-free survival, according to a systematic reviw and meta-analysis of individual participant data (pp. 1561–71). The study included trials that started after Jan. 1965. Results showed: “Analyses of 15 randomised controlled trials (2,385 patients) showed a significant benefit of preoperative chemotherapy on survival (hazard ratio [HR] 0.87, 95% CI 0.78–0.96, p = 0.007), a 13% reduction in the relative risk of death (no evidence of a difference between trials; p = 0.18, I2 = 25%). This finding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a difference in the effect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defined by age, sex, performance status, histology, or clinical stage benefited more or less from preoperative chemotherapy. Recurrence-free survival (HR 0.85, 95% CI 0.76–0.94, p = 0.002) and time to distant recurrence (0.69, 0.58–0.82, p < 0.0001) results were both significantly in favour of preoperative chemotherapy although most patients included were stage IB–IIIA. Results for time to locoregional recurrence (0.88, 0.73–1.07, p = 0.20), although in favour of preoperative chemotherapy, were not statistically significant.” (NSCLC Meta-analysis Collaborative Group)
Multidrug-Resistant Tuberculosis Disease in Children: Based on a systematic review that provides global estimates, investigators find that “many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children” (pp. 1572–9). Two models were used to detect setting-specific risk of multidrug-resistant tuberculosis and tuberculosis disease in children. Based on 97 studies that met inclusion criteria, the group found: “We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999,792 (95% CI 937,877–1,055,414) children developed tuberculosis disease in 2010, of whom 31,948 (25,594–38,663) had multidrug-resistant disease.” (M. C. Becerra, mbecerra@post.harvard.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Dietary Fiber Intake & Mortality After MI: In the Nurses’ Health Study and the Health Professionals Follow-Up Study, dietary intake of fiber was associated with decreased mortality risk in patients surviving myocardial infarction, researchers report (g2659). Cereal fiber was especially beneficial, the authors note, adding these details on 2,258 women and 1,840 men: “Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87).” (S. Li, shl607@mail.harvard.edu)

>>>PNN JournalWatch
* Normalizing Metabolism in Diabetic Pregnancy: Is It Time to Target Lipids?, in
Diabetes Care, 2014; 37: 1484–93. (H. L. Barrett, h.barrett@uq.edu.au)
* Maternal Obesity and Infant Mortality: A Meta-Analysis, in
Pediatrics, 2014; 133: 863–71. (S. Meehan)
* Gastrointestinal Symptoms in Autism Spectrum Disorder: A Meta-analysis, in
Pediatrics, 2014; 133: 872–83. (B. O. McElhanon)
* Cognitive Training in Mental Disorders: Update and Future Directions, in
American Journal of Psychiatry, 2014; 171: 510–22. (M. S. Keshavan)
* The Need for PGY2-Trained Clinical Pharmacy Specialists, in
Pharmacotherapy, 2014; 10.1002/phar.1430. (K. R. Ragucci, raguccik@musc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 6, 2014 * Vol. 21, No. 87
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 6 issue of the Annals of Internal Medicine (2014; 160).
Economic Value of the Women’s Health Initiative: The role of public funding in clinical research is examined through an analysis of the economic return of the Women’s Health Initiative (WHI) estrogen plus progestin (E+P) trial (pp. 594–602). Results of the trial prompted “a substantial reduction in use of combined hormone therapy (cHT) among postmenopausal women in the United States,” the authors note, and this resulted in “high-value use of public funds with a substantial return on investment.” Based on a time horizon of 2003–12 and payer perspective, the group found these base-case and sensitivity results: “The WHI scenario resulted in 4.3 million fewer cHT users, 126,000 fewer breast cancer cases, 76,000 fewer cardiovascular disease cases, 263,000 more fractures, 145,000 more quality-adjusted life-years, and expenditure savings of $35.2 billion. The corresponding net economic return of the trial was $37.1 billion ($140 per dollar invested in the trial) at a willingness-to-pay level of $100,000 per quality-adjusted life–year.…
“The 95% CI for the net economic return of the trial was $23.1 to $51.2 billion.” (S. Ramsey,
sramsey@fhcrc.org)
Behavioral Interventions for Childhood/Adolescent Illicit Drug Use: Providing the basis for a recommendation statement (pp. 634–9; USPSTF, www.uspreventiveservicestaskforce.org), a systematic review compiles the following evidence concerning primary care behavioral interventions for preventing or reducing illicit pharmaceutical use by children and adolescents (pp. 612–20): “Six trials were included, 4 of which examined the effect of the intervention on a health or social outcome. One trial found no effect of the intervention on marijuana-related consequences or driving under the influence of marijuana; 3 trials generally found no reduction in depressed mood at 12 or 24 months. Four of the 5 trials assessing self-reported marijuana use found statistically significant differences favoring the intervention group participants (such as a between-group difference of 0.10 to 0.17 use occasions in the past month). Three trials also reported positive outcomes in nonmedical prescription drug use occasions.” (AHRQ, www.ahrq.gov)
Mortality After Health Care Reform: In Massachusetts, all-cause mortality and deaths from causes “amenable to health care” fell significantly following implementation of health care reform in 2006 (pp. 585–93). The Massachusetts approach provided much of the basis for the Affordable Care Act and is thus watched closely as a harbinger of potential national trends. Mortality rates at the county level in 2001–05 (prereform) and 2007–10 (postreform) showed these patterns: “Reform in Massachusetts was associated with a significant decrease in all-cause mortality compared with the control group (−2.9%; P = 0.003, or an absolute decrease of 8.2 deaths per 100,000 adults). Deaths from causes amenable to health care also significantly decreased (−4.5%; P < 0.001). Changes were larger in counties with lower household incomes and higher prereform uninsured rates. Secondary analyses showed significant gains in coverage, access to care, and self-reported health. The number needed to treat was approximately 830 adults gaining health insurance to prevent 1 death per year.” (B. D. Sommers, bsommers@hsph.harvard.edu)
Social Media & Nerve Gas: Videos posted on social media can be used to evaluate the clinical presentation and management of clinical syndromes, including effects of a nerve-gas attack, researchers report (pp. 644–8). Analysis of 210 YouTube videos posted after the Aug. 21, 2013, sarin dispersal on the outskirts of Damascus, the investigators counted 130 casualties and found the “most common clinical signs were dyspnea (53.0%), diaphoresis (48.5%), and loss of consciousness (40.7%). Important findings included a severe shortage of supporting measures and lack of antidotal autoinjectors.” (Y. Rosman, rosmanyossi@gmail.com)

>>>PNN NewsWatch
* Because of potential malfunctions, the Gemstar Docking Station should be turned on before being connected to the docking station, Hospira said in a nationwide correction. Proper use of the external battery pack is also detailed in the correction, which is available on the FDA website.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 7, 2014 * Vol. 21, No. 88
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 7 issue of JAMA (2014; 311).
Tdap During Pregnancy: Administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy is safe and may induce passive immunity in newborns during the first 2 months of life, researchers report (pp. 1760–9). A total of 48 pregnant women received Tdap vaccinations at 30–32 weeks’ gestation or postpartum, with these effects on primary outcomes of maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months: “No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%–91.0%]) and 12 (80% [95% CI, 51.9%–95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%–54.9%]) and 11 (73.3% [95% CI, 44.9%–92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1–70.1] and 9.1 EU/mL [95% CI, 4.6–17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1–90.8] and 14.0 EU/mL [95% CI, 7.3–26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4–29.6] and 5.3 EU/mL [95% CI, 3.0–9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP.” (F. M. Munoz, florm@bcm.edu)
“Continued reporting of pertussis cases will … be necessary to assess the effectiveness of administering Tdap during pregnancy,” editorialists write in response to this study (
pp. 1736–7). “In addition, the assessment of potential interference with DTaP and other vaccine antigens administered during infancy will require large prospective studies. Last, future research must address the safety and immunogenicity of repeated doses of Tdap during each pregnancy, because frequent immunization might lead to a blunted antibody response.” (K. M. Edwards, kathryn.edwards@vanderbilt.edu)
Fluconazole Prophylaxis in Premature Infants: In premature infants with birth weights less than 750 g, fluconazole prophylaxis for 42 days did not reduce the incidence of mortality or invasive candidiasis, a study of 361 infants shows (pp. 1742–9). At 32 neonatal intensive-care units, premature infants were randomized at birth to fluconazole or placebo twice weekly. A primary composite end point of death or definite or probable invasive candidiasis prior to study day 49 showed the following: “Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio, 0.73 [95% CI, 0.43–1.23]; P = .24; treatment difference, −5% [95% CI, −13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%]) vs the placebo group (9% [95% CI, 5%–14%]; P = .02; treatment difference, −6% [95% CI, −11% to −1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%–41%] vs placebo, 27% [95% CI, 18%–37%]; P = .60; treatment difference, 4% [95% CI, −10% to 17%]).” (D. K. Benjamin Jr., danny.benjamin@duke.edu)
Corticosteroids in Infants With Biliary Atresia: In the Steroids in Biliary Atresia Randomized Trial (START), I.V. methylprednisolone followed by oral prednisolone or placebo led investigators to reach this conclusion: “Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded” (pp. 1750–9). “Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia,” the group adds. (J. A. Bezerra, jorge.bezerra@cchmc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 8, 2014 * Vol. 21, No. 89
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 8 issue of the New England Journal of Medicine (2014; 370).
Letermovir for Cytomegalovirus Prophylaxis: In patients undergoing allogeneic hematopoietic-cell transplants, prophylactic letermovir (AIC246) reduced the incidence of cytomegalovirus (CMV) infections, a Phase II study shows (pp. 1781–9). The dose-ranging study of the anti-CMV drug lasted for 12 weeks after engraftment and produced these results: “The reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P = 0.32), 32% at a dose of 120 mg (P = 0.01), and 29% at a dose of 240 mg (P = 0.007). Kaplan–Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P = 0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.” (G. Ehninger, mailto:)
These results “are only the beginning of this exciting new development in the therapeutic control of CMV infection,” editorialists write of the prospects for an inhibitor of the terminase complex (
pp. 1844–6). “Given the potent antiviral effect of letermovir, the issue of drug resistance will need to be investigated, especially in patients with breakthrough viremia during the prophylactic period, and the incidence of postprophylaxis infection and late CMV disease must be assessed. Nevertheless, the potential availability of a new class of antiviral drug with high potency and a low side-effect profile, and one that could be used alongside existing therapy, is a welcome development. The safety and potency of these agents should be assessed in babies born with congenital CMV infection for whom ganciclovir and valganciclovir are the current treatments. It also offers the possibility of evaluating combination therapy with these agents in patients who have undergone transplantation to see whether the troll of transplantation can finally be suppressed into hiding.” (P. D. Griffiths)
Evolocumab in Hyperlipidemia: Added to several lipid-lowering regimens, the monoclonal antibody evolocumab significantly reduced LDL cholesterol in a group of 901 patients with varying cardiovascular risks, researchers report (pp. 1809–19). During a 4–12-week run-in period, study participants were assigned to the following therapies based on their ATP III categories: diet alone, diet plus atorvastatin 10 mg daily, diet plus atorvastatin 80 mg daily, or diet plus atorvastatin 80 mg daily and ezetimibe 10 mg daily. Results showed: “The overall least-squares mean (± SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0 ± 2.1% (P <0.001). The mean reduction was 55.7 ± 4.2% among patients who underwent background therapy with diet alone, 61.6 ± 2.6% among those who received 10 mg of atorvastatin, 56.8 ± 5.3% among those who received 80 mg of atorvastatin, and 48.5 ± 5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P <0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non–high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.” (E. A. Stein, esteinmrl@aol.com)
Background on Paroxetine Approval for Hot Flushes: Taking the unusual step of defending approval of a new indication, FDA authors provide their rationale for approving paroxetine for menopausal hot flushes (pp. 1777–9). An FDA advisory panel voted 10–4 against approval, but agency officials considered “Brisdelle to be a useful and reasonably safe nonhormonal option for treating moderate-to-severe vasomotor symptoms in menopausal women,” the group writes. They detail the clinical evidence of efficacy and safety and discuss the possibility of suicidal ideation associated with use of the antidepressant in the target age group. Drug interactions are an important consideration with this agent, the writers add, since women undergoing treatment for breast cancer would find the nonhormonal option attractive, and paroxetine interacts with tamoxifen. (R. J. Orleans)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 9, 2014 * Vol. 21, No. 90
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
May 6 issue of Circulation (2014; 129).
Lipidomics Profiling & CVD: Molecular lipid species “constitute promising new biomarkers that outperform the conventional biochemical measurements of lipid classes currently used in clinics,” conclude authors who used mass spectrometry to study lipid signatures (pp. 1821–31). Bruneck Study plasma samples were analyzed to identify and quantify 135 lipid species from 8 lipid classes. Analysis of these species and tracking of patients over 10 years provided these insights: “Among the lipid species with the strongest predictive value were [triacylglycerols (TAGs)] and [cholesterol esters (CEs)] with a low carbon number and double-bond content, including TAG(54:2) and CE(16:1), as well as [phosphatidylethanolamine (PE)](36:5) (P = 5.1×10−7, 2.2×10−4, and 2.5×10−3, respectively). Consideration of these 3 lipid species on top of traditional risk factors resulted in improved risk discrimination and classification for cardiovascular disease (cross-validated ∆C index, 0.0210 [95% confidence interval, 0.0010–0.0422]; integrated discrimination improvement, 0.0212 [95% confidence interval, 0.0031–0.0406]; and continuous net reclassification index, 0.398 [95% confidence interval, 0.175–0.619]). A similar shift in the plasma fatty acid composition was associated with cardiovascular disease in the UK Twin Registry (n = 1,453, 45 cases).” (M. Mayr, manuel.mayr@kcl.ac.uk)
“Lipidomic approaches provide a powerful discovery platform that has promise both to identify new biomarkers of chronic disease and to provide clues into unrecognized lipid metabolic pathways with potential mechanistic links to disease pathogenesis and untapped therapeutic potential,” editorialists write in reaction to this article (
pp. 1799–803). The study should be viewed as hypothesis generating, the authors add, noting, “Moving beyond the provision of descriptive lipidomic lists to mechanistic studies using defined animal model systems represents the next and more challenging step. Indeed, it is an exciting time for the field of lipidomics. We are no longer limited by technology; innovative ideas will be the only limitation moving forward. Undoubtedly, lipidomics provides a rich resource of new information linking metabolism to human disease and will be an important tool for drug discovery in the future.” (S. L. Hazen, hazens@ccf.org)

>>>Cardiology Report
Source:
May 13 issue of the Journal of the American College of Cardiology (2014; 63).
Digoxin in Worsening Chronic Heart Failure: “A therapeutic trial of digoxin may be appropriate in patients with worsening chronic heart failure (HF) who remain symptomatic,” conclude authors based on this assessment in a state-of-the-art review article (pp. 1823–32): “In the pivotal DIG (Digitalis Investigation Group) trial, digoxin therapy was shown to reduce all-cause and HF-specific hospitalizations but had no effect on survival. With the discovery of neurohormonal blockers capable of reducing mortality in HF with reduced ejection fraction, the results of the DIG trial were viewed as neutral, and the use of digoxin declined precipitously. Although modern drug and device-based therapies have dramatically improved the survival of ambulatory patients with HF, outcomes for patients with worsening chronic HF, defined as deteriorating signs and symptoms on standard therapy often leading to unscheduled clinic or emergency department visits or hospitalization, have largely remained unchanged over the past 2 decades.” (A. P. Ambrosy)

>>>PNN NewsWatch
* Vorapaxar (Zontivity, Merck Sharp & Dohme) yesterday became the first protease-activated receptor-1 (PAR-1) antagonist approved by FDA. Formulated as oral tablets, the drug is indicated to reduce the risk of heart attack, stroke, cardiovascular death, and need for coronary revascularization in patients with a previous heart attack or blockages in the arteries to the legs. In a clinical trial with more than 25,000 participants, vorapaxar—added to aspirin, clopidogrel, and/or other antiplatelet agents—reduced the rate of a combined endpoint of heart attack, stroke, cardiovascular death, and emergent coronary revascularization by about 0.5% per year, compared with placebo. As with other inhibitors of clotting, bleeding is a risk with vorapaxar, and the product labeling carries a boxed warning about the possibility.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 12, 2014 * Vol. 21, No. 91
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 10 issue of Lancet (2014; 383).
Angiotensin II Blockade in Postherpetic Neuralgia: In 183 patients with postherpetic neuralgia of at least 6 months’ duration, EMA401 was superior to placebo in relief of symptoms and was well tolerated during a 28-day trial (pp. 1637–47). The agent, a highly selective antagonist of the angiotensin II type 2 receptor, is in clinical trials for relief of neuropathic pain. In this trial, adults aged 22–89 years were randomized to oral EMA401 100 mg twice daily or placebo at 29 centers in 6 countries, with these results: “The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores –2.29 [SD 1.75] vs –1.60 [1.66]; difference of adjusted least square means –0.69 [SE 0.25]; 95% CI –1.19 to –0.20; p = 0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo.” (A. S. C. Rice, a.rice@imperial.ac.uk)

>>>Chest Highlights
Source:
May issue of Chest (2014; 145).
Drug Therapy for Pulmonary Arterial Hypertension: Monotherapy of pulmonary arterial hypertension (PAH) is associated with significantly improved 6-min walk distance (6MWD) and reduced hospitalization rates, according to results of a systematic review and meta-analysis of endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids (pp. 1055–63): “We identified 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insufficient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively).” (R. R. Coeytaux, remy.coeytaux@dm.duke.edu)
Macrolides in Community-Acquired Pseudomonal Pneumonia: Administered during the first 48 hours of hospitalization, macrolide therapy provided no significant benefits among patients with community-acquired pneumonia (CAP) caused by Pseudomonas aeruginosa (pp. 1114–20). In a study of patients at VA facilities, these outcomes were noted for those on macrolides: “We included 402 patients with P aeruginosa CAP, of whom 171 (42.5%) received a macrolide during the first 48 h of admission. These patients were older and white. Macrolide use was not associated with lower 30-day mortality (hazard ratio, 1.14; 95% CI, 0.70–1.83; P = .5). In addition, patients treated with macrolides had no differences in ICU admission, use of mechanical ventilation, use of vasopressors, and length of stay compared with patients not treated with macrolides. A subgroup analysis among patients with P aeruginosa CAP in the ICU showed no differences in baseline characteristics and outcomes.” (M. I. Restrepo, restrepom@uthscsa.edu)

>>>PNN JournalWatch
* Illness in Travelers Returned From Brazil: The GeoSentinel Experience and Implications for the 2014 FIFA World Cup and the 2016 Summer Olympics, in
Clinical Infectious Diseases, 2014; 58: 1347–56. (M. E. Wilson, mewilson@hsph.harvard.edu)
* Challenges and Opportunities in Pediatric Heart Failure and Transplantation: Cardiac Resynchronization Therapy for Pediatric Patients With Heart Failure and Congenital Heart Disease—A Reappraisal of Results, in
Circulation, 2014; 129: 1879–91. (K. S. Motonaga, sachie@stanford.edu)
* Pre-Eclampsia and Future Cardiovascular Risk Among Women: A Review, in
Journal of the American College of Cardiology, 2014; 63: 1815–22. (R. Ahmed)
* Effects of Antioxidant Supplements and Nutrients on Patients With Asthma and Allergies, in
Journal of Allergy and Clinical Immunology, 2014; 133: 1237–44. (H. Moreno–Macias, hmm@xanum.uam.mx)
* Nutrition in the ICU: An Evidence-Based Approach, in
Chest, 2014; 145: 1148–57. (T. W. Rice, todd.rice@vanderbilt.edu)
* Influenza Vaccination by Pharmacists on a Health Sciences Center: A 3-Year Experience, in
Journal of the American Pharmacists Association, 2014; 54: 295–301. (T. Hagemann, Tracy-Hagemann@ouhsc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 13, 2014 * Vol. 21, No. 92
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May issue of JAMA Internal Medicine (2014; 174).
High-Risk Opioid Use: In Tennessee, high-risk use of opioids is “frequent and increasing” and “is associated with increased overdose mortality,” researchers report (pp. 661–2). Using prescription data from the Tennessee Controlled Substances Monitoring Program, high-risk opioid use was defined as four or more prescribers or pharmacies per year, and high-risk dosage as more than 100 morphine milligram equivalents (MMEs) per year. Data analysis and a case–control study of 932 opioid-related deaths during a 24-month period yielded these results: “From January 1, 2007, through December 31, 2011, one-third of the population of Tennessee filled an opioid prescription each year, and opioid prescription rates increased from 108.3 to 142.5 per 100 population per year. Among all patients in Tennessee prescribed opioids during 2011, 7.6% used more than 4 prescribers, 2.5% used more than 4 pharmacies, and 2.8% had a mean daily dosage greater than 100 MMEs. Increased risk of opioid-related overdose death was associated with 4 or more prescribers (adjusted odds ratio [aOR], 6.5; 95% CI, 5.1–8.5), 4 or more pharmacies (aOR, 6.0; 95% CI, 4.4–8.3), and more than 100 MMEs (aOR, 11.2; 95% CI, 8.3–15.1). Persons with 1 or more risk factor [physicians, pharmacies, high opioid dosages] accounted for 55% of all overdose deaths.” (S. A. Flanders, flanders@umich.edu)
Omega-3 Supplementation in CVD: Reacting to negative results in the Cardiovascular Outcome Study (COS) of long-chain omega-3 fatty acids and macular xanthophylls (lutein plus zeaxanthin) in patients with intermediate or advanced age-related macular degeneration in 1 eye (pp. 763–71; D. E. Bonds, bondsde@nhlbi.nih.gov), editorialists make these observations about the future of research into effects of the supplements on cardiovascular disease (CVD) (pp. 771–2): “After many years of randomized evidence accumulated on various outcomes across a variety of diseases, omega-3 supplementation still fails to find its place in everyday clinical practice. With more than 2,000 PubMed-indexed clinical trials (more than 600 published after 2010), almost 200 systematic reviews and meta-analyses, and more than 700 registered ‘closed’ trials awaiting results, the omega-3 research agenda seems to be losing focus. There are 22 [randomized controlled trials [RCTs]] addressing the effect of omega-3 on CVD; 9 of them are mega-trials with more than 1000 participants. What is evident so far is that omega-3 supplementation with daily doses close to 1 g in patients with or without established CVD shows no clear, considerable benefit. Continuing to conduct more RCTs seems unjustified. The time is ripe for a meta-analysis of individual participant data where investigators will have the valuable opportunity to carry out time-to-event and subgroup analyses uniformly across all studies and draw conclusions on the postulated omega-3 varying effects based on the participants’ characteristics.” (E. C. Rizos, vagrizos@gmail.com)
Why Antimicrobial Overuse Persists in Hospitals: Balancing the needs of the patient against potential harms to society, physicians will err on the side of their patients, Viewpoint authors write, muting effects of efforts to reduce overuse of antimicrobial agents (pp. 796–801). Stewardship programs are especially effective in countering this tendency, the authors write: “The needed solutions should play to physicians’ ‘individualistic needs’ but also provide for a greater societal benefit. Fortunately, many promising strategies have been tested and found effective. The development of robust antimicrobial stewardship programs have been particularly important. Stewardship programs, often led by infectious diseases physicians in partnership with clinical pharmacists, use strategies such as formulary restrictions, guideline development, and audit and feedback to clinicians to better monitor and direct antimicrobial use. Despite the successes of such programs, however, they may be difficult to implement and are only part of the solution. The institutions that have done the most have also worked hard to actively engage clinicians. Hospitalists, who are responsible for the care of an increasingly large percentage of hospitalized patients and therefore much of the antimicrobial prescribing, should figure prominently in engagement efforts.” (J. A. Gwira Baumblat)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 14, 2014 * Vol. 21, No. 93
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 14 issue of JAMA (2014; 311).
Drug Therapy of Alcohol Use Disorders: Acamprosate and naltrexone are similarly effective in patients seeking to avoid returns to drinking, according to authors who conducted a systematic review and meta-analysis of 123 studies of 22,803 participants (pp. 1889–900). The group concluded that “factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice,” adding these details about numbers needed to treat (NNT) and harm (NNH) and other results: “The NNT to prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD], −0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to −0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0; 95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate.” (D. E. Jonas, daniel_jonas@med.unc.edu)
Under the Affordable Care Act, treatment of alcohol use disorders (AUDs) is an essential health benefit, editorialists write, and this should drive demand for patient-centered care of the conditions (
pp. 1861–2). Noting that the Jonas et al. article found the oldest FDA-approved medication, disulfiram, lacking in evidence from well-controlled trials, the editorialists conclude: “[This] article … should encourage patients and their clinicians to engage in shared decision making about AUD treatment options. By identifying 4 effective medications for AUD [naltrexone, acamprosate, topiramate, and nalmefene], the authors highlight treatment options for a common medical condition for which patient-centered care is not currently the norm. Patients with AUDs should be offered options, including medications, evidence-based behavioral treatments, and mutual support for recovery. Moreover, patients should expect shared decision making about the best options for them.” (K. Bradley, bradley.k@ghc.org)
Evolocumab for Hypercholesterolemia: Added to moderate- or high-intensity statin therapy, the human monoclonal PCSK9 antibody evolocumab provided additional lowering of LDL cholesterol, according to results of the LAPLACE-2 (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) study (pp. 1870–82). Administered every 2 weeks or monthly, evolocumab reduced LDL-C levels by 66–75% and 63–75%, respectively. “For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL,” the authors add. (J. G. Robinson, jennifer-g-robinson@uiowa.edu)

>>>PNN NewsWatch
* Dabigatran (Pradaxa, Boehringer Ingelheim) lowers patients’ risk of embolic events but increases the risk of major gastrointestinal bleeding, compared with warfarin, FDA warned yesterday. New data underlying the notice are from a study of a much larger and older patient population than previously considered.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 15, 2014 * Vol. 21, No. 94
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 15 issue of the New England Journal of Medicine (2014; 370).
Ledipasvir & Sofosbuvir for Hepatitis C Virus Infection: Two research studies and an editorial examine treatment options for hepatitis C virus (HCV) infections.
Among 647 previously untreated patients with HCV genotype 1 infections without cirrhosis, ledipasvir plus sofosbuvir produced high rates of sustained virologic responses, researchers report, and inclusion of ribavirin yielded no additional benefit in a 12-week, Phase III, open-label trial (
pp. 1879–88). Participants received ledipasvir–sofosbuvir with or without ribavirin for 8 weeks or ledipasvir–sofosbuvir for 12 weeks, with these results: “The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir–sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir–sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir–sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir–sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, −4 to 6) and the rate in the group that received 8 weeks of ledipasvir–sofosbuvir with ribavirin was 1 percentage point lower (95% CI, −6 to 4); these results indicated noninferiority of the 8-week ledipasvir–sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir–sofosbuvir discontinued treatment owing to adverse events.” (K. V. Kowdley, kris.kowdley@vmmc.org)
In a second Phase III, open-label trial, previously untreated patients with HCV-1 infection had significantly improved sustained virologic responses during 12 or 24 weeks of once-daily ledipasvir–sofosbuvir treatment with or without ribavirin (
pp. 1889–98): “Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir–sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir–sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir–sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir–sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir–sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea.” (N. Afdhal, nafdhal@bidmc.harvard.edu)
In identifying avenues for access to these drugs for millions of HCV-infected people in low- and middle-income countries, editorialists discuss the huge gap between the manufacturing cost of oral anti-HCV agents ($100–270 for a 3-month supply) and the annual cost of the regimen in developed countries ($90,000) (
pp. 1869–71; C. R. Jayasekera).

>>>PNN NewsWatch
* Adults at risk of acquiring HIV through sexual activity or injection drug use should take a daily, fixed-dose pre-exposure prophylactic drug product, CDC said yesterday. After decades of recommending safe-sex practices based on condom use, the agency added chemoprophylaxis to its recommendation after reviewing data that show declining use of safe-sex practices and a steady stream of about 50,000 newly infected Americans each year, the New York Times reports. CDC recommended daily use of Truvada, Gilead’s fixed-dose combination product containing tenofovir disoproxil fumarate 300 mg and emcitrabine 200 mg. Pre-exposure prophylaxis is now recommended “as one prevention option” for sexually active men who have sex with men and are at substantial risk of HIV acquisition; adult heterosexually active men and women who are at substantial risk of HIV acquisition; and adult injection drug users who are at substantial risk of HIV acquisition. The Times said the annual cost of the therapy is about $13,000 and that the product is covered by most third-party payers. Before therapy begins, patients should be screened for HIV infection and renal function measured. HIV status should be checked every 3 months and renal function every 6 months while on the drugs.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 16, 2014 * Vol. 21, No. 95
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
May Journal of the American Geriatrics Society (2014; 62).
New Oral Anticoagulants in Older Adults: In patients 75 years of age or older, the new oral anticoagulants (NOACs)— rivaroxaban, apixaban, and dabigatran—were at least as efficacious as conventional therapies in randomized clinical trials (RCTs) and did not produce excess bleeding, a meta-analysis shows (pp. 857–64): “Ten RCTs included 25,031 elderly participants. Risk of major or clinically relevant bleeding was not significantly different between NOACs and conventional therapy in elderly adults (OR = 1.02, 95% confidence interval = 0.73–1.43). Similar results were observed when comparing NOACs and pharmacologically active agents. In atrial fibrillation (AF) trials, NOACs were more effective than conventional therapy in prevention of stroke or systemic embolism in an elderly population with AF. In non-AF trials, NOACs also had a significantly lower risk of venous thromboembolism (VTE) or VTE-related death than conventional therapy in elderly adults. Analysis for individual NOACs showed that the NOAC was noninferior or more effective than conventional therapy for efficacy and safety outcomes.” (P. Sardar, parthasardarmd@gmail.com)
Antibiotic Stewardship in Nursing Homes: Through prescriber and family education about antibiotic guidelines, investigators achieved a 10-fold reduction in use of anti-infective agents in intervention nursing homes, compared with control facilities (pp. 907–12). The 9-month quasi-experimental trial of the quality improvement (QI) program in 12 North Carolina nursing homes produced these outcomes: “The QI program reduced the number of prescriptions ordered between baseline and follow-up more in intervention than in comparison nursing homes (adjusted incidence rate ratio = 0.86, 95% confidence interval = 0.79–0.95). Based on baseline prescribing rates of 12.95 prescriptions per 1,000 resident–days, this estimated adjusted incidence rate ratio implies 1.8 prescriptions avoided per 1,000 resident–days.” (S. Zimmerman, sheryl_zimmerman@unc.edu)

>>>Allergy/Immunology Report
Source:
May Journal of Allergy and Clinical Immunology (2014; 133).
Asthma Phenotypes & Anti-inflammatory Medications: In children with asthma, the long-term need for prednisone or additional controller medications can be predicted through a phenotypic clustering technique, researchers report (pp. 1289–300.e12). The findings have “implications for targeted therapeutic strategies and clinical trials design,” the authors conclude based on these findings in 1,041 participants in the Childhood Asthma Management Program: “We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.” (B. A. Raby, rebar@channing.harvard.edu)

>>>PNN NewsWatch
* The starting dose for eszopiclone (Lunesta, Sunovion) has been cut in half, FDA said yesterday. Based on evidence of driving impairment in some people the morning after using 2-mg doses of the drug, the agency has set the starting dose at 1 mg for both men and women. Doses can be advanced when need to 2 mg or 3 mg, FDA said, “but the higher doses are more likely to result in next-day impairment of driving and other activities that require full alertness. Using lower doses means less drug will remain in the body in the morning hours.”
* Hospira has recalled to the user level for one lot of
Dobutamine Injection, USP, 250 mg, 20 mL, single-dose fliptop vial, lot 27-352-DK, FDA said yesterday. Visible particulate matter has been observed in the lot, which was distributed nationwide to wholesalers, hospitals, and clinics in Aug/Sept 2013.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 19, 2014 * Vol. 21, No. 96
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 17 issue of Lancet (2014; 383).
Infliximab for Kawasaki Disease: In a Phase III trial of intensification of primary therapy in children with acute Kawasaki disease, infliximab “did not reduce treatment resistance” but “was safe and well tolerated and reduced fever duration, some markers of inflammation, left anterior descending coronary artery Z score, and intravenous immunoglobulin reaction rates,” researchers report (pp. 1731–8). The disease, an acquired heart condition with a self-limited vasculitis, is treated with high doses of I.V. immunoglobulins. Resistance to these agents increases the risk of coronary artery aneurysms.
In the study, 196 infants, children, and adolescents at two U.S. children’s hospitals had these responses to infliximab or placebo: “Treatment resistance rate did not differ significantly (11 [11.2%] for infliximab and 11 [11.3%] for placebo; p = 0.81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p <0.0001). At week 2, infliximab-treated patients had greater mean reductions in erythrocyte sedimentation rate (p = 0.009) and a two-fold greater decrease in Z score of the left anterior descending artery (p = 0.045) than did those in the placebo group, but this difference was not significant at week 5. Participants in the infliximab group had a greater mean reduction in C-reactive protein concentration (p = 0.0003) and in absolute neutrophil count (p = 0.024) at 24 h after treatment than did those given placebo, but by week 2 this difference was not significant. At week 5, none of the laboratory values differed significantly compared with baseline. No significant differences were recorded between the two groups at any timepoint in proximal right coronary artery Z scores, age-adjusted haemoglobin values, duration of hospital stay, or any other laboratory markers of inflammation measured. No reactions to intravenous immunoglobulin infusion occurred in patients treated with infliximab compared with 13 (13.4%) patients given placebo (p <0.0001). No serious adverse events were directly attributable to infliximab infusion.” (A. H. Tremoulet,
atremoulet@ucsd.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Long-Term Drug Prevention of Asthma Exacerbations: “Strategies with combined inhaled corticosteroids and long acting beta agonists are most effective and safe in preventing severe exacerbations of asthma,” according to results of a network meta-analysis (g3009). Using low-dose inhaled corticosteroids as the comparator strategy, the analysis found these results in 64 trials of 15 strategies/placebo in 59,622 patient–years: “For prevention of severe exacerbations, combined inhaled corticosteroids and long acting beta agonists as maintenance and reliever treatment and combined inhaled corticosteroids and long acting beta agonists in a fixed daily dose performed equally well and were ranked first for effectiveness. The rate ratios compared with low dose inhaled corticosteroids were 0.44 (95% credible interval 0.29 to 0.66) and 0.51 (0.35 to 0.77), respectively. Other combined strategies were not superior to inhaled corticosteroids and all single drug treatments were inferior to single low dose inhaled corticosteroids. Safety was best for conventional best (guideline based) practice and combined maintenance and reliever therapy.” (R. J. B. Loymans, r.j.loijmans@amc.nl)

>>>PNN JournalWatch
* Effects of Nutritional Supplementation for HIV Patients Starting Antiretroviral Treatment: Randomised Controlled Trial in Ethiopia, in
BMJ, 2014; 348: g3187. (M. F. Olsen, mette.frahm.olsen@gmail.com)
* Long Term Maintenance of Weight Loss With Non-Surgical Interventions in Obese Adults: Systematic Review and Meta-Analyses of Randomised Controlled Trials, in
BMJ, 2014; 348: g2646. (F. F. Sniehotta, falko.sniehotta@ncl.ac.uk)
* Review: Antinucleosome Antibodies: A Critical Reflection on Their Specificities and Diagnostic Impact, in
Arthritis & Rheumatology, 2014; 66: 1061–9. (O. P. Rekvig, lepr@fagmed.uit.no">olepr@fagmed.uit.no)
* New Hepatitis C Therapies: The Toolbox, Strategies, and Challenges, in
Gastroenterology, 2014; 146: 1176–92. (J–M Pawlotsky, jean-michel.pawlotsky@hmn.aphp.fr)
* KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD, in
American Journal of Kidney Disease, 2014; 63: 713–35. (L. A. Inker, linker@tuftsmedicalcenter.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 20, 2014 * Vol. 21, No. 97
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 20 issue of the Annals of Internal Medicine (2014; 160).
Vaccine v. Nonpharmaceutical Interventions in Influenza Pandemic: In a modeling pandemic study, investigators calculate the deaths that could be averted through faster provision of influenza vaccine and ways nonpharmaceutical interventions could be used to prevent deaths before vaccine availability (pp. 684–94). The scenario used in the model is a city similar in characteristics to New York City and an influenza pandemic with characteristics similar to influenza A(H7N9) and A(H5N1).Using a societal perspective with a lifetime horizon, the base-case and sensitivity analyses yielded these results: “In 12 months, 48,254 persons would die. Vaccinating at 9 months would avert 2,365 of these deaths. Vaccinating at 6 months would save 5,775 additional lives and $51 million at a city level. Accelerating delivery to 4 months would save an additional 5,633 lives and $50 million.…
“If vaccination were delayed for 9 months, reducing contacts by 8% through nonpharmaceutical interventions would yield a similar reduction in infections and deaths as vaccination at 4 months.” (N. Khazeni,
nayer@stanford.edu)
Low-Dose Aspirin in Preeclampsia: In a systematic evidence review conducted for the U.S. Preventive Services Task Force regarding use of aspirin in preeclampsia, researchers conclude that “daily low-dose aspirin beginning as early as the second trimester prevented clinically important health outcomes” (pp. 695–703): “Two large, multisite [randomized controlled trials (RCTs)] and 13 smaller RCTs of high-risk women (8 good-quality) were included, in addition to 6 RCTs and 2 observational studies of average-risk women to assess harms (7 good-quality). Depending on baseline risk, aspirin use was associated with absolute risk reductions of 2% to 5% for preeclampsia (relative risk [RR], 0.76 [95% CI, 0.62 to 0.95]), 1% to 5% for intrauterine growth restriction (RR, 0.80 [CI, 0.65 to 0.99]), and 2% to 4% for preterm birth (RR, 0.86 [CI, 0.76 to 0.98]). No significant perinatal or maternal harms were identified, but rare harms could not be ruled out. Evidence on long-term outcomes was sparse, but 18-month follow-up from the largest trial found no developmental harms.” (Agency for Healthcare Research and Quality, www.ahrq.gov)
Biological Agents for Ulcerative Colitis: Used for treating moderately to severely active ulcerative colitis (UC), biologic agents are effective but evidence from head-to-head trials is lacking, authors of a systematic review and network meta-analysis conclude (pp. 704–11): “There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo.” (S. Danese, silvio.danese@humanitas.it)
Screening for Suicide Risk in Primary Care: In a final recommendation statement, the U.S. Preventive Services Task Force (USPSTF) finds insufficient evidence to recommend for or against screening adolescents, adults, and older adults for suicide risk (pp. 719–26). USPSTF did recommend that health care professionals consider identifying patients with risk factors or those who seem to have high levels of emotional distress and referring them for further evaluation. Some risk factors for suicide include having a mental health disorder, such as depression, schizophrenia, or posttraumatic stress disorder, having a substance abuse issue, or being socially isolated. American Indians or Alaskan natives also have higher rates of suicide. The Task Force continues to recommend that adults and adolescents be screened for depression, as evidence has shown that screening for depression coupled with available treatments is effective. (USPSTF website, www.uspreventiveservicestaskforce.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 21, 2014 * Vol. 21, No. 98
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 21 issue of JAMA (2014; 311).
Maintenance Treatment of Schizophrenia: A long-acting formulation of the second-generation antipsychotic agent paliperidone palmitate is equivalent in efficacy failure to depot haloperidol decanoate, researchers report, but confidence intervals from the study “do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate” (pp. 1978–87). Among 311 adult patients with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic, the two agents differed in adverse effects, as described in these results: “There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65–1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25–3.09) and was decreased for those taking haloperidol decanoate (−0.96 kg; 95% CI, −1.88 to −0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75–39.37] vs 15.41 µg/L [95% CI, 10.73–20.08]; P <.001, and for women, 75.19 [95% CI, 63.03–87.36] vs 26.84 [95% CI, 13.29–40.40]; P <.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59–0.87] vs 0.45 [95% CI, 0.31–0.59]; P = .006).” (T. S. Stroup, stroups@nyspi.columbia.edu)
“Setting aside the substantial differences in cost between haloperidol decanoate and paliperidone palmitate, the results from [this] ACLAIMS trial suggest that drug selection should be based on anticipated adverse effects rather than efficacy,” an editorialist writes (
pp. 1973–4). “This is true for most antipsychotics, with the notable exception of clozapine, which has established superior efficacy for treatment-resistant schizophrenia but is limited in use due to more serious adverse effects. Although patients may try medications sequentially to identify an optimal agent, this approach may be problematic if adverse effects persist after drug discontinuation, such as weight gain or involuntary movements. Additional data from patient samples exposed for a longer duration to a wider range of antipsychotics are needed to better characterize the relative risk of adverse effects, examine their longer term consequences, and identify biomarkers that will allow a personalized medicine approach. Not only is the compilation of reliable data about these drugs essential, so also is the clear communication of this information to patients as part of the shared decision-making process.” (D. C. Goff, donald.goff@nyumc.org)
Antibiotic Prescribing for Adults With Acute Bronchitis: Despite years of education about the lack of benefit of antibiotics in adults with acute bronchitis, a research letter finds that the drugs were prescribed during 71% of ambulatory care visits involving a diagnosis of the condition (pp. 2020–2). Nationally representative data showed these patterns for 1996–2010: “The overall antibiotic prescription rate was 71% (95% CI, 66%–76%) and increased between 1996 and 2010 (adjusted odds ratio per 10-year period, 1.75 [95% CI, 1.06–2.90]; P = .03). There was a statistically significant increase in antibiotic prescribing in [emergency departments]. Physicians prescribed extended macrolides at 36% (95% CI, 32%–41%) of acute bronchitis visits and extended macrolide prescribing increased from 25% of visits in 1996–1998 to 41% in 2008–2010 (P = .01). Other antibiotics were prescribed at 35% (95% CI, 30%–39%) of visits, and most commonly were fluoroquinolones, aminopenicillins, and cephalosporins. The antibiotic prescribing rate for other antibiotics did not change significantly over time (48% of visits in 1996–1998 to 35% of visits in 2008–2010; P = .55).” (J. A. Linder, jlinder@partners.org)

>>>PNN NewsWatch
* Vedolizumab (Entyvio, Takeda) has been approved by FDA for treatment of adults with moderate to severe ulcerative colitis or Crohn’s disease.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 22, 2014 * Vol. 21, No. 99
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 22 issue of the New England Journal of Medicine (2014; 370).
Treatment of HCV Infection: Three studies and an editorial present evidence on treatments for hepatitis C virus (HCV) infections.
High rates of sustained virologic response resulted from open-label therapy of HCV infection with cirrhosis with ABT-450 with ritonavir (ABT-450/r), ombitasvir (ABT-267), dasabuvir (ABT-333), and ribavirin, Phase III investigators write (
pp. 1973–82): “A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events.” (F. Poordad, poordad@uthscsa.edu)
In a study of ABT-450/r, ombitasvir, and dasabuvir with or without ribavirin therapy in patients with HCV genotype 1a or 1b infections, higher rates of virologic failure were observed with ribavirin in those with 1a (7.8% versus 2.0% without the drug) but not 1b infections (
pp. 1983–92). The PEARL III and PEARL IV studies report “high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively).” (P. Ferenci, peter.ferenci@meduniwien.ac.at)
Among patients with HCV genotype 2 or 3 infection, therapy with sofosbuvir–ribavirin for 12 or 24 weeks, respectively, produced high rates of sustained virologic response (93% and 85%, respectively) (
pp. 1993–2001). “Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively,” the investigators report. “The most common adverse events were headache, fatigue, and pruritus.” (S. Zeuzem, zeuzem@em.uni-frankfurt.de)
Despite these positive results, editorialists write that the “book on treatment of HCV infection” is not closed (
pp. 2043–7): “The regimens have been tested predominantly in middle-aged, white men without cirrhosis. More-difficult-to-treat patients, such as those with cirrhosis, human immunodeficiency virus and HCV coinfection, or renal failure, remain a challenge. It is also not clear whether these regimens will be effective in those infected with HCV genotypes 4, 5, and 6, which are common in many parts of the world. Finally, the cost of treatment, which was highlighted in a recent editorial in the Journal, will continue to be a deterrent for population-wide applications of these highly effective regimens. This dilemma is not only a topic of ongoing debate in the more developed countries, such as the United States and western European countries, but it is also a truly global public health problem of enormous impact— the majority of people with HCV infection live in lower-income, resource-constrained regions of the world. As pointed out in our previous review article and a recent Perspective article in the Journal, the challenge will indeed continue to be how we can leverage modern medical advances, such as the treatment of HCV infection, to benefit those who are most in need.” (T. J. Liang)

>>>PNN NewsWatch
* The evidence supporting pharmacists’ positive impact on clinical and economic outcomes is growing, according to an Avalere Health report released yesterday. Continued research is needed to “further inform policy makers and health care providers,” the report concluded, according to a news article on pharmacist.com. “The report also concluded that reimbursement policies should be aligned to increase use of pharmacists’ services to deliver the highest value health care to patients,” the news article stated. The report, produced with full editorial control by Avalere, was funded by APhA, ASHP, AACP, ASCP, NACDS, and the National Alliance of State Pharmacy Associations.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 23, 2014 * Vol. 21, No. 100
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
May issue of Health Affairs (2014; 33).
Growth in Cost of Treatment: Programs that target reduction of average spending growth in treatment of disease are unlikely to be very successful, an analysis shows, given the rate of population growth (pp. 823–31). Data for 1980–2006 from four nationally representative surveys enabled study authors to examine the divide over whether treatment costs are driven more by population growth or increases in treatment costs: “We found that rising costs of treatment accounted for 70 percent of growth in real average health care spending from 1980 to 2006. The contribution of shares of the population treated for given diseases increased in 1997–2006, but even then it accounted for only one-third of spending growth. We highlight the fact that Thorpe’s inclusion of population growth as part of disease prevalence explains the appreciable difference in results. An important policy implication is that programs to better manage chronic diseases may only modestly reduce average spending growth.” (A. Aizcorbe, ana1@vbi.vt.edu)
Age- and Gender-Adjusted Health Spending Trends: During 2002–10, aggregate data show interesting trends in age- and gender-specific per-capita spending (pp. 815–22): “Our research found that in this period, aggregate spending on children’s health care increased at the slowest rate. However, per capita spending for children grew more rapidly than that for working-age adults and the elderly. Per capita spending for the elderly remained about five times higher than spending for children. Overall, females spent more per capita than males, but the gap had decreased by 2010. The implementation of Medicare Part D, the effects of the recent recession, and the aging of the baby boomers affected the spending trends and distributions during the period of this study.” (D. Lassman, avid.Lassman2@cms.hhs.gov">David.Lassman2@cms.hhs.gov)

>>>Medical Care Report
Source:
June issue of Medical Care (2014; 52).
Medicare Part D & Generic Drugs: Among Medicare beneficiaries covered under Part D, cost-sharing features and utilization management are driving generic use for antidepressants, antidiabetics, and statins, researchers report (pp. 541–8). Data from 2009 for 1.6 million fee-for-service enrollees aged 65 years or older show these patterns: “Generic cost-sharing ranged from $0 to $9 for antidepressants and statins, and from $0 to $8 for antidiabetics (across 5th–95th percentiles). Brand-generic cost-sharing differences were smallest for statins (5th–95th percentiles: $16–$37) and largest for antidepressants ($16–$64) across plans. Beneficiaries with higher generic cost-sharing had lower generic use [adjusted odds ratio (OR) = 0.97, 95% confidence interval (CI), 0.95–0.98 for antidepressants; OR = 0.97, 95% CI, 0.96–0.98 for antidiabetics; OR = 0.94, 95% CI, 0.92–0.95 for statins]. Larger brand-generic cost-sharing differences and prior authorization were significantly associated with greater generic use in all categories. Plans could increase generic use by 5–12 percentage points by reducing generic cost-sharing from the 75th ($7) to 25th percentiles ($4–$5), increasing brand-generic cost-sharing differences from the 25th ($25–$26) to 75th ($32–$33) percentiles, and using prior authorization and step therapy.” (Y. Tang)
Practitioners in Rural Primary Care: Shifting primary care toward nurse practitioners (NPs) and physician assistants (PAs) in rural America might reduce the availability of services traditionally provided by physicians outside the outpatient clinic setting, an analysis of data from 13 states shows (pp. 549–56): “Compared with physicians, average weekly outpatient visit quantity was 8% lower for PAs and 25% lower for NPs (P <0.001). After multivariate adjustment, this gap became negligible for PAs (P = 0.56) and decreased to 10% for NPs (P <0.001). Compared with PAs and NPs, primary care physicians were more likely to provide services beyond the outpatient setting, including hospital care, emergency care, childbirth attending deliveries, and after-hours call coverage (all P <0.001).” (M. P. Doescher)

>>>PNN NewsWatch
* Baxter’s ABACUS TPN calculation software is the target of a Class I recall, FDA said yesterday. System failures can place patients at risk for toxic or overdose symptoms.
*
PNN will not be published on Mon., May 26, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 27, 2014 * Vol. 21, No. 101
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
In-Hospital Time to Epinephrine Administration in Nonshockable Cardiac Arrest: In 570 U.S. hospitals in 2000–09, patients with nonshockable cardiac arrest had better outcomes when epinephrine was administered within 3–6 minutes, shows a post-hoc analysis of the Get With The Guidelines-Resuscitation database (g3028). Data for nearly 120,000 adults (mean age, 72; 57% men) had these outcomes after treatment for asystole (55%) or pulseless electrical activity (45%): “25,095 adults had in-hospital cardiac arrest with non-shockable rhythms. Median time to administration of the first dose of epinephrine was 3 minutes (interquartile range 1–5 minutes). There was a stepwise decrease in survival with increasing interval of time to epinephrine (analyzed by three minute intervals): adjusted odds ratio 1.0 for 1–3 minutes (reference group); 0.91 (95% confidence interval 0.82 to 1.00; P = 0.055) for 4–6 minutes; 0.74 (0.63 to 0.88; P <0.001) for 7–9 minutes; and 0.63 (0.52 to 0.76; P <0.001) for >9 minutes. A similar stepwise effect was observed across all outcome variables.” (M. W. Donnino, mdonnino@bidmc.harvard.edu)
Helicobacter pylori Eradication & Gastric Cancer Prevention: In healthy, asymptomatic patients of Asian descent, identification and treatment of Helicobacter pylori was linked to reduced incidence of gastric cancer, according to a systematic review and meta-analysis of randomized controlled trials (g3174): “The search strategy identified 1,560 citations, of which six individual randomised controlled trials were eligible. Fifty one (1.6%) gastric cancers occurred among 3,294 individuals who received eradication therapy versus 76 (2.4%) in 3,203 control subjects (relative risk 0.66, 95% confidence interval 0.46 to 0.95), with no heterogeneity between studies (I2 = 0%, P = 0.60). If the benefit of eradication therapy was assumed to persist lifelong the number needed to treat was as low as 15 for Chinese men and as high as 245 for US women.” (A. C. Ford, alexf12399@yahoo.com)

>>>PNN NewsWatch
* Dalbavancin (Dalvance, Durata Therapeutics) on Friday became the first product approved by FDA as a Qualified Infectious Disease Product (QIDP). The intravenous agent is approved for treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria such as Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains) and Streptococcus pyogenes. FDA granted QIDP status because dalbavancin is an antibacterial or antifungal human drug intended to treat serious or life-threatening infections, FDA said. As part of its QIDP designation, Dalvance was given priority review and also qualifies for an additional 5 years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug and Cosmetic Act. The drug’s safety and efficacy were evaluated in two clinical trials with a total of 1,289 adults with ABSSSI. Results showed dalbavancin was as effective as vancomycin for the treatment of these infections. The most common adverse effects identified in the clinical trials were nausea, headache, and diarrhea. In the trials, more participants in the dalbavancin group had elevations in one of their liver enzyme tests. The drug label provides recommendations on dosage adjustment in patients with renal impairment.

>>>PNN JournalWatch
* Oral Anticancer Drugs: How Limited Dosing Options and Dose Reductions May Affect Outcomes in Comparative Trials and Efficacy in Patients, in
Journal of Clinical Oncology, 2014; 32: 1620–9. (V. Prasad, vinayak.prasad@nih.gov)
* Effects of Cannabis on Cognition in Patients with MS: A Psychometric and MRI Study, in
Neurology, 2014; 10.1212/WNL.0000000000000446. (A. Feinstein, ant.feinstein@utoronto.ca)
* Insulin Analogs—Are They Worth It? Yes!, in
Diabetes Care, 2014; 37: 1767–70. (G. Grunberger, grunberger@comcast.net) and Insulin Analogs—Is There a Compelling Case to Use Them? No!, in Diabetes Care, 2014; 37: 1771–4. (M. B. Davidson, mayerdavidson@cdrewu.edu)
* Computer-Based Interventions To Improve Self-management in Adults With Type 2 Diabetes: A Systematic Review and Meta-analysis, in
Diabetes Care, 2014; 37: 1759–66. (K. Pal, k.pal@ucl.ac.uk)
* Antimicrobial Treatment of Asymptomatic Bacteriuria in Noncatheterized Adults: A Systematic Review, in
Pharmacotherapy, 2014; 10.1002/phar.1437. (R. B. Dull, ryandull@creighton.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 28, 2014 * Vol. 21, No. 102
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 28 issue of JAMA (2014; 311).
Vitamin C & Smoking During Pregnancy: In women who were smoked while pregnant, vitamin C 500 mg daily improved pulmonary outcomes in offspring at birth and during the first year of life, researchers report (pp. 2074–82). In 2007–11, these pulmonary test function (PFT) and other results were recorded for 159 newborns of pregnant women randomized to vitamin C or placebo and 76 newborns of pregnant nonsmokers: “Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by [the ratio of the time to peak tidal expiratory flow to expiratory time] (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011–0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02–0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33–0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the alpha-5 nicotinic receptor (rs16969968) (P <.001 for interaction).” (C. T. McEvoy, mcevoyc@ohsu.edu)
“Smoking cessation for all individuals—especially for women planning to have children—remains among the most important public health efforts to improve maternal and fetal health outcomes,” an editorialist writes (
pp. 2070–1). When cessation is not achievable, the writer notes that “the findings from the study by McEvoy et al. offer an approach for potentially minimizing the harmful effects of maternal smoking during pregnancy on the respiratory health of infants.” (G. L. Hall, graham.hall@telethonkids.org.au)
Vitamin D & Asthma: In adult patients with persistent asthma and vitamin D insufficiency, supplementation with oral vitamin D3 or placebo yielded statistically similar results, report VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) investigators (pp. 2083–91). Among 408 patients, those randomized to vitamin D3 received 100,000 IU once and 4,000 IU/d for 28 weeks, with these results: “Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%–34%] with vitamin D3 vs 29% [95% CI, 23%–35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6–1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2–120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2–135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1–27.7 µg/d]).” (T. S. King, tking@phs.psu.edu)
Durability of Clinical Practice Guideline Recommendations: Class I cardiology guidelines varied in their durability between 2006 and 2013, a study shows (pp. 2092–100). Of 619 recommendations made in guidelines of the American College of Cardiology/American Heart Association, 495 (80%) were retained in subsequent versions. Across guidelines, the percentage of retained recommendations varied from 15.4% to 94.1%. “After accounting for guideline-level factors, the probability of being downgraded, reversed, or omitted was greater for recommendations based on opinion (odds ratio, 3.14; 95% CI, 1.69–5.85; P <.001) or on 1 trial or observational data (odds ratio, 3.49; 95% CI, 1.45–8.41; P = .005) vs recommendations based on multiple trials,” the authors report. (M. D. Neuman, neumanm@mail.med.upenn.edu)
“The need for surveillance and updating of practice guidelines is increasingly gaining attention,” an editorialist writes (
pp. 2072–3). “To meet the need, guideline development organizations need to change their focus. This change is not easy. It is not just a matter of resources, although guideline organizations are going to have to devote more resources to active surveillance and maintenance of their guidelines than most probably do at present. It also has to be a change to the mindset, recognizing that keeping existing guidelines up-to-date in a timely way is an important goal for good patient care.” (P. G. Shekelle, paul.shekelle@va.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 29, 2014 * Vol. 21, No. 103
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 29 issue of the New England Journal of Medicine (2014; 370).
Treatment of Pulmonary Fibrosis: Three studies and an editorial examine new and existing therapies for pulmonary fibrosis.
Nintedanib, an inhibitor of multiple tyrosine kinases, reduced patients’ declining forced vital capacity (FVC), according to results of two 52-week Phase III trials in 1,066 patients with idiopathic pulmonary fibrosis (
pp. 2071–82). This “is consistent with a slowing of disease progression,” the authors write, but “nintedanib was frequently associated with diarrhea.” This occurred in 61.5% of patients on active therapy, compared with 18.6% of those on placebo, but the adverse effect “led to discontinuation of the study medication in less than 5% of patients.” (L. Richeldi, l.richeldi@soton.ac.uk)
Pirfenidone, an oral antifibrotic agent, “reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis,” compared with placebo, in a Phase III trial (
pp. 2083–92). “Treatment was associated with an acceptable side-effect profile and fewer deaths,” the authors add. (T. E. King, Jr., tking@medicine.ucsf.edu)
Acetylcysteine, used alone or in a three-drug regimen with prednisone and azathioprine, “offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function,” report investigators in the Idiopathic Pulmonary Fibrosis Clinical Research Network (
pp. 2093–101). Among 264 patients receiving acetylcysteine alone or placebo, these outcomes were noted: “At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (−0.18 liters and −0.19 liters, respectively; P = 0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P = 0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P >0.99).” (G. Raghu, graghu@uw.edu)
These studies provide “new hope for idiopathic pulmonary fibrosis,” an editorialist writes (
pp. 2142–3): “The publication of the results of Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in Idiopathic Pulmonary Fibrosis (PANTHER-IPF) completes a separate trilogy of studies. However, unlike the results for the drugs evaluated in the INPULSIS and ASCEND trials, the initial promise of this three-drug regimen has now faded. As reported in the Journal, it appears that acetylcysteine does not slow the rate of decline in FVC, although it may reduce the toxicity of prednisone and azathioprine in patients with idiopathic pulmonary fibrosis. From these findings, it is reasonable to shift our understanding of the pathogenesis of this disease. It is now clear that idiopathic pulmonary fibrosis is a disease perpetuated by aberrant wound healing, rather than primarily by chronic inflammation. With new understanding comes new hope. As in the 1977 episode of the Star Wars series, the force is finally with us. May we learn to use it wisely.” (G. M. Hunninghake)
Medication-Assisted Therapies in the Opioid Epidemic: The availability of medication-assisted therapies (MATs)—such as methadone, buprenorphine, and naltrexone—in treatment of opioid addiction is associated with increased rates of fatal overdoses, write officials from NIH, CDC, and other federal agencies (pp. 2063–6). MATs used for reversing opioid overdoses can help, the writers note, but broader solutions could be on the way: “The Centers for Disease Control and Prevention is working to empower states to implement comprehensive strategies, including MATs, for preventing prescription-drug overdoses. These strategies focus primarily on addressing the overdose epidemic through enhanced surveillance, effective policies, and clinical practices that establish statewide prescribing norms. Such efforts can be enhanced by using data sources to identify and intervene in cases of patients or providers who fall outside those norms. And the Centers for Medicare and Medicaid Services is working to enhance access to MATs by Medicaid programs through improved benefit design and application of the Mental Health Parity and Addiction Equity Act. But to be successful, all these initiatives require the active engagement and participation of the medical community.” (N. D. Volkow)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 30, 2014 * Vol. 21, No. 104
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (2014; 37).
Insulin Therapy in Type 2 Diabetes: “Opportunities and challenges” in providing insulin therapy to those with type 2 diabetes are explored in an article from a group of diabetes specialists (pp. 1499–508): “The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes.” (W. T. Cefalu, william.cefalu@pbrc.edu)
Glucose Control & Postsurgical Infections: Among 447 patients in surgical intensive-care units, intensive insulin therapy (IT) reduces the incidence of surgical site infections (SSIs), compared with intermediate IT, researchers report (pp. 1516–24). Target blood glucose levels were 4.4–6.1 mmol/L for those in the perioperative intensive IT group and 7.7–10.0 mmol/L in the intermediate IT group. Results showed: “No patients in either group became hypoglycemic (<4.4 mmol/L) during their stay in the surgical ICU. In our series, the rate of SSI after hepato-biliary–pancreatic surgery was 6.7%. Patients in the intensive IT group, compared with the intermediate IT group, had fewer postoperative SSIs (9.8% vs. 4.1%, P = 0.028) and a lower incidence of postoperative pancreatic fistula after pancreatic resection (P = 0.040). The length of hospitalization required for patients in the intensive IT group was significantly shorter than that in the intermediate IT group (P = 0.017).” (T. Okabayashi, tokabaya@kochi-u.ac.jp)
Empagliflozin in Type 2 Diabetes: As an add-on to metformin therapy in 420 patients with type 2 diabetes, empagliflozin significantly improved clinical outcomes and was well tolerated, a study shows (pp. 1650–9). Patients had initial A1C levels of 7–10%. Treatment with metformin plus empagliflozin 10 or 25 mg or placebo yielded these results: “At week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.13% (0.05)% (−1.4 [0.5] mmol/mol) with placebo, −0.70% (0.05)% (−7.7 [0.5] mmol/mol) with empagliflozin 10 mg, and −0.77% (0.05)% (−8.4 [0.5] mmol/mol) with empagliflozin 25 mg (both P < 0.001). Empagliflozin significantly reduced [mean daily glucose] level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were −0.45 kg (0.17 kg) with placebo, −2.08 kg (0.17 kg) with empagliflozin 10 mg, and −2.46 kg (0.17 kg) with empagliflozin 25 mg (both P < 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5–57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively.” (H-U Häring, hans-ulrich.haering@med.uni-tuebingen.de)
Health Care Cost Burden in Diabetes: “The past decade has seen a narrowing of insurance coverage and income-related disparities in high [out-of-pocket (OOP)] burden in people with diabetes,” an analysis of U.S. data shows, “yet, almost one-fourth of all people with diabetes still face a high OOP burden” (pp. 1629–35). No significant change was noted among patients with private insurance or middle/high incomes between 2001–02 and 2011, but the proportion with high OOP costs decreased among those with low income and/or public insurance. (R. Li, eok8@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 2, 2014 * Vol. 21, No. 105
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 31 issue of Lancet (2014; 383).
Fixed-Dose Nebivolol/Valsartan in Hypertension: In an 8-week, Phase III trial, a fixed-dose combination of nebivolol and valsartan was effective and well tolerated among patients with hypertension at 401 sites in the U.S. (pp. 1889–98). Study participants were adults with hypertensive blood pressures under 180/110 mm Hg. Various dosages of combination and monotherapy products yielded these results: “Between Jan 6, 2012, and March 15, 2013, 4,161 patients were randomly assigned (277 to placebo and 554–555 to each active comparator group), 4,118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference −1.2 mm Hg, 95% CI −2.3 to −0.1; p = 0.030) and valsartan 320 mg/day (−4.4 mm Hg, −5.4 to −3.3; p <0.0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p <0.0001). All systolic blood pressure comparisons were also significant (all p <0.01). At least one treatment-emergent adverse event was experienced by 30–36% of participants in each group.” (T. D. Giles, tgiles4@cox.net)
Blood Pressure & Cardiovascular Disease: “Despite modern treatments, the lifetime burden of hypertension is substantial,” conclude investigators who analyzed the electronic health records of 1.25 million people in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) program (pp. 1899–911). “The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study,” the authors conclude. “These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.” (E. Rapsomaniki, e.rapsomaniki@ucl.ac.uk)
Hypertension Management in England: Management of hypertension among English patients improved considerably between 1994 and 2011, researchers report (pp. 1912–9). If the progress continues, 80% of patients with treated hypertension will have controlled blood pressures by 2022, the group concludes, which will avert about 50,000 major cardiovascular events per year. Other findings from this cross-sectional study of five Health Survey for England reports are as follows: “The mean blood pressure levels of men and women in the general population and among patients with treated hypertension progressively improved between 1994 and 2011. In patients with treated hypertension, blood pressure improved from 150.0 (SE 0.59)/80.2 (0.27) mm Hg to 135.4 (0.58)/73.5 (0.41) mm Hg. Awareness, treatment, and control rates among men and women combined also improved significantly across each stage of this 17-year period, with the prevalence of control among treated patients almost doubling from 33% (SE 1.4) in 1994 to 63% (1.7) in 2011. Nevertheless, of all adults with survey-defined hypertension in 2011, hypertension was controlled in only 37%.” (E. Falaschetti, e.falaschetti@imperial.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Diabetes & High-Potency Statins: Used for secondary prevention, higher-potency statins are associated with moderately increased risk of new-onset diabetes, compared with less potency agents, a study shows (g3244). Cohort analysis of 136,966 patients newly treated with statins in 1997–2011 and a meta-analysis showed the following: “In the first two years of regular statin use, we observed a significant increase in the risk of new onset diabetes with higher potency statins compared with lower potency agents (rate ratio 1.15, 95% confidence interval 1.05 to 1.26). The risk increase seemed to be highest in the first four months of use (rate ratio 1.26, 1.07 to 1.47).” (C. R. Dormuth, colin.dormuth@ti.ubc.ca)

>>>PNN JournalWatch
* Management of Cutaneous Viral Warts, in
BMJ, 2014; 348: g3339. (M. D. Lynch, magnus.lynch@nhs.net)
* Stimulant Treatment of ADHD and Cigarette Smoking: A Meta-Analysis, in
Pediatrics, 2014; 133: 1070–80. (E. N. Schoenfelder)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 3, 2014 * Vol. 21, No. 106
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 3 issue of the Annals of Internal Medicine (2014; 160).
Transitional Care Interventions in Heart Failure: For patients with heart failure (HF) being discharged from hospitals, home-visiting programs and multidisciplinary interventions are most effective for averting rehospitalization, according to a systematic review and meta-analysis of 47 trials (pp. 774–84). Telephone support showed some benefit, the report notes: “Most [trials] enrolled adults with moderate to severe HF and a mean age of 70 years. Few trials reported 30-day readmission rates. At 30 days, a high-intensity home-visiting program reduced all-cause readmission and the composite end point (all-cause readmission or death; low [strength of evidence (SOE)]). Over 3 to 6 months, home-visiting programs and multidisciplinary heart failure (MDS-HF) clinic interventions reduced all-cause readmission (high SOE). Home-visiting programs reduced HF-specific readmission and the composite end point (moderate SOE). Structured telephone support (STS) interventions reduced HF-specific readmission (high SOE) but not all-cause readmissions (moderate SOE). Home-visiting programs, MDS-HF clinics, and STS interventions produced a mortality benefit. Neither telemonitoring nor primarily educational interventions reduced readmission or mortality rates.” (C. Feltner, cindy_feltner@med.unc.edu)
Rate v. Rhythm Control in Atrial Fibrillation: A systematic review of 200 reports of 28,836 patients shows that “pharmacologic rate- and rhythm-control strategies have comparable efficacy across outcomes in primarily older patients with mild [atrial fibrillation (AF)] symptoms” (pp. 760–73). The investigators also conclude that in younger patients with paroxysmal AF and mild structural heart disease, “pulmonary vein isolation is better than antiarrhythmic medications at reducing recurrences.” Other findings are as follows: “When pharmacologic rate- and rhythm-control strategies were compared, strength of evidence (SOE) was moderate supporting comparable efficacy with regard to all-cause mortality (odds ratio [OR], 1.34 [95% CI, 0.89 to 2.02]), cardiac mortality (OR, 0.96 [CI, 0.77 to 1.20]), and stroke (OR, 0.99 [CI, 0.76 to 1.30]) in older patients with mild AF symptoms. Few studies compared rate-control therapies and included outcomes of interest, which limited conclusions. For the effect of rhythm-control therapies in reducing AF recurrence, SOE was high favoring pulmonary vein isolation versus antiarrhythmic medications (OR, 5.87 [CI, 3.18 to 10.85]) and the surgical maze procedure (including pulmonary vein isolation) done during other cardiac surgery versus other cardiac surgery alone (OR, 7.94 [CI, 3.63 to 17.36]).” (S. M. Al-Khatib, alkha001@mc.duke.edu)
Quality of Care in Patient-Centered Medical Homes: In an analysis of the effects of the patient-centered medical home (PCMH) model of primary care and the influence of electronic health records (EHRs) on quality, researchers report “modest quality improvement” with PCMHs and distinct influences on care when EHRs are used (pp. 741–9). A prospective cohort study was conducted in a seven-county area of New York involving 675 physicians in 312 practices and 143,489 patients: “The PCMH group improved significantly more over time than either the paper group or the EHR group for 4 of the 10 measures (by 1 to 9 percentage points per measure): eye examinations and hemoglobin A1c testing for patients with diabetes, chlamydia screening, and colorectal cancer screening (adjusted P < 0.05 for each). The odds of overall quality improvement in the PCMH group were 7% higher than in the paper group and 6% higher than in the EHR group (adjusted P < 0.01 for each).” (L. M. Kern, lmk2003@med.cornell.edu)
Tanning Beds & Vitamin D Toxicity: Tanning beds may be associated with vitamin D toxicity, according to authors of a letter (p. 807). After a 26-year-old white woman presented with asymptomatic vitamin D toxicity, clinicians advised the patient to stop using a tanning bed three times weekly since other causes of her elevated vitamin D levels could not be identified. One month later, the patient’s serum vitamin D levels had decreased. The authors note that tanning beds could be an alternative source of vitamin D for deficient patients who cannot get adequate vitamin D from oral sources, but the risks of skin cancer would have to be weighed against the benefits of increased vitamin D. (B. Frei)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 4, 2014 * Vol. 21, No. 107
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 7 issue of JAMA (2014; 311).
Azithromycin & Cardiovascular Events: Compared with other antibiotics, azithromycin was associated with lower 90-day mortality risks and smaller increased risks of myocardial infarction among older patients with pneumonia, researchers report (pp. 2199–208). National VA data for patients older than 65 who were hospitalized for pneumonia and treated with antibiotics showed these patterns for 2002–12: “Of 73,690 patients from 118 hospitals identified, propensity-matched groups were composed of 31,863 patients exposed to azithromycin and 31,863 matched patients who were not exposed. There were no significant differences in potential confounders between groups after matching. Ninety-day mortality was significantly lower in those who received azithromycin (exposed, 17.4%, vs unexposed, 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70–0.76). However, we found significantly increased odds of myocardial infarction (5.1% vs 4.4%; OR, 1.17; 95% CI, 1.08–1.25) but not any cardiac event (43.0% vs 42.7%; OR, 1.01; 95% CI, 0.98–1.05), cardiac arrhythmias (25.8% vs 26.0%; OR, 0.99; 95% CI, 0.95–1.02), or heart failure (26.3% vs 26.2%; OR, 1.01; 95% CI, 0.97–1.04).” (E. M. Mortensen, eric.mortensen@utsouthwestern.edu)
Prophylactic Antibiotic Therapy in COPD: In patients with chronic obstructive pulmonary disorder, continuous macrolide prophylaxis is associated with clinically significant reductions in COPD exacerbations, but pulsed antibiotics were not associated with benefits in the only available study of that intervention, according to authors of a Clinical Evidence Synopsis article (pp. 2225–6). While antibiotic resistance is a concern with long-term prophylaxis, the writers conclude, “This review supports cautious use of continuous macrolide prophylaxis with close monitoring for patients with frequent infective COPD exacerbations after other standard therapies have been prescribed.” They add: “Use of continuous macrolide prophylaxis was associated with a clinically significant reduction in COPD exacerbations in older patients with COPD of at least moderate severity (forced expiratory volume in the first second of expiration [FEV1], 1.2 liters [43% predicted]). However, continuous macrolide prophylaxis was not associated with clinically meaningful improvement in quality of life among COPD patients. Although evidence does not suggest a benefit for pulsed prophylactic antibiotic therapy, only a single published trial addressed this question.” (S. C. Herath, scherath@yahoo.com)
Treating Resistant Hypertension: Management of hypertension that is uncontrolled by three or more antihypertensive agents is discussed in a Grand Rounds article (pp. 2216–24): “Clinicians should exclude pseudoresistant hypertension, which results from nonadherence to medications or from elevated blood pressure related to the white coat syndrome. In patients with truly resistant hypertension, thiazide diuretics, particularly chlorthalidone, should be considered as one of the initial agents. The other 2 agents should include calcium channel blockers and angiotensin-converting enzyme inhibitors for cardiovascular protection. An increasing body of evidence has suggested benefits of mineralocorticoid receptor antagonists, such as eplerenone and spironolactone, in improving blood pressure control in patients with resistant hypertension, regardless of circulating aldosterone levels. Thus, this class of drugs should be considered for patients whose blood pressure remains elevated after treatment with a 3-drug regimen to maximal or near maximal doses. Resistant hypertension may be associated with secondary causes of hypertension including obstructive sleep apnea or primary aldosteronism. Treating these disorders can significantly improve blood pressure beyond medical therapy alone. The role of device therapy for treating the typical patient with resistant hypertension remains unclear.” (W. Vongpatanasin, wanpen.vongpatanasin@utsouthwestern.edu)
Alternative Obesity Model: Viewpoint authors propose that dietary quality, genetics, and lifestyle factors lead to obesity, an alternative to the prevailing model of “convenient, highly palatable, energy-dense food” and sedentary lifestyle (pp. 2167–8): “Treatment focused on dietary quality, rather than advice to eat less, could help address this sequence of events at the source and produce better long-term weight loss.” (D. S. Ludwig, david.ludwig@childrens.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 5, 2014 * Vol. 21, No. 108
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 5 New England Journal of Medicine (2014; 370).
Once-Weekly Dalbavancin for Skin Infection: Dalbavancin, recently approved by FDA (see PNN, May 27), was noninferior to standard therapies for acute bacterial skin/skin-structure infections in the DISCOVER 1 and 2 trials, researchers report (pp. 2169–79). Patients received intravenous dalbavancin on days 1 and 8 or intravenous vancomycin for at least 3 days with an option to switch to oral linezolid for a total of 10–14 days of therapy. Results showed: “Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin–linezolid group had an early clinical response indicating treatment success (weighted difference, −0.1 percentage point; 95% confidence interval, −4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator’s assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin–linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin–linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus.” (H. W. Boucher, hboucher@tuftsmedicalcenter.org)
Single-Dose Oritavancin in Bacterial Skin Infections: In the SOLO 1 trial, oritavancin as a single dose was noninferior to twice-daily vancomycin for treatment of acute bacterial skin/skin-structure infections, investigators conclude (pp. 2180–90). Compared with twice-daily vancomycin for 7–10 days, oritavancin 1200 mg as a single intravenous dose produced these outcomes based on a composite end point of cessation of spreading or reduction in lesion size, absence of fever, and no need for administration of a rescue antibiotic 48 to 72 hours after administration of oritavancin: “The modified intention-to-treat population comprised 475 patients who received oritavancin and 479 patients who received vancomycin. All three efficacy end points met the prespecified noninferiority margin of 10 percentage points for oritavancin versus vancomycin: primary end point, 82.3% versus 78.9% (95% confidence interval [CI] for the difference, −1.6 to 8.4 percentage points); investigator-assessed clinical cure, 79.6% versus 80.0% (95% CI for the difference, −5.5 to 4.7 percentage points); and proportion of patients with a reduction in lesion area of 20% or more, 86.9% versus 82.9% (95% CI for the difference, −0.5 to 8.6 percentage points). Efficacy outcomes measured according to type of pathogen, including methicillin-resistant Staphylococcus aureus, were similar in the two treatment groups. The overall frequency of adverse events was also similar, although nausea was more common among those treated with oritavancin.” (G. R. Corey, g.corey@duke.edu)
“Dalbavancin and oritavancin are semisynthetic lipoglycopeptide analogues of teicoplanin and vancomycin, respectively,” an editorialist explains (
pp. 2238–9): “The pharmacologic features of these two agents make them therapeutically attractive. Terminal half-lives for both are approximately 2 weeks, and serum free-drug concentrations exceed MICs for a week or more. They have concentration-dependent killing; the ratio of the area under the concentration curve to MIC correlates with in vivo efficacy. The clinical trials of dalbavancin and oritavancin were designed to take advantage of these properties by means of the administration of one or two large, pulse doses instead of smaller, closely spaced, multiple doses.” (H. F. Chambers)
Adverse Marijuana Effects: While viewed as a “harmless pleasure,” marijuana has many adverse effects on health, write NIH authors in a review article (pp. 2219–27). Alcohol and tobacco currently account “for the greatest burden of disease associated with drugs,” the group concludes, and this is because of their “widespread exposure.” Because of legalization of marijuana in an increasing number of states, “it is reasonable and probably prudent to hypothesize that its use will increase and that, by extension, so will the number of persons for whom there will be negative health consequences.” (N. D. Volkow, nvolkow@nida.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 6, 2014 * Vol. 21, No. 109
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
June 10 issue of the Journal of the American College of Cardiology (2014; 63).
Dronedarone Safety: In routine clinical use in Sweden, dronedarone has not increased patients’ risk of death or liver disease, according to an analysis of the Swedish Patient Register (pp. 2376–84). Among nearly 175,000 patients with heart failure and atrial fibrillation (AF) in 2010–12, dronedarone was used by 4,856 patients. Compared with the other patients in the cohort, those taking dronedarone had these outcomes: “Patients prescribed dronedarone were younger (age 65.5 years vs. 75.7 years, p <0.0001) and healthier than control patients. The annual mortality rate among patients who received dronedarone was 1.3% compared with 14.0% in the control population. There were no sudden cardiac deaths and no deaths related to liver failure among patients who received treatment with dronedarone. After propensity score matching and adjustment for cofactors, patients who received dronedarone had lower mortality than other AF patients (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.33 to 0.51). Dronedarone patients with heart failure had lower mortality than other heart failure patients (HR: 0.40; 95% CI: 0.30 to 0.53). They also had lower mortality than expected from the general population (standardized mortality ratio: 0.67; 95% CI: 0.55 to 0.78), which indicates the selection of low-risk patients. The risk of liver disease was not increased (HR: 0.57; 95% CI: 0.34 to 0.92).” (L. Friberg)

>>>Pediatrics Highlights
Source:
June issue of Pediatrics (2014; 133).
Seizures & Vaccine Timing: On-time versus delayed vaccinations in infants and young children does not affect the incidence of postvaccination seizures, and delaying administration of the first dose of measles–mumps–rubella vaccine (MMR) past 15 months results in higher risk of seizures, according to analysis of 323,247 American children in the Vaccine Safety Datalink for births in 2004–08 (pp. e1492–9). Using a self-controlled series analysis, the investigators found these associations between vaccine timing and first occurrence of seizure: “In infants, there was no association between the timing of infant vaccination and postvaccination seizures. In the second year of life, the incident rate ratio (IRR) for seizures after receipt of the first [MMR] dose at 12 to 15 months was 2.65 (95% confidence interval [CI] 1.99–3.55); the IRR after an MMR dose at 16 to 23 months was 6.53 (95% CI 3.15–13.53). The IRR for seizures after receipt of the first measles–mumps–rubella–varicella vaccine (MMRV) dose at 12 to 15 months was 4.95 (95% CI 3.68–6.66); the IRR after an MMRV dose at 16 to 23 months was 9.80 (95% CI 4.35 –22.06).” (S. J. Hambidge)
Hepatitis B Vaccine Protection: More than 90% of newborns receiving a challenge dose of hepatitis B vaccine within 7 days of birth or after week 4 (with the three-dose series completed by 12 months) had seroprotection that lasted into adolescence, a study shows (pp. e1500–7; A. B. Middleman).

>>>Psychiatry Report
Source:
June issue of the American Journal of Psychiatry (2014; 171).
Pharmacologic Support of Extinction Learning in PTSD: Mixed results are reported from use of d-cycloserine 50 mg or alprazolam 0.25 mg as support agents during a six-session virtual reality treatment of 156 veterans with posttraumatic stress disorder (PTSD) (pp. 640–8). Study results produced this conclusion from the 12-month study: “There was no advantage of d-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and d-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. d-Cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.” (B. O. Rothbaum, brothba@emory.edu)
“The results from this trial do not invalidate the strategy of pharmacologic augmentation of exposure therapy,” an editorialist writes (
pp. 597–9). “This approach continues to have great promise, particularly with simple phobias and social anxiety disorder. However, the trial data from this report suggest that agents that enhance extinction learning will need to have greater potency than d-cycloserine to make a significant mark on combat-related PTSD.” (T. C. Neylan, thomas.neylan@ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 9, 2014 * Vol. 21, No. 110
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 7 issue of Lancet (2014; 383).
Gender-Related Stroke Risk in Diabetes: Researchers find that the increased risk of stroke in patients with diabetes is greater for women than men, suggesting a “need for further work to clarify the biological, behavioural, or social mechanisms involved” (pp. 1973–80). Using prospective, population-based cohort studies published in 1966–2013, investigators pooled gender-specific estimates of relative risk (RR) for stroke associated with diabetes. Results showed: “Data from 64 cohort studies, representing 775,385 individuals and 12,539 fatal and non-fatal strokes, were included in the analysis. The pooled maximum-adjusted RR of stroke associated with diabetes was 2.28 (95% CI 1.93–2.69) in women and 1.83 (1.60–2.08) in men. Compared with men with diabetes, women with diabetes therefore had a greater risk of stroke–the pooled ratio of RRs was 1.27 (1.10–1.46; I2 = 0%), with no evidence of publication bias. This sex differential was seen consistently across major predefined stroke, participant, and study subtypes.” (R. R. Huxley, r.huxley@uq.edu.au)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Data Sources for Estimating Drug Benefits & Harms: Unpublished clinical study reports filed with drug agencies “should be used as the data source for systematic reviews of drugs,” authors conclude based analysis of data on the antidepressant duloxetine, “but they should first be checked against protocols and within themselves for accuracy and consistency” (g3510). Data for 9 randomized placebo-controlled trials of duloxetine involving 2,878 patients that were filed with the European Medicines Agency for marketing approval for treatment of major depressive disorder showed the following: “Clinical study reports fully described the primary efficacy analysis and major harms (deaths [including suicides], suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177–645) and 166 (100–241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.” (E. Maund, em@cochrane.dk)

>>>PNN NewsWatch
* FDA on Friday approved Biogen’s Eloctate, Antihemophilic Factor (Recombinant), Fc fusion protein, for use in adults and children with hemophilia A. The agency said Eloctate, an orphan product, is the first hemophilia A treatment designed to require less frequent injections when used to prevent or reduce the frequency of bleeding. Efficacy and safety were confirmed in a 164-patient comparison of prophylactic versus on-demand therapy.

>>>PNN JournalWatch
* Glucagon-Like Peptide-1 Receptor Agonists for Diabetes Mellitus: A Role in Cardiovascular Disease, in
Circulation, 2014; 129: 2305–12. (A. Schwartzbard, Arthur.Schwartzbard@nyumc.org)
* Atrial Remodeling and Atrial Fibrillation: Recent Advances and Translational Perspectives, in
Journal of the American College of Cardiology, 2014; 63: 2335–45. (S. Nattel)
* Alkaline Phosphatase: A Possible Treatment for Sepsis-Associated Acute Kidney Injury in Critically Ill Patients, in
American Journal of Kidney Diseases, 2014; 63: 1038–48. (P. Pickkers, peter.pickkers@radboudumc.nl)
* Antipsychotic Treatment in Breast Cancer Patients, in
American Journal of Psychiatry, 2014; 171: 616–21. (T. Rahman, rahmantahi@health.missouri.edu)
* Hepatitis B Testing and Vaccination Among Adults With Sexually Transmitted Infections in a Large Managed Care Organization, in
Clinical Infectious Diseases, 2014; 58: 1739–45. (R. C. Hechter, rulin.c.hechter@kp.org)
* Screening, Assessment, and Management of Fatigue in Adult Survivors of Cancer: An American Society of Clinical Oncology Clinical Practice Guideline Adaptation, in
Journal of Clinical Oncology, 2014; 32: 1840–50. (American Society of Clinical Oncology, guidelines@asco.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 10, 2014 * Vol. 21, No. 111
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June issue of JAMA Internal Medicine (2014; 174).
Reducing Inappropriate Benzodiazepine in Older Adults: A direct-to-consumer educational campaign on benzodiazepine use in older adults demonstrated promise for this intervention for stemming the overuse of medications that increase the risk of harm in older adults, researchers report (pp. 890–8). In the EMPOWER (Eliminating Medications Through Patient Ownership of End Results) trial (reported previously as an early-release article in the Apr. 22 PNN), community pharmacies were allocated to intervention or control arms in blocks of 4. Intervention pharmacies provided a “deprescribing patient empowerment intervention describing the risks of benzodiazepine use and a stepwise tapering protocol.” During 2000–12, these results were recorded for the protocol as compared with usual care: “A total of 261 participants (86%) completed the 6-month follow-up. Of the recipients in the intervention group, 62% initiated conversation about benzodiazepine therapy cessation with a physician and/or pharmacist. At 6 months, 27% of the intervention group had discontinued benzodiazepine use compared with 5% of the control group (risk difference, 23% [95% CI, 14%–32%]; intracluster correlation, 0.008; number needed to treat, 4). Dose reduction occurred in an additional 11% (95% CI, 6%–16%). In multivariate subanalyses, age greater than 80 years, sex, duration of use, indication for use, dose, previous attempt to taper, and concomitant polypharmacy (10 drugs or more per day) did not have a significant interaction effect with benzodiazepine therapy discontinuation.” (C. Tannenbaum, cara.tannenbaum@umontreal.ca)
Antidepressants & Self-harm: “Children and young adults initiating therapy with antidepressants at high-therapeutic (rather than modal-therapeutic) doses seem to be at heightened risk of deliberate self-harm,” conclude investigators who looked at SSRI therapy and outcomes among 162,625 U.S. residents with depression who were ages 10–64 years (pp. 899–909). In this propensity score–matched cohort study, SSRI therapy at modal or higher doses in 1998–2010 showed the following relationships with injuries: “The rate of deliberate self-harm among children and adults 24 years of age or younger who initiated high-dose therapy was approximately twice as high as among matched patients initiating modal-dose therapy (hazard ratio [HR], 2.2 [95% CI, 1.6–3.0]), corresponding to approximately 1 additional event for every 150 such patients treated with high-dose (instead of modal-dose) therapy. For adults 25 to 64 years of age, the absolute risk of suicidal behavior was far lower and the effective risk difference null (HR, 1.2 [95% CI, 0.8–1.9]).” (M. Miller, mmiller@hsph.harvard.edu)
Long-Term Sequelae of Diethylene Glycol Poisoning: Among survivors of a 2006 mass diethylene glycol (DEG) poisoning in Panama, neurologic symptoms improved over time, but renal function varied little after an initial improvement in non–dialysis-dependent patients, a study shows (pp. 912–7). Researchers found no evidence of delayed-onset neurologic or renal damage. (L. Conklin, lconklin@cdc.gov)
Sildenafil & Melanoma: Men using sildenafil may be at increased risk of developing melanoma, according to a prospective cohort study of 25,848 men in the Health Professionals’ Follow-up Study (pp. 964–70). A decade after reporting sildenafil use for erectile dysfunction in 2000, patients had these outcomes for melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC): “We identified 142 melanoma, 580 SCC, and 3,030 BCC cases during follow-up (2000–2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04–3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59–1.20) or BCC (1.08; 0.93–1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95% CI, 1.14–3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05–4.78) for sildenafil use at baseline and 2.77 (1.32–5.85) for ever use.” (J. Han, jialhan@iu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 11, 2014 * Vol. 21, No. 112
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 11 issue of JAMA (2014; 311).
Insulin v. Sulfonylureas for Intensification Therapy in Diabetes: Compared with sulfonylureas, insulin therapy increased a composite of nonfatal cardiovascular outcomes and all-cause mortality in patients with diabetes who needed intensification beyond metformin therapy, researchers report (pp. 2288–96). A retrospective cohort of veterans who were initially treated with metformin for diabetes in 2001–08 had these risks based on a composite outcome of acute myocardial infarction (AMI), stroke hospitalization, or all-cause death after intensification: “Among 178,341 metformin monotherapy patients, 2,948 added insulin and 39,990 added a sulfonylurea. Propensity score matching yielded 2,436 metformin + insulin and 12,180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5–30), and hemoglobin A1c level was 8.1% (IQR, 7.2%–9.9%). Median follow-up after intensification was 14 months (IQR, 6–29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1,000 person–years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07–1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1,000 person–years; aHR, 0.88; 95% CI, 0.59–1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1,000 person–years; aHR, 1.44; 95% CI, 1.15–1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1,000 person–years; aHR, 0.98; 95% CI, 0.71–1.34; P = .87).” (C. L. Roumie, christianne.roumie@vanderbilt.edu)
“Because it is unlikely that most physicians in practice will have a working knowledge of the sophisticated methods used in [comparative effectiveness (CE)] research, such as those used in study by Roumie et al, many readers may increasingly rely on peer review and therefore the opinion of just a few experts rather than their own informed opinion when interpreting CE research results,” an editorialist writes (
pp. 2275–6). “The role of journals and peer reviewers in their evaluation of studies that use complex statistical methods is likely to be increasingly important not only in ensuring validity, but also in presenting findings clearly and with appropriate caveats. Doing so could help prevent readers from adopting the results of CE research and immediately changing clinical practice, which could be worriedly premature for findings from observational studies.” (M. M. Safford, msafford@uab.edu)
Insulin in Type 2 Diabetes: Insulin is effective for helping patients with type 2 diabetes reach A1C goals, authors of a review article conclude (pp. 2315–25). Noting that “barriers such as adherence, patient preferences, clinician preferences, and resource allocation must be addressed,” the authors provide this summary of available literature from 1998–2014: “The hemoglobin A1c target for most patients with type 2 diabetes is 7% but needs to be modified when there is increased risk of hypoglycemia, reduced life expectancy, extensive comorbidities, or reduced resources. Insulin therapy may be considered early or late in the disease course; adverse effects include weight gain and hypoglycemia. Basal insulin can be added to oral hypoglycemic agents (generally stopping sulfonylureas) initially, and later, prandial insulin can be added in a stepwise fashion. Insulin treatment must be individualized, and there are a number of challenges to insulin initiation and intensification.” (M. E. Molitch, molitch@northwestern.edu)
Diabetes Overtreatment in Older Patients: In VA facilities in 2009, investigators found overtreatment rates of older patients receiving insulin and/or sulfonylureas of 6.1% to 23.0% (pp. 2326–7). “Patients with risk factors for serious hypoglycemia represent a large subset of individuals receiving hypoglycemic agents; approximately one-half had evidence of intensive treatment,” the authors conclude. “A patient safety indicator derived from administrative data can identify high-risk patients for whom reevaluation of glycemic management may be appropriate, consistent with meaningful use criteria for electronic medical records.” (P. G. O’Malley, patrick.omalley@usuhs.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 12, 2014 * Vol. 21, No. 113
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 12 issue of the New England Journal of Medicine (2014; 370).
Resistance Mechanisms With Ibrutinib: Mechanisms of resistance to the irreversible Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib provide insights into “the importance of the B-cell–receptor pathway” in the drug’s actions in chronic lymphocytic leukemia (CLL), researchers conclude (pp. 2286–94). Whole-exome sequencing at baseline and relapse in six patients with CLL showed the following: “We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLC-gamma-2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLC-gamma-2 are both potentially gain-of-function mutations that lead to autonomous B-cell–receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib.” The group concludes, “This finding, combined with two additional mutations in PLC-gamma-2 that are immediately downstream of BTK, underscores the importance of the B-cell–receptor pathway in the mechanism of action of ibrutinib in CLL.” (J. C. Byrd, john.byrd@osumc.edu)
Brodalumab in Psoriatic Arthritis: Treatment of patients with psoriatic arthritis with the human monoclonal interleukin-17 receptor A (IL17RA) antibody brodalumab improved response rates in a short-term study (pp. 2295–306). Patients received one of two brodalumab doses at baseline and weekly or biweekly through week 10, with these results based on 20% or 50% improvement in American College of Rheumatology response criteria (ACR 20/ACR50) at weeks 12, 24, and 52: “Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P = 0.03] and 39% [P = 0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P = 0.05] and 14% [P = 0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group.” (P. J. Mease, pmease@philipmease.com)
CPAP, Oxygen, Weight Loss & Obstructive Sleep Apnea: Responding to two studies on interventions for obstructive sleep apnea (pp. 2265–75, J. A. Chirinos, julio.chirinos@uphs.upenn.edu; pp. 2276–85, D. J. Gottlieb, djgottlieb@partners.org), an editorialist writes (pp. 2339–41): “Two important explicit and complicit treatment considerations for obstructive sleep apnea emerge from these two studies. First, in obese patients with moderate-to-severe obstructive sleep apnea, the use of [continuous positive airway pressure (CPAP)] alone, but not oxygen supplementation alone, during sleep may ameliorate systemic hypertension and cardiovascular risk, even in patients treated for hypertension and cardiovascular risk who do not have ‘subjective’ sleepiness. Second, weight loss may decrease cardiovascular morbidity and risk when CPAP is prescribed for these patients.” (R. C. Basner)
Politics & ACA: Written before Tuesday’s primary defeat of House Majority Leader Eric Cantor, a Perspective article explores political implications for the Affordable Care Act (ACA) based on 2014 and 2016 election results (pp. 2257–9): “Although repeal of the ACA is … unlikely, amendments are certain. If ACA opponents win control of Congress and the presidency, they will probably try to scale it back.… If ACA supporters prevail in 2016, some desirable and overdue technical changes may become feasible.” (H. J. Aaron)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 13, 2014 * Vol. 21, No. 114
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
July 1 issue of Clinical Infectious Diseases (2014; 59).
Deaths From Contaminated Pharmacy-Prepared Parenteral Nutrition: At a compounding pharmacy, “failure to follow recommended compounding standards contributed to an outbreak” of Serratia marcescens bloodstream infections (BSIs) in patients receiving parenteral nutrition (PN) (pp. 1–8). The pharmacy used nonsterile amino acid components during a shortage. Cases identified in Jan. and Mar. 2011 had these outcomes: “Nineteen case patients were identified; 9 died. The attack rate for patients receiving PN in March was 35%. No case patients were younger than 18 years. In October 2010, the pharmacy began compounding and filter-sterilizing amino acid solution for adult PN using nonsterile amino acids due to a national manufacturer shortage. Review of this process identified breaches in mixing, filtration, and sterility testing practices. S. marcescens was identified from a pharmacy water faucet, mixing container, and opened amino acid powder. These isolates were indistinguishable from the outbreak strain by [pulsed-field gel electrophoresis].” (N. Gupta, ngupta1@cdc.gov)
Colistin v. Polymyxin B: Despite indistinguishable in vitro microbiological activity, colistin and polymyxin B are very different agents when administered parenterally, authors of an opinion article write (pp. 88–94). Colistin is administered as the prodrug colistin methanesulfonate (CMS), the authors write, adding: “Polymyxin B has superior clinical pharmacological properties compared with CMS/colistin. We propose that in countries such as the United States where parenteral products of both colistin and polymyxin B are available, prospective studies should be conducted to formally examine their relative efficacy and safety in various types of infections and patients. In the meantime, where clinicians have access to both polymyxins, they should carefully consider the relative merits of each in a given circumstance.” (R. L. Nation, roger.nation@monash.edu)

>>>Oncology Highlights
Source:
June 10 issue of the Journal of Clinical Oncology (2014; 32).
Thromboprophylaxis in Cancer: Hospitalized patients with cancer often receive pharmacologic thromboprophylaxis despite contraindications, a study of 775 patients shows (pp. 1792–6). Patients prescribed thromboprophylaxis at five academic hospitals showed these patterns: “Two hundred forty-seven patients (31.9%) had relative contraindications to pharmacologic prophylaxis. Accounting for contraindications to anticoagulation, the overall rate of pharmacologic thromboprophylaxis was 74.2% (95% CI, 70.4% to 78.0%; 392 of 528 patients). Among the patients with cancer without contraindications for anticoagulation, individuals hospitalized with nonhematologic malignancies were significantly more likely to receive pharmacologic thromboprophylaxis than those with hematologic malignancies (odds ratio [OR], 2.34; 95% CI, 1.43 to 3.82; P = .007). Patients with cancer admitted for cancer therapy were significantly less likely to receive pharmacologic thromboprophylaxis than those admitted for other reasons (OR, 0.37; 95% CI, 0.22 to 0.61; P < .001). Sixty-three percent of patients with cancer classified as low risk, as determined by the Padua Scoring System, received anticoagulant thromboprophylaxis. Among the 136 patients who did not receive anticoagulation, 58.8% were considered to be high risk by the Padua Scoring System.” (J. I. Zwicker, jzwicker@bidmc.harvard.edu)

>>>Pharmacotherapy Report
Source:
Early-release article from Pharmacotherapy (2014; 34).
Pharmacist Credentialing & Care Outcomes: Hospitals employing one or more inpatient pharmacists with Added Qualifications in Cardiology (AQCV) have better care outcomes, researchers report (doi: 10.1002/phar.1444). Comparing 34 hospitals with such pharmacists to 102 non-AQCV hospitals, the study found: “Hospitals with AQCV pharmacists performed better on process of care measures than hospitals without AQCV pharmacists (odds ratio 1.41, 95% confidence interval 1.25–1.58, p <0.0001, p <0.001 for heterogeneity), which was mainly driven by the aspirin on discharge for AMI and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker on discharge for [heart failure] measures. No differences were observed between the groups for either readmission or mortality at 30 days.” (M. P. Dorsch, mdorsch@med.umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 16, 2014 * Vol. 21, No. 115
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Medical Management of Breast Cancer: Authors of a review article reach these main points after reviewing the literature on medical management of breast cancer (g3608; A. Jones, Alisonjones6@nhs.net):
* “Despite the increasing incidence of breast cancer, death rates are falling owing to earlier diagnosis, better surgical and radiotherapy techniques, and improved systemic therapies.”
* “The best management of the axilla in clinically node negative disease is unclear.”
* “Adjuvant decision making is driven by tumour biology, with particular attention to the distinct molecular subtypes of breast cancer.”
* “There is substantial evidence for extended hormone therapy in premenopausal and postmenopausal women with hormone receptor positive early breast cancer.”
* “In metastatic HER2 positive breast cancer there are now multiple lines of HER2 targeted therapies.”
Dietary Protein & Breast Cancer: Women could reduce their risks of breast cancer by replacing red meat in their diets with legumes, poultry, nuts, and fish, according to an analysis of data from the Nurses’ Health Study II (g3437). Among 88,803 premenopausal women who completed a dietary questionnaire in 1991, these long-term outcomes were recorded in the prospective cohort study: “We documented 2,830 cases of breast cancer during 20 years of follow-up. Higher intake of total red meat was associated with an increased risk of breast cancer overall (relative risk 1.22, 95% confidence interval 1.06 to 1.40; Ptrend = 0.01, for highest fifth v lowest fifth of intake). However, higher intakes of poultry, fish, eggs, legumes, and nuts were not related to breast cancer overall. When the association was evaluated by menopausal status, higher intake of poultry was associated with a lower risk of breast cancer in postmenopausal women (0.73, 0.58 to 0.91; Ptrend = 0.02, for highest fifth v lowest fifth of intake) but not in premenopausal women (0.93, 0.78 to 1.11; Ptrend = 0.60, for highest fifth v lowest fifth of intake). In estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Also, substituting one serving/day of poultry for one serving/day of red meat was associated with a 17% lower risk of breast cancer overall (0.83, 0.72 to 0.96) and a 24% lower risk of postmenopausal breast cancer (0.76, 0.59 to 0.99). Furthermore, substituting one serving/day of combined legumes, nuts, poultry, and fish for one serving/day of red meat was associated with a 14% lower risk of breast cancer overall (0.86, 0.78 to 0.94) and premenopausal breast cancer (0.86, 0.76 to 0.98).” (M. S. Farvid, mfarvid@hsph.harvard.edu)

>>>PNN JournalWatch
* Hypercaloric Enteral Nutrition in Patients With Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Placebo-Controlled Phase 2 Trial, in
Lancet, 2014; 383: 2065–72. (A-M Wills, awills@partners.org)
* Point/Counterpoint: Should Storefront Clinics Provide Case Finding and Chronic Care for COPD?, in
Chest, 2014; 145: 1191–3, 1193–4. (P. Enright, lungguy@gmail.com; B. R. Celli, bcelli@partners.org)
* Early Management of Severe Sepsis: Concepts and Controversies, in
Chest, 2014; 145: 1407–18. (P. Marik, marikpe@evms.edu)
* Tissue Engineering in the Gut: Developments in Neuromusculature, in
Gastroenterology, 2014; 146: 1614–24. (K. N. Bitar, kbitar@wakehealth.edu)
* Is There a Window of Opportunity for Treatment of Systemic Juvenile Idiopathic Arthritis?, in
Arthritis & Rheumatology, 2014; 66: 1405–13. (P. A. Nigrovic, pnigrovic@partners.org)
* A Comparison of the Malignancy Incidence Among Patients With Psoriatic Arthritis and Patients With Rheumatoid Arthritis in a Large US Cohort, in
Arthritis & Rheumatology, 2014; 66: 1472–81. (A. Broder, abroder@montefiore.org)
* Potential Food Allergens in Medications, in
Journal of Allergy and Clinical Immunology, 2014; 133: 1509–18. (J. M. Kelso, kelso.john@scrippshealth.org)
* Androgen Deficiency as a Biological Determinant of Frailty: Hope or Hype?, in
Journal of the American Geriatrics Society, 2014; 62: 1174–8. (J. Afilalo, jonathan.afilalo@mcgill.ca)
* A Quarter Century in Developing Geriatric Programs at Three Academic Health Centers: Highlights and Lessons Learned, in
Journal of the American Geriatrics Society, 2014; 62: 1179–83. (W. R. Hazzard, whazzard@wakehealth.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 17, 2014 * Vol. 21, No. 116
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
June 17 issue of the Annals of Internal Medicine (2014; 160).
Needed Research in Osteoarthritis: Looking for gaps in the evidence base for patient-centered comparative effectiveness studies in patients with osteoarthritis, authors find these needs (pp. 836–41): “Prioritized evidence gaps included the need to determine or evaluate key patient-centered outcomes; optimal duration, intensity, and frequency of nonsurgical interventions; whether the comparative effectiveness of nonsurgical interventions varies by socioeconomic factors; when and how to transition from nonsurgical to surgical interventions; effective ways to engage patients in self-management and promote long-term behavior change; standardized screening tools that improve early diagnosis; biomechanical strategies that improve symptoms; mechanisms for promoting and delivering coordinated, longitudinal care; and comparative effectiveness of nonsurgical therapies. Searches of PubMed and ClinicalTrials.gov showed many recent and ongoing studies addressing comparative effectiveness of nonsurgical interventions; relatively few of these evaluated treatments across categories (for example, drug therapy vs. weight management) or combined categories of treatment. Few studies addressed other high-priority evidence gaps.” (J. M. Gierisch, j.gierisch@dm.duke.edu)
Starting Young To Reduce Stroke Risk in Women: While stroke typically affects women in old age, gender-specific guidelines from the American Heart Association and American Stroke Association recommend that physicians assess a woman’s health history for unique events that increase her risk of stroke later in life, such as being diagnosed with preeclampsia or use of hormonal contraceptives (pp. 853–7). Each year, more than 3.8 million women and 3 million men will have a stroke in the United States and several risk factors for stroke are more common in women than in men, the Feb. 2014 guideline notes. Women are more likely than men to suffer from hypertension, atrial fibrillation, migraine headache with aura, and depression and psychosocial stress. The guideline says internal medicine physicians are uniquely poised to assess a woman’s risk for stroke and implement prevention strategies because internists care for patients from early adulthood to end-of-life. Recommended stroke prevention strategies include healthy lifestyle interventions that encourage patients to maintain a healthy weight, eat a healthy diet, abstain from smoking, get regular physical activity, and limit alcohol consumption. A healthy lifestyle also includes interventions that help to maintain normal blood pressure and cholesterol and blood glucose levels, as women with diabetes have a 27% higher risk for stroke than do men with the condition. (C. Bushnell, cbushnel@wakehealth.edu)

>>>Internal Medicine Report II
Source:
Early-release article from JAMA Internal Medicine (2014; 174).
Genotype-Guided Warfarin Dosing: Controlled studies of genotype-guided versus clinically dosed warfarin therapy show no significant differences in the percentage of time patients are in the therapeutic INR range, according to a meta-analysis of randomized clinical trials (doi: 10.1001/jamainternmed.2014.2368). The investigators also found no difference in the two approaches in terms of the number of patients with INRs greater than 4 or with major bleeding or thromboembolic events. Using evidence published in Medline journals and studies listed in EMBASE or the Cochrane Library Central Register of Controlled Trials through 2013, the authors found: “In 9 trials, 2,812 patients were randomized to receive warfarin, acenocoumarol, or phenprocoumon according to a genotype-guided algorithm or a clinical dosing algorithm. Follow-up ranged from 4 weeks to 6 months (median, 12 weeks). The standardized difference in means of the percentage of time that the INR was within the therapeutic range was 0.14 (95% CI, −0.10 to 0.39) in the genotype-guided dosing cohort (P = .25). The risk ratio for an INR greater than 4 was 0.92 (95% CI, 0.82 to 1.05) for genotype-guided dosing vs clinical dosing. The risk ratios for major bleeding and thromboembolic events were 0.60 (95% CI, 0.29 to 1.22) and 0.97 (95% CI, 0.46 to 2.05), respectively, for genotype-guided vs clinical dosing.” (D. L. Brown, dbrown@dom.wustl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 18, 2014 * Vol. 21, No. 117
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 18 issue of JAMA (2014; 311).
Selumetinib in Uveal Melanoma: Modestly improved outcomes resulted when the MEK inhibitor selumetinib was compared with chemotherapy in treatment of 101 patients with uveal melanoma, researchers report (pp. 2397–405). Participants received either selumetinib 75 mg orally twice daily or chemotherapy (investigator’s choice of temozolomide 150 mg/sq m orally daily for 28 days or dacarbazine 1000 mg/sq m I.V. every 21 days) with these effects on a primary end point of progression-free survival: “Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3–8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3–16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4–21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1–25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30–0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1–11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8–15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41–1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction.” (R. D. Carvajal, carvajar@mskcc.org)
Cancer Risks with TNF Inhibitors in IBD: During a median follow-up of 3.7 years, cancer risk in patients with inflammatory bowel disease (IBD) was not significantly increased by exposure to tumor necrosis factor (TNF) alpha inhibitors, according to a registry-based analysis from Denmark (pp. 2406–13). The nationwide cohort study included 56,146 patients aged 15 years or older with IBD. Exposure to TNF-alpha inhibitors showed these risk ratios (RRs) of incident cancer: “During 489,433 person–years of follow-up (median, 9.3 years [interquartile range, 4.2–14.0]), 81 of 4,553 patients exposed to TNF-alpha antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8–6.0]) and 3,465 of 51,593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85–1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-alpha antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67–1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77–1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54–1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88–2.03]) and in analyses according to the number of TNF-alpha antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71–1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55–1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90–1.85]). No site-specific cancers were in significant excess in fully adjusted models.” (N. N. Andersen, nyna@ssi.dk)
Thrombolysis in Pulmonary Embolism: Reacting to a meta-analysis that finds that “thrombolytic therapy was associated with lower rates of all-cause mortality and increased risks of major bleeding and [intracranial hemorrhage] in patients with pulmonary embolism (PE) (pp. 2414–21; J. Giri, giri.jay@gmail.com), an editorialist writes (pp. 2385–6): “[This] meta-analysis … raises new questions. For example, should thrombolytic therapy in intermediate-risk patients older than 65 years be avoided? While the risk of bleeding is increased in older patients, the point estimate for mortality is similar to that in younger patients. Risk stratification for bleeding may favor use of thrombolysis in patients older than 65 years. Second, would the net clinical benefit be better with consistent use of catheter-based thrombolysis using lower doses of fibrinolytic agents for significant pulmonary artery thrombus reduction? Additional clinical trials are needed to guide optimal use of thrombolytic therapy in patients with PE.” (J. A. Beckman, jbeckman@partners.org)
Physicians & Lethal Injection: In the realm of lethal injection as a means of capital punishment, “medical professionals cannot permit state law and regulation to subvert an ethical commitment that has uniform support across virtually the entire profession around the world,” writes a Viewpoint author (pp. 2375–6; R. D. Truog, robert.truog@childrens.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 19, 2014 * Vol. 21, No. 118
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 19 issue of the New England Journal of Medicine (2014; 370).
Antimicrobial Prophylaxis in Childhood Vesicoureteral Reflux: In the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial, antimicrobial prophylaxis following febrile urinary-tract infections (UTIs) reduced the risks of recurrence but not renal scarring (pp. 2367–76). Vesicoureteral reflux—abnormal reflux of urine in the ureters toward the kidneys—is common in children and infants following febrile UTIs. Investigators assigned 607 children with vesicoureteral reflux after a first or second febrile or symptomatic urinary tract infection to trimethoprim–sulfamethoxazole prophylaxis or placebo. Results showed: “Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim–sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group.” (A. Hoberman, hoberman@chp.edu)
“Sadly, the decision to use antibiotic prophylaxis in children with reflux remains a clinical dilemma, despite this well-done study,” editorialists write (
pp. 2440–1). Citing the testing of only one antibiotic product and the relatively short time period involved in evaluating renal scarring (2 years), the writers conclude: “In the face of the emergence of antibiotic resistance, the lack of a significant between-group difference in renal parenchymal scarring, and questions about generalizability, the RIVUR study results would imply that the general recommendation of prophylactic antibiotics for vesicoureteral reflux in young children awaits more evidence before universal adoption.” (J. R. Ingelfinger)
Tofacitinib in Rheumatoid Arthritis: In 956 patients with rheumatoid arthritis who had not received methotrexate or had received inadequate doses of the drug, tofacitinib provided superior outcomes than did methotrexate (pp. 2377–86). The oral Janus kinase inhibitor also reduced progression of structural joint damage, researchers report, but “confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels.” (B. Wilkinson, bethanie.wilkinson@pfizer.com)
Naloxegol for Opioid-Induced Constipation: In two Phase III trials of 652 and 700 participants with noncancer pain, naloxegol reduced constipation and associated symptoms without interfering with opioid analgesia, compared with placebo (pp. 2387–96). Over 12 weeks, naloxegol 12.5 or 25 mg daily or placebo produced these results: “A shorter time to the first postdose spontaneous bowel movement and a higher mean number of days per week with one or more spontaneous bowel movements were observed with 25 mg of naloxegol versus placebo in both studies (P <0.001) and with 12.5 mg of naloxegol in study 04 (P <0.001). Pain scores and daily opioid dose were similar among the three groups.” (W. D. Chey, wchey@umich.edu)
Antidepressant Use in Pregnancy: Used during the first trimester of pregnancy, antidepressants produced no increase in risk of cardiac malformations in a large, population-based cohort study (pp. 2397–407). Data from the nationwide Medicaid Analytic eXtract for 2000–07 showed that cardiac defects per 10,000 infants occurred in 72.3 unexposed and 90.1 exposed infants. While the unadjusted relative risks of any cardiac defect was increased significantly (by 25%) with use of SSRIs, the increase in women with depression was not significant (6%). Risk of right ventricular outflow tract obstruction was not increased significantly with paroxetine (7%). (K. F. Huybrechts, khuybrechts@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 20, 2014 * Vol. 21, No. 119
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
June issue of Health Affairs (2014; 33).
Blindness Drugs & Part B Costs: Paying for administration of the ophthalmic agents bevacizumab and ranibizumab now consumes one-sixth of the Medicare Part B budget, authors note, and “altering patterns of use with these therapies by encouraging bevacizumab use and hastening approval of biosimilar therapies would dramatically reduce spending without substantially affecting patient outcomes” (pp. 931–9). The group explains: “The two drugs have similar efficacy and potentially minor differences in adverse-event rates; however, at $2,023 per dose, ranibizumab costs forty times more than bevacizumab. Using modeling methods, we predict ten-year (2010–20) population-level costs and health benefits of using bevacizumab and ranibizumab. Our results show that if all patients were treated with the less expensive bevacizumab instead of current usage patterns, savings would amount to $18 billion for Medicare Part B and nearly $5 billion for patients. With an additional $6 billion savings in other health care expenses, the total savings would be almost $29 billion.” (D. Hutton, dwhutton@umich.edu)
Reducing Cost of Medicare Part D Low-Income Subsidies: Of the $60 billion spent on the Medicare Part D benefit in 2013, 75% went to enrollees with low-income subsidies, note authors who develop this idea for reducing costs by $5 billion (pp. 940–5): “The government randomly assigns any new beneficiary who automatically qualifies for the subsidy, or who successfully applies for it without indicating a preferred plan, to a stand-alone Part D plan whose premium is equal to or below the average premium for the basic Part D benefit in the region. We used an intelligent reassignment algorithm and 2008–09 Part D drug use and spending data to match enrollees to available plans according to their medication needs. We found that such a reassignment approach could have saved the federal government over $5 billion in 2009, for mean government savings of $710 (median: $368) per enrollee with a low-income subsidy.” (Y. Zhang, ytzhang@pitt.edu)

>>>Medical Care Report
Source:
July issue of Medical Care (2014; 52).
Pharmacy-Based Cancer Comorbidity Index: In patients with colorectal, breast, gynecologic, stomach/liver, or renal/bladder cancers, a pharmacy-based comorbidity index (PBCI) provided a valid alternative to hospitalization data for risk-adjustment purposes, researchers report (pp. 586–93). Using the New Zealand Cancer Registry, the investigators created development and validation cohorts using 2006–09 data. Figures from community pharmacies for 10 conditions showed the following when compared with the hospital-based Charlson Index: “Kappa coefficients for conditions identified in notes review compared with pharmaceutical data ranged from 0.83 (diabetes) to 0.26 (anxiety/depression). Correlation coefficients with the Charlson ranged from 0.37 to 0.45 across cancers. All comorbidity indices were significant predictors of mortality, and differences between models were small. The PBCI generally performed as well or better than the Charlson index for predicting noncancer death within all cancer sites and slightly outperformed other indices in predicting noncancer mortality for breast cancer.” (D. Sarfati)
HEDIS & Cardiovascular Care: An adherence measure with “predictive ability as good as that of the [Healthcare Effectiveness Data and Information Set (HEDIS)] definition” allows more timely interventions in patients after myocardial infarction (MI) who are on beta-blockers, a study shows (pp. 669–76). Assessment of a retrospective cohort of 8,672 such patients compared change in C-statistics and continuous net reclassification improvement indices (NRIs) when adherence was included or not included in models: “Adherence was associated with clinical outcome reductions, with hazard ratios ranging from 0.48 (95% CI, 0.27–0.85) to 0.81 (95% CI, 0.67–0.99). None of the adherence measures, including the HEDIS definition, significantly changed the C-statistic relative to a model that did not include adherence. However, the short-term adherence measure (having 72 d covered during the first 90 d postdischarge) showed a large change in NRI (correctly reclassifying 12% of cases and 16% of noncases; NRI: 28%; 95% CI, 22%–38%), although did not significantly differ from the change in NRI with the HEDIS measure.” (G. Sanfélix-Gimeno)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 23, 2014 * Vol. 21, No. 120
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Antidepressant Use After FDA Suicide Warnings: “Unintended consequences” is the chief lesson of an article that analyzes suicide attempts among young people following FDA warnings about suicidality with antidepressants and related media coverage (g3596). Finding that the warnings were followed by decreased antidepressant use and an increase in suicide attempts, the authors report: “Trends in antidepressant use and poisonings changed abruptly after the warnings. In the second year after the warnings, relative changes in antidepressant use were −31.0% (95% confidence interval −33.0% to −29.0%) among adolescents, −24.3% (−25.4% to −23.2%) among young adults, and −14.5% (−16.0% to −12.9%) among adults. These reflected absolute reductions of 696, 1,216, and 1,621 dispensings per 100,000 people among adolescents, young adults, and adults, respectively. Simultaneously, there were significant, relative increases in psychotropic drug poisonings in adolescents (21.7%, 95% confidence interval 4.9% to 38.5%) and young adults (33.7%, 26.9% to 40.4%) but not among adults (5.2%, −6.5% to 16.9%). These reflected absolute increases of 2 and 4 poisonings per 100 000 people among adolescents and young adults, respectively (approximately 77 additional poisonings in our cohort of 2.” (C. Y. Lu, christine_lu@harvardpilgrim.org)
ADHD Medications & Suicidality: Trends identified from several Swedish national registries show no association between suicidal behavior and current use of medications for attention-deficit/hyperactivity disorder (ADHD) (g3769). For those born in 1960–96 who began drug treatment for ADHD in 2006–09, the patterns were noted: “Among 37,936 patients with ADHD, 7,019 suicide related events occurred during 150,721 person years of follow-up. At the population level, drug treatment of ADHD was associated with an increased rate of suicide related events (hazard ratio 1.31, 95% confidence interval 1.19 to 1.44). However, the within patient comparison showed a reverse association between ADHD drug treatment and rate of suicide related events (0.89, 0.79 to 1.00). Among stimulant users, a reduced within patient rate of suicide related events was seen during treatment periods (0.81, 0.70 to 0.94). Among non-stimulant/mixed users, no significantly increased within patient rate of suicide related events during non-stimulant treatment periods was seen (0.96, 0.72 to 1.30).” (Q. Chen, qi.chen@ki.se)
Vitamin D & Mortality: The relationships between vitamin D levels and all-cause and cause-specific mortality were “remarkably consistent” in a meta-analysis of individual data from eight prospective cohort studies from Europe and the U.S., researchers report (g3656): “During follow-up, 6,695 study participants died, among whom 2,624 died of cardiovascular diseases and 2,227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality.” (B. Schöttker, b.schoettker@dkfz.de)

>>>PNN NewsWatch
* FDA on Friday approved oral and I.V. tedizolid phosphate (Sivextro, Cubist) for treatment of acute bacterial skin and skin structure infections caused by certain susceptible bacteria, including methicillin-resistant and -susceptible Staphylococcus aureus, various Streptococcus species, and Enterococcus faecalis. FDA designated the drug a qualified infectious disease product—which provides an extra 5 years of marketing exclusivity—and granted it an expedited review. In clinical trials, tedizolid was as effective as linezolid in treating skin infections caused by susceptible bacteria. Common adverse reactions to the drug have been nausea, headache, diarrhea, vomiting, and dizziness.

>>>PNN JournalWatch
* Prehospital Stroke Scales in Urban Environments: A Systematic Review, in
Neurology, 2014; 82: 2241–9. (E. S. Brandler, ethan.brandler@downstate.edu)
* Regulatory and Cost Barriers Are Likely To Limit Biosimilar Development And Expected Savings in the Near Future, in
Health Affairs, 2014; 33: 1048–57. (H. G. Grabowski, grabow@econ.duke.edu)
* Reinventing the Health Services Researcher, in
Medical Care, 2014; 52: 573–5. (R. Russ-Sellers)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 24, 2014 * Vol. 21, No. 121
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2014; 174).
Medical Home Results in VHA: Factors yielding improved outcomes in the Patient Aligned Care Team (PACT) initiative in Veteran Health Administration primary care clinics—where pharmacists, dietitians, social workers, and mental health professionals are often deployed—are identified in a study of the organization’s patient-centered medical home (PCMH) activities (doi: 10.1001/jamainternmed.2014.2488). The observational study used data on 5.6 million veterans receiving care at 913 primary care clinics and from 5,404 primary care staff. Results for eight domains of PACT showed the following: “Fifty-three items were included in the PACT Implementation Progress Index (Pi2). Compared with the 87 clinics in the lowest decile of the Pi2, the 77 sites in the top decile exhibited significantly higher patient satisfaction (9.33 vs 7.53; P <.001), higher performance on 41 of 48 measures of clinical quality, lower staff burnout (Maslach Burnout Inventory emotional exhaustion subscale, 2.29 vs 2.80; P = .02), lower hospitalization rates for ambulatory care–sensitive conditions (4.42 vs 3.68 quarterly admissions for veterans 65 years or older per 1000 patients; P <.001), and lower emergency department use (188 vs 245 visits per 1,000 patients; P <.001).” (K. M. Nelson, karin.nelson@va.gov)
An editorialist writes that “not all (medical) homes are built alike” and makes these observations (
doi: 10.1001/jamainternmed.2014.2497): “The study by Nelson et al helps inform our understanding of the core structural elements requisite to success in a PCMH model, the 8 elements of the Pi2: access, continuity of care, care coordination, comprehensiveness, self-management support, patient-centered care and communication, shared decision making, and team-based care (including delegation, staffing, and team functioning). Just as the VHA had to adapt the PCMH concept to its own context in developing and implementing the PACT model, practices that aspire to be a successful PCMH could assess their own performance for the constructs that underlie the Pi2 (asking, for example, “Are we providing access? Do we have continuity? Do we offer shared decision making?&rdquoWinking and use that assessment as a less bureaucratic and more authentic measure of how likely the practice is to improve the patient experience, decrease staff burnout, and decrease total costs of care. Practices need not measure as precisely as the VHA investigators did, and they probably cannot without the same rich data environment. But the current findings outline, in accessible terms, where a primary care practice needs to go, and they could support the development of other assessment tools for PCMH-ness.” (R. J. Baron, rbaron@abim.org)
Gender Differences in Research & Practice: Reacting to a study showing that women with left bundle branch block benefited from cardiac resynchronization therapy at a shorter QRS duration than did men (doi: 10.1001/jamainternmed.2014.2717, D. G. Strauss, david.strauss@fda.hhs.gov), an editoralist supports “initiatives to increase awareness of [sex and gender] differences, develop a common knowledge basis and exchange between researchers of different disciplines, develop career opportunities for young scientists, provide common training tools to introduce students early into the disciplines, and establish systematic sex- and gender- specific medicine research as an independent discipline” (doi: 10.1001/jamainternmed.2014.320): “Personalized medicine is genome based, successful in predicting genome-based risks and responses—single gene effects—but it is currently too expensive for use in clinical care and incomplete because epigenetic modifications are not covered. Sex- and gender-specific medicine considers an important genetic difference—sex—and includes effects of lifestyle and environment transmitted by epigenetic modifications. It is known that the environment affects the phenotype through sex-specific epigenetic modifications such as methylation patterns that are permanently modified. For example, if the fetus is exposed to severe nutrient limitation during gestation, in later life, the men and women display different epigenetic profiles, which will impact future health. Sex- and gender-specific medicine is also attractive because it is easy and economical to recognize the sex of the patient and because our existing substantial body of registry and clinical trial data includes women and men.” (C. N. Bairey Merz, merz@cshs.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 25, 2014 * Vol. 21, No. 122
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 25 issue of JAMA (2014; 311).
Diffuse Cutaneous Systemic Sclerosis Treatments: In the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, patients with diffuse cutaneous systemic sclerosis receiving autologous hematopoietic stem cell transplantation (HSCT) had higher treatment-related mortality in the first year after treatment, compared with high-dose cyclophosphamide, but they also had significantly greater long-term event-free survival, researchers report (pp. 2490–8). The Phase III trial was conducted in 10 countries and 29 centers. HSCT was compared with 12 successive monthly intravenous pulses of cyclophosphamide, with these outcomes based on a primary end point of event-free survival (time from randomization until the occurrence of death or persistent major organ failure): “A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16–0.74) at 2 years and 0.34 (95% CI, 0.16–0.74) at 4 years.” (J. M. van Laar, j.m.vanlaar@umcutrecht.nl)
“Recommendations are needed about which patients should be offered HSCT and whether HSCT should be offered as an up-front treatment (especially in patients with diffuse cutaneous systemic sclerosis and internal organ involvement) or as a salvage procedure,” editorialists write (
pp. 2485–7). “Currently, consideration should be limited to patients with (1) diffuse cutaneous systemic sclerosis within the first 4 to 5 years of onset with mild-to-moderate internal organ involvement (severe internal organ involvement will make patients ineligible because of risks associated with HSCT) or (2) limited cutaneous systemic sclerosis with progressive internal organ involvement. This consideration also should generally be restricted to patients who have failed to improve or have worsened on conventional immunosuppressive agents and who are not active smokers; the SCOT study may help confirm the association of smoking (former or current) and mortality in the transplant group.” (D. Khanna, khannad@med.umich.edu)
Antimicrobial Therapy for Venous Leg Ulcers: Use of systemic antibiotic therapy for venous leg ulcers is neither supported nor refuted by available evidence, authors conclude in a JAMA Clinical Evidence Synopsis (pp. 2534–5). Analysis of 45 randomized clinical trials (RCTs) led to these results: “Two pooled RCTs (50 patients) found that ciprofloxacin was not associated with better venous leg ulcer healing at 12- to 16-week follow-up compared with usual care or placebo (8 of 31 patients [26%] receiving ciprofloxacin vs 3 of 19 patients [16%] receiving usual care/placebo; risk ratio [RR], 1.74 [95% CI, 0.57–5.30]). Single RCTs found no association with healing for antibiotics selected by antibiotic sensitivity compared with usual care; trimethoprim compared with placebo; ciprofloxacin compared with trimethoprim; or amoxicillin compared with topical povidone iodine. Limited data (2 pooled RCTs; 48 patients) suggest that antibiotic-resistant microorganisms emerge more frequently with ciprofloxacin treatment than without.” (S. O’Meara, s.m.omeara@leeds.ac.uk)

>>>PNN NewsWatch
* APhA has endorsed “any willing provider” legislation now before Congress. The bill would give “Medicare patients more convenient access to discounted or ‘preferred’ copays at independent community pharmacies willing to accept the terms and conditions of Medicare Part D prescription drug plans,” pharmacist.com reports. Also supporting the bill are NCPA and other pharmacy organizations and a wide variety of patient advocacy, health provider, and business organizations.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 26, 2014 * Vol. 21, No. 123
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 26 issue of the New England Journal of Medicine (2014; 370).
Antiretroviral Timing After Cryptococcal Meningitis: Survival was improved when antiretroviral therapy (ART) was deferred for 5 weeks, compared with 1–2 weeks, after diagnosis of cryptococcal meningitis in a study of 177 HIV-infected adults in Uganda and South Africa (pp. 2487–98). Antifungal therapy with amphotericin B plus fluconazole was administered for 14 days followed by consolidation therapy with fluconazole. Deferral of ART for 1–2 or 5 weeks had these effects on outcomes: “The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P = 0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P = 0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P = 0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P = 0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.” (D. R. Boulware, boulw001@umn.edu)
Venous Thromboembolism Prophylaxis in Cancer: In ambulatory patients with cancer, “empirical prophylaxis against venous thromboembolism … remains controversial,” the author of a review article writes, reaching this conclusion (pp. 2515–9): “Venous thromboembolism results in increased morbidity, mortality, and complexity of care in all patient populations, but in patients with cancer, this complication may also lead to delays in surgery and the administration of chemotherapy as well as an increased risk of bleeding associated with full-intensity anticoagulation. The increased use of prophylaxis against venous thromboembolism in high-risk ambulatory patients with cancer who are eligible for this therapy could lead to improved outcomes. Further studies are needed to assess the effects of this prophylaxis on morbidity, mortality, and the costs of care for patients with cancer.” (J. M. Connors, jconnors@partners.org)
NewMedia@FDA: The impact of the digital age on drug safety—and the implications for FDA’s regulations of drugs in the U.S.—is explored in a Perspective article (pp. 2460–2). The authors conclude: “New media provide new opportunities for the FDA and patient- and consumer-safety organizations to communicate public health messages. Given the frequency with which patients seek information outside the clinic, and particularly on the Internet, taking advantage of those media appears to be a promising means for the FDA to ensure that patients have ready access to accurate and comprehensive information, including timely updates pertaining to drug-safety issues. Integrating online public health communication into medical training and consumer-facing websites could be an important step toward more fully realizing the Internet’s potential in the promotion of public health.” (T. J. Hwang)
Dying with Dignity in ICUs: A review article examines the issue of dying with dignity in intensive care units (ICUs) and offers recommendations, including how care can be withdrawn and palliative care instituted (pp. 2506–14): “Palliative care in the ICU has come of age. Its guiding principles are more important than ever in increasingly pluralistic societies. Ensuring that patients are helped to die with dignity begs for reflection, time, and space to create connections that are remembered by survivors long after a patient’s death. It calls for humanism from all clinicians in the ICU to promote peace during the final hours or days of a patient’s life and to support the bereaved family members. Ensuring death with dignity in the ICU epitomizes the art of medicine and reflects the heart of medicine. It demands the best of us.” (D. Cook, debcook@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 27, 2014 * Vol. 21, No. 124
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (2014; 37).
Metformin & Cancer: A cohort study that avoids time-related bias of previous research shows that metformin use is not associated with lower risks of bladder cancer (pp. 1910–7). Among 87,600 patients with type 2 diabetes in the Health Improvement Network database, use of metformin or sulfonylureas (SUs) showed these results: “We identified 196 incident bladder cancers in the metformin cohort and 66 cancers in the SU cohort. Use of metformin was not associated with decreased bladder cancer risk (HR 0.81 [95% CI 0.60–1.09]). This association did not differ by sex (P for interaction = 0.20). We observed no association with duration of metformin relative to SU use (3 to <4 years of use: 0.57 [0.25–1.34]; 4 to <5 years of use: 0.93 [0.30–2.85; ≥5 years of use: 1.18 [0.44–3.19]; P for trend = 0.26).” (R. Mamtani, ronac.mamtani@uphs.upenn.edu)
This study “joins a growing set of observational studies reporting null effects of metformin use on cancer prevention and treatment,” editorialists write (
pp. 1786–8). “Because of their observational nature, these studies may have been affected by other biases, but are generally free of major time-related biases that are known to potentially exaggerate the benefits of drugs. Indeed, observational studies with time-related biases have reported extraordinary effects ranging from 20 to 94% reductions in the risk of cancer, suggesting that metformin may be more effective at preventing or treating cancer than preventing the cardiovascular complications of diabetes. Moving forward, it will be essential to critically appraise the current scientific literature, and conduct rigorous studies using designs and methods of analysis that avoid these vexing biases. It is well accepted that properly conducted observational studies can contribute significantly to the knowledge base on the effects of drugs and that computerized health databases can play a major role in providing this important information quickly and accurately.” (S. Suissa, samy.suissa@mcgill.ca)
Mediterranean Diet & Antidiabetic Drugs: Patients newly diagnosed with type 2 diabetes can delay the need for antidiabetic medications through adoption of a low-carbohydrate Mediterranean diet (LCMD), researchers report (pp. 1824–30). Study participants (n = 215) were randomized to LCMD or low-fat diet and followed for 4 years. Those not using antidiabetic medications at that point were followed further. Results showed: “The primary end point was reached in all participants after a total follow-up of 6.1 years in the low-fat group and 8.1 years in the LCMD group; median survival time was 2.8 years (95% CI 2.4–3.2) and 4.8 years (4.3–5.2), respectively. The unadjusted hazard ratio for the overall follow-up was 0.68 (0.50–0.89; P < 0.001). LCMD participants were more likely to experience any remission (partial or complete), with a prevalence of 14.7% (13.0–16.5%) during the first year and 5.0% (4.4–5.6%) during year 6 compared with 4.1% (3.1–5.0%) at year 1 and 0% at year 6 in the low-fat diet group.” (K. Esposito, katherine.esposito@unina2.it)
High-Dose Vitamin D During Pregnancy: Among pregnant women with plasma 25-hydroxyvitamin D (25OHD) levels lower than 32 ng/mL before 20 weeks’ gestation, institution of vitamin D3 in doses of 5,000 IU/d failed to improve glucose levels, but the doses were well tolerated and neonatal vitamin D deficiency was prevented, a study shows (pp. 1837–44). The 179 women in the study received low-dose (LD, 400 IU/d)or high-dose vitamin D3 daily, with these effects on an oral glucose tolerance test (OGTT) at 26–28 weeks’ gestation and secondary outcomes (neonatal 25OHD, obstetric and other neonatal outcomes, and maternal homeostasis model assessment of insulin resistance): “There was no difference in maternal glucose levels on OGTT. Twelve LD women (13%) developed [gestational diabetes mellitus] versus seven (8%) HD women (P = 0.25). Neonatal cord 25OHD was higher in HD offspring (46 ± 11 vs. 29 ± 12 ng/mL, P < 0.001), and deficiency was more common in LD offspring (24 vs. 10%, P = 0.06). Post hoc analysis in LD women showed an inverse relationship between pretreatment 25OHD and both fasting and 2-h blood glucose level on OGTT (both P < 0.001). Baseline 25OHD remained an independent predictor after multiple regression analysis.” (C. Yap, constanceyap@yahoo.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 30, 2014 * Vol. 21, No. 125
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 28 issue of Lancet (2014; 383).
High-Dose Simvastatin in Multiple Sclerosis: Results of a 140-patient study support expanded research into use of high-dose simvastatin in patients with secondary progressive multiple sclerosis, authors conclude (pp. 2213–21). Adults with the condition were randomly assigned in blocks of 8 to simvastatin 80 mg or placebo, with these effects on whole-brain atrophy as measured by serial volumetric MRI: “The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0.288% per year [SD 0.521]) than in those in the placebo group (0.584% per year [0.498]). The adjusted difference in atrophy rate between groups was –0.254% per year (95% CI –0.422 to –0.087; p = 0.003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]).” (J. Chataway, jeremy.chataway@uclh.nhs.uk)
Dolutegravir in HIV Infection: Compared with once-daily darunavir plus ritonavir, once-daily dolutegravir produced superior efficacy outcomes in an open-label trial of 484 patients with HIV-1 infection (pp. 2222–31). Study participants, all antiretroviral therapy–naive, had HIV-1 RNA concentrations of 1,000 copies/mL or more when they were randomized to dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Results showed: “At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7.1%, 95% CI 0.9–13.2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p = 0.025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four [2%] patients) than for darunavir plus ritonavir (ten [4%] patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 [17%] patients vs darunavir plus ritonavir 70 [29%] patients), nausea (39 [16%] vs 43 [18%]), and headache (37 [15%] vs 24 [10%]). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 [2%] vs 36 [7%]; p = 0.0001).” (B. Clotet, bclotet@irsicaixa.es)
Colchicine for Recurrent Pericarditis: Added to conventional NSAID therapy, colchicine “reduced the rate of subsequent recurrences of pericarditis in patients with multiple recurrences,” researchers report (pp. 2232–7). The agent was previously known to be effective for treating acute pericarditis and first recurrences. This study adds evidence supporting use of the drug in those with multiple recurrences: “The proportion of patients who had recurrent pericarditis was 26 (21.6%) of 120 in the colchicine group and 51 (42.5%) of 120 in the placebo group (relative risk 0.49; 95% CI 0.24–0.65; p = 0.0009; number needed to treat 5). Adverse effects and discontinuation of study drug occurred in much the same proportions in each group. The most common adverse events were gastrointestinal intolerance (nine patients in the colchicine group vs nine in the placebo group) and hepatotoxicity (three vs one). No serious adverse events were reported.” (M. Imazio, massimo_imazio@yahoo.it)

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* A rapid-acting inhaled insulin product, Afrezza (MannKind Corp.), was approved for marketing on Friday by FDA. Efficacy and safety were established in a 24-week trial of 3,017 patients who had either type 1 or type 2 diabetes. FDA approved the product with a REMS program designed to warn health professionals of the risk for acute bronchospasm with Afrezza. The agency is also requiring postmarketing assessment the product’s use in pediatric patients, risk for pulmonary malignancy, and pharmacokinetics/pharmacodynamics.

>>>PNN JournalWatch
* The Management of Lower Urinary Tract Symptoms in Men, in
BMJ, 2014; 348: g3861. (J. Rees, drjonrees@gmail.com)
* Patient Preferences for Noninsulin Diabetes Medications: A Systematic Review, in
Diabetes Care, 2014; 37: 2055–62. (T. S. Purnell, tpurnel1@jhmi.edu)

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