Dec 2015

PNN October–December 2015

PNN Pharmacotherapy Line
Oct. 1, 2015 * Vol. 22, No. 189
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 1 issue of the New England Journal of Medicine (2015; 373).
Brodalumab in Psoriasis: In the Phase III AMAGINE-2 and AMAGINE-3 trials, an anti-interleukin-17 receptor A monoclonal antibody, brodalumab, performed significantly better than either placebo and the approved drug ustekinumab in patients with moderate-to-severe psoriasis (pp. 1318–28). These results were recorded based on a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment (sPGA) score of 0 or 1 (clear or almost clear skin): “At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P <0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P <0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P <0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P = 0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P = 0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient–years of exposure to brodalumab.” (M. Lebwohl, mark.lebwohl@mountsinai.org)
Secukinumab in Psoriatic Arthritis: Another interleukin-17A inhibitor, secukinumab, “was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target,” investigators in a Phase III trial conclude (pp. 1329–39). With a primary end point of proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, the study yielded these results in 606 patients with psoriatic arthritis: “ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P <0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient–years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient–years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group.” (P. J. Mease, pmease@philipmease.com)
Benznidazole for Chronic Chagas’ Cardiomyopathy: Reacting to mixed results in a clinical trial of the trypanocidal agent benznidazole for treatment of patients with established Chagas’ cardiomyopathy (pp. 1295–306; C. A. Morillo, morillo@hhsc.ca), an editorialist writes that the need for action is now (pp. 1369–70): “The dramatic success of vector control and screening of blood donors in reducing the rate of transmission of Trypanosoma cruzi stands in stark contrast to the lack of progress in providing adequate care for patients with chronic infection. Less than 1% of persons with T. cruzi infection have received treatment, despite current recommendations, and the proportion of the approximately 300,000 infected persons in the United States who are treated is even less. There is an urgent need for new drugs, new strategies for treatment, and new assays to track results. As the BENEFIT trial illustrates, clinical studies to evaluate the effectiveness of such efforts will take time. The infected population is aging, and time for them is running out.” (J. H. Maguire)

>>>PNN NewsWatch
* FDA recently awarded ASHP with a 3-year contract to improve the safety of I.V. and oral liquid medications. ASHP will collaborate with member experts and other stakeholders to develop nationally standardized concentrations for I.V. and oral liquid medications.

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 © 2015, 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
Oct. 2, 2015 * Vol. 22, No. 190
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Oct. issue of Pediatrics (2015; 136).
Cannabis Vaporization With Electronic Cigarettes: In a 2014 survey in Connecticut, high school (HS) students reported high rates of use of electronic cigarettes to vaporize cannabis, leading authors to express “concerns about the lack of e-cigarette regulations and the potential use of e-cigarettes for purposes other than vaping nicotine” (pp. 611–6). Anonymous surveys completed by 3,847 HS students showed these patterns: “Vaporizing cannabis using e-cigarettes was common among lifetime e-cigarette users, lifetime cannabis users, and lifetime dual users (e-cigarette 18.0%, cannabis 18.4%, dual users 26.5%). Students reported using e-cigarettes to vaporize hash oil (e-cigarette 15.4%, cannabis 15.5%, dual users 22.9%) and wax infused with [∆-9-tetrahydrocannabinol] (e-cigarette 10.0%, cannabis 10.2%, dual users 14.8%) and using portable electronic vaporizers to vaporize dried cannabis leaves (e-cigarette 19.6%, lifetime cannabis 23.1%, lifetime dual users 29.1%). Binary logistic regression indicated that male students (odds ratio [OR] = 2.05), younger students (OR = 0.64), lifetime e-cigarette users (OR = 5.27), and lifetime cannabis users (OR = 40.89) were most likely to vaporize cannabis using e-cigarettes.…” (M. E. Morean)
High-Dose Vitamin D Supplementation During Lactation: Maternal supplementation with high doses of vitamin D during lactation provides an alternate means of raising infants’ serum levels, researchers report (pp. 625–34). Exclusively breastfeeding women in Charleston, SC, or Rochester, NY, were randomized to daily vitamin D3 doses of 400, 2400, or 6400 IU for 6 months. Infants in the low-dose group received oral supplements of 400 IU/d; those in the two higher groups received placebo. Results at baseline, month 4, and month 7 showed: “Of the 334 mother–infant pairs in 400 IU and 6400 IU groups at enrollment, 216 (64.7%) were still breastfeeding at visit 1; 148 (44.3%) continued full breastfeeding to 4 months and 95 (28.4%) to 7 months. Vitamin D deficiency in breastfeeding infants was greatly affected by race. Compared with 400 IU vitamin D3 per day, 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline (P <.0001). Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement, infants in the 6400 IU group whose mothers only received supplement did not differ.” (B. W. Hollis)
Febrile Seizures After Influenza Vaccine: Administration of the 2010–11 trivalent inactivated influenza vaccine (TIV) alone or with 13-valent pneumococcal conjugate vaccine (PCV13) was not associated with increased risk of febrile seizures (FS), according to a self-controlled risk interval design study (pp. e848–55). Adjusted for concomitant diphtheria tetanus acellular pertussis–containing vaccines (DTaP), results were as follows: “No statistically significant TIV–FS associations were found in unadjusted or adjusted models (incidence rate ratio [IRR] adjusted for age, seasonality, and concomitant PCV13 and DTaP: 1.36, 95% confidence interval [CI] 0.78 to 2.39). Adjusted for age and seasonality, PCV13 was significantly associated with FS (IRR 1.74, 95% CI 1.06 to 2.86), but not when further adjusting for concomitant TIV and DTaP (IRR 1.61, 95% CI 0.91 to 2.82). Same-day TIV and PCV13 vaccination was not associated with excess risk of FS when compared with separate-day vaccination (1.08 fewer FS per 100,000 with same day administration, 95% CI −5.68 to 6.09).” (A. T. Kawai)

>>>Psychiatry Highlights
Source:
Oct. issue of the American Journal of Psychiatry (2015; 172).
Citicoline for Cocaine Dependence in Bipolar Disorder: Among 130 outpatients with bipolar I disorder with depressed or mixed mood state, 12 weeks of citicoline therapy was effective for treatment of cocaine dependence, a study shows, but effects diminished over time (pp. 1014–21). Patients received citicoline or placebo add-on therapy and had urine drug screens three times weekly. Results with the Inventory of Depressive Symptomatology–Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale showed the following: “In the intent-to-treat sample (N = 61 in both groups), significant treatment group and group-by-time effects were observed.…. The group effect was greatest early in the study and tended to decline with time.” (E. S. Brown)

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 © 2015, 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
Oct. 5, 2015 * Vol. 22, No. 191
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Recommended Drugs & Mortality in Older Adults: In a real-world population-based cohort study, medications recommended in guidelines for common conditions performed similarly with respect to mortality in older adults as in clinical trials, but some differences were noted in those with coexisting conditions (h4984). Using the nationally representative Medicare Current Beneficiary Cohort Study, investigators identified 8,578 older adults with two or more of these conditions: atrial fibrillation, coronary artery disease, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, and thromboembolic disease.
Use of beta-blockers, calcium channel blockers, clopidogrel, metformin, renin-angiotensin system (RAS) blockers; selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs); statins; thiazides; and warfarin provided these results: “Over 50% of participants with each condition received the recommended drugs regardless of coexisting conditions; 1,287/8,578 (15%) participants died during the three years of follow-up. Among cardiovascular drugs, beta-blockers, calcium channel blockers, RAS blockers, and statins were associated with reduced mortality for indicated conditions. For example, the adjusted hazard ratio for beta-blockers was 0.59 (95% confidence interval 0.48 to 0.72) for people with atrial fibrillation and 0.68 (0.57 to 0.81) for those with heart failure. The adjusted hazard ratios for cardiovascular drugs were similar to those with common combinations of four coexisting conditions, with trends toward variable effects for beta-blockers. None of clopidogrel, metformin, or SSRIs/SNRIs was associated with reduced mortality. Warfarin was associated with a reduced risk of death among those with atrial fibrillation (adjusted hazard ratio 0.69, 95% confidence interval 0.56 to 0.85) and thromboembolic disease (0.44, 0.30 to 0.62). Attenuation in the association with reduced risk of death was found with warfarin in participants with some combinations of coexisting conditions.” (M. E. Tinetti,
mary.tinetti@yale.edu)

>>>Lancet Highlights
Source:
Oct. 3 issue of Lancet (2015; 386).
Aromatase Inhibitors in Early Breast Cancer: Compared with 5 years of tamoxifen in 31,920 postmenopausal women with estrogen-receptor-positive early breast cancer, investigators conclude that aromatase inhibitor therapy for 5 years reduced 10-year breast cancer mortality rates by about 40% (pp. 1341–52; Early Breast Cancer Trialists’ Collaborative Group).
Adjuvant Bisphosphonates in Early Breast Cancer: Data on 18,766 participants in clinical trials show that adjuvant bisphosphonate therapy reduced breast cancer recurrence in bone and improved survival, but definite benefit was observed “only in women who were postmenopausal when treatment began,” researchers report (pp. 1353–61; Early Breast Cancer Trialists’ Collaborative Group).

>>>PNN NewsWatch
* FDA on Friday granted accelerated approval for pembrolizumab (Keytruda, Merck) to treat patients with advanced (metastatic) nonsmall cell lung cancer whose disease has progressed after other treatments and with tumors that express PD-L1. The agent is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test (Dako North America), the first test designed to detect PD-L1 expression in non-small cell lung tumors.

>>>PNN JournalWatch
* Alternate Approaches for Pediatric Type 1 Diabetes Drug Development and Potential Regulatory Approval: A Perspective, in
Diabetes Care, 2015; 38: 1986–91. (J. R. Turner, rick.turner@quintiles.com)
* Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression, in
American Journal of Psychiatry, 2015; 172: 950–66. (D. J. Newport)
* Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review, in
Pediatrics, 2015; 136: 687–701. (L. Zhang)
* Are Pediatricians Complicit in Vitamin K Deficiency Bleeding?, in
Pediatrics, 2015; 136: 753–7. (M. Weddle)
* Fructose and Cardiometabolic Health: What the Evidence From Sugar-Sweetened Beverages Tells Us, in
Journal of the American College of Cardiology, 2015; 66: 1615–24– (V. S. Malik)
* Estimates of Global and Regional Premature Cardiovascular Mortality in 2025, in
Circulation, 2015; 132: 1270–82. (G. A. Roth, rothg@uw.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 © 2015, 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
Oct. 6, 2015 * Vol. 22, No. 192
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 6 issue of the Annals of Internal Medicine (2015; 163).
Cost-Effectiveness of Shingles Vaccine at Age 50: Results of a cost-effectiveness study of herpes zoster (HZ) vaccine administered to 50-year-olds support recommendations of the “Advisory Committee on Immunization Practices not to recommend the vaccine for adults in this age group,” researchers report (pp. 489–97). Using a lifetime horizon and societal perspective, the analysis produced these results for base-case and sensitivity analyses: “For every 1,000 persons receiving the vaccine at age 50 years, 25 HZ cases and 1 [postherpetic neuralgia] case could be prevented. The incremental cost-effectiveness ratio (ICER) for HZ vaccine versus no vaccine was $323,456 per QALY.…
“In deterministic and scenario sensitivity analyses, the only variables that produced an ICER less than $100,000 per [quality-adjusted life-year (QALY)] were vaccine cost (at a value of $80) and the rate at which efficacy wanes. In probabilistic sensitivity analysis, the mean ICER was $500,754 per QALY (95% CI, $93,510 to $1,691,211 per QALY). At a willingness-to-pay threshold of $100,000 per QALY, the probability that vaccination would be cost-effective was 3%.” (P. Le,
lep@ccf.org)
Artesunate for Severe, Complicated Malaria: Intravenous artesunate provided “a safe and clinically beneficial alternative to quinidine” for treatment of 102 patients with severe and complicated malaria in U.S. hospitals, according to a retrospective case series analysis (pp. 498–506). Patients, ages 1 to 72 years, were treated using a CDC protocol; 35% had cerebral malaria and 17% severe hepatic impairment. Clinical and laboratory data in hospital records showed the following: “7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients’ symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug–drug interactions.” (P. S. Twomey, patrick.s.twomey.mil@mail.mil)
Corticosteroid Therapy During CAP Hospitalizations: A systematic review and meta-analysis demonstrates reductions in mortality, need for mechanical ventilation, and hospital lengths of stay among patients with community-acquired pneumonia (CAP) who received systemic corticosteroid therapy (pp. 519–28): “The median age was typically in the 60s, and approximately 60% of patients were male. Adjunctive corticosteroids were associated with possible reductions in all-cause mortality (12 trials; 1,974 patients; risk ratio [RR], 0.67 [95% CI, 0.45 to 1.01]; risk difference [RD], 2.8%; moderate certainty), need for mechanical ventilation (5 trials; 1,060 patients; RR, 0.45 [CI, 0.26 to 0.79]; RD, 5.0%; moderate certainty), and the acute respiratory distress syndrome (4 trials; 945 patients; RR, 0.24 [CI, 0.10 to 0.56]; RD, 6.2%; moderate certainty). They also decreased time to clinical stability (5 trials; 1,180 patients; mean difference, −1.22 days [CI, −2.08 to −0.35 days]; high certainty) and duration of hospitalization (6 trials; 1,499 patients; mean difference, −1.00 day [CI, −1.79 to −0.21 days]; high certainty). Adjunctive corticosteroids increased frequency of hyperglycemia requiring treatment (6 trials; 1,534 patients; RR, 1.49 [CI, 1.01 to 2.19]; RD, 3.5%; high certainty) but did not increase frequency of gastrointestinal hemorrhage.” (R. A. C. Siemieniuk, reed.siemieniuk@medportal.ca)
It’s “time to change practice” for managing inpatients with severe CAP, editorialists write, providing these guidelines for which patients fall into that category (
pp. 560–1): “Obviously, severe CAP is present in those requiring mechanical ventilation, vasopressors, or both, but only one third of hospitalized patients with CAP need these interventions. We advocate the use of biomarkers, such as C-reactive protein levels, as indicators of the degree of systemic inflammation. In CAP, elevated serum C-reactive protein levels are associated with higher rates of treatment failure and mortality.” (A. Anzueto, anzueto@uthscsa.edu)

>>>PNN NewsWatch
* Based on articles released yesterday by the New England Journal of Medicine, FDA warned of possible leaflet thrombosis with bioprosthetic valves.

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 © 2015, 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
Oct. 7, 2015 * Vol. 22, No. 193
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Oct. 13 issue of the Journal of the American College of Cardiology (2015; 66).
CHD Risk Prediction With Coronary Artery Calcium: Using algorithms from the prospective community-based cohort MESA (Multi-Ethnic Study of Atherosclerosis), investigators were able to accurately estimate patients’ 10-year risks of coronary heart disease (CHD) using coronary artery calcium (CAC) and traditional risk factors (pp. 1643–53). Among 6,814 participants aged 45–84 years without clinical atherosclerotic cardiovascular disease at baseline, follow-up over 10 years yielded these results: “Inclusion of CAC in the MESA risk score offered significant improvements in risk prediction (C-statistic 0.80 vs. 0.75; p <0.0001). External validation in both the [Heinz Nixdorf Recall Study (HNR)] and [Dallas Heart Study (DHS)] studies provided evidence of very good discrimination and calibration. Harrell’s C-statistic was 0.779 in HNR and 0.816 in DHS. Additionally, the difference in estimated 10-year risk between events and nonevents was approximately 8% to 9%, indicating excellent discrimination. Mean calibration, or calibration-in-the-large, was excellent for both studies, with average predicted 10-year risk within one-half of a percent of the observed event rate.” (R. L. McClelland)
Coronary Artery Calcium Testing Among Statin Candidates: When applying the American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guidelines, inclusion of coronary artery calcium (CAC) is needed to rule out statin therapy for about one-half of patients without this marker, a study shows (pp. 1657–68). MESA data formed the basis of the analysis, with portions of patients excluded for various reasons. Results showed: “The study population consisted of 4,758 participants (age 59 ± 9 years; 47% males). A total of 247 (5.2%) ASCVD and 155 (3.3%) hard coronary heart disease events occurred over a median (interquartile range) follow-up of 10.3 (9.7 to 10.8) years. The new ACC/AHA guidelines recommended 2,377 (50%) MESA participants for moderate- to high-intensity statins; the majority (77%) was eligible because of a 10-year estimated [atherosclerotic cardiovascular disease (ASCVD)] risk ≥7.5%. Of those recommended statins, 41% had CAC = 0 and had 5.2 ASCVD events/1,000 person–years. Among 589 participants (12%) considered for moderate-intensity statin, 338 (57%) had a CAC = 0, with an ASCVD event rate of 1.5 per 1,000 person–years. Of participants eligible (recommended or considered) for statins, 44% (1,316 of 2,966) had CAC = 0 at baseline and an observed 10-year ASCVD event rate of 4.2 per 1,000 person–years.” (K. Nasir)

>>>Circulation Report
Source:
Oct. 6 issue of Circulation (2015; 132).
Medication Initiation Burden in Heart Failure: Paitents being discharged from hospitals with primary diagnoses of heart failure (HF) need help managing medication initiation and polypharmacy, a study shows (pp. 1347–53): “Among 158,922 patients from 271 hospitals with a primary discharge diagnosis of HF, initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was indicated in 18.1% of all patients (55.5% of those eligible at discharge were not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at admission), beta-blockers in 20.3% (50.5% of eligible), aldosterone antagonists in 24.1% (87.4% of eligible), hydralazine/isosorbide dinitrate in 8.6% (93.1% of eligible), and anticoagulants in 18.0% (58.0% of eligible). Cumulatively, 0.4% of patients were eligible for 5 new medication groups, 4.1% for 4 new medication groups, 9.4% for 3 new medication groups, 10.1% for 2 new medication groups, and 22.7% for 1 new medication group; 15.0% were not eligible for new medications because of adequate prescribing at admission; and 38.4% were not eligible for any medications recommended by HF quality measures. Compared with newly indicated medications (mean, 1.45±1.23), actual new prescriptions were lower (mean, 1.16±1.00). (L. A. Allen, larry.allen@ucdenver.edu)

>>>PNN NewsWatch
* FDA on Tuesday approved aripiprazole lauroxil (Aristada) extended-release injection to treat adults with schizophrenia. .
*
FDA has launched a public education campaign to prevent and reduce tobacco use among multicultural youth who identify with the hip-hop peer crowd.

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 © 2015, 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
Oct. 8, 2015 * Vol. 22, No. 194
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 8 issue of the New England Journal of Medicine (2015; 373).
Daclizumab HYP in Relapsing Multiple Sclerosis: Daclizumab high-yield process (HYP), a humanized monoclonal antibody that modulates interleukin-2 signaling by binding to CD25, “showed efficacy superior to that of interferon beta-1a” in 1,841 patients with relapsing–remitting multiple sclerosis, researchers report (pp. 1418–28). However, the agent “was not associated with a significantly lower risk of disability progression confirmed at 12 weeks,” the authors add, along with these results from the 144-week trial: “The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P <0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P <0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P = 0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).” (L. Kappos, kapposl-pa@usb.ch)
Treating Insomnia: Resetting expectations and improving sleep hygiene are important aspects of treating insomnia in older patients, writes the author of a clinical practice article that analyzes management of a 77-year-old woman with overweight, hypertension, arthritis, and chronic insomnia (pp. 1437–44): “The woman in the vignette has a long history of insomnia, now complicated by nocturia and pain. Recently, owing to her physician’s concerns about her benzodiazepine use, she was switched to a low dose of trazodone, but she reports frequent and prolonged awakenings. Attempting to discontinue lorazepam and replacing it with trazodone were reasonable, given the amnestic and psychomotor side effects of benzodiazepines, although data from studies that directly compare these agents are limited. I would strongly recommend a trial of [cognitive behavioral therapy], including (but not limited to) educating her that 7 hours is an adequate amount of sleep, reducing the time from bedtime to final awakening to that amount, and advising her to get in bed only when sleepy and to get out of bed when not sleeping. Over time, these approaches should reduce the duration of nocturnal awakenings, although she should be cautioned initially about an increase in daytime sleepiness. Attention to her nocturia and nocturnal pain will further minimize her nocturnal awakenings and their duration. If these approaches are ineffective, I would consider an increase in the trazodone dose (if this does not cause unacceptable side effects) or a return to lorazepam, informing her of (and regularly reassessing) benefits and potential risks.” (J. W. Winkelman, jwwinkelman@partners.org)
Treatment of Invasive Candidiasis: “The management of invasive candidiasis has changed markedly during the past decade,” conclude authors of a review article that emphasizes prophylaxis, early treatment, and emerging resistance to antifungal agents (pp. 1445–56): “Accumulating evidence points to the importance of early and appropriate antifungal treatment as a major driver of outcomes. Echinocandins appear to be the drugs of first choice for most patients, irrespective of the severity of illness. This development has marked a paradigm shift in the treatment of invasive candidiasis: treat early with an echinocandin and step down early to a triazole, giving consideration to the clinical stabilization of the patient, the candida species, and its susceptibility. By defining the most effective approach to the management of invasive candidiasis, we may finally begin to see declining mortality among patients with candidemia.” (B. J. Kullberg, bj.kullberg@radboudumc.nl)

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 © 2015, 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
Oct. 9, 2015 * Vol. 22, No. 195
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Oct. 15 issue of Clinical Infectious Diseases (2015; 61).
Hep B Reactivation During Hep C Treatment: DNA levels of hepatitis B virus (HBV) should be closely monitored during treatment of hepatitis C virus (HCV) with the new interferon-free, direct-acting antiviral regimens, authors conclude based on two case reports described in this article (pp. 1304–6). “Current HCV treatment guidelines do not offer specific guidance on treatment and monitoring of patients coinfected with HBV,” the group writes. “Although patient 1 was a candidate for HBV therapy with cirrhosis, elevated ALT, and detectable [viral load (VL)], HBV treatment guidelines do not routinely recommend treatment in [hepatitis B e antigen]-negative patients with a VL <2000 IU/mL.… In patients with a positive [hepatitis B core antibody] but a negative [hepatitis B surface antigen] and [hepatitis B surface antibody], HBV VL should be obtained prior to treatment and monitored during therapy. Early initiation of anti-HBV therapy in the setting of an increasing HBV VL should be strongly considered to prevent significant hepatitis. Further studies are needed to determine whether routine initiation of dual treatment for HCV and HBV should be standard of care for all coinfected individuals when using interferon-free regimens to treat HCV.” (J. M. Collins, jmcoll4@emory.edu)
“HBV reactivation in HBV/HCV-coinfected patients can occur during [direct-acting agent (DAA)] therapy for HCV, so it is important to check for chronic hepatitis B before starting HCV therapy,” commentators write (
pp. 1307–9). “The optimal management of HBV reactivation with DAA therapy for HCV is not known. It is likely that not all patients with HBV reactivation need to start treatment for HBV, as illustrated by our case from Johns Hopkins. However, additional studies are needed to determine which patients will benefit from HBV treatment after DAA-induced reactivation. If treatment of HBV is not initiated after initial HBV reactivation, then HBV DNA should be monitored frequently (perhaps every 2 weeks) and treatment initiated if HBV DNA continues to rise.” (C. L. Thio, cthio@jhmi.edu)

>>>Oncology Highlights
Source:
Oct. 10 issue of the Journal of Clinical Oncology, a special series issue on advances in head and neck cancer(2015; 33).
Immunotherapy of Head and Neck Cancer: An “article provides a brief overview of key components of the immune infiltrating cells in the tumor microenvironment, reviewing immunological principles related to head and neck cancer, including the concept of cancer immunosurveillance and immune escape” in head and neck squamous cell carcinoma (HNSCC) (pp. 3293–304): “The immune system plays a key role in the development, establishment, and progression of … HNSCC. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of HNSCC provides the basis for improved therapies and outcomes for patients.…” (R. L. Ferris, ferrisrl@upmc.edu)
Treatment Options for Head and Neck Squamous Cell Carcinoma: While advances have improved outcomes for patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), prognosis remains poor, authors conclude (pp. 3305–13): “The only regimen to demonstrate survival superiority is platinum, fluorouracil, and cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR). EGFR inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have achieved only modest success in R/M HNSCC, illustrating the importance of identifying predictive biomarkers and finding ways to overcome mechanisms of resistance. Although phosphoinositide 3-kinase pathway alterations are present at a high rate in HNSCC, the identification of efficacious agents in patients with activating alterations has yet to be discovered. Immunotherapy represents an attractive treatment strategy for R/M HNSCC, with promising preliminary data from studies involving immune checkpoint blockade and toll-like receptor agonists.…” (E. E. Cohen, ecohen@ucsd.edu)

>>>PNN NewsWatch
* Causes of and ways to prevent major birth defects is the topic of an article in this week’s MMWR. It includes discussion of medications and vaccines.
*
PNN will not be published on Mon., Oct. 12, Columbus 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 © 2015, 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
Oct. 13, 2015 * Vol. 22, No. 196
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 10 issue of Lancet (2015; 386).
Pediatric H. pylori Vaccine: In a Phase III trial of 4,464 children in China, an oral Helicobacter pylori vaccine “was effective, safe, and immunogenic,” researchers report, showing the potential to “substantially reduce the incidence of H. pylori infection” (pp. 1457–64). Study participants, all H. pylori-naive and ages 6–15 years at randomization, were assigned to a three-dose H. pylori vaccine regimen or placebo, with these results: “We recorded 64 events of H pylori infection within the first year (14 events in 2074.3 person–years at risk in the vaccine group vs 50 events in 2089.6 person–years at risk in the placebo group), resulting in a vaccine efficacy of 71.8% (95% CI 48.2–85.6). 157 (7%) participants in the vaccine group and 161 (7%) participants in the placebo group reported at least one adverse reaction. Serious adverse events were reported in five (<1%) participants in the vaccine group and seven (<1%) participants in the placebo group, but none was considered to be vaccination related.” (F-C Zhu, jszfc@vip.sina.com)
Antisense Lipoprotein(a) Therapy: A second-generation antisense drug that targets hepatic synthesis of apolipoprotein(a), ISIS-APO(a)Rx, was safe and tolerable in a Phase I dose-ranging trial (pp. 1472–83). Subcutaneous injection of doses ranging from 50 mg to 400 mg provided these lipoprotein(a) (Lp(a))results in 206 volunteers: “Whereas single doses of ISIS-APO(a)Rx (50–400 mg) did not decrease Lp(a) concentrations at day 30, six doses of ISIS-APO(a)Rx (100–300 mg) resulted in dose-dependent, mean percentage decreases in plasma Lp(a) concentration of 39.6% from baseline in the 100 mg group (p = 0.005), 59.0% in the 200 mg group (p = 0.001), and 77.8% in the 300 mg group (p = 0.001). Similar reductions were observed in the amount of oxidized phospholipids associated with apolipoprotein B-100 and apolipoprotein(a). Mild injection site reactions were the most common adverse events.” (S. Tsimikas, stsimikas@ucsd.edu)

>>>Internal Medicine Report
Source:
Oct. issue of JAMA Internal Medicine (2015; 175).
Opioid Laws in Florida: Opioid prescribing and use have fallen modestly in Florida since institution of prescription drug monitoring program (PDMP) and pill mill laws, a study shows (pp. 1642–9). Analysis of IMS Health LifeLink LRx data for Florida and Georgia (as a comparator) shows these patterns: “From July 2010 through September 2012, a cohort of 2.6 million patients, 431,890 prescribers, and 2,829 pharmacies was associated with approximately 480 million prescriptions in Florida and Georgia, 7.7% of which were for opioids. Total monthly opioid volume, [mean morphine milligram equivalent (MME)] per transaction, days’ supply, and prescriptions dispensed were higher in Florida than Georgia before implementation. Florida’s laws were associated with statistically significant declines in opioid volume (2.5 kg/mo, P <.05; equivalent to approximately 500,000 5-mg tablets of hydrocodone bitartrate per month) and MME per transaction (0.45 mg/mo, P <.05), without any change in days’ supply. Twelve months after implementation, the policies were associated with approximately a 1.4% decrease in opioid prescriptions, 2.5% decrease in opioid volume, and 5.6% decrease in MME per transaction. Reductions were limited to prescribers and patients with the highest baseline opioid prescribing and use. Sensitivity analyses, varying time windows, and enrollment criteria supported the main results.” (L. Rutkow)

>>>PNN NewsWatch
* FDA on Friday expanded use of nivolumab (Opdivo, Bristol-Myers Squibb) to include treatment of metastatic nonsmall-cell lung cancer that has progressed during or after platinum-base chemotherapy.

>>>PNN JournalWatch
* Treatment of Vitamin D Insufficiency in Postmenopausal Women: A Randomized Clinical Trial, in
JAMA Internal Medicine, 2015; 175: 1622–30. (J. E. F. Moonen)
* Recent Updates on the Role of Pharmacokinetics–Pharmacodynamics in Antimicrobial Susceptibility Testing as Applied to Clinical Practice, in
Clinical Infectious Diseases, 2015; 61: 1446–52. (H. M. Nguyen, hien.m.nguyen@kp.org)
* New and Future Strategies to Improve Asthma Control in Children, in
Journal of Allergy and Clinical Immunology, 2015; 136: 848–59. (S. J. Szefler, Stanley.Szefler@childrenscolorado.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 © 2015, 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
Oct. 14, 2015 * Vol. 22, No. 197
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 13 issue of JAMA (2015; 314).
Nonmedical Prescription Opioid Use & Use Disorders: Based on data for 472,200 adult Americans aged 18–64 years, the percentage of people using prescription opioids for nonmedical purposes declined in the decade beginning in 2003, but the prevalence of prescription opioid use disorders, frequency of use, and related mortality increased, researchers report (pp. 1468–78). Prevalence data and risk factors were identified using the 2003–13 National Surveys on Drug Use and Health. Combined with mortality information in the 2003–13 National Vital Statistics System’s Multiple Cause of Death Files, trends showed: “Among adults aged 18 through 64 years, the prevalence of nonmedical use of prescription opioids decreased from 5.4% (95% CI, 5.08%–5.70%) in 2003 to 4.9% (95% CI, 4.58%–5.22%) in 2013 (absolute difference, −0.5%; 95% CI, −0.11% to −0.89%), but the prevalence of prescription opioid use disorders increased from 0.6% (95% CI, 0.54%–0.76%) in 2003 to 0.9% (95% CI, 0.75%–1.01%) in 2013 (absolute difference, 0.3%; 95% CI, 0.03%–0.43%). The 12-month prevalence of high-frequency use (≥200 days) also increased from 0.3% (95% CI, 0.19%–0.35%) in 2003 to 0.4% (95% CI, 0.31%–0.48%) in 2013 (absolute difference, 0.1%; 95% CI, 0.01%–0.29%). Mortality assessed by drug overdose death rates involving prescription opioids increased from 4.5 per 100,000 (95% CI, 4.42–4.61) in 2003 to 7.8 per 100,000 (95% CI, 7.64–7.89) in 2013 (absolute difference, 3.3; 95% CI, 3.09–3.41) among adults aged 18 through 64 years. The mean number of days of nonmedical use of prescription opioids increased from 2.1 (95% CI, 1.83–2.37) in 2003 to 2.6 (95% CI, 2.27–2.85) in 2013 (absolute difference, 0.5, 95% CI, 0.05–0.86). The model-adjusted prevalence of having prescription opioid use disorders among nonmedical users increased to 15.7% (95% CI, 13.87%–17.67%) in 2010, 16.1% (95% CI, 14.36%–17.99%) in 2011, 17.0% (95% CI, 15.07%–19.12%) in 2012, and 16.9% (95% CI, 14.95%–19.03%) in 2013 from 12.7% (95% CI, 11.04%–14.53%) in 2003.” (B. Han, beth.han@samhsa.hhs.gov)
“The chronic, relapsing nature of opioid addiction means most patients are never ‘cured,’ and the best outcome is long-term recovery,” editorialists write (
pp. 1453–4). “The lifelong implications of this disease far outweigh the limited benefits of opioids in the treatment of chronic pain, and in many cases the risks inherent in the treatment of acute pain with opioids. The encouraging finding of declining opioid initiation rates should be tempered by the increasing rates of nonmedical opioid use disorders and the limited utilization of treatment programs. Although multifaceted approaches are needed to successfully address the opioid epidemic, an important step is to start at the beginning and keep opioid-naive patients opioid naive.” (L. S. Nelson, lewis.nelson@nyumc.org)
CAP & Influenza Vaccine: Children and adults hospitalized with community-acquired pneumonia are more likely to have influenza-associated pneumonia when they have not received influenza vaccine during the relevant season, according to the Etiology of Pneumonia in the Community (EPIC) study (pp. 1488–97). A prospective observational multicenter study, EPIC used a case–control method at four U.S. sites to make these associations between laboratory-confirmed influenza infection and verified vaccination status during influenza seasons in 2010–12: “Overall, 2,767 patients hospitalized for pneumonia were eligible for the study; 162 (5.9%) had laboratory-confirmed influenza. Twenty-eight of 162 cases (17%) with influenza-associated pneumonia and 766 of 2,605 controls (29%) with influenza-negative pneumonia had been vaccinated. The adjusted odds ratio of prior influenza vaccination between cases and controls was 0.43 (95% CI, 0.28–0.68; estimated vaccine effectiveness, 56.7%; 95% CI, 31.9%–72.5%).” (C. G. Grijalva, carlos.grijalva@vanderbilt.edu)
Goal-Based Lipid Guidelines: FDA approval of the first proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitor for treatment of high cholesterol means that a return to goal-based lipid guidelines would help clinicians and payers “achieve consensus around management strategies for patients with hyperlipidemia,” Viewpoint authors write (pp. 1443–4; W. H. Shrank, william.shrank@cvshealth.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 © 2015, 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
Oct. 15, 2015 * Vol. 22, No. 198
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 15 issue of the New England Journal of Medicine (2015; 373).
Emergency Department Visits Associated With Dietary Supplement Use: Use of a variety of dietary supplements is responsible for an estimated 23,000 visits to American emergency departments each year, according to a CDC analysis (pp. 1531–40). Nationally representative data from 63 emergency departments show that unsupervised use of dietary supplements by children, cardiovascular problems associated with ingestion of energy drinks and weight-loss products by young people, and swallowing problems with micronutrients in older adults are common: “On the basis of 3,667 cases, we estimated that 23,005 (95% confidence interval [CI], 18,611 to 27,398) emergency department visits per year were attributed to adverse events related to dietary supplements. These visits resulted in an estimated 2,154 hospitalizations (95% CI, 1,342 to 2,967) annually. Such visits frequently involved young adults between the ages of 20 and 34 years (28.0% of visits; 95% CI, 25.1 to 30.8) and unsupervised children (21.2% of visits; 95% CI, 18.4 to 24.0). After the exclusion of unsupervised ingestion of dietary supplements by children, 65.9% (95% CI, 63.2 to 68.5) of emergency department visits for single-supplement–related adverse events involved herbal or complementary nutritional products; 31.8% (95% CI, 29.2 to 34.3) involved micronutrients. Herbal or complementary nutritional products for weight loss (25.5%; 95% CI, 23.1 to 27.9) and increased energy (10.0%; 95% CI, 8.0 to 11.9) were commonly implicated. Weight-loss or energy products caused 71.8% (95% CI, 67.6 to 76.1) of supplement-related adverse events involving palpitations, chest pain, or tachycardia, and 58.0% (95% CI, 52.2 to 63.7) involved persons 20 to 34 years of age. Among adults 65 years of age or older, choking or pill-induced dysphagia or globus caused 37.6% (95% CI, 29.1 to 46.2) of all emergency department visits for supplement-related adverse events; micronutrients were implicated in 83.1% (95% CI, 73.3 to 92.9) of these visits.” (A. I. Geller, ageller@cdc.gov)
Early Inhaled Budesonide in Bronchopulmonary Dysplasia: Results were mixed with early budesonide use in extremely preterm infants, with a lower incidence of bronchopulmonary dysplasia offset by higher mortality, researchers report (pp. 1497–506). Random assignment of 863 infants with gestational ages of 23–27 weeks to early inhaled budesonide or placebo yielded these results based on a primary outcome of death or bronchopulmonary dysplasia: “A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P = 0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P = 0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P = 0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P = 0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P = 0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups.” (D. Bassler, dirk.bassler@usz.ch)
“Uncertainly prevails with respect to the use of early inhaled glucocorticoids to prevent bronchopulmonary dysplasia in extremely preterm infants,” concludes an editorialist (
pp. 1566–7). “Composite outcomes [that include mortality] work well when the rate of death is not affected by the study intervention or when rates of death move in the same direction as the nonfatal component or components of interest. Interpretation of these neonatal composite outcomes is more problematic when treatment effects move in opposite directions, as in the trial by Bassler et al.” (B. Schmidt)

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 © 2015, 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
Oct. 16, 2015 * Vol. 22, No. 199
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Oct. issue of the Journal of Allergy and Clinical Immunology (2015; 136).
Probiotics for Allergy Prevention: Evidence supporting use of probiotics by pregnant or breastfeeding women or infants for prevention of allergies is sparse and where significant, uncertain because of bias, inconsistency, and imprecision in published studies, according to a systematic review and meta-analysis (pp. 952–61): “Of 2,403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60–0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47–0.69), or when given to infants (RR, 0.80; 95% CI, 0.68–0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research.” (J. L. Brozek, brozekj@mcmaster.ca)
Efficacy of Chinese Herbal Medicine for Food Allergy: While a nine-herb concoction based on traditional Chinese herbal medicines showed promise in vitro for peanut-induced anaphylaxis, the product faltered in clinical trials at the dose and duration studied (pp. 962–70.e1). Among 68 adolescents and adults with challenge-confirmed allergies to peanut, tree nut, sesame, fish, and/or shellfish, randomization to Food Allergy Herbal Formula-2 (FAHF-2) or placebo yielded these changes in double-blind, placebo-controlled oral food challenges (DBPCFCs) after 6 months: “Treatment was well tolerated, with no serious adverse events. By using intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (P = .05) at the end-of-treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (P = .55). There were no significant differences in allergen-specific IgE and IgG4 levels, cytokine production by [peripheral blood mononuclear cell (PBMC)], or basophil activation between the active and placebo groups. In vitro immunologic studies performed on subjects’ baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 levels, and increased numbers of regulatory T cells than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one third of the study period.” (J. Wang, julie.wang@mssm.edu)
Prediction & Prevention of Allergic Rhinitis: Among 1,314 Multicenter Allergy Study newborns in five German cities, development of allergic rhinitis (AR) during the first 20 years of life was predicted only by nonmodifiable factors such as early allergic sensitization or eczema and parental AR, researchers report (pp. 932–400.e12). Evaluation of children at 19 time points yielded these results: “Two hundred ninety subjects had AR within 13,179 person–years observed. The risk of AR was higher with a parental history of AR (adjusted hazard ratio [aHR], 2.49; 95% CI, 1.93–3.21), urticaria (aHR, 1.32; 95% CI, 1.00–1.74), or asthma (aHR, 1.29; 95% CI, 0.95–1.75). Early allergic sensitization (aHR, 4.53; 95% CI, 3.25–6.32), eczema within the first 3 years of life (aHR, 1.83; 95% CI, 1.38–2.42), male sex (aHR, 1.28; 95% CI, 1.02–1.61), and birthday in summer or autumn (aHR, 1.26; 95% CI, 1.00–1.58) were independent predictors of AR up to age 20 years. None of the other socioeconomic, environmental, lifestyle, pregnancy, and birth-related factors were associated with AR.” (L. B. Grabenhenrich, linus.grabenhenrich@charite.de)

>>>Chest Highlights
Source:
Oct. issue of Chest (2015; 148).
New-Onset AF Management During and After Intensive Care: Commentary authors “suggest increased efforts to improve communication of [atrial fibrillation (AF)] events between inpatient and outpatient providers and to reassess patients who had experienced new-onset AF during critical illness after they transition to the post-ICU setting” (pp. 859–64). The writers “describe various strategies for the assessment and long-term management of patients with new-onset AF during critical illness.” (A. J. Walkey, alwalkey@bu.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 © 2015, 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
Oct. 19, 2015 * Vol. 22, No. 200
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 17 issue of Lancet (2015; 386).
Once-Daily HCV Genotype 1 Therapy in CKD: An all-oral, ribavirin-free regimen was effective and safe in a group of 224 patients with chronic hepatitis C virus (HCV) infection and stage 4–5 chronic kidney disease, researchers report (pp. 1537–45). In the Phase III study, participants received the NS3/4A protease inhibitor grazoprevir 100 mg and the NS5A inhibitor elbasvir 50 mg (immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks, or were assigned to an intensive pharmacokinetic population, with these results: “Overall, 179 (76%) [patients] were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n = 2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. [sustained virological response at 12 weeks] in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95.3–100.0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis.” (D. Roth, d.roth@med.miami.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
PPIs for GI Bleeding After MI: In patients who have had myocardial infarction and are taking both antithrombotic agents and NSAIDs, treatment with PPIs “was independently associated with a decreased risk of gastrointestinal bleeding…, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used,” according to an observational nationwide study from Denmark (h5096). Administrative registry data from 1997 to 2011 showed these patterns for adults older than 30 years with a first myocardial infarction who survived 30 days or more after discharge: “The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82,955 post-myocardial infarction patients (mean age 67.4 years, 64% (n = 53,070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n = 35,233) filled at least one prescription for NSAIDs and 45.5% (n = 37,771) received PPIs. Over a mean follow-up of 5.1 years, 3,229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person–years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used.… The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding.” (A. Schjerning Olsen, aols0073@geh.regionh.dk)

>>>PNN NewsWatch
* FDA on Friday granted accelerated approval to idarucizumab (Praxbind, Boehringer Ingelheim) for use in patients who are taking dabigatran (Pradaxa, Boehringer Ingelheim) during emergency situations when there is a need to reverse dabigatran’s blood-thinning effects.

>>>PNN JournalWatch
* Estimations of Worldwide Prevalence of Chronic Hepatitis B Virus Infection, in
Lancet, 2015; 386: 1546–55. (J. J. Ott, Joerdis.Ott@helmholtz-hzi.de)
* Chronic Care Coordination, in
Chest, 2015; 148: 1115–9. (S. G. Peters, Peters.Steve@Mayo.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 © 2015, 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
Oct. 20, 2015 * Vol. 22, No. 201
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 20 issue of the Annals of Internal Medicine (2015; 163).
Moderate Wine Intake & Cardiometabolic Risk in Type 2 Diabetes: Initiation of long-term moderate wine intake, especially of red wine, among patients with well-controlled type 2 diabetes “is apparently safe and modestly decreases cardiometabolic risk,” a study from Israel shows (pp. 569–79). White wine, red wine, or water were randomly assigned for consumption with an evening meal based on the Mediterranean diet for a 2-year period, with these results and relationships with genes and possible benefits of red wine’s nonalcoholic constituents: “Of the 224 patients who were randomly assigned, 94% had follow-up data at 1 year and 87% at 2 years. In addition to the changes in the water group (Mediterranean diet only), red wine significantly increased high-density lipoprotein cholesterol (HDL-C) level by 0.05 mmol/L (2.0 mg/dL) (95% CI, 0.04 to 0.06 mmol/L [1.6 to 2.2 mg/dL]; P < 0.001) and apolipoprotein(a)1 level by 0.03 g/L (CI, 0.01 to 0.06 g/L; P = 0.05) and decreased the total cholesterol–HDL-C ratio by 0.27 (CI, −0.52 to −0.01; P = 0.039). Only slow ethanol metabolizers (alcohol dehydrogenase alleles [ADH1B*1] carriers) significantly benefited from the effect of both wines on glycemic control (fasting plasma glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c) compared with fast ethanol metabolizers (persons homozygous for ADH1B*2). Across the 3 groups, no material differences were identified in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life, except that sleep quality improved in both wine groups compared with the water group (P = 0.040). Overall, compared with the changes in the water group, red wine further reduced the number of components of the metabolic syndrome by 0.34 (CI, −0.68 to −0.001; P = 0.049).” (I. Shai, irish@exchange.bgu.ac.il)
Tobacco Cessation in Adults: A clinical review forms the evidence base for clinical guidelines on behavioral and pharmacotherapy interventions for tobacco cessation in pregnant and other adults.
A robust body of evidence supports use of behavioral and pharmacotherapy interventions for getting adults to stop using tobacco, the review article concludes, but the role of electronic nicotine delivery systems in this process is poorly understood (
pp. 608–21): “54 reviews were included. Behavioral interventions increased smoking cessation at 6 months or more (physician advice had a pooled risk ratio [RR] of 1.76 [95% CI, 1.58 to 1.96]). Nicotine replacement therapy (RR, 1.60 [CI, 1.53 to 1.68]), bupropion (RR, 1.62 [CI, 1.49 to 1.76]), and varenicline (RR, 2.27 [CI, 2.02 to 2.55]) were also effective for smoking cessation. Combined behavioral and pharmacotherapy interventions increased cessation by 82% compared with minimal intervention or usual care (RR, 1.82 [CI, 1.66 to 2.00]). None of the drugs were associated with major cardiovascular adverse events. Only 2 trials addressed efficacy of electronic cigarettes for smoking cessation and found no benefit. Among pregnant women, behavioral interventions benefited cessation and perinatal health; effects of nicotine replacement therapy were not significant.” (Agency for Healthcare Research and Quality, www.ahrq.gov)
Based on this evidence, the U.S. Preventive Services Task Force (USPSTF) updates its 2009 advice by recommending that (
pp. 622–34; USPSTF, www.uspreventiveservicestaskforce.org):
* Clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and U.S. Food and Drug Administration–approved pharmacotherapy for cessation to adults who use tobacco. (A recommendation)
* Clinicians ask all pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who use tobacco. (A recommendation)
* Current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant women. (I statement)
* Current evidence is insufficient to recommend electronic nicotine delivery systems for tobacco cessation in adults, including pregnant women. The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety (previously stated). (I statement)

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 © 2015, 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
Oct. 21, 2015 * Vol. 22, No. 202
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 20 issue of JAMA (2015; 314).
Treatment of Acute Low Back Pain: Results of a 323-patient study do not support addition of other agents to naproxen for treating acute, nontraumatic, nonradicular low back pain (LBP) in the emergency department (ED) setting (pp. 1572–80). At ED discharge, patients with scores of 6 or greater on the Roland-Morris Disability Questionnaire (RMDQ; 0, no functional impairment; 24, maximum impairment) were randomized to placebo, cyclobenzaprine, or oxycodone/acetaminophen in addition to naproxen 500 mg twice daily for 10 days. Results showed no improvement in functional outcomes or pain at 1-week follow-up with the added agents: “At baseline, median RMDQ score in the placebo group was 20 (interquartile range [IQR],17–21), in the cyclobenzaprine group 19 (IQR,17–21), and in the oxycodone/acetaminophen group 20 (IQR,17–22). At 1-week follow-up, the mean RMDQ improvement was 9.8 in the placebo group, 10.1 in the cyclobenzaprine group, and 11.1 in the oxycodone/acetaminophen group. Between-group difference in mean RMDQ improvement for cyclobenzaprine vs placebo was 0.3 (98.3% CI, −2.6 to 3.2; P = .77), for oxycodone/acetaminophen vs placebo, 1.3 (98.3% CI, −1.5 to 4.1; P = .28), and for oxycodone/acetaminophen vs cyclobenzaprine, 0.9 (98.3% CI, −2.1 to 3.9; P = .45).” (B. W. Friedman, bwfriedmanmd@gmail.com)
Tdap Vaccination of Pregnant Women After Prior Tetanus-Containing Immunizations: Among 29,155 women who had previously received tetanus-containing immunizations, acute adverse events or adverse birth outcomes with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy did not increase during a retrospective cohort study (pp. 1581–7). Using timeframes since receipt of other tetanus-containing products of less than 2 years before, 2–5 years before, or more than 5 years before, the investigators found: “There were no statistically significant differences in rates of medically attended acute adverse events or adverse birth outcomes related to timing since prior tetanus-containing vaccination. For example, local reactions occurred at a rate (per 10,000 women) of 4.2 in those who received Tdap in pregnancy less than 2 years before (adjusted risk ratio [RR], 0.49 [95% CI, 0.11–2.20]; P = .35) and 7.0 two to 5 years before (adjusted RR, 0.77 [95% CI, 0.31–1.95]; P = .59) a prior tetanus-containing vaccine compared with 11.2 in controls. Preterm delivery occurred in 6.6% of women receiving Tdap in pregnancy less than 2 years before (adjusted RR, 1.15 [95% CI, 0.98–1.34]; P = .08) and 6.4% two to 5 years before (adjusted RR, 1.06 [95% CI, 0.94–1.19]; P = .33) a prior tetanus-containing vaccine compared with 6.8% of controls. Small for gestational age delivery occurred in 9.0% of women less than 2 years before (adjusted RR, 0.99 [95% CI, 0.87–1.13]; P = .88) and 8.7% of women 2 to 5 years before (adjusted RR, 0.96 [95% CI, 0.87–1.06]; P = .45) a prior tetanus-containing vaccine compared with 9.1% of controls.” (L. Sukumaran, xfq3@cdc.gov)
Next Era of Palliative Care: For patients with serious illness to receive better palliative care, specialists need to teach other clinicians “to provide patient and family-centered care, [design] systems, and [advocate] for policy changes that help make the involvement of specialists less necessary,” authors of a Viewpoint write (pp. 1565–6). Three changes are needed, the authors conclude: “First, palliative care specialists need to develop skills in clinician behavior change, system change, and quality improvement. Second, health systems need to expand their focus to develop programs that measure and improve the quality of palliative care that every patient receives. Third, federal funding must be aligned with a national goal of improving the experience of seriously ill patients and their loved ones.” (Y. Schenker, schenkery@upmc.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first Factor X concentrate for treating patients with hereditary Factor X deficiency. Coagulation Factor X (Human) (Coagadex, Bio Products Laboratory) was evaluated in 16 participants (208 bleeding episodes) for treatment of spontaneous, traumatic, and heavy menstrual bleeding episodes and in five participants with mild to severe Factor X deficiency who were undergoing surgery.

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 © 2015, 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
Oct. 22, 2015 * Vol. 22, No. 203
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 22 New England Journal of Medicine (2015; 373).
Nicotinamide for Skin-Cancer Chemoprevention: Orally administered, vitamin B3 was safe and effective for prevention of new nonmelanoma skin cancers in a Phase III trial (pp. 1618–26). Participants included 386 patients with at least two nonmelanoma skin cancers in the past 5 years. They were randomized to nicotinamide 500 mg or placebo twice daily, with these results: “At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P = 0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, −6 to 39] lower rate with nicotinamide, P = 0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P = 0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P = 0.01), 14% lower at 6 months (P <0.001), 20% lower at 9 months (P <0.001), and 13% lower at 12 months (P = 0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued.” (D. L. Damian, diona.damian@sswahs.nsw.gov.au)

Nivolumab in Advanced Nonsquamous NSCLC: A fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, nivolumab produced longer overall survival times in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) than did the standard-of-care drug docetaxel (pp. 1627–39). Researchers reported these results in an open-label, international Phase III trial: “Overall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P = 0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab versus 39% (95% CI, 33 to 45) with docetaxel. With additional follow-up, the overall survival rate at 18 months was 39% (95% CI, 34 to 45) with nivolumab versus 23% (95% CI, 19 to 28) with docetaxel. The response rate was 19% with nivolumab versus 12% with docetaxel (P = 0.02). Although progression-free survival did not favor nivolumab over docetaxel (median, 2.3 months and 4.2 months, respectively), the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel (19% and 8%, respectively). Nivolumab was associated with even greater efficacy than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression (≥1%, ≥5%, and ≥10%) of the PD-1 ligand. Treatment-related adverse events of grade 3 or 4 were reported in 10% of the patients in the nivolumab group, as compared with 54% of those in the docetaxel group.” (H. Borghaei, hossein.borghaei@fccc.edu)
Specialty Pharmaceuticals for Hyperlipidemia: A Perspective article asks who will “bear the costs” of the new PCSK9 inhibitors for reducing elevated cholesterol levels (pp. 1591–3): “At its core, the current pricing model for these products is driven by a transformation in the pharmaceutical industry, whereby 84% of prescriptions are filled with generic products and follow-on biologics have the potential to disrupt many established markets and firms.… Pricing pressure on innovative products would drive a fundamental restructuring of the industry and further increase the financial challenges of bringing scientific innovations to the market. It is important that we manage these downside risks carefully as we work toward a more sustainable pricing model in this market.” (K. A. Schulman)

>>>PNN NewsWatch
* FDA yesterday approved patiromer for oral suspension (Veltassa, Relypsa) to treat hyperkalemia. The powdered medication is mixed with water and taken by mouth; it acts by binding potassium in the gastrointestinal tract. A boxed warning notes that the product should be administered at least 6 hours before or after other drugs, as it can decrease their absorption and reduce their effects.

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 © 2015, 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
Oct. 23, 2015 * Vol. 22, No. 204
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Oct. issue of Health Affairs (2015; 34).
Part D at 10: “Firmly established” 10 years after its implementation, the Medicare Part D program is serving 39 million beneficiaries through dozens of private plans, but it “faces challenges, including projected spending growth,” authors write (pp. 1682–7). The article reviews enrollment trends, low-income subsidies, plan availability and consumer choice, market concentration, Part D premiums, benefit design and cost sharing, cost and utilization management strategies, and program cost trends. The authors conclude: “After ten years, Part D is a firmly established source of Medicare drug coverage, with a steady rise in enrollment. Since 2006, plans have increased cost sharing for brand-name drugs, imposed prior authorization requirements on more drugs, and adopted tiered pharmacy networks. In the future, plans and policy makers face the challenge of slowing spending growth while protecting beneficiaries’ gains in access and affordability for prescription drugs.” (J. F. Hoadley, jfh7@georgetown.edu)
Hepatitis C Treatment Capacity: The breakthrough treatments for hepatitis C virus infections are cost-effective over a long time horizon from a societal perspective, researchers report, but the upfront costs will challenge capacity of the health care system (pp. 1666–74): “To quantify the benefit of these treatments to society, including the value of reduced transmission, we estimated the effects of several hepatitis C treatment strategies on cost and population health. Treating patients at all disease stages could generate $610–$1,221 billion in additional quality-adjusted life–years, plus an additional $139 billion in saved medical expenditures over fifty years, and minimize the disease burden, but up-front treatment costs would exceed $150 billion. An intermediate scenario—treating 5 percent of the infected population annually, regardless of patients’ disease stages—would also return substantial benefits and would be much more affordable under current financing schemes.” (D. P. Goldman, dana.goldman@usc.edu)

>>>Medical Care Highlights
Source:
Nov. issue of Medical Care (2015; 53).
Prescription Opioid Dispensations and Deaths: Large numbers of people dying in British Columbia (BC) from prescription opioid–related deaths did not have an active opioid prescription within 60 days of death, an analysis of administrative records shows (pp. 954–9). Concluding that “targeted efforts to reduce high levels of opioid prescribing” in the province could “substantially reduce opioid-related harms,” the authors report: “Many individuals who suffered a prescription opioid-related death did not have an active opioid prescription in the 60 days before death (46% of women and 71% of men). Rates of prescription opioid dispensing and opioid-related deaths vary substantially across geographic regions in BC. The area-level relationship between rate of prescription opioid dispensing and rate of unintentional prescription opioid-related death is positive and statistically significant for both men and women (P <0.001). This relationship holds when opioid prescribing is limited to strong opioids.” (E. J. Gladstone)

>>>PNN NewsWatch
* FDA yesterday approved irinotecan liposome injection (Onivyde, Merrimack Pharmaceuticals), in combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy. A boxed warning in product labeling cautions of severe neutropenia and diarrhea with the drug.
* Because of 26 cases of possible or probable serious liver injury mostly in patients with underlying advanced liver disease,
FDA is requiring the manufacturer of the hepatitis C treatments Viekira Pak and Technivie to revise product labeling for the products. Liver injury generally occurs within 1–4 weeks of therapy initiation.
*
FDA is requiring the Kayexalate (sodium polystyrene sulfonate) manufacturer to conduct studies to investigate the product’s potential to bind to other medications administered by mouth. The approved labeling for Kayexalate describes its potential to decrease absorption of lithium and thyroxine; however, extensive drug–drug interaction studies with Kayexalate have not been performed.

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 © 2015, 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
Oct. 26, 2015 * Vol. 22, No. 205
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 24 issue of Lancet (2015; 386).
Eltrombopag in Chronic Immune Thrombocytopenia: In 92 children with chronic symptomatic immune thrombocytopenia, the thrombopoietin receptor agonist eltrombopag produced sustained platelet responses in 40% of participants in the PETIT2 trial (pp. 1649–58). Patients were stratified by age before randomization in the study, which was conducted in 12 countries on four continents. Results showed: “25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 109 per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18.0, 95% CI, 2.3–140.9; p = 0.0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12–17 years, 42% vs 0% for patients aged 6–11 years, and 36% vs 0% for patients aged 1–5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1–4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2–4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 109 per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial.” (J. D. Grainger, john.grainger@cmft.nhs.uk)
Web-Based Handwashing Intervention & Flulike Illness: Tested in nonpandemic influenza seasons, an Internet-delivered handwashing intervention showed the potential to “have an important effect in reduction of infection transmission,” authors conclude (pp. 1631–9). “In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic,” the group continues, adding these details about the effects on respiratory tract infections (RTIs) of their automated Web-based intervention that “maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs”: “Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20,066 participants and randomly assigned them to receive intervention (n=10,040) or no intervention (n=10,026). 16,908 (84%) participants were followed up with the 16 week questionnaire (8,241 index participants in intervention group and 8,667 in control group). After 16 weeks, 4,242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0.86, 95% CI 0.83–0.89; p <0.0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 [4%] of 5,429 in intervention group vs 79 [1%] of 6,087 in control group) and no reported serious adverse events.” (P. Little, p.little@soton.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved two new drugs: asfotase alfa (Strensiq, Alexion Pharmaceuticals) as the first approved treatment for perinatal, infantile, and juvenile-onset hypophosphatasia and trabectedin (Yondelis, Janssen) for treatment of unresectable, metastatic liposarcoma and leiomyosarcoma.

>>>PNN JournalWatch
* Recognition and Management of Hypertension in Older Persons: Focus on African Americans, in
Journal of the American Geriatrics Society, 2015; 63: 2130–8. (C. H. Still, cwh11@case.edu)
* The Microbiome in Mental Health: Potential Contribution of Gut Microbiota in Disease and Pharmacotherapy Management, in
Pharmacotherapy, 2015; 35: 910–6. (V. L. Ellingrod, vellingr@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 © 2015, 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
Oct. 27, 2015 * Vol. 22, No. 206
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Early-release article from and Oct. Journal of the American Geriatrics Society (2015; 63).
2015 Updated Beers Criteria: The 2015 American Geriatrics Society (AGS) Beers Criteria—potentially inappropriate medications to be avoided in older adults that are presented in an early-release article—for the first time “include lists of select drugs that should be avoided or have their dose adjusted based on the individual’s kidney function and select drug–drug interactions documented to be associated with harms in older adults,” a 13-member expert panel reports (doi: 10.1111/jgs.13702). Medications added since the 2012 update are proton-pump inhibitors, desmopressin, and meclizine based on diagnoses or conditions, and several medications based on consideration of specific diseases or syndromes: opioids (falls and fractures), armodafanil and modafinil (insomnia), eszopiclone and zaleplon (dementia and cognitive impairment), and antipsychotics (delirium).
“Long-term proton-pump inhibitor use in the absence of a strong indication” was added “because of risk of
C. difficile infection, bone loss, and fractures,” the panel wrote. Opioids were added “in the diagnosis and condition table for older adults with a history of falls and fractures. If opioids must be used, it is recommended that reducing the use of other CNS-active medications be considered. This statement is in recognition of the need to have adequate pain control while balancing the potential harms from opioids and untreated pain. The panel balanced the difficulty and challenges of poorly treated pain with the harms of opioids and available alternatives in older adults. Another critical change was to the language for use of antipsychotics in the dementia and delirium drug–disease, drug–syndrome category and the addition of avoiding antipsychotics in persons with delirium as first-line treatment. With increasing evidence of harm associated with antipsychotics and conflicting evidence on their effectiveness in delirium and dementia, the rationale to avoid was modified to ‘avoid antipsychotics for behavioral problems unless nonpharmacological options (e.g., behavioral interventions) have failed or are not possible, and the older adult is threatening substantial harm to self or others.’ The table of medications with strong anticholinergic properties has been updated. Anticholinergic burden and measurement is an area of literature that is continually evolving. Use of anticholinergic medications remains a concern because it is associated with impaired cognitive and physical function and risk of dementia.”
The panel was cochaired by pharmacist Todd P. Semla of the VA and Northwestern U. and included several other pharmacists or representatives of pharmacy organizations (Judith Beizer, St. Johns U.; Nicole Brandt, U. Maryland; Robert Dombrowski, CMS; Woody Eisenberg, MD, Pharmacy Quality Alliance; Joseph Hanlon, U. Pittsburgh and the VA; and Sunny Linnebur, University of Colorado). (M. J. Samuel,
msamuel@americangeriatrics.org)
Physician Task Delegation & Quality of Geriatric Care: In 4,766 older patients seen in community practices, quality indicators (QIs) were significantly higher when care for falls, urinary incontinence, and dementia were delegated by physicians to other health professionals, researchers report (pp. 2164–70). In the Assessing Care of Vulnerable Elders (ACOVE) study, “QI pass probabilities were 0.36 for physician-performed tasks, 0.55 for nurse practitioner (NP)–, physician assistant (PA)–, and registered nurse (RN)–performed tasks; and 0.61 for medical assistant– and licensed vocational nurse–performed tasks,” the authors report. “In multiply adjusted models, the independent pass-probability effect of delegation to NPs, PAs, and RNs was 1.37 (P = .05). These findings suggest that delegation of selected tasks to nonphysician healthcare providers is associated with higher quality of care for these geriatric conditions in community practices and supports the value of interdisciplinary team management for common outpatient conditions in older adults.” (B. J. Lichtenstein, blichtenstein@mednet.ucla.edu)

>>>PNN NewsWatch
* After finding “no clear evidence of an increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson’s disease,” FDA said no changes are needed in the labeling for the Novartis products Comtan (entacapone) and Stalevo (entacapone, carbidopa, and levodopa).

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 © 2015, 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
Oct. 28, 2015 * Vol. 22, No. 207
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 27 issue of JAMA (2015; 314).
Crystalloid Solution v. Saline in Acute Kidney Injury: Compared with saline therapy in patients in intensive care units, crystalloid therapy failed to reduce the risk of acute kidney injury (AKI) in the 0.9% Saline vs Plasma-Lyte 148 for ICU fluid Therapy (SPLIT) trial, researchers report (pp. 1701–10). At four ICUs in New Zealand, 2,278 patients received buffered crystalloids or saline in 7-week treatment blocks, with these effects on the proportion of patients with AKI: “In the buffered crystalloid group, 102 of 1,067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1,025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, −2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1,152 patients (3.3%) compared with 38 of 1,110 patients (3.4%) in the saline group (absolute difference, −0.1% [95% CI, −1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1,152 patients (7.6%) in the buffered crystalloid group and 95 of 1,110 patients (8.6%) in the saline group died in the hospital (absolute difference, −1.0% [95% CI, −3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40).” (P. Young, paul.young@ccdhb.org.nz)
“The results of [this] trial … provide reassurance that neither 0.9% saline nor a low-chloride electrolyte solution appears to be particularly hazardous when the total dose used in patients at low to moderate risk is about 2 L,” editorialists conclude after analyzing the state of research in this area (
pp. 1695–7): “[The] fundamental premise that large pragmatic studies can be used to assess the effectiveness of fluids on outcomes such as AKI, requirement for dialysis, and mortality should be carefully considered when the intervention is not being used specifically for these purposes. Drugs such as 0.9% saline or other electrolyte solutions might result in differences in these outcomes, but it will be as a result of differences in toxicity, not efficacy, and studies should be designed accordingly. In particular, such studies need to deliver a plausible dose of fluids to a population at sufficient risk for adverse outcomes to uncover the hazard, if one exists. If there is a hazard with one or another of these fluids, then it will be important to discover and quantify that risk, however small, because of the sheer enormity of the exposed population that receive intravenous fluids. This hazard will not be unmasked by treating healthier patients with small doses of fluids, but rather by treating sicker patients with larger fluid volumes.” (J. A. Kellum, kellumja@upmc.edu)
Treating Asthma in Black Adults: In the Blacks and Exacerbations on LABA vs Tiotropium (BELT) study, results do not support superiority of long-acting beta-agonists (LABAs) plus inhaled corticosteroids (ICS) in black adults with asthma, compared with tiotropium plus ICS (pp. 1720–30). Participants in the open-label, pragmatic trial had moderate to severe asthma. With a primary outcome of asthma exacerbation requiring oral or parenteral corticosteroids, results showed no significant differences in time to first exacerbation or changes in FEV1 at 12 or 18 months. “There were no differences in other patient-reported outcomes,” the authors added. “Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS (hazard ratio for time to first exacerbation, 0.84 [95% CI, 0.47 to 1.51] for Arg/Arg vs 0.85 [95% CI, 0.63 to 1.15] for Arg/Gly or Gly/Gly, P = .97).” (E. Israel, eisrael@partners.org)

>>>PNN NewsWatch
* FDA yesterday approved talimogene laherparepvec (Imlygic, BioVex), the first genetically modified oncolytic viral therapy, for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The therapy is a genetically modified herpes simplex virus type 1 designed to replicate within tumors and produce granulocyte-macrophage colony-stimulating factor (GM-CSF). Talimogene laherparepvec causes cell lysis, which ruptures tumors, releasing tumor-derived antigens, which along with GM-CSF, may promote an anti-tumor immune response. However, the exact mechanism of action is unknown, Amgen subsidiary BioVex said in a news release. Use of the live viral product is contraindicated in those with suppressed immune function or who are pregnant.

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 © 2015, 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
Oct. 29, 2015 * Vol. 22, No. 208
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 29 issue of the New England Journal of Medicine (2015; 373).
Olaparib in Metastatic Prostate Cancer: In a Phase II trial, the poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitor olaparib produced a high response rate in men with prostate cancers that had stopped responding ton standard therapies and who had defects in DNA-repair genes, researchers report (pp. 1697–708). Based on a primary end point of response rate, olaparib 400 mg twice daily produced these results: “Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes—including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2—in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.” (J. S. de Bono, johann.de-bono@icr.ac.uk)
Vemurafenib in Hairy-Cell Leukemia: Targeting the genetic lesion in patients with relapsed or refractory hairy-cell leukemia using the oral BRAF inhibitor vemurafenib proved “highly effective” in two Phase II trials of the drug in the U.S. and Italy (pp. 1733–47). The Italian study used complete response rate as a primary end point to test a median administration time of 16 weeks; the American trial tested the drug for a median of 18 weeks and used a primary end point of overall response rate. Results showed: “The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK–positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.” (B. Falini, brunangelo.falini@unipg.it)
Excess Mortality in Type 2 Diabetes: “Younger age, worse glycemic control, and greater severity of renal complications” were factors that increased risk of mortality among patients with type 2 diabetes in an analysis of the Swedish Registry for Cause-Specific Mortality (pp. 1720–32). Based on experiences from 1998 through 2011, the authors note: “The overall excess risk of death among persons with type 2 diabetes has dropped to a historically low level of approximately 15%. However, mortality remains high in certain patient groups and remains substantially higher among patients younger than 55 years of age, as compared with controls, even among patients whose glycemic values are within the target range and who have normoalbuminuria.” (M. Lind, lind.marcus@telia.com)

>>>PNN NewsWatch
* Ipilimumab (Yervoy, Bristol-Myers Squibb) yesterday became the first and only product approved by FDA for cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm (Stage III) who have undergone complete resection including total lymphadenectomy.

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 © 2015, 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
Oct. 30, 2015 * Vol. 22, No. 209
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (2015; 38).
Insulin Dose & Cardiovascular Mortality: Using data from the ACCORD trial, investigators found “no support for the hypothesis that insulin dose contributed to [the higher cardiovascular (CV)] mortality” observed in patients with type 2 diabetes who received intensive therapy (pp. 2000–8). Among 10,163 participants followed for a mean of 5 years, these results are reported: “More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.” (E. S. Siraj, esiraj@temple.edu)
Personalized Sulfonylurea Therapy in Neonatal Diabetes: In patients with neonatal diabetes secondary to mutations in potassium-channel subunits, treatment with sulfonylureas (SUs) can improve neuropsychomotor impairments, researchers report (pp. 2033–41). Since such impairments occur more often in younger patients, these findings support early genetic testing so that therapy can be changed to SUs, the authors conclude. The study, conducted prospectively at one center, included 19 patients with ages up to 18 years who were switched from insulin to SU therapy. Based on MRIs at baseline and other tests at 0, 6, and 12 months, the investigators report: “At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change −1.55% [range −3.8 to 0.1]; P <0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin.” (M. Polak, michel.polak@nck.aphp.fr)
eGFR-Based Metformin Prescribing: Basing the eligibility for metformin on estimated glomerular filtration rate (eGFR) rather than serum creatinine (sCr) could “expand the adult population with diabetes for whom metformin is likely safe, particularly among non-Hispanic blacks and men,” according to an analysis of 3,902 adults with diabetes (pp. 2059–67). Data from the 1999–2010 National Health and Nutrition Examination Surveys show these patterns for conventional sCr thresholds and eGFR categories as determined by different equations: “Among adults with sCr above conventional cutoffs, [four-variable] MDRD eGFR ≥45 mL/min/1.73 m2 was most common among men (adjusted odds ratio [aOR] 33.3 [95% CI 7.4–151.5] vs. women) and non-Hispanic Blacks (aOR vs. whites 14.8 [4.27–51.7]). No individuals with sCr below conventional cutoffs had an MDRD eGFR <30 mL/min/1.73 m2. All estimating equations expanded the population of individuals for whom metformin is likely safe, ranging from 86,900 ([Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine (CKD-EPIcr)]) to 834,800 ([Cockcroft-Gault (CG)]). All equations identified larger populations with eGFR 30–44 mL/min/1.73 m2, for whom metformin safety is indeterminate, ranging from 784,700 (CKD-EPIcr) to 1,636,000 (CG).” (D. S. Tuot, delphine.tuot@ucsf.edu)

>>>PNN NewsWatch
* Based on 26 reports in the U.S. and Canada, Sanofi US is voluntarily recalling all Auvi-Q (epinephrine injection, USP) because of potentially have inaccurate dosage delivery, FDA said yesterday. The recall involves all Auvi-Q currently on the market and includes both the 0.15 mg and 0.3 mg strengths for hospitals, retailers, and consumers (lots 2299596 through 3037230, expiring in Mar. through December 2016). In these reports, patients have described symptoms of the underlying hypersensitivity reaction. No fatal outcomes have been reported.

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 © 2015, 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
Nov. 2, 2015 * Vol. 22, No. 210
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 31 issue of Lancet (2015; 386).
Tasimelteon for Sleep–Wake Disorder in Totally Blind People: Once-daily doses of the novel dual-melatonin receptor agonist tasimelteon entrain totally blind people with non-24-hour sleep–wake disorder, report researchers who conducted the SET and RESET trials, but continued therapy is needed to maintain the effect (pp. 1754–64). At 27 American and 6 German centers, 84 patients received placebo or tasimelteon 20 mg every 24 hours at a fixed clock time 1 hour before a target bedtime for 26 weeks, with these results: “Circadian entrainment occurred in eight (20%) of 40 patients in the tasimelteon group compared with one (3%) of 38 patients in the placebo group at month 1 (difference 17%, 95% CI 3.2–31.6; p = 0.0171). Nine (24%) of 38 patients showed a clinical response, compared with none of 34 in the placebo group (difference 24%, 95% CI 8.4–39.0; p = 0.0028). Between Sept 15, 2011, and Oct 4, 2012, we screened 58 patients for eligibility in RESET, 48 (83%) of whom had [a non-24-hour circadian period] assessed and entered the open-label tasimelteon run-in phase. 24 (50%) patients entrained, and 20 (34%) were enrolled in the randomisation phase. Two (20%) of ten patients who were withdrawn to placebo remained entrained compared with nine (90%) of ten who continued to receive tasimelteon (difference 70%, 95% CI 26.4–100.0; p = 0.0026). No deaths were reported in either study, and discontinuation rates due to adverse events were comparable between the tasimelteon (3 [6%] of 52 patients) and placebo (2 [4%] of 52 patients) treatment courses. The most common side-effects associated with tasimelteon in SET were headache (7 [17%] of 42 patients given tasimelteon vs 3 [7%] of 42 patients given placebo), elevated liver enzymes (4 [10%] vs 2 [5%]), nightmares or abnormal dreams (4 [10%] vs none), upper respiratory tract infection (3 [7%] vs none], and urinary tract infections (3 [7%] vs 1 [2%]).” (S. W. Lockley, slockley@hms.harvard.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Liraglutide in Type 2 Diabetes with Multiple Daily Insulin Doses: “Adding liraglutide to multiple daily insulin injections in people with type 2 diabetes improves glycaemic control without an increased risk of hypoglycaemia, reduces body weight, and enables patients to lower their insulin doses,” conclude authors of a Swedish parallel group design study (h5364). Based on change in A1C levels at week 24 in 124 participants with inadequate glycemic control (A1C levels of 7.5%–11.5%), researchers found: “Liraglutide was associated with a significant reduction of 16.9 mmol/mol (1.5%) in HbA1c versus 4.6 mmol/mol (0.4%) for placebo, difference −12.3 mmol/mol (95% confidence interval −15.8 to −8.8 mmol/mol; −1.13%, −1.45 to −0.81 mmol/mol). Body weight was significantly reduced in participants in the liraglutide compared with placebo group (3.8 v 0.0 kg, difference −3.8, −4.9 to −2.8 kg), and total daily insulin doses were significantly reduced, by 18.1 units and 2.3 units (difference −15.8, −23.1 to −8.5 units). Reductions in mean and standard deviation of glucose levels estimated by masked continuous glucose monitoring were significantly greater in the liraglutide group than placebo group (−1.9 and −0.5 mmol/L). Neither group experienced severe hypoglycaemic events nor were there any significant differences in symptomatic or asymptomatic non-severe hypoglycaemia (<4.0 or <3.0 mmol/L). The mean number of non-severe symptomatic hypoglycaemic events (<4.0 mmol/L) during follow-up was 1.29 in the liraglutide group and 1.24 in the placebo group (P = 0.96).… Nausea was experienced by 21 (32.8%) participants in the liraglutide group and 5 (7.8%) in the placebo group and 3 (5%) and 4 (7%) participants in these groups, respectively, had any serious adverse event.” (M. Lind, lind.marcus@telia.com)

>>>PNN JournalWatch
* The Risk of Fall and Fracture With the Initiation of a Prostate-Selective Alpha Antagonist: A Population Based Cohort Study, in
BMJ, 2015; 351: h5398. (B. Welk, bkwelk@gmail.com)
* Complications of Central Venous Access Devices: A Systematic Review, in
Pediatrics, 2015; 136: e1331–44. (A. J. Ullman)
* Inflammation: Depression Fans the Flames and Feasts on the Heat, in
American Journal of Psychiatry, 2015; 172: 1075–91. (J. K. Kiecolt-Glaser, janice.kiecolt-glaser@osumc.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 © 2015, 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
Nov. 3, 2015 * Vol. 22, No. 211
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 3 issue of the Annals of Internal Medicine (2015; 163).
DPP-4 Inhibitors v. Sulfonylureas in Patients With Type 2 Diabetes: When compared with sulfonylureas as additions to metformin therapy in adults with type 2 diabetes mellitus, dipeptidyl peptidase-4 (DPP-4) inhibitors were associated with lower risks of all-cause mortality, major adverse cardiovascular events (MACEs), ischemic stroke, and hypoglycemia, researchers report (pp. 663–72). An analysis of Taiwan’s National Health Insurance Research Database identified 10,089 propensity score–matched pairs of DPP-4 inhibitor users and sulfonylurea users. Between their identification in 2009–12 and death or Dec. 31, 2013, these outcomes were noted: “DPP-4 inhibitors were associated with lower risks for all-cause death (hazard ratio [HR], 0.63 [95% CI, 0.55 to 0.72]), MACEs (HR, 0.68 [CI, 0.55 to 0.83]), ischemic stroke (HR, 0.64 [CI, 0.51 to 0.81]), and hypoglycemia (HR, 0.43 [CI, 0.33 to 0.56]) compared with sulfonylureas as add-on therapy to metformin but had no effect on risks for myocardial infarction and hospitalization for heart failure.” (S-Y Li, syli@vghtpe.gov.tw)
This “study raises questions it cannot answer,” an editorialist writes (
pp. 719–20). “It could not evaluate the effect of add-on therapy on glucose control. How the observed rates of adverse outcomes might be weighed in clinical decision making would depend on whether the addition of a sulfonylurea resulted in lower hemoglobin A1c levels than the addition of a DPP-4 inhibitor. Is this greater efficacy worth the risk? One could conclude that this study supports moving away from sulfonylureas to safer drug alternatives if other studies suggest similar effects on glucose control.” (R. J. Comi)
HBV Infection During Pre-HAART & HAART Periods: Among 2,375 men who have sex with men (MSM) participating in the Multicenter AIDS Cohort Study, the risk of acquiring hepatitis B virus (HBV) was lower during highly active antiretroviral therapy (HAART) than before the drugs were started, an analysis shows (pp. 673–80). However, the incidence of HBV infection remained high, the authors conclude. The observational cohort study used Poisson regression to compare HBV infection incidence rates in the pre-HAART and HAART eras and identify HBV risk factors: “In 25,322 person–years of follow-up, 244 incident HBV infections occurred. The unadjusted incidence rate was higher in HIV-infected MSM than in HIV-uninfected MSM (incidence rate ratio [IRR], 1.9 [95% CI, 1.5 to 2.4]) and was significantly lower in the HAART era than in the pre-HAART era among HIV-infected (IRR, 0.2 [CI, 0.1 to 0.4]) and HIV-uninfected (IRR, 0.3 [CI, 0.2 to 0.4]) MSM. Age younger than 40 years (IRR, 2.3 [CI, 1.7 to 3.0]), more than 1 recent sexual partner (IRR, 3.1 [CI, 2.3 to 4.2]), and HIV infection (IRR, 2.4 [CI, 1.8 to 3.1]) were independently associated with higher incidence of HBV infection, whereas HBV vaccination was protective (IRR, 0.3 [CI, 0.2 to 0.4]). Highly active antiretroviral therapy with HIV RNA levels less than 400 copies/mL was associated with protection (IRR, 0.2 [CI, 0.1 to 0.5]), but HAART in those with HIV RNA levels of 400 copies/mL or greater was not.” (O. Falade-Nwulia, falade1@jhmi.edu">ofalade1@jhmi.edu)
Ambulatory & Home Blood Pressure Monitoring: Authors review evidence and propose needed research into measurement of blood pressures outside the clinic setting (pp. 691–700): “Over the past several decades, evidence has accumulated on the following 2 approaches for measuring blood pressure outside of the clinic: ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM). Both of these methods have a stronger association with cardiovascular disease outcomes than clinic blood pressure measurement. Controversy exists about whether ABPM or HBPM is superior for estimating risk for cardiovascular disease and under what circumstances these methods should be used in clinical practice for assessing blood pressure outside of the clinic. This review describes ABPM and HBPM procedures, the blood pressure phenotypic measurements that can be ascertained, and the evidence that supports the use of each approach to measuring blood pressure outside of the clinic. It also describes barriers to the successful implementation of ABPM and HBPM in clinical practice, proposes core competencies for the conduct of these procedures, and highlights important areas for future research.” (D. Shimbo, ds2231@cumc.columbia.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 © 2015, 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
Nov. 4, 2015 * Vol. 22, No. 212
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 3 issue of JAMA (2015; 314).
Efavirenz-Based Antiretroviral Therapy After Perinatal Nevirapine: A study of children with HIV despite exposure to nevirapine for prevention of mother-to-child transmission provides support for shifting from ritonavir-boosted lopinavir–based therapy to efavirenz-based therapy around age 3 years (pp. 1808–17). Among 300 South African children with plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir–based therapy, these results were recorded for those randomized to efavirenz-based therapy or continuation of ritonavir-boosted lopinavir–based therapy: “The Kaplan–Meier probability of viral rebound by 48 weeks was 0.176 (n = 26) in the efavirenz group and 0.284 (n = 42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n = 4) in the efavirenz group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to ) and for viral failure was −0.007 (1-sided 95% CI, −0.036 to ). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.” (L. Kuhn, lk24@columbia.edu)
“Several studies in adults have suggested that monotherapy with ritonavir-boosted protease inhibitors (eg, lopinavir, darunavir) may be able to maintain viral suppression almost as well as standard therapy that included the addition of 2 nucleoside reverse transcriptase inhibitors (NRTIs),” writes an editorialist (
pp. 1801–2). “Monotherapy with a boosted protease inhibitor with a high barrier to resistance would help to avoid NRTI toxicity and decrease cost. In contrast, monotherapy with ritonavir-boosted atazanavir has shown a higher failure rate, and this option should be avoided. Such simplification studies should be cautiously explored in the pediatric population.” (R. Yogev, ryogev@luriechildrens.org)
Prescription Drug Use Trends: Americans increased their use of prescription medications significantly in the first decade of the 2000s, a study shows, resulting in increased polypharmacy and greater use of the majority of drug classes (pp. 1818–30). Comparison of data from the National Health and Nutrition Examination Surveys (NHANES) for 1999–2000 through 2011–12 show these temporal trends across cycles: “Results indicate an increase in overall use of prescription drugs among US adults between 1999–2000 and 2011–2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999–2000 and an estimated 59% reporting use of any prescription drugs in 2011–2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend <.001). The prevalence of polypharmacy (use of ≥5 prescription drugs) increased from an estimated 8.2% in 1999–2000 to 15% in 2011–2012 (difference, 6.6% [95% CI, 4.4%-8.2%]; P for trend <.001). These trends remained statistically significant with age adjustment. Among the 18 drug classes used by more than 2.5% of the population at any point over the study period, the prevalence of use increased in 11 drug classes including antihyperlipidemic agents, antidepressants, prescription proton-pump inhibitors, and muscle relaxants.” (E. D. Kantor, kantore@mskcc.org)
Off-Label Drug Promotions v. First Amendment: An Aug. 7 federal court decision permitting Amarin Pharma to promote off-label uses of icosapent ethyl (Vascepa) could herald a return to “a time of more [drug product] claims and less evidence to guide clinical care,” the author of a Viewpoint article writes (pp. 1795–6). “If [this and other recent] court decisions are not reversed, the FDA will have to choose among unattractive alternative approaches. The agency might focus its energy on identifying off-label statements that are demonstrably false and the cause of significant public health harm. Alternatively, the FDA might offer pathways for off-label marketing to companies based on clinical experience and other evidence that are far short of usual standards. Even if successful, these approaches still leave an enormous gray zone of equivocal evidence that could be used in marketing, to the detriment of physician decision making and patient therapy.” (J. M. Sharfstein, Joshua.Sharfstein@jhu.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 © 2015, 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
Nov. 5, 2015 * Vol. 22, No. 213
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 5 issue of the New England Journal of Medicine (2015; 373).
New Drugs in Advanced Renal-Cell Carcinoma: Studies examine utility of two new drugs in patients with advanced renal-cell carcinoma, and an editorial considers their relative costs versus benefits.
The programmed death 1 checkpoint inhibitor nivolumab produced longer overall survival and fewer grade 3 or 4 adverse events than standard treatment everolimus in 821 previously treated patients with advanced renal-cell carcinoma, researchers report (
pp. 1803–13). Randomized to nivolumab 3 mg/kg I.V. or everolimus 10 mg/kg orally once daily, participants had these outcomes: “The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002), which met the prespecified criterion for superiority (P ≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P <0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P = 0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).” (R. J. Motzer, motzerr@mskcc.org)
Also compared with everolimus, cabozantinib enabled longer progression-free survival that had progressed despite therapy that targeted vascular endothelial growth factor receptor (VEGFR) (
pp. 1814–23). Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets VEGFR, MET, and AXL, the authors write, adding these results from an open-label, Phase III trial: “Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P <0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P <0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.” (T. K. Choueiri, toni_choueiri@dfci.harvard.edu)
Value versus cost is a “practical question” with new therapies such as these agents, editorialists write, particularly in “resource-constrained health care environments” where new drugs may end up as “buried treasure” (
pp. 1872–4): “New cancer treatments are typically marketed at a price that most patients cannot afford without insurance. In the United States, federally funded programs cover approximately 50% of patients with advanced renal-cell cancer. We are obligated to ensure that medicines provide maximal therapeutic benefit with the fewest side effects and smallest fiscal burden. Currently, Medicare is unable to negotiate for the best terms across its entire patient base; this represents a contrivance of free-market economics that is in no one’s best interest. Effective treatments will work only if they are accessible to the patients they are designed to help. Buried treasure and value must coexist.” (D. I. Quinn)

>>>PNN NewsWatch
* FDA yesterday approved mepolizumab (Nucala, GlaxoSmithKline) as an add-on maintenance treatment of patients with severe asthma aged 12 years and older and with an eosinophilic phenotype. The drug is the first and only approved biologic therapy that targets interleukin-5, the company said in a news release, but is not approved for the treatment of other eosinophilic conditions or relief of acute bronchospasm or status asthmaticus.

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 © 2015, 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
Nov. 6, 2015 * Vol. 22, No. 214
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
Nov. 10 issue of the Journal of the American College of Cardiology (2015; 66).
Clinical Pharmacists & Cardiology: “Multidisciplinary organizations, including the American College of Cardiology, should support efforts to overcome [policy, legislation, and compensation] barriers, allowing pharmacists to deliver high-quality patient care to the full extent of their education and training,” according to a Joint Council Perspectives paper from the ACC Cardiovascular Team and Prevention Councils (pp. 2129–39): The article “provides background information on the clinical pharmacist’s role, training, certification, and potential utilization in a variety of practice models. Selected systematic reviews and meta-analyses, highlighting the benefit of clinical pharmacy services, are summarized. Clinical pharmacists have a substantial effect in a wide variety of roles in inpatient and ambulatory settings, largely through optimization of drug use, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education. Expansion of clinical pharmacy services is often impeded by policy, legislation, and compensation barriers.” (S. P. Dunn)

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (2015; 136).
Adolescent Opioid Prescriptions & Future Misuse: Among adolescents with little drug experience and strong opinions against illegal drug use, legitimate use of prescribed opioids before the 12th grade predicts a 33% increase in risk of future opioid misuse, researchers report (pp. e1169–77). Twelfth-grade surveys of 6,220 participants in the Monitoring the Future study and follow-up through age 23 showed the following: “This association varies by risk of future opioid misuse at baseline. Specifically, among respondents with low predicted risk of future opioid misuse in 12th grade (a 1.75% to 3% probability), an opioid prescription by 12th grade increases risk for opioid misuse after high school threefold. In the next highest risk stratum (with a predicted baseline risk of 3% to 5%), an opioid prescription doubles the risk for opioid misuse after high school. In no other risk stratum does an opioid prescription strongly or significantly predict future opioid misuse.” (R. Miech, ramiech@umich.edu)
HPV Vaccination in Male Adolescents: Uptake of human papillomavirus (HPV) vaccine has been low among male adolescents, authors write, adding, “Increased efforts are needed to improve vaccination coverage, especially for those who are least likely to be vaccinated” (pp. 839–49). Analysis of 2013 National Immunization Survey-Teen data showed these patterns of HPV vaccine uptake (≥1 dose) and series completion (≥3 doses) among adolescent boys aged 13–17 years: “HPV vaccination coverage with ≥1 dose was 34.6%, and series completion (≥3 doses) was 13.9%. Coverage was significantly higher among non–Hispanic blacks and Hispanics compared with non–Hispanic white male adolescents. Multivariable logistic regression showed that characteristics independently associated with a higher likelihood of HPV vaccination (≥1 dose) included being non-Hispanic black race or Hispanic ethnicity; having mothers who were widowed, divorced, or separated; having 1 to 3 physician contacts in the past 12 months; a well-child visit at age 11 to 12 years; having 1 or 2 vaccination providers; living in urban or suburban areas; and receiving vaccinations from >1 type of facility (P < .05). Having mothers with some college or college education, having a higher family income to poverty ratio, living in the South or Midwest, and receiving vaccinations from all sexually transmitted diseases/school/teen clinics or other facilities were independently associated with a lower likelihood of HPV vaccination (P < .05).” (P. Lu, lhp8@cdc.gov)

>>>PNN NewsWatch
* FDA yesterday approved a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Genvoya, Gilead) as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. The product is the first tenofovir alafenamide–based regimen approved by the agency.
* An advisory panel yesterday recommended that FDA add warnings to labeling of
fluoroquinolones about rare but sometimes life-altering adverse effects, the Wall Street Journal 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 844/270-0717 (fax). Copyright © 2015, 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
Nov. 9, 2015 * Vol. 22, No. 215
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 7 issue of Lancet (2015; 386).
Immunosuppression in Crohn Disease: Compared with standard therapy of Crohn disease, early combined immunosuppression (ECI) with a TNF antagonist and antimetabolite produced similar efficacy outcomes and fewer major adverse events, researchers report (pp. 1825–34). In the Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT) trial, open-label management of up to 60 consecutive adult patients in each of 41 community gastroenterologic practices in Belgium and Canada produced these results: “921 (85%) of the 1,084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66.0% [SD 14.0] and 61.9% [16.9]; adjusted difference 2.5%, 95% CI −5.2% to 10.2%, p = 0.5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27.7% and 35.1%, absolute difference [AD] 7.3%, hazard ratio [HR]: 0.73, 95% CI 0.62 to 0.86, p = 0.0003). There were no differences in serious drug-related adverse events.” (B. G. Feagan, brian.feagan@robartsinc.com)
Prophylactic Antibiotics After Acute Stroke: Based on findings from an open-label, cluster-randomized trial, “antibiotic prophylaxis cannot be recommended for prevention of post-stroke pneumonia in patients with dysphagia after stroke managed in stroke units,” a study shows (pp. 1835–44). At 48 U.K. stroke units randomized to prophylactic antibiotics for 7 days plus standard stroke unit care or standard stroke unit care only within 48 hours of stroke onset, these outcomes were recorded for 1,224 patients: “Prophylactic antibiotics did not affect the incidence of algorithm-defined post-stroke pneumonia (71 [13%] of 564 patients in antibiotics group vs 52 [10%] of 524 in control group; marginal adjusted odds ratio [OR] 1.21 [95% CI 0.71–2.08], p = 0.489, intraclass correlation coefficient [ICC] 0.06 [95% CI 0.02–0.17]. Algorithm-defined post-stroke pneumonia could not be established in 129 (10%) patients because of missing data. Additionally, we noted no differences in physician-diagnosed post-stroke pneumonia between groups (101 [16%] of 615 patients vs 91 [15%] of 602, adjusted OR 1.01 [95% CI 0.61–1.68], p = 0.957, ICC 0.08 [95% CI 0.03–0.21]). The most common adverse events were infections unrelated to post-stroke pneumonia (mainly urinary tract infections), which were less frequent in the antibiotics group (22 [4%] of 615 vs 45 [7%] of 602; OR 0.55 [0.32–0.92], p = 0.02). Diarrhoea positive for Clostridium difficile occurred in two patients (<1%) in the antibiotics group and four (<1%) in the control group, and meticillin-resistant Staphylococcus aureus colonisation occurred in 11 patients (2%) in the antibiotics group and 14 (2%) in the control group.” (L. Kalra, lalit.kalra@kcl.ac.uk)

>>>PNN NewsWatch
* An FDA review has determined that long-term use of clopidogrel does not increase or decrease overall mortality risk in patients with, or at risk for, heart disease, the agency said on Friday. FDA added that its evaluation of the Dual Antiplatelet Therapy (DAPT) trial and several other clinical trials shows no change in overall mortality risk with long-term (12 months or more) versus short-term (6 months or less) clopidogrel. Results also indicated that long-term dual antiplatelet therapy with clopidogrel plus aspirin did not increase risks of cancer-related deaths or adverse events.

>>>PNN JournalWatch
* Examining Variations in Prescribing Safety in UK General Practice: Cross Sectional Study Using the Clinical Practice Research Datalink, in
BMJ, 2015; 351: h5501. (S. .J Stocks, jill.stocks@manchester.ac.uk)
* Isavuconazole: A New Broad-Spectrum Triazole Antifungal Agent, in
Clinical Infectious Diseases, 2015; 61: 1558–65. (M. H. Miceli, mmiceli@umich.edu)
* Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials, in
Journal of Clinical Oncology, 2015; 33: 3817–25. (M. Schwaederle, mschwaederle@ucsd.edu)
* Cardiac Arrest in Pregnancy: A Scientific Statement From the American Heart Association, in
Circulation, 2015; 132: 1747–73. (F. M. Jeejeebhoy)

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 © 2015, 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
Nov. 10, 2015 * Vol. 22, No. 216
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. issue of JAMA Internal Medicine (2015; 175).
Fluoroquinolones & Aortic Dissection/Aneurysm: Using Taiwan’s National Health Insurance Research Database, researchers found an increased risk of aortic aneurysm and dissection in patients who had recently used oral quinolones (pp. 1839–47). Nested case–control analysis of 1,477 case patients and 147,700 matched controls showed these patterns of risk for current (within 60 days), past (61–365 days), and prior-year use of the drugs: “After propensity score adjustment, current use of fluoroquinolones was found to be associated with increased risk for aortic aneurysm or dissection (rate ratio [RR], 2.43; 95% CI, 1.83–3.22), as was past use, although this risk was attenuated (RR, 1.48; 95% CI, 1.18–1.86). Sensitivity analysis focusing on aortic aneurysm and dissection requiring surgery also demonstrated an increased risk associated with current fluoroquinolone use, but the increase was not statistically significant (propensity score–adjusted RR, 2.15; 95% CI, 0.97–4.60).” (C-C Lee, cclee100@gmail.com)
“Risk for this serious yet rare adverse event should be considered in any benefit–risk calculation for fluoroquinolone use, and further research into the impact of these important antibiotics effect on collagen is needed,” an editorialist writes (
p. 1847). “However, physicians and other health care professionals should be aware of this potential risk so that they can act swiftly to address aortic aneurysms and dissections when they do occur.” (J. S. Ross)
Narrow Pharmacy Networks & Medication Adherence: Implementation of a narrow pharmacy network for four medication types was not associated with reduced medication adherence, a CVS/caremark study shows (pp. 1850–3). In fact, the authors report “slight but consistent adherence improvements.” Medication-possession ratios (MPRs) before (2012) and after (2013) network implementation for statins, antihypertensive medications, oral antidiabetic medications, and antidepressant medications showed these patterns in two narrow network plans and three nonnetwork plans with nearly 68,000 and 150,000 members, respectively: “Although both network and nonnetwork plans’ MPRs improved between 2012 and 2013, individuals enrolled in narrow network plans had greater increases in MPR than individuals enrolled in nonnetwork plans (MPR for statins: 1.65% [95% CI, 1.35%–1.92%]; for antihypertensive medications: 1.34% [95% CI, 1.11%–1.56%]; for antidiabetic medications: 0.95% [95% CI, 0.43%–1.45%]; and for antidepressants, 1.00% [95% CI, 0.73%–1.31%]). The difference in MPR improvements before and after network implementation between network plans and nonnetwork plans was greater for plans that had 90-day programs already in place. Increases in MPR among patients who were taking statins were 0.63% (95% CI, 0.58%–0.68%) greater after narrow network implementation in plans with programs vs those without programs; among those taking antihypertensive medications, the MPR increase was 0.89% (95% CI, 0.72%–1.05%), the MPR increase among those taking antidiabetic medications was 1.72% (95% CI, 1.45%–1.99%), and the MPR increase among those taking antidepressant medications was 1.02% (95% CI, 1.01%–1.03%)” (J. M. Polinski)
FDA “Breakthrough” Language: FDA news releases that use neutral terms “might help consumers make more accurate judgments about [newly approved] drugs,” authors conclude based on a study of consumers’ interpretations of terms such as “breakthrough” or “promising” and language explaining limited evidence supporting accelerated approvals (pp. 1856–8). Participants reacted to an FDA news release for a metastatic lung cancer breakthrough drug conditionally approved based on the surrogate outcome tumor shrinkage but described in five different ways. When the drug was described as promising or breakthrough more participants rated the drug as “very” or “completely effective” compared with a facts-only description (23% and 25% vs 11%), and more thought evidence supporting the drug was “strong” or “extremely strong” (59% and 63% vs 43%). More consumers also incorrectly believed a “breakthrough” or “promising” drug had been “proven to save lives.” (T. Krishnamurti, tamar@cmu.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 © 2015, 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
Nov. 11, 2015 * Vol. 22, No. 217
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and Nov. 10 issue of JAMA (2015; 314).
Financial Incentives & Lipid Levels: Financial incentives provided to both patients and primary care physicians (PCPs) improved LDL cholesterol levels at 12 months of therapy, researchers report, but changes were not significant if incentives were provided to either group alone (pp. 1926–35). At 2011–14 at three U.S. practices, 340 PCPs and 1,503 patients were enrolled and randomly assigned to four group clusters (control, physician incentives, patient incentives, or shared physician–patient incentives). PCPs in intervention groups received $1,024 for each enrolled patient achieving LDL-C goals; intervention patients were eligible to receive this amount through daily lotteries tied to medication adherence.
Results showed the following: “Patients in the shared physician-patient incentives group achieved a mean reduction in LDL-C of 33.6 mg/dL (95% CI, 30.1–37.1; baseline, 160.1 mg/dL; 12 months, 126.4 mg/dL); those in physician incentives achieved a mean reduction of 27.9 mg/dL (95% CI, 24.9–31.0; baseline, 159.9 mg/dL; 12 months, 132.0 mg/dL); those in patient incentives achieved a mean reduction of 25.1 mg/dL (95% CI, 21.6–28.5; baseline, 160.6 mg/dL; 12 months, 135.5 mg/dL); and those in the control group achieved a mean reduction of 25.1 mg/dL (95% CI, 21.7–28.5; baseline, 161.5 mg/dL; 12 months, 136.4 mg/dL; P < .001 for comparison of all 4 groups). Only patients in the shared physician–patient incentives group achieved reductions in LDL-C levels statistically different from those in the control group (8.5 mg/dL; 95% CI, 3.8–13.3; P = .002).” (K. G. Volpp,
volpp70@wharton.upenn.edu)
PCSK-9 Inhibitors Destined for Overuse? In a Viewpoint article, authors predict that the recently approved proprotein convertase subtilisin-kexin type 9 (PCSK-9) inhibitors will be overused in clinical practice (pp. 1909–10). They cite prescribing of PCSK-9 inhibitors in those with statin intolerance, failure, or nonadherence, and the “return of LDL-C targets … fueled by the large LDL-C lowering effect achieved when combining PCSK-9 inhibitors with statins.” In the last case, the authors predict that “new targets will be set at pre-2013 levels or perhaps lower.… With these new targets firmly in place, the prescription of PCSK-9 drugs will diffuse as ‘best practice’ before trustworthy evidence of their benefits and harms is available.” (V. M. Montori, montori.victor@mayo.edu)
Clopidogrel for Migraines After Atrial Septal Defect Closure: In the 3 months following transcatheter atrial septal defect (ASD) closure, patients on clopidogrel plus aspirin had fewer migraine attacks than those on aspirin alone, according to results of a randomized, double-blind trial of 171 patients (doi: 10.1001/jama.2015.13919). The study, conducted in 2008–15, produced these results based on a primary outcome of monthly number of migraine days within the 3 months following ASD closure in the entire study population: “The mean (SD) age of the participants was 49 (15) years and 62% (106) were women. Patients in the clopidogrel group had a reduced mean (SD) number of monthly migraine days within the 3 months following the procedure (0.4 [95% CI, 0.07 to 0.69] days) vs the placebo group (1.4 [95% CI, 0.54 to 2.26] days; difference, −1.02 days [95% CI, −1.94 to −0.10 days]; incident risk ratio [IRR], 0.61 [95% CI, 0.41 to 0.91]; P = .04) and a lower incidence of migraine attacks following ASD closure (9.5% for the clopidogrel group vs 21.8% for the placebo group; difference, −12.3% [95% CI, −23% to −1.6%]; odds ratio [OR], 0.38 [95% CI, 0.15 to 0.89]; P = .03). Among patients with migraines, those in the clopidogrel group had less-severe migraine attacks (zero patients with moderately or severely disabling migraine attacks vs 37% [7 patients] in the placebo group; difference, −36.8% [95% CI, −58.5% to −15.2%]; P = .046). There were no between-group differences in the rate of patients with at least 1 adverse event (16.7% [14 patients] in the clopidogrel group vs 21.8% [19 patients] in the placebo group; difference, −5.2% [95% CI, −17% to 6.6%]; P = .44).” (J. Rodés-Cabau, josep.rodes@criucpq.ulaval.ca)

>>>PNN NewsWatch
* FDA yesterday approved cobimetinib (Cotellic, Genentech) for treatment of BRAF V600E or V600K mutation–positive advanced melanoma in combination with vemurafenib.

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 © 2015, 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
Nov. 12, 2015 * Vol. 22, No. 218
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 12 issue of the New England Journal of Medicine (2015; 373).
Everolimus-Eluting Bioresorbable Scaffolds in CAD: Compared with everolimus-eluting cobalt–chromium stents (Xience), everolimus-eluting bioresorbable vascular scaffolds (Absorb) were noninferior in 2,008 patients with stable or unstable angina, ABSORB III investigators report, but event rates were higher with the newer device (pp. 1905–15). Also tested for superiority using a margin of 4.5 percentage points, a primary end point of target-lesion failure (cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization) at 1 year provided these findings: “Target-lesion failure at 1 year occurred in 7.8% of patients in the Absorb group and in 6.1% of patients in the Xience group (difference, 1.7 percentage points; 95% confidence interval, −0.5 to 3.9; P = 0.007 for noninferiority and P = 0.16 for superiority). There was no significant difference between the Absorb group and the Xience group in rates of cardiac death (0.6% and 0.1%, respectively; P = 0.29), target-vessel myocardial infarction (6.0% and 4.6%, respectively; P = 0.18), or ischemia-driven target-lesion revascularization (3.0% and 2.5%, respectively; P = 0.50). Device thrombosis within 1 year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (P = 0.13).” (G. W. Stone, gs2184@columbia.edu)
“Although the concept of self-degrading stents is intuitively attractive, promise alone is not enough to make us unconditionally embrace this technology,” an editorialist writes (
pp. 1969–71). “For the moment, the trends toward higher event rates with the Absorb scaffold and the additional challenges associated with implantation must be considered. Against this background, the advantages of the Absorb scaffold must be evident and tangible; otherwise, acceptance of these limitations will not be broad. Ultimately, long-term follow-up data from ongoing trials enrolling even larger numbers of patients and testing whether hypothesized late benefits are detectable (e.g., in the ABSORB IV trial; ClinicalTrials.gov number, NCT02173379) will go a long way toward determining whether this promise will become a reality.” (R. A. Byrne)
Soluble Urokinase Receptor & Chronic Kidney Disease: Among 3,683 persons enrolled in the Emory Cardiovascular Biobank, increased levels of plasma soluble urokinase-type plasminogen activator receptor (suPAR) were associated with incident chronic kidney disease and an accelerated decline in estimated glomerular filtration rate (eGFR), a study shows (pp. 1916–25). Of the total population of patients (mean age, 63 years; 65% men), 2,292 had data from baseline and subsequent visits: “A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was −0.9 ml per minute per 1.73 m2 among participants in the lowest quartile of suPAR levels as compared with −4.2 ml per minute per 1.73 m2 among participants in the highest quartile (P <0.001). The 921 participants with a normal eGFR (≥90 ml per minute per 1.73 m2) at baseline had the largest suPAR-related decline in the eGFR. In 1,335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.” (J. Reiser, jochen_reiser@rush.edu)

>>>PNN NewsWatch
* ASHP’s Pharmacy Practice Model Initiative is now the Practice Advancement Initiative (PAI), the Society and its Foundation said in a news release this week. The name change and debut of an updated website reflect pharmacists’ expanding patient care roles in both acute and ambulatory care settings as clinical specialists and generalists, the news release stated. PAI also focuses more broadly on transitions throughout the continuum of care. The new PAI website features tools and resources for acute and ambulatory care practitioners, including the debut of an Ambulatory Care Self-Assessment tool and “Ambulatory Care Pharmacy Progress Measures,” which incorporate recommendations from ASHP’s 2014 Ambulatory Care Summit.

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 © 2015, 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
Nov. 13, 2015 * Vol. 22, No. 219
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Nov. issue of Chest (2015; 148).
Steroid Discontinuation in COPD & Pneumonia Risk: Patients with chronic obstructive pulmonary disorder (COPD) who discontinue inhaled corticosteroids (ICSs)—especially fluticasone—have a reduction in the increased risk of serious pneumonia associated with these drugs, according to a cohort study of new ICS users in Quebec (pp. 1177–83). Analysis of the provincial health insurance database showed these results for new ICS users in 1990–2005 who were followed to 2007 or until a serious pneumonia event: “The cohort included 103,386 users of ICSs, of whom 14,020 had a serious pneumonia event during 4.9 years of follow-up (incidence rate, 2.8/100/y). Discontinuation of ICSs was associated with a 37% decrease in the rate of serious pneumonia (rate ratio [RR], 0.63; 95% CI, 0.60–0.66). The risk reduction was rapidly evident, going from 20% in the first month to 50% by the fourth month after discontinuation. The risk reduction was particularly marked with fluticasone (RR, 0.58; 95% CI, 0.54–0.61) but less so with budesonide (RR, 0.87; 95% CI, 0.78–0.97).” (S. Suissa, samy.suissa@mcgill.ca)
Olprinone for Preventing Postoperative Atrial Fibrillation: In 40 patients at increased risk of postoperative atrial fibrillation (AF) because of elevated B-type natriuretic peptide (BNP) levels before surgery, the specific phosphodiesterase III inhibitor olprinone safely reduced AF incidence after pulmonary resection for lung cancer, researchers report (pp. 1285–92). Low-dose infusions that began just before anesthesia showed: “The incidence of postoperative [AF] was significantly lower in the olprinone group than in the placebo group (10% vs 60%, P < .001). Patients in the olprinone group showed significantly lower BNP, WBC counts, and C-reactive protein levels after surgery.” (T. Nojiri, nojirit@thoracic.med.osaka-u.ac.jp)

>>>Nephrology Report
Source:
Nov. issue of the American Journal of Kidney Diseases (2015; 66).
PPIs & Hypomagnesemia: In the prospective cohort Rotterdam Study, PPI use was associated with hypomagnesemia in the general population, and the effect was increased with concomitant use of loop diuretics (pp. 775–82). Similar but smaller effects were seen with H2 antagonists but without the interaction with loop diuretics, as shown in these data for 9,818 individuals: “Serum magnesium level was 0.022 mEq/L lower in PPI users (n = 724; 95% CI, −0.032 to −0.014 mEq/L) versus those with no use. PPI use was associated with increased risk of hypomagnesemia (n = 36; OR, 2.00; 95% CI, 1.36–2.93) compared to no use. Effect modification was found between the use of PPIs and loop diuretics; in participants using loop diuretics (n = 270), PPI use was associated with a further increased risk of hypomagnesemia (n = 5; OR, 7.22; 95% CI, 1.69-30.83) compared to no use. The increased risk with PPIs was only seen after prolonged use (range, 182–2,618 days; OR, 2.99; 95% CI, 1.73–5.15). Including dietary magnesium intake into the model did not alter results (available for 2,504 participants, including 231 PPI users). H2RA users (n = 250) also had a lower serum magnesium level (−0.016 [95% CI, −0.032 to −0.002] mEq/L) and increased risk of hypomagnesemia (n = 12; OR, 2.00; 95% CI, 1.08-3.72) compared to those with no use, but no interaction with loop diuretics.” (B. H. Stricker, b.stricker@erasmusmc.nl)
Drug-Induced Thrombotic Microangiopathy in Cancer: Although evidence is lacking, thrombotic microangiopathy (TMA) induced by oncologic agents is often managed with plasmapheresis and steroids, followed by immunosuppressive agents in refractory cases, authors of a review article write (pp. 857–68): “Type I cancer drug–induced TMA includes chemotherapy regimens (ie, mitomycin C) that can potentially promote long-term kidney injury, as well as increased morbidity and mortality. Type II cancer drug–induced TMA includes anti-VEGF agents that are not typically associated with cumulative dose–dependent cell damage.… There are no randomized controlled trials to provide physician guidance in the management of TMA.… The emerging trend includes the use of immunosuppressive agents if a refractory or relapsing clinical course that does not respond to plasmapheresis and steroids is observed.” (H. Izzedine, hassan.izzedine@clinique-monceau.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 © 2015, 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
Nov. 16, 2015 * Vol. 22, No. 220
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 14 issue of Lancet (2015; 386).
cPMP Substitution in Molybdenum Cofactor Deficiency: In 16 neonates with severe molybdenum cofactor deficiency (MoCD), substitution treatment with the biosynthetic precursor compound cyclic pyranopterin monophosphate (cPMP) provided effective therapy with a favorable safety profile, researchers report (pp. 1955–63). Observational cohort data showed these patterns with I.V. administration of cPMP for up to 5 years in some patients: “We observed no drug-related serious adverse events after more than 6,000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease.” (B. C. Schwahn, bernd.schwahn@cmft.nhs.uk)
Clinical Outcomes With Alcohol Consumption: Current use of alcohol lowers patients’ cardiovascular risks but raises the odds of developing alcohol-related cancers, according to the Prospective Urban Rural Epidemiological (PURE) study (pp. 1945–54). Data from high-, upper-middle–, lower-middle–, and low-income countries (HICs, UMICs, LMICs, and LICs respectively) showed “reduced myocardial infarction (hazard ratio [HR] 0.76 [95% CI 0.63–0.93]), but increased alcohol-related cancers (HR 1.51 [1.22–1.89]) and injury (HR 1.29 [1.04–1.61]).” Mortality was increased by 31% with heavy use of alcohol. Alcohol reduced rates of a composite outcome in HICs and UMICs but not in LMICs and LICs. (Andrew Smyth, andrew.smyth@phri.ca)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 351).
Infant Mortality After Maternal H1N1 Vaccination: In seven Swedish regions, a prospective population-based cohort study found no association between maternal influenza H1N1 vaccination during pregnancy and adverse fetal outcomes (h5585). Investigators report these results based on analysis of 275,000 births from 137,886 mothers, 41,193 of whom had received a monovalent AS03-adjuvanted H1N1 influenza vaccine during fetal life: “The results of this study suggest that AS03 adjuvanted H1N1 vaccination during pregnancy does not affect the risk of stillbirth, early neonatal death, or later mortality in the offspring. During follow-up, 1,172 stillbirths, 380 early neonatal deaths, and 706 deaths thereafter occurred. Compared with general population controls, this corresponded to adjusted hazard ratios of 0.83 (95% confidence interval 0.65 to 1.04) for stillbirth, 0.71 (0.44 to 1.14) for early neonatal death, and 0.97 (0.69 to 1.36) for later death. When siblings were used as controls, adjusted hazard ratios were 0.88 (0.59 to 1.30) for stillbirth, 0.82 (0.46 to 1.49) for early neonatal death, and 0.78 (0.52 to 1.19) for later death. Limitations of the study include lack of data on miscarriage before gestational week 22, inability to ascertain which mothers had pandemic flu during pregnancy, and lack of data on factors influencing the decision to vaccinate during pregnancy.” (J. F. Ludvigsson, jonasludvigsson@yahoo.com)

>>>PNN NewsWatch
* FDA on Friday granted accelerated approval for the oral medication osimertinib (Tagrisso, Astra Zeneca) to treat patients with advanced nonsmall cell lung cancer whose tumors have the epidermal growth factor receptor (EGFR) mutation T790M and whose disease has progressed after treatment with other EGFR-blocking therapies.
* Also on Friday,
FDA approved Antihemophilic Factor (Recombinant), PEGylated (Adynovate, Baxalta) for on-demand and prophylactic use in adults and adolescents, aged 12 years and older, who have hemophilia A. The product is modified to last longer in the blood and potentially require less frequent injections than unmodified antihemophilic factor when used to reduce the frequency of bleeding.

>>>PNN JournalWatch
* How Next-Generation Sequencing and Multiscale Data Analysis Will Transform Infectious Disease Management, in
Clinical Infectious Diseases, 2015; 61: 1695–702. (A. Kasarskis, andrew.kasarskis@mssm.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 © 2015, 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
Nov. 17, 2015 * Vol. 22, No. 221
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 17 issue of the Annals of Internal Medicine (2015; 163).
Leukotriene-Receptor Antagonists in Asthma: While leukotriene-receptor antagonists (LTRAs) are effective as monotherapy for treating adults and adolescents with asthma, patient selection with the drugs “remains unclear,” according to authors of a systematic review and meta-analysis (pp. 756–67). In placebo-controlled trials of LTRAs given alone or with inhaled corticosteroids, these results were identified: “Of the 2,008 abstracts that were screened, 50 trials met eligibility criteria. Random-effects meta-analyses of 6 trials of LTRA monotherapy showed that LTRAs reduced the risk for an exacerbation (summary risk ratio [RR], 0.60 [95% CI, 0.44 to 0.81]). In 4 trials of LTRAs as add-on therapy to inhaled corticosteroids, the summary RR for exacerbation was 0.80 (CI, 0.60 to 1.07). Leukotriene-receptor antagonists either as monotherapy or as add-on therapy to inhaled corticosteroids increased FEV1, whereas FEV1 percentage of predicted values was improved only in trials of LTRA monotherapy. Adverse event rates were similar in the intervention and comparator groups.” (M. Miligkos, mmiligkos@med.uth.gr)
Accuracy of Peripheral Thermometers: When temperature measurement will affect clinical diagnosis and management, central thermometers such as a rectal device should be used rather than peripheral thermometers now in common use, according to a second review and meta-analysis (pp. 768–77). Central devices include rectal, pulmonary artery catheter, urinary bladder, and esophageal thermometers, while peripheral devices use tympanic membrane, temporal artery, axillary, or oral measurements. The authors assessed findings from 75 studies of 8,682 patients and found the following: “Compared with central thermometers, peripheral thermometers had pooled 95% limits of agreement (random-effects meta-analysis) outside the predefined clinically acceptable range (± 0.5 °C), especially among patients with fever (−1.44 °C to 1.46 °C for adults; −1.49 °C to 0.43 °C for children) and hypothermia (−2.07 °C to 1.90 °C for adults; no data for children). For detection of fever (bivariate random-effects meta-analysis), sensitivity was low (64% [95% CI, 55% to 72%]; I2 = 95.7%; P < 0.001) but specificity was high (96% [CI, 93% to 97%]; I2 = 96.3%; P < 0.001). Only 1 study reported sensitivity and specificity for the detection of hypothermia.” (D. J. Niven, aniel.niven@albertahealthservices.ca">Daniel.niven@albertahealthservices.ca)
High Blood Pressure Screening in Adults: Adults without known hypertension should be screened for high blood pressure, but measurements taken outside the clinical setting should be obtained before treatment begins, according to a U.S. Preventive Services Task Force (USPSTF) recommendation statement (pp. 778–86). Updating its 2003 and 2007 recommendations, USPSTF noted: “Previous evidence reviews commissioned by the USPSTF found good-quality evidence that screening for hypertension has few major harms and provides substantial benefits. However, these reviews did not address the diagnostic accuracy of different blood pressure measurement protocols or identify a reference standard for measurement confirmation. For the current recommendation, the USPSTF examined the diagnostic accuracy of office blood pressure measurement, ambulatory blood pressure monitoring (ABPM), and home blood pressure monitoring.…
“The USPSTF found convincing evidence that ABPM is the best method for diagnosing hypertension. Although the criteria for establishing hypertension varied across studies, there was significant discordance between the office diagnosis of hypertension and 12- and 24-hour average blood pressures using ABPM, with significantly fewer patients requiring treatment based on ABPM. Elevated ambulatory systolic blood pressure was consistently and significantly associated with increased risk for fatal and nonfatal stroke and cardiovascular events, independent of office blood pressure.…” (USPSTF Web site,
www.uspreventiveservicestaskforce.org)

>>>PNN NewsWatch
* FDA has granted accelerated approval for daratumumab (Darzalex, Janssen Biotech) to treat patients with multiple myeloma who have received at least three prior treatments. This product is the first monoclonal antibody approved for treating multiple myeloma.

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 © 2015, 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
Nov. 18, 2015 * Vol. 22, No. 222
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 16 issue of JAMA (2015; 314).
Early Azithromycin for Respiratory Tract Illnesses: Early use of azithromycin in young children with apparent lower respiratory tract illness (LRTI) reduced the likelihood of severe illness, researchers report (pp. 2034–44). Study participants had histories of recurrent severe LRTIs when they were enrolled at nine academic U.S. medical centers in 2011–14. Randomization to azithromycin 12 mg/kg/d for 5 days or placebo produced these results: “A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41–0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00–0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.” (L. B. Bacharier, bacharier_l@kids.wustl.edu)
An editorialist warns of excessive antibiotic use if these results are applied too broadly (
pp. 2027–9): “Without an objective measure of whether or not a specific child’s episodes are modified by this approach (not simply parent/guardian report), it is likely to promote widespread use despite the benefit being limited to a few. Limiting children’s loss of days from school (or parents’ days from work) and relieving the anxiety that an RTI that may progress to a hospitalization is almost certainly to be of benefit to children and families. The question is how to determine (through studies incorporating biomarkers, airway endotyping, or genetics) which children are most likely to obtain the largest benefit from early initiation of azithromycin. Until a higher-risk population can be prospectively identified (rather than all children with intermittent wheezing associated with viral RTI) for progression to severe LRTI, the consequences of widespread use of azithromycin, both known and hypothesized, outweigh the benefit for most children.” (R. T. Cohen, robyn.cohen@bmc.org)
Antimicrobials in End-of-Life Care: While “antimicrobials are commonly prescribed at the end of life,” Viewpoint authors write that “improving palliative care requires reassessment of the best use of antimicrobials in the final weeks of life” (pp. 2017–8). The authors call for increased “evidence-based and goal-directed counseling about infection management at the end of life,” “clinical algorithms aimed at improving antimicrobial stewardship from an infectious disease standpoint,” and for researchers to “consider whether there is adequate clinical equipoise and need to justify a carefully designed randomized trial comparing symptom control and survival among patients with advanced illness who receive antimicrobials vs high-quality palliative care for suspected infections.” (M. Juthani-Mehta, manisha.juthani@yale.edu)
Anaphylaxis With IV Iron Products: In a retrospective cohort analysis of Medicare fee-for-service beneficiaries, new users of intravenous (IV) iron products were most likely to have anaphylaxis with iron dextran and least likely with iron sucrose (pp. 2062–8). Data from 2003 to 2013 showed the following: “A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8–78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0–29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0–3.3; P <.001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4–5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1–4.3).” (C. Wang, cunlin.wang@fda.hhs.gov)

>>>PNN NewsWatch
* A criminal case against USPlabs LLC and some of its corporate officers is among the results of a yearlong sweep of dietary supplements by FDA and other federal agencies to identify potentially unsafe or tainted supplements. USPlabs markets the popular workout and weight loss supplements Jack3d and OxyElite Pro, FDA said in a news release.

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 © 2015, 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
Nov. 19, 2015 * Vol. 22, No. 223
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 19 issue of the New England Journal of Medicine (2015; 373).
Oral ALS-008176 in RSV Infection: Administered after a challenge with respiratory syncytial virus (RSV) in healthy adults, the oral nucleoside analogue ALS-008176 increased RSV clearance and reduced viral load compared with placebo, researchers report (pp. 2048–58). Treatments were administered every 12 hours for 5 days beginning 12 hours after confirmation of RSV infection or 6 days after inoculation, with these effects on a primary end point of area under the curve (AUC) for viral load: “A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P ≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P <0.001), the peak viral load (P ≤0.001), the AUC for symptom score (P <0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose—viral clearance was accelerated (P ≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug.” (J. P. DeVincenzo, jdevincenzo@uthsc.edu)
Genetic Diversity & Malaria Vaccine Efficacy: In a trial conducted in seven African countries, fewer than 10% of Plasmodium falciparum had circumsporozoite protein alleles that matched antigens in a vaccine (pp. 2025–37). DNA extracted from samples from 4,985 study participants provided these insights into the relative matches between vaccine and target organism: “In the per-protocol group of 4,577 RTS,S/AS01-vaccinated participants and 2,335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P = 0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P = 0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy.” (D. F. Wirth, dfwirth@hsph.harvard.edu)
The picture with this malaria vaccine is not good, writes an editorialist, pointing to 50% to 60% efficacy “at best,” lower efficacy in younger children, and protection that wanes over time (
pp. 2082–3). But, he adds, “The news is not all bad. The modest loss of efficacy against divergent parasites implies that RTS,S/AS01 offers some degree of cross-protection—vaccine escape is not complete. A multivalent version of RTS,S with carefully chosen circumsporozoite protein variants, possibly combined with additional antigens, might offer broader protection. The large set of molecular epidemiologic data on the prevalence of circumsporozoite protein variants across Africa that was generated for this study should provide the evidence needed to select a combination of strains for a more broadly efficacious, next-generation malaria vaccine.” (C. V. Plowe)

>>>PNN NewsWatch
* Following fast-track designation and priority review, FDA yesterday approved naloxone HCl nasal spray (Narcan, Adapt Pharma) for treatment of potential opioid overdoses. The agency noted recent and widespread use of unapproved naloxone kits that combine an injectable formulation of naloxone with an atomizer that can deliver naloxone nasally as deaths from prescription drug overdoses became the leading cause of injury deaths in the U.S. over the past decade.

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 © 2015, 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
Nov. 20, 2015 * Vol. 22, No. 224
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Dec. issue of Medical Care (2015; 53).
Antibiotic Use in Cold and Flu Season: Patients who are prescribed antibiotics during the cold and influenza season are also unlikely to be prescribed beta-blockers after myocardial infarction, a study shows (pp. 1066–71). “These findings suggest that excessive antibiotic use reflects low-quality prescribing,” the authors write. “They imply that practice and policy solutions should go beyond narrow, antibiotic specific, approaches to encourage evidence-based prescribing for the elderly Medicare population.” The study used data from Medicare fee-for-service beneficiaries in 2010–11 to make these findings: “Flu-activity associated antibiotic use varied substantially across states—lowest in Vermont and Connecticut, highest in Mississippi and Florida. There was a robust positive correlation between flu-activity associated prescribing and use of medications that often cause adverse events in the elderly (0.755; P <0.001), whereas there was a strong negative correlation with beta-blocker use after a myocardial infarction (−0.413; P = 0.003).” (M. Alsan)
Racial/Ethnic Differences in Analgesic Access in EDs: The likelihood of patients with acute abdominal pain being prescribed analgesics in emergency departments (EDs) varies based on patient race and ethnicitiy, researchers report (pp. 1000–9). Data for 2006–10 show these patterns of analgesic prescribing for ED patients with primary diagnoses of nontraumatic acute abdominal pain: “A total of 6,710 ED visits were included: 61.2% (n = 4106) non-Hispanic white, 20.1% (n = 1,352) non-Hispanic black, 14.0% (n = 939) Hispanic, and 4.7% (n = 313) other racial/ethnic group patients. Relative to non-Hispanic white patients, non-Hispanic black patients and patients of other races/ethnicities had 22%–30% lower risk-adjusted odds of analgesic receipt [OR (95% CI) = 0.78 (0.67–0.90); 0.70 (0.56–0.88)]. They had 17%–30% lower risk-adjusted odds of narcotic analgesic receipt (P <0.05). Associations persisted for patients with moderate-severe pain but were insignificant for mild pain presentations. When stratified by the proportion of minority patients treated and the proportion of patients reporting severe pain, discrepancies in analgesic receipt were concentrated in hospitals treating the largest percentages of both.” (A. A. Shah)

>>>Health Affairs Report
Source:
Nov. issue of Health Affairs (2015; 34).
Diabetes-Appropriate Foods in Food Banks: Among 687 patients with diabetes in three states, provision of diabetes-appropriate food by food banks improved glycemic control during a 6-month pilot project (pp. 1956–63). The 2012–14 intervention was supplemented with blood sugar monitoring, primary care referral, and self-management support provided at food pantries, which distribute goods from food banks. Results showed: “Improvements were seen in pre–post analyses of glycemic control (hemoglobin A1c decreased from 8.11 percent to 7.96 percent), fruit and vegetable intake (which increased from 2.8 to 3.1 servings per day), self-efficacy, and medication adherence. Among participants with elevated HbA1c (at least 7.5 percent) at baseline, HbA1c improved from 9.52 percent to 9.04 percent. Although food pantries are nontraditional settings for diabetes support, this pilot study suggests a promising health promotion model for vulnerable populations. Policies supporting such interventions may be particularly effective because of food pantries’ food access and distribution capacity.” (H. K. Seligman, hseligman@medsfgh.ucsf.edu)
Healthy Food in Inner-City Stores: Food quality in 118 Baltimore City stores improved during the time when regulations mandated healthier food availability for those covered by the Women, Infants, and Children (WIC) program (pp. 1849–57). The WIC policy change occurred in 2009, and healthy food availability from 2006 to 2012 showed these patterns: “Healthy food availability improved significantly between 2006 and 2012, with the greatest increases in corner stores and in census tracts with more than 60 percent black residents. On an 11-point scale measuring availability of fruit (3 points), vegetables (4 points), bread (2 points), and milk (2 points), the WIC policy change was associated with a 0.72-point increase in WIC-relevant healthy food availability, while joining WIC was associated with a 0.99-point increase.” (C. A. M. Anderson, c1anderson@ucsd.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 © 2015, 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
Nov. 23, 2015 * Vol. 22, No. 225
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 21 issue of Lancet (2015; 386).
Optimal Treatment for Drug-Resistant Hypertension: Spironolactone performed well as add-on treatment for resistant hypertension, researchers report, supporting “a primary role of sodium retention in this condition” (pp. 2059–68). In the PATHWAY-2 trial, 314 patients with elevated clinic or home blood pressure readings while on maximally tolerated doses of three drugs were randomized to add-on therapy with spironolactone, doxazosin, bisoprolol, or placebo, with these results: “The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8.70 mm Hg [95% CI −9.72 to −7.69]; p <0.0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4.26 [–5.13 to −3.38]; p <0.0001), and superior when compared with the individual treatments; versus doxazosin (–4.03 [–5.04 to −3.02]; p<0.0001) and versus bisoprolol (–4.48 [–5.50 to −3.46]; p <0.0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6.0 mmol/L on one occasion.” (B. Williams, bryan.williams@ucl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Stroke & Hemorrhage After Antithrombotic Retreatment: In patients with atrial fibrillation who experienced gastrointestinal bleeding with antithrombotic therapy, restarting these agents yielded better all-cause mortality and thromboembolism outcomes than not providing antithrombotic coverage, a nationwide cohort study shows (h5876). In Denmark in 1996–2012, these results were noted for 4,602 patients with atrial fibrillation who were discharged from the hospital after gastrointestinal bleeding while receiving antithrombotic therapy: “Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n = 1,745) of the patients had died, 12.0% (11.0% to 13.0%, n = 526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n = 788) major bleeding, and 12.1% (11.1% to 13.1%, n = 546) recurrent gastrointestinal bleeding. 27.1% (n = 924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment.” (L. Staerk, Lailastaerk@gmail.com)

>>>PNN NewsWatch
* FDA on Friday granted approval for ixazomib (Ninlaro, Takeda) in combination with two other therapies to treat patients with multiple myeloma who have received at least one prior therapy. This is the third agent approved this year for multiple myeloma (see PNN, Nov. 17, Feb. 24).
* A $150 billion merger set for announcement today by
Pfizer and Allergan will create the world’s largest pharmaceutical company, the Wall Street Journal reports this morning.

>>>PNN JournalWatch
* Cholesterol Metabolism in CKD, in
American Journal of Kidney Diseases, 2015; 66: 1071–82. (A. B. Reiss, areiss@winthrop.org)
* Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency, in
Journal of Allergy and Clinical Immunology, 2015; 136: 1186–205.e78. (F. A. Bonilla, francisco.bonilla@childrens.harvard.edu)
* The Long View of Long-Term Care: Our Personal Take on Progress, Pitfalls, and Possibilities, in
Journal of the American Geriatrics Society, 2015; 63: 2400–6. (R. L. Kane, kanex001@umn.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 © 2015, 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
Nov. 24, 2015 * Vol. 22, No. 226
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from the Annals of Internal Medicine (2015; 163).
Use of Generic Medications: When possible, “clinicians should prescribe generic medications … rather than more expensive brand-name medications,” the American College of Physicians said in a “best practice advice” document released yesterday online (doi: 10.7326/M14-2427). The “underuse of generic medications” is an important example of excessive health care spending in the U.S. that fails to achieve better health outcomes, the College said. Five questions about generic medications were addressed: (1) How commonly are brand-name medications used when a generic version is available? (2) How does the use of generic medications influence adherence? (3) What is the evidence that brand-name and generic medications have similar clinical effects? (4) What are the barriers to increasing the use of generic medications? (5) What strategies can be used to promote cost savings through greater generic medication use? The College summarized the evidence supporting its conclusion in these two points (A. Qaseem, aqaseem@acponline.org):
* Brand-name medications show no superiority in effectiveness compared with molecularly identical generic medications.
* Using generic medications reduces out-of-pocket costs for patients and helps to encourage better adherence to therapy, especially in chronic diseases.

>>>Geriatrics Highlights
Source:
Nov. issue of the Journal of the American Geriatrics Society (2015; 63).
2015 Updated Beers Criteria: As reported when the document was released early (see PNN, Oct. 27). the 2015 American Geriatrics Society (AGS) Beers Criteria for the first time “include lists of select drugs that should be avoided or have their dose adjusted based on the individual’s kidney function and select drug–drug interactions documented to be associated with harms in older adults” (pp. 2227–46). Medications added since the 2012 update are proton-pump inhibitors, desmopressin, and meclizine based on diagnoses or conditions, and several medications based on consideration of specific diseases or syndromes: opioids (falls and fractures), armodafanil and modafinil (insomnia), eszopiclone and zaleplon (dementia and cognitive impairment), and antipsychotics (delirium).
“Long-term proton-pump inhibitor use in the absence of a strong indication” was added “because of risk of
C. difficile infection, bone loss, and fractures,” the panel wrote. Opioids were added “in the diagnosis and condition table for older adults with a history of falls and fractures. If opioids must be used, it is recommended that reducing the use of other CNS-active medications be considered. This statement is in recognition of the need to have adequate pain control while balancing the potential harms from opioids and untreated pain. The panel balanced the difficulty and challenges of poorly treated pain with the harms of opioids and available alternatives in older adults. Another critical change was to the language for use of antipsychotics in the dementia and delirium drug–disease, drug–syndrome category and the addition of avoiding antipsychotics in persons with delirium as first-line treatment. With increasing evidence of harm associated with antipsychotics and conflicting evidence on their effectiveness in delirium and dementia, the rationale to avoid was modified to ‘avoid antipsychotics for behavioral problems unless nonpharmacological options (e.g., behavioral interventions) have failed or are not possible, and the older adult is threatening substantial harm to self or others.’ The table of medications with strong anticholinergic properties has been updated. Anticholinergic burden and measurement is an area of literature that is continually evolving. Use of anticholinergic medications remains a concern because it is associated with impaired cognitive and physical function and risk of dementia.”

>>>PNN NewsWatch
* FDA yesterday approved nivolumab (Opdivo, Bristol-Myers Squibb) for second-line treatment of patients with advanced (metastatic) renal cell carcinoma.
*
FDA also yesterday approved Anthrax Vaccine Adsorbed (BioThrax, Emergent BioDefense Operations Lansing LLC) to prevent disease following suspected or confirmed exposure to Bacillus anthracis.

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 © 2015, 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
Nov. 25, 2015 * Vol. 22, No. 227
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 24 issue of JAMA (2015; 314).
Ranibizumab for Proliferative Diabetic Retinopathy: Compared with panretinal photocoagulation (PRP) in patients with type 1 or 2 diabetes and proliferative diabetic retinopathy (PDR), intravitreous ranibizumab “resulted in visual acuity that was noninferior to … PRP treatment at 2 years,” according to the Diabetic Retinopathy Clinical Research Network (pp. 2137–46). Using a primary outcome of mean visual acuity change at 2 years and a margin of noninferiority of five letters, the study produced these results in 394 eyes treated randomly with PRP treatment or protocol-based ranibizumab 0.5 mg at baseline and as frequently as every 4 weeks: “Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (difference, +2.2; 95% CI, −0.5 to +5.0; P < .001 for noninferiority). The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI, +3.0 to +5.4; P < .001). Mean peripheral visual field sensitivity loss was worse (−23 dB vs −422 dB; difference, 372 dB; 95% CI, 213-531 dB; P < .001), vitrectomy was more frequent (15% vs 4%; difference, 9%; 95% CI, 4%-15%; P < .001), and [diabetic macular edema] development was more frequent (28% vs 9%; difference, 19%; 95% CI, 10%-28%; P < .001) in the PRP group vs the ranibizumab group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different (35% in the ranibizumab group vs 30% in the PRP group; difference, 3%; 95% CI, −7% to 12%; P = .58). One eye in the ranibizumab group developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified.” (A. R. Glassman, drcrstat2@jaeb.org)
“This important study … represents a major step forward for patients with PDR by providing the ophthalmologists who manage their retinal disease with new options,” an editorialist writes (
pp. 2135–6). “The short-term role (2 years) for using anti–[vascular endothelial growth factor (VEGF)] agents seems to represent a viable alternative therapy for adherent patients with high-risk PDR. Nevertheless, PRP represents the standard of care for PDR and may represent the best long-term treatment option for high-risk PDR. It is certainly not time to abandon PRP in favor of exclusively treating patients with PDR using only intravitreal anti-VEGF injections. Clinical judgment and timing of initiation of either therapy are viable options, and the findings reported by the DRCR.net researchers provide clinicians with evidence to support the alternative option of anti-VEGF pharmacotherapy for high-risk PDR. Further advances in pharmacologic management and sustained delivery systems will help expand this alternative therapy for PDR.” (T. W. Olsen, tolsen@emory.edu)
Clopidogrel for Postoperative Migraine Headaches: Clopidogrel plus aspirin produced a lower monthly frequency of migraine attacks over the 3-month period following closure of transcatheter atrial septal defect (ASD), compared with aspirin alone, researchers report (pp. 2147–54). The mean number of monthly migraine days during the 3-month postoperative period was 0.4 with the drug combination and 1.4 with aspirin plus placebo. When migraines occurred, they were less severe, with none of those on the combination having moderate to severe headaches, compared with 37% of those on aspirin alone. (J. Rodés-Cabau, josep.rodes@criucpq.ulaval.ca)

>>>PNN NewsWatch
* FDA yesterday approved necitumumab (Portrazza, Lilly) in combination with two forms of chemotherapy to treat patients with advanced (metastatic) squamous non-small cell lung cancer who have not previously received medication specifically for treating their advanced lung cancer. The agent is a monoclonal antibody that blocks the binding site on epidermal growth factor receptor 1.
*
FDA also yesterday approved the first seasonal influenza vaccine containing an adjuvant, the squalene oil–based MF59. Fluad (Novartis Vaccines and Diagnostics Limited) is a trivalent product indicated for people aged 65 years or older. In clinical trials, Fluad produced immune responses in older people similar to those of the unadjuvanted Agriflu product, also manufactured by Novartis Vaccines.
*
PNN will not be published on Thurs. and Fri., Nov. 26 and 27, Thanksgiving.

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 © 2015, 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
Nov. 30, 2015 * Vol. 22, No. 228
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 26 issue of the New England Journal of Medicine (2015; 373).
CVD Outcomes With Empagliflozin in Type 2 Diabetes: Frequency of a primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was lower in high-risk patients with type 2 diabetes when they were treated with the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, researchers report, as compared with placebo (pp. 2117–28). Doses of 10 or 25 mg of the drug were used in the randomized trial, which produced these results: “A total of 7,020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4,687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2,333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P = 0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P = 0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.” (B. Zinman, zinman@lunenfeld.ca)
“It will be important to confirm these results with findings from other ongoing trials of SGLT2 inhibitors, including an evaluation of canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]; ClinicalTrials.gov number, NCT01032629) and of dapagliflozin (DECLARE–TIMI58, NCT01730534),” editorialists write (
pp. 2178–9). “For now, the study by Zinman et al. provides some hope that the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease can indeed be modified.” (J. R. Ingelfinger)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Methylphenidate in ADHD: Evidence on methylphenidate use in children and adolescents with attention-deficit hyperactivity disorder (ADHD) shows improvements in teacher ratings, general behavior, and parent-reported quality of life, according to a systematic review and meta-analysis of 185 trials of 12,245 participants (h5203). However, “given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain,” the authors write, and the drug “is associated with an increased risk of non-serious but not serious adverse events”: “Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3,132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD −0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0–100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE.” (O. J. Storebø, jst@regionsjaelland.dk">ojst@regionsjaelland.dk)

>>>PNN JournalWatch
* Global, Regional, and National Disability-Adjusted Life Years (DALYs) for 306 Diseases and Injuries and Healthy Life Expectancy (HALE) for 188 Countries, 1990–2013: Quantifying the Epidemiological Transition, in
Lancet, 2015; 386: 2145–91. (GBD 2013 DALYs and HALE Collaborators)
* Treatment of Tuberculosis, in
New England Journal of Medicine, 2015; 373: 2149–60. (C. R. Horsburgh, rhorsbu@bu.edu)
* Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport—From Bench to Bedside, in
Diabetes Care, 2015; 38: 2344–53. (S. Mudaliar, smudaliar@vapop.ucsd.edu)
* Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis, in
Diabetes Care, 2015; 38: 2354–69. (C. Gorst, catherine.gorst@postgrad.manchester.ac.uk)

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 © 2015, 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
Dec. 1, 2015 * Vol. 22, No. 229
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 1 issue of the Annals of Internal Medicine (2015; 163).
Hepatitis C Virus Therapies: Research articles examine use of sofosbuvir plus velpatasvir in patients with infections of various genotypes of hepatitis C virus (HCV).
In 321 treatment-experienced patients with genotype 1 or 3 HCV infection, sofosbuvir–velpatasvir proved highly effective and was well tolerated, researchers report (
pp. 809–17). At sites in Australia, New Zealand, and the U.S., adults received sofosbuvir 400 mg once daily plus velpatasvir 25 or 100 mg once daily with or without ribavirin. Based on clinical condition (genotype 3 without cirrhosis, cohort 1, or with compensated cirrhosis, cohort 2; or treatment-resistant genotype 1, cohort 3), sustained virologic responses at week 12 after treatment (SVR12) showed: “In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea.” (S. Pianko, spianko@geds.com.au)
Similar results were produced in an open-label, Phase II trial of the drugs in 377 treatment-naive patients with HCV genotypes 1 to 6 (
pp. 818–26). Study participants were noncirrhotic at randomization to sofosbuvir 400 mg plus velpatasvir 25 or 100 mg for 12 weeks (part A, patients with HCV genotypes 1 to 6) or to sofosbuvir 400 mg plus velpatasvir 25 or 100 mg with or without ribavirin for 8 weeks (part B, patients with HCV genotypes 1 or 2). Results showed: “In part A, SVR12 rates were 96% (26 of 27) with velpatasvir, 25 mg, and 100% (28 of 28) with velpatasvir, 100 mg, for genotype 1; 93% (25 of 27) in both groups for genotype 3; and 96% (22 of 23) with velpatasvir, 25 mg, and 95% (21 of 22) with velpatasvir, 100 mg, for genotypes 2, 4, 5, and 6. In part B, for genotype 1, SVR12 rates were 87% (26 of 30) with velpatasvir, 25 mg; 83% (25 of 30) with velpatasvir, 25 mg, plus ribavirin; 90% (26 of 29) with velpatasvir, 100 mg; and 81% (25 of 31) with velpatasvir, 100 mg, plus ribavirin. For genotype 2, SVR12 rates were 77% (20 of 26) with velpatasvir, 25 mg; 88% (22 of 25) with velpatasvir, 25 mg, plus ribavirin; 88% (23 of 26) with velpatasvir, 100 mg; and 88% (23 of 26) with velpatasvir, 100 mg, plus ribavirin. Adverse events included fatigue (21%), headache (20%), and nausea (12%). One patient committed suicide.” (G. T. Everson, greg.everson@ucdenver.edu)
Behavioral Programs for Diabetes: Behavioral approaches for self-management programs for types 1 and 2 diabetes are examined in systematic reviews and meta-analyses.
For patients with type 1 diabetes, “Behavioral programs … offer some benefit for glycemic control, at least at short-term follow-up, but improvement for other outcomes has not been shown,” authors conclude (
pp. 836–47). Based on 36 prospective controlled studies, evidence indicates that behavioral programs lowered A1C levels by a mean of 0.29 percentage points at 6 months after intervention, compared with standard care, but that levels were not significantly different at the 12 months or later. (J. Pillay, jpillay@ualberta.ca)
For those with type 2 diabetes, “Diabetes self-management education offering 10 or fewer hours of contact with delivery personnel provided little benefit,” the investigators found based on evidence in 132 randomized controlled trials comparing diabetes behavioral programs with usual care, active controls, or other behavioral programs (
pp. 848–60). “Behavioral programs seem to benefit persons with suboptimal or poor glycemic control more than those with good control.” (J. Pillay, jpillay@ualberta.ca)

>>>PNN NewsWatch
* Less than 2 weeks after approval of the first monoclonal antibody indicated for multiple myeloma (see PNN, Nov. 17), FDA yesterday approved the second such agent, elotuzumab (Empliciti, Bristol-Myers Squibb). As with daratumumab, elotuzumab was approved on a priority basis and designated as a breakthrough agent and an orphan drug.

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 © 2015, 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
Dec. 2, 2015 * Vol. 22, No. 230
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 1 issue of JAMA (2015; 314).
Metformin Plus Insulin in Type 1 Diabetes: In adolescents with type 1 diabetes and overweight/obesity, metformin added to insulin did not improve glycemic control after 6 months, researchers report (pp. 2241–50). Among several secondary outcomes, metformin reduced only insulin dose and measures of adiposity. At 26 pediatric endocrinology clinics, these results were identified for patients aged 12.1 to 19.6 years and with mean body mass indices (BMI) above the 94th percentile: “Between October 2013 and February 2014, 140 participants were enrolled. Baseline HbA1c was 8.8% in each group. At 13-week follow-up, reduction in HbA1c was greater with metformin (−0.2%) than placebo (0.1%; mean difference, −0.3% [95% CI, −0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, −0.3% to 0.3%]; P = .92). At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003), and 24% (17) of participants in the metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01). Gastrointestinal adverse events were reported by more participants in the metformin group than in the placebo group (mean difference, 36% [95% CI, 19% to 51%]; P < .001).” (K. M. Miller, T1DStats@jaeb.org)
Vericiguat in Worsening Chronic Heart Failure: A soluble guanylate cyclase stimulator, vericiguat had no significant effect on log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with worsening chronic heart failure (HF) and reduced left ventricular ejection fraction (LVEF), compared with placebo (pp. 2251–62). The dose-ranging study ran for 12 weeks and pooled results for the three highest doses of vericiguat (2.5, 5, 10 mg) in its primary analysis: “Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, −0.402; geometric means: baseline, 2,890 pg/mL; 12 weeks, 1,932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, −0.280; geometric means: baseline, 3,955 pg/mL; 12 weeks, 2,988 pg/mL) (difference of means, −0.122; 90% CI, −0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73–1.08; P = .15). The exploratory secondary analysis suggested a dose–response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P< .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.” (M. Gheorghiade, mgheorgh@nm.org)
Optimizing Phase 2 Dose-Finding Trials: Using the above vericiguat study as an example, authors discuss the use of dose-ranging and dose–response trials in the development of new drugs (pp. 2294–5): “Figure 2 in [this study] shows the key dose–response relationship and suggests that the 10-mg target dose is the most or possibly only effective dose. However, the primary analysis was null, and the protocol called for the statistical secondary analysis only if the primary analysis were significant at P < .05. Therefore, although the 10-mg dose appears to be the most promising for investigation in a phase 3 trial, the dose-ranging findings must be considered very tentative. There remains uncertainty regarding how best to estimate the effect of the 10-mg dose. The primary analysis did not evaluate the effect of the 10-mg dose alone, and separate analyses for each dose would be prone to high variation and false-positive results due to multiple comparisons. The exploratory linear model produced an estimated effect for the 10-mg dose under an assumption of linearity. This analysis and its results were considered only exploratory.” (K. Viele, kert@berryconsultants.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 © 2015, 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
Dec. 3, 2015 * Vol. 22, No. 231
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 3 issue of the New England Journal of Medicine (2015; 373).
Acetaminophen Antipyresis in Critically Ill Patients: Testing whether immune responses are decreased by treatment of fever in critically ill patients with suspected infection, investigators found that intravenous acetaminophen had no significant effect on outcomes, with similar numbers of ICU-free days and mortality rates as in those receiving placebo (pp. 2215–24). Among 700 patients in intensive care with body temperature of 38˚C or more, I.V. acetaminophen 1 g or placebo every 6 hours until ICU discharge produced these results: “The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges–Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P = 0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P = 0.84).” (P. Young, paul.young@ccdhb.org.nz)
On-Demand HIV Preexposure Prophylaxis: Among men who have unprotected anal sex with men, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) used before and after sexual activity protected against HIV-1 infection, researchers report (pp. 2237–46). Compared with placebo, the prophylactic drug combination had these effects on HIV-1 infection rates: “Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person–years) and 14 in the placebo group (incidence, 6.60 per 100 person–years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P = 0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P = 0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P = 0.002) and renal adverse events (18% vs. 10%, P = 0.03).” (J-M Molina, jean-michel.molina@aphp.fr)
Lixisenatide in Diabetes & ACS: Among patients with type 2 diabetes and myocardial infarction or hospitalization for unstable angina within the prior 180 days, lixisenatide failed to alter clinical outcomes in a comparison with placebo, a study shows, with no differences in rates of major cardiovascular events or other serious adverse events (pp. 2247–57). Provided with locally determined standards of care, lixisenatide was tested for noninferiority and superiority to placebo using a primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina: “The 6,068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P <0.001) but did not show superiority (P = 0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo.” (M. A. Pfeffer, mpfeffer@rics.bwh.harvard.edu)

>>>PNN NewsWatch
* Insulet Corporation initiated a lot-specific voluntary field safety notification for 15 lots of the OmniPod distributed in the U.S. and 3 lots distributed internationally, FDA said yesterday. The company noticed a slight increase in reported cases of the product’s needle mechanism failing to deploy or delays in deploying, prompting the action.

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 © 2015, 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
Dec. 4, 2015 * Vol. 22, No. 232
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Dec. issue of the Diabetes Care (2015; 38).
Biosimilarity of Approved Insulin Products: Pharmacokinetic (PK) and pharmacodynamic (PD) evaluation of lantus insulin glargine products—including the Lantus (IGlar) product approved in the U.S. and the European Union—demonstrate similar properties following single doses in healthy participants (pp. 2226–33). LY2963016 (LY IGlar) is made using a different process than the IGlar products, the authors note, a situation similar to biosimilars. In three studies, 211 fasted healthy participants received 0.5 units/kg s.c. doses of two different insulin glargine products on two occasions each, with these euglycemic clamp results: “The PK (area under the curve [AUC]; maximum observed concentration [Cmax]) and PD (maximum glucose infusion rate [Rmax]; total glucose infusion during the clamp [Gtot]) were similar between LY IGlar and IGlar, with the ratios of geometric means ranging from 0.90 to 0.95 for PK parameters and from 0.91 to 0.99 for PD parameters across studies. In all cases, the 90% CIs for the ratios of geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. Adverse events were similar between treatments.” (H. Linnebjerg, linnebjerg_helle@lilly.com)
This study opens a number of questions on how PK/PD equivalence should be established for long-acting insulins, editorialists write (
pp. 2237–40). To be relevant for clinicians and not just regulatory agencies, such studies “should be done in experimental conditions as close to the real life of persons with diabetes,” the authors note. “The similarity between PK/PD of LY IGlar and IGlar reported by Linnebjerg et al. in normal volunteers cannot be immediately extrapolated to the [types 1 and 2 diabetic] populations, primarily because of the confounder endogenous insulin secretion in the population studied. Additional studies in [patients with type 1 or 2 diabetes] at steady state, at a clinically relevant dose given in the evening, and with assessment of glargine metabolism (plasma M1) are needed to convincingly document the similarity of these products in the population that is going to use them under everyday real-life conditions.” (G. B. Bolli, geremia.bolli@unipg.it)
Insulin in Diabetes Management: Reflecting on a collection of articles about insulin in this issue, editorialists note the continued utility of an agent 93 years after the first report of its clinical potential in patients with diabetes (pp. 2200–3): “Although it has always been the mainstay of type 1 diabetes treatment, we recognize now its effectiveness and safety in type 2 diabetes and continue to learn to use it in new ways. To a great extent, the newer classes of glucose-lowering agents are being studied as ‘add-on’ tactics on a background of insulin rather than as a replacement for insulin in subjects with type 2 diabetes. Thus, we think insulin is and will continue to hold the place of the ‘black dress’ among therapies … meeting a basic need, never out of fashion, and always adaptable to everyday needs.” (W. T. Cefalu, cefaluwt@pbrc.edu)

>>>Psychiatry Report
Source:
Dec. issue of the American Journal of Psychiatry (2015; 172).
Extended-Release Guanfacine for Hyperactivity in Autism: Hyperactivity, impulsiveness, and distractibility were reduced by extended-release guanfacine in 62 children with autism spectrum disorder (ASD), compared with placebo, researchers report (pp. 1197–206). The central alpha-2a-adrenergic receptor agonist showed these efficacy and safety effects in an 8-week trial: “The guanfacine group showed a 43.6% decline in scores on the Aberrant Behavior Checklist–hyperactivity subscale (least squares mean from 34.2 to 19.3) compared with a 13.2% decrease in the placebo group (least squares mean from 34.2 to 29.7; effect size = 1.67). The rate of positive response (much improved or very much improved on the Clinical Global Impression–Improvement scale) was 50% (15 of 30) for guanfacine compared with 9.4% (3 of 32) for placebo. A brief cognitive battery tapping working memory and motor planning showed no group differences before or after 8 weeks of treatment. The modal dose of guanfacine at week 8 was 3 mg/day (range: 1–4 mg/day), and the modal dose was 3 mg/day (range: 2–4 mg/day) for placebo.… The most common adverse events included drowsiness, fatigue, and decreased appetite.” (L. Scahill)

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 © 2015, 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
Dec. 7, 2015 * Vol. 22, No. 233
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Warfarin, Sulfonylureas & Serious Hypoglycemia: An important drug interaction between warfarin and commonly used sulfonylureas is uncovered using a retrospective review of Medicare pharmacy and medical claims from 2006 through 2011 (h6223). A 20% random sample of claims for beneficiaries aged 65 years or older shows these patterns in calendar quarters when patients with diabetes had prescription fills for both warfarin and either glipizide or glimepiride and quarters with fills of only the two latter agents: “In quarters with glipizide/glimepiride use, hospital admissions or emergency department visits for hypoglycemia were more common in person quarters with concurrent warfarin use compared with quarters without warfarin use (294/416,479 v 1,903/3,938,939; adjusted odds ratio 1.22, 95% confidence interval 1.05 to 1.42). The risk of hypoglycemia associated with concurrent use was higher among people using warfarin for the first time, as well as in those aged 65–74 years. Concurrent use of warfarin and glipizide/glimepiride was also associated with hospital admission or emergency department visit for fall related fractures (3,919/416,479 v 20,759/3,938,939; adjusted odds ratio 1.47, 1.41 to 1.54) and altered consciousness/mental status (2,490/416,479 v 14,414/3,938,939; adjusted odds ratio 1.22, 1.16 to 1.29). Unmeasured factors could be correlated with both warfarin use and serious hypoglycemic events, leading to confounding. The findings may not generalize beyond the elderly Medicare population.” (A. Peters, momofmax@mac.com)

>>>Lancet Highlights
Source:
Dec. 5 issue of Lancet (2015; 386).
Disease & Health in England: “Health in England is improving although substantial opportunities exist for further reductions in the burden of preventable disease,” conclude authors of an analysis prepared for the Global Burden of Disease Study 2013 (pp. 2257–74). “The gap in mortality rates between men and women has reduced, but marked health inequalities between the least deprived and most deprived areas remain. Declines in mortality have not been matched by similar declines in morbidity, resulting in people living longer with diseases. Health policies must therefore address the causes of ill health as well as those of premature mortality. Systematic action locally and nationally is needed to reduce risk exposures, support healthy behaviours, alleviate the severity of chronic disabling disorders, and mitigate the effects of socioeconomic deprivation.” (J. N. Newton, john.newton@phe.gov.uk)

>>>PNN NewsWatch
* The 50th ASHP Midyear Clinical Meeting opened in New Orleans over the weekend, and this morning, former President George W. Bush and his wife Laura address the more than 20,000 in attendance. That’s quite a contrast from the 250 in attendance at the first Midyear Clinical Meeting in 1966 in Washington, DC, when one of the ASHP staff flattened all four tires on his car transporting the name badges and handouts from headquarters to the convention hotel. Now the largest meeting of pharmacists in the world, the Midyear annually features “top-notch clinical programming,” writes ASHP President John A. Armistead in this year’s program book, designed for “students, new practitioners, federal pharmacists, and practitioners in settings across the entire spectrum of care.”
* Based on a safety review,
FDA is adding warnings to the labels of sodium–glucose cotransporter-2 (SGLT2) inhibitors about increased risks of ketoacidosis and serious urinary tract infections associated with use of the drugs. Since 2013, FDA has received 73 reports of ketoacidosis and 19 reports of urosepsis or pyelonephritis in patients using SGLT2 inhibitors.

>>>PNN JournalWatch
* Stimulant Medications and Sleep for Youth With ADHD: A Meta-analysis, in
Pediatrics, 2015; 136: 1144–53. (K. M. Kidwell)
* Management of Alcohol Use Disorder in Patients Requiring Liver Transplant, in
American Journal of Psychiatry, 2015; 172: 1182–9. (M. R. Lee)
* The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association, in
Circulation, 2015; 132: 2167–92. (S. S. Gidding)
* Is Post-Graduate Training Essential for Practice Readiness?, in
Pharmacotherapy, 2015; 35: 10.1002/phar.1654. (D. Robinson, drobinson@westernu.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 © 2015, 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
Dec. 8, 2015 * Vol. 22, No. 234
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. issue of JAMA Internal Medicine (2015; 175).
Number & Timing of Pneumococcal Vaccines in Seniors: Two Viewpoint articles spar over recent recommendations of the CDC’s Advisory Committee on Immunization Practices (ACIP) concerning the sequential administration of the two available pneumococcal vaccines for older patients.
In June 2015, ACIP recommended that the newer pneumococcal conjugate vaccine 13 (PCV13) be administered first in adults 65 years or older who have not received either vaccine followed by the less expensive pneumococcal polysaccharide vaccine 23 (PPSV23) 12 or more months later, authors of the first article write (
pp. 1895–6). “In our view, a simpler and less costly way to reduce pneumococcal disease would be to improve systems to increase pneumococcal vaccination among children and adults (more than one-third of US adults ≥65 years have not received PPSV23),” the authors conclude. “Pneumococcal diseases remain an important health challenge. Health care professionals and public health officials should not lose sight of the most straightforward way to address this challenge.” The group is critical of the Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA), a Pfizer-sponsored comparison of PCV13 with placebo among patients in the Netherlands, where these authors note most patients do not routinely receive PPSV23 and herd immunity is thus low. (M. Hochman, meh1979@gmail.com)
A CDC official defends the decision by noting that ACIP has promised to review this recommendation in 2018 (after changes in herd immunity are known as a result of uptake of the 7-valent conjugate vaccine in the pediatric vaccine schedule) and that “evidence from the CAPITA trial suggests that widespread vaccination of older adults with the PCV-13 vaccine can prevent an important proportion of nonbacteremic pneumonias attributable to the pneumococcal types covered by the vaccine” (
pp. 1897–8). The author adds: “Pneumococcal morbidity has remained substantial among the elderly population even though most have received … PPSV-23. Diagnostic tests for pneumonia are relatively insensitive and nonspecific. Thus, it is difficult to evaluate the efficacy of pneumococcal vaccines against pneumonias that do not lead to detectable bloodstream infection.” (A. Schuchat, aschuchat@cdc.gov)
Treatment Deintensification in Older Patients With Diabetes: Clinicians are missing opportunities to reduce risks of medication harm in older patients with good glycemic and blood pressure (BP) control and decreased life expectancy, a study shows (pp. 1942–9). Retrospective cohort analysis of VA health system data for patients older than 70 years with diabetes show little relationship among control, life expectancy, and treatment deintensification: “The actively treated BP cohort included 211,667 participants, more than half of whom had moderately or very low BP levels. Of 104,486 patients with BP levels that were not low, treatment in 15.1% was deintensified. Of 25,955 patients with moderately low BP levels, treatment in 16.0% was deintensified. Among 81,226 patients with very low BP levels, 18.8% underwent BP medication deintensification. Of patients with very low BP levels whose treatment was not deintensified, only 0.2% had a follow-up BP measurement that was elevated (BP ≥140/90 mm Hg). The actively treated HbA1c cohort included 179,991 participants. Of 143,305 patients with HbA1c levels that were not low, treatment in 17.5% was deintensified. Of 23,769 patients with moderately low HbA1c levels, treatment in 20.9% was deintensified. Among 12,917 patients with very low HbA1c levels, 27.0% underwent medication deintensification. Of patients with very low HbA1c levels whose treatment was not deintensified, fewer than 0.8% had a follow-up HbA1c measurement that was elevated (≥7.5%).” (J. B. Sussman, jeremysu@med.umich.edu)

>>>PNN NewsWatch
* Awards were the order of the day at the 50th ASHP Midyear Clinical Meeting yesterday in New Orleans. The Best Practices Award in Health-System Pharmacy went to six pharmacy teams; Richard L. Lucarotti of Michigan received the Award for Distinguished Leadership in Health-System Pharmacy Practice, and Roberto Frontini of Leipzig, Germany, was honored with the 2015 Donald E. Francke Medal.

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 © 2015, 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
Dec. 9, 2015 * Vol. 22, No. 235
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 8 issue of JAMA, a theme issue on medical education (2015; 314).
Depression Among Resident Physicians: One of every four physician residents has clinical depression or symptoms of depression, according to a systematic review and meta-analysis of 54 studies that included 17,560 participants (pp. 2373–83). Prevalence reached nearly 16% within a year of starting residency training and increased with each calendar year, the authors report along with these details: “The overall pooled prevalence of depression or depressive symptoms was 28.8% (4,969/17,560 individuals, 95% CI, 25.3%–32.5%), with high between-study heterogeneity (Q = 1,247, 2 = 0.39, I2 = 95.8%, P < .001). Prevalence estimates ranged from 20.9% for the 9-item Patient Health Questionnaire with a cutoff of 10 or more (741/3,577 individuals, 95% CI, 17.5%–24.7%, Q = 14.4, 2 = 0.04, I2 = 79.2%) to 43.2% for the 2-item PRIME-MD (1,349/2,891 individuals, 95% CI, 37.6%–49.0%, Q = 45.6, 2 = 0.09, I2 = 84.6%). There was an increased prevalence with increasing calendar year (slope = 0.5% increase per year, adjusted for assessment modality; 95% CI, 0.03%–0.9%, P = .04). In a secondary analysis of 7 longitudinal studies, the median absolute increase in depressive symptoms with the onset of residency training was 15.8% (range, 0.3%–26.3%; relative risk, 4.5). No statistically significant differences were observed between cross-sectional vs longitudinal studies, studies of only interns vs only upper-level residents, or studies of nonsurgical vs both nonsurgical and surgical residents.” (D. A. Mata, dmata@bwh.harvard.edu)
Physician Training & High-Value, Cost-Conscious Care: With a goal of “educating physicians to deliver high-value, cost-conscious care,” educational interventions should combine “specific knowledge transmission, reflective practice, and a supportive environment,” according to a review of 79 studies, including 14 randomized controlled trials (pp. 2384–400): “The data analysis suggested that 3 factors aid successful learning: (1) effective transmission of knowledge, related, for example, to general health economics and prices of health services, to scientific evidence regarding guidelines and the benefits and harms of health care, and to patient preferences and personal values (67 articles); (2) facilitation of reflective practice, such as providing feedback or asking reflective questions regarding decisions related to laboratory ordering or prescribing to give trainees insight into their past and current behavior (56 articles); and (3) creation of a supportive environment in which the organization of the health care system, the presence of role models of delivering high-value, cost-conscious care, and a culture of high-value, cost-conscious care reinforce the desired training goals (27 articles).” (L. A. Stammen, l.stammen@maastrichtuniversity.nl)
Pedagogical Pimping in Medical Education: “Unless pimping generates a better evidence base and moves to the benign end of the spectrum, this art will become lost,” argue authors of a Viewpoint article (pp. 2347–8). The term is defined as “a series of difficult and often intentionally unanswerable questions posed to a medical student or house staff in quick succession,” the article notes. Without a better database to support efficacy of this pedagogy, the practice is at risk of falling “foul of political correctness,” the group notes. Increased “awareness of student mistreatment and malignant pimping” is needed—and is a “real threat” to pimping in teaching. (J. W. McEvoy, jmcevoy1@jhmi.edu)
“The secret in the care of students is to care for the students,” an editorialist responds (
pp. 2355–6). “More data and more creative innovations are always welcome, and yet [that] simple rule is already available to distinguish good pimping from bad, supportive educational practices from student mistreatment.” (D. R. Reifler, douglas.reifler@temple.edu)

>>>PNN NewsWatch
* Attendance topped 22,000 at the 50th edition of the ASHP Midyear Clinical Meeting. A special video celebrated the anniversary, and ASHP’s first CEO, Joseph A. Oddis, was honored at the opening session.
* The ASHP Foundation released the
Pharmacy Forecast 2016–2020 at a Midyear session on Tuesday. The report provides trend data in areas useful for strategic planning, including health care delivery and financing, population health management, drug development and therapeutics, and pharmacy workforce.

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 © 2015, 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
Dec. 10, 2015 * Vol. 22, No. 236
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 10 issue of the New England Journal of Medicine (2015; 373).
Mass Drug Administration for Scabies Control: In populations with endemic scabies and associated impetigo, mass drug administration is efficacious, researchers report (pp. 2305–13). Three island communities in Fiji were randomly assigned to standard care with permethrin used in affected individuals or mass administration of topical permethrin or oral ivermectin. Prevalence of scabies and impetigo at 12 months showed these patterns: “From baseline to 12 months, the prevalence of scabies declined significantly in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 36.6% to 18.8% in the standard-care group (relative reduction in prevalence, 49%; 95% confidence interval [CI], 37 to 60), from 41.7% to 15.8% in the permethrin group (relative reduction, 62%; 95% CI, 49 to 75), and from 32.1% to 1.9% in the ivermectin group (relative reduction, 94%; 95% CI, 83 to 100). The prevalence of impetigo also declined in all groups, with the greatest reduction seen in the ivermectin group. The prevalence declined from 21.4% to 14.6% in the standard-care group (relative reduction, 32%; 95% CI, 14 to 50), from 24.6% to 11.4% in the permethrin group (relative reduction, 54%; 95% CI, 35 to 73), and from 24.6% to 8.0% in the ivermectin group (relative reduction, 67%; 95% CI, 52 to 83). Adverse events were mild and were reported more frequently in the ivermectin group than in the permethrin group (15.6% vs. 6.8%).” (A. C. Steer, andrew.steer@rch.org.au)
Scabies-control programs “will depend on coordination with and integration into existing clinical and public health programs,” an editorialist concludes (
pp. 2371–2). “Although the administration of topical permethrin and oral ivermectin may have similar efficacy in individual persons with scabies, the practical aspects of oral therapy translate to superior effectiveness on a large scale. Unhatched scabies eggs are refractory to ivermectin. Approximately 7 to 14 days after the initial dose of ivermectin was administered, a second dose of ivermectin was given only to persons with clinical scabies, but the authors suggest that a more pragmatic approach may be to provide both doses to everyone in the community. The importance of this second dose in the mass administration of ivermectin for scabies control remains to be evaluated, as do the diagnostic and epidemiologic algorithms that determine when to initiate a program of mass drug administration, the time interval between interventions, and when to cease providing the interventions. Issues related to ivermectin use during pregnancy and in small children and the management of crusted scabies require further assessment. Scabies moves with people, and population mobility across regions must be factored into program delivery models to prevent rapid reintroduction of infection.” (B. J. Currie)
Isosorbide Mononitrate in Heart Failure: Compared with placebo, isosorbide mononitrate produced poor outcomes in patients with heart failure and preserved ejection fraction, a study shows, with less activity and similar quality of life and exercise capacity (pp. 2314–24). Among 110 patients, a 6-week escalation regimen of isosorbide mononitrate (30 to 60 to 120 mg once daily) or placebo produced these changes in a primary end point of daily activity level: “In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (−381 accelerometer units; 95% confidence interval [CI], −780 to 17; P = 0.06) and a significant decrease in hours of activity per day (−0.30 hours; 95% CI, −0.55 to −0.05; P = 0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (−439 accelerometer units; 95% CI, −792 to −86; P = 0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.” (M. M. Redfield, redfield.margaret@mayo.edu)

>>>PNN NewsWatch
* FDA this week has approved von Willebrand factor (recombinant) (Vonvendi, Baxalta) for use in adults with von Willebrand disease and sebelipase alfa (Kanuma, Alexion) for treatment of lysosomal acid lipase deficiency.

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 © 2015, 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
Dec. 11, 2015 * Vol. 22, No. 237
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
Dec. 8 issue of Circulation (2015; 132).
Multichannel Blockers for AF: Investigators report preclinical data supporting addition of potassium-channel blockade to sodium-channel blockade in management of atrial fibrillation (AF) (pp. 2203–11). Using mathematical models, optical mapping, and action potential recording, the group produced data that led to this conclusion: “K+-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na+-channel blockade. Combining optimized Na+-channel block with blockade of atrial K+ currents is a potentially valuable AF-selective antiarrhythmic drug strategy.” (S. Nattel, stanley.nattel@icm-mhi.org)
“We congratulate the authors on producing a sophisticated study that provides greater insight into combined Na and K channel inhibition as a potential mechanism for the effective treatment of AF, while minimizing the risks of proarrhythmia and toxicity,” editorialists write (
pp. 2195–7). “Their study demonstrates the importance of considering channel-binding properties of drugs to maximize atrial selectivity, and suggests that [ultrapid potassium current] block in conjunction with [sodium current] block, may be a particularly promising combination.” (P. R. Kowey, koweyp@mlhs.org)

>>>Chest Highlights
Source:
Dec. issue of Chest (2015; 148).
ACE Levels Ordered During ACE Inhibitor Therapy: At an academic medical center, clinicians frequently ordered serum angiotensin-converting enzyme (ACE) levels for patients taking ACE inhibitors (ACEIs), a study shows, but a point-of-care alert reduced such errors by more than 60% (pp. 1447–53). Records were reviewed retrospectively for a 54-month preintervention period and compared with a deidentified database from a national reference laboratory, with these results: “Over a 54-month period, 1,292 patients had ACE levels measured, with 108 patients (8.4%) receiving ACEI therapy at the time of testing. ACE levels measured for patients receiving ACEI therapy were substantially lower. In general, clinical teams did not recognize a medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced the ordering of ACE levels in patients receiving ACEIs by > 60% in a 17-month postintervention time period. The deidentified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using liquid chromatography time-of-flight mass spectrometry, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations.” (M. D. Krasowski, mkrasows@healthcare.uiowa.edu)
Asthma Biomarkers & Disease Control: In patients with high reversibility (HR) and low reversibility (LR) of bronchodilators, HR indicated reduced lung function and predicted elevations in T-helper 2 (Th2) biomarkers in those with moderate to severe asthma (pp. 1489–96). Investigators analyzed data retrospectively from two completed clinical trials by dividing patients into HR and LR subgroups and looking at a variety of biomarkers. “The majority of patients with HR and LR asthma in this analysis had a Th2-low biomarker profile,” the group concludes. “Moreover, a Th2-high biomarker profile was not associated with worse disease control,” they add, based on these findings: “The majority of patients in the HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarker profiles (40.1% vs 29.4%, P = .006), lower lung function (FEV1, 63.5 ± 7.7% predicted vs 67.9 ± 8.4% predicted; P < .001), and atopy (93.7% vs 86.5%, P = .005).” (E. P. Ingenito, ingenito@amgen.com)

>>>PNN NewsWatch
* In remarks submitted for the record during this week’s Senate Special Committee on Aging hearing on generic drug prices, ASHP urged consideration of policy options to ensure medication accessibility for patients and thereby avoid “serious public health consequences.” ASHP wrote that it was “eager to learn about why these price spikes are occurring and … explore potential policy options and market-based solutions that may exist to minimize the likelihood of this occurring in the future.”

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 © 2015, 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
Dec. 14, 2015 * Vol. 22, No. 238
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 12 issue of Lancet (2015; 386).
Aripiprazole for Treatment-Resistant Depression in Late Life: In adults aged 60 years or older, addition of aripriprazole enabled remission in treatment-resistant depression, researchers report (pp. 2404–12). At U.S. and Canadian centers, 181 study participants who did not respond to pretrial venlafaxine therapy were randomly assigned to aripiprazole or placebo, with these results: “A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2.0 [95% CI 1.1–3.7], p = 0.03; number needed to treat [NNT] 6.6 [95% CI 3.5–81.8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.” (E. J. Lenze, lenzee@psychiatry.wustl.edu)
Revised Polio Vaccine Schedule: A new vaccination schedule tested in India improved “immunogenicity against polioviruses, especially against poliovirus type 3,” a study shows (pp. 2413–21). Investigators tested three or four doses of bivalent type 1 and type 3 oral poliovirus vaccine (bOPV) with or without one dose of inactivated poliovirus vaccine (IPV) in 900 newborn babies. Immunogenicity findings showed the following: “Superiority was achieved for vaccine regimens including IPV against poliovirus type 3 compared with those not including IPV (tOPV plus IPV vs tOPV alone, p = 0.0008; and bOPV plus IPV vs bOPV alone, p = 0.0153). 12 serious adverse events occurred (six in the tOPV group, one in the tOPV plus IPV group, three in the bOPV group, zero in the bOPV plus IPV group, and two in the bOPV plus 2IPV group), none of which was attributed to the trial intervention.” (R. W. Sutter, sutterr@who.int)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2015; 351).
LAIV in Egg Allergy: Among children and adolescents (aged 2–18 years) with egg allergy, immunization with live attenuated influenza vaccine (LAIV) produced few systemic reactions in a Phase IV trial in the U.K. (h6291). Patients with well controlled asthma or recurrent wheeze were similarly unaffected by LAIV administration, the authors add. (P. J. Turner, p.turner@imperial.ac.uk)
A1C Overtesting & Related Overtreatment of Type 2 Diabetes: Among U.S. adults with well controlled type 2 diabetes whose records were in a national database, 61% had excessive A1C tests, and these led to overtreatment with oral hypoglycemic drugs and insulin, investigators conclude (h6138): “Despite good glycemic control at baseline, treatment was further intensified by addition of glucose lowering drugs or insulin in 8.4% of patients (comprising 13%, 9%, and 7% of those tested excessively, frequently, and per guidelines, respectively; P <0.001). Compared with guideline recommended testing, excessive testing was associated with treatment intensification (odds ratio 1.35 (95% confidence interval 1.22 to 1.50)).” (R. G. McCoy, mccoy.rozalina@mayo.edu)

>>>PNN NewsWatch
* FDA on Friday approved alectinib (Alecensa, Genentech) for treatment of advanced (metastatic) ALK-positive nonsmall cell lung cancer resistant to therapy with crizotinib and uridine triacetate (Vistogard, Wellstat Therapeutics Corp.) for emergency treatment of adults and children who receive an overdose of fluorouracil or capecitabine or who develop certain severe or life-threatening toxicities within 4 days of receiving these agents.

>>>PNN JournalWatch
* Comparative Benefits and Harms of Second Generation Antidepressants and Cognitive Behavioral Therapies in Initial Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis, in
BMJ, 2015; 351: h6019. (H. R. Amick, amick@med.unc.edu)
* Cardio-Oncology: How New Targeted Cancer Therapies and Precision Medicine Can Inform Cardiovascular Discovery, in
Circulation, 2015; 132: 2248–58. (J. J. Moslehi, javid.moslehi@vanderbilt.edu)
* Rhinovirus in the Pathogenesis and Clinical Course of Asthma, in
Chest, 2015; 148: 1508–16. (D. Proud, dproud@ucalgary.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 © 2015, 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
Dec. 15, 2015 * Vol. 22, No. 239
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 15 issue of the Annals of Internal Medicine (2015; 163).
4-Week HCV Regimens: Four weeks of therapy for chronic hepatitis C virus (HCV) genotype 1 infection with direct-acting antivirals (DAAs) produced “limited cure rates,” researchers report (pp. 899–907). In an open-label, Phase IIa trial, 50 treatment-naive and predominantly black patients with HCV genotype 1 infection and early-stage liver fibrosis sequentially received ledipasvir and sofosbuvir plus GS-9451 for 4 weeks or ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. Sustained virologic response (SVR) at week 12 showed these patterns: “Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up.” (S. Kottilil, SKottilil@ihv.umaryland.edu)
HIV Salvage Therapy Without NRTIs: Among treatment-experienced patients with HIV infection and viral resistance, “a new optimized regimen can safely omit [nucleoside reverse transcriptase inhibitors (NRTIs)] without compromising virologic efficacy,” a study finds (pp. 908–17). “Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population,” the authors conclude based on these open-label results from 360 participants at outpatient HIV clinics: “The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, −6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group.” (K. T. Tashima, ktashima@lifespan.org)
Preexposure Prophylaxis for HIV Prevention: In a Beyond the Guidelines article, experts debate the need for preexposure prophylaxis (PrEP) for preventing HIV infection in a discordant couple (pp. 941–8): “The guidelines, based on randomized trials showing substantial reduction in HIV transmission among those receiving a daily combination of tenofovir and emtricitabine, suggest physicians offer PrEP to patients at high risk, including nonmonogamous men who have sex with men, serodiscordant couples (in both male–male and male–female relationships), heterosexual men and women in other risk groups (such as sex workers or those with recent sexually transmitted infection), and injection drug users. Here, 2 prominent HIV experts debate the use of PrEP in a 45-year-old man whose husband has HIV infection with an undetectable viral load on treatment. They discuss the patient’s risk for HIV transmission from his husband and from other partners, the magnitude of the risk reduction he would gain with PrEP, and nonpharmacologic alternatives to reduce his likelihood of contracting HIV infection.” (E. E. Reynolds, ereynold@bidmc.harvard.edu)
Lactation & Diabetes: In a 2-year study of type 2 diabetes mellitus (DM) after gestational diabetes mellitus (GDM) pregnancy, investigators find that lactation may be preventive (pp. 889–98). The effect was stronger with higher lactation intensity and longer duration, according to the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy, which showed the following in 959 women: “There were graded inverse associations for lactation intensity at baseline with incident DM and adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding, respectively (P trend = 0.016). Time-dependent lactation duration showed graded inverse associations with incident DM and adjusted hazard ratios of 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months, respectively, versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios.” (E. P. Gunderson, Erica.Gunderson@.kp.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 © 2015, 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
Dec. 16, 2015 * Vol. 22, No. 240
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 15 issue of JAMA (2015; 314).
Treatment of Glioblastoma: An interim analysis indicates efficacy of an electrical device in treatment of glioblastoma following completion of standard chemoradiation therapy (pp. 2535–43). “Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly,” authors write. Randomized to maintenance treatment with either TTFields plus temozolomide or temozolomide alone, 315 patients had these outcomes: “The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18–60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9–8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3–5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43–0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7–25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3–19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42–0.98]; P = .004).” (R. Stupp, roger.stupp@usz.ch)
Why an intervention of this type would work remains unclear, an editorialist writes, but given the lack of successful treatments for glioblastoma, medical researchers should make it a priority to look into this possibility (
pp. 2511–3): “The TTFields device produces locally delivered [alternating electric field] that are purported to arrest mitosis in tumor cells deep inside the brain. The mechanisms whereby this novel approach can treat tumors and leverage chemotherapy, however, remain unclear. Given the survival benefit reported in this study, it should now be a priority to understand the scientific basis for the efficacy of TTFields; achieving this may require the development of robust and widely available large animal models for glioblastoma, which do not currently exist. Perhaps most concerning, because of the study design chosen, doubts may remain as to the true efficacy of this therapy. So, if TTFields therapy fails to be adopted, will this decision be attributed to professional parochialism or to data that are not trusted? The current study provides additional important data on a novel device for the treatment of glioblastoma, but it will not completely resolve that debate.” (J. H. Sampson, john.sampson@duke.edu)

>>>Oncology Report
Source:
Dec. 10 issue of the Journal of Clinical Oncology (2015; 33).
Short-Course Radiation Therapy for Glioblastoma: In older and/or frail patients with newly diagnosed glioblastoma, a 1-week radiotherapy regimen (5 doses; arm 1) produced similar outcomes as a 3-week regimen (15 doses; arm 2), researchers report (pp. 4145–50). Given the similar results, the short course “may be recommended” for such patients, the group concludes based on these results: “The short-course radiotherapy was noninferior to commonly used radiotherapy. The median overall survival time was 7.9 months (95% CI, 6.3 to 9.6 months) in arm 1 and 6.4 months (95% CI, 5.1 to 7.6 months) in arm 2 (P = .988). Median progression-free survival time was 4.2 months (95% CI, 2.5 to 5.9) in arm 1 and 4.2 months (95% CI, 2.6 to 5.7) in arm B (P = .716). With a median follow-up time of 6.3 months, the quality of life between both arms at 4 weeks after treatment and 8 weeks after treatment was not different.” (W. Roa, wilson.roa@albertahealthservices.ca)
Based on these findings, “one and done” is a reasonable option in older and frail patients, a group that has “the worst prognoses for a disease with an already poor prognosis,” an editorialist writes (
pp. 4129–30). Shorter courses “will facilitate the integration of radiation therapy into the management of these patients, and the rapid completion of radiotherapy should permit the rapid introduction of systemic therapy to perhaps avoid potential cytopenias and immunological dysfunctions associated with protracted courses of combined modality treatment.” (J. P. S. Knisely, jknisely@nshs.edu)

>>>PNN NewsWatch
* FDA yesterday approved sugammadex (Bridion, Merck) injection to reverse the effects of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide.

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 © 2015, 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
Dec. 17, 2015 * Vol. 22, No. 241
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 17 issue of the New England Journal of Medicine (2015; 373).
Andexanet Alfa for Reversing Factor Xa Inhibitor Activity: In healthy older volunteers, andexanet alfa reversed factor Xa inhibitor activity “within minutes after [intravenous] administration and for the duration of the infusion,” researchers of two trials report (pp. 2413–24). Based on a primary outcome of the mean percent change in anti–factor Xa activity, ANNEXA-A and ANNEXA-R investigators report these results for participants taking apixaban 5 mg twice daily or rivaroxaban 20 mg daily: “Among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P <0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P <0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P <0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti–factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P <0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P <0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P <0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.” (D. M. Siegal)
A “real world” Phase IIIb–IV study that uses the same dosing strategies as these studies is under way, an editorialist writes, and it should provide useful guidance in practice about this antidote (
pp. 2471–2): “Even if the concentration of anticoagulant in plasma could be measured immediately and the precise required dose of andexanet could be calculated for each anticoagulant, it is unknown whether andexanet use would improve outcomes for patients with major bleeding. Additional studies will be needed to optimize the use of andexanet and to determine its true efficacy and safety. Despite these current limitations in knowledge, andexanet represents a giant step forward in our ability to control anticoagulation therapy.” (J. M. Connors)
First-Line Ibrutinib for Chronic Lymphocytic Leukemia: Compared with chlorambucil in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, ibrutinib was superior for improving progression-free survival, overall survival, response rate, and hematologic variables, a study shows (pp. 2425–37). A total of 269 previously untreated patients aged 65 or older had these outcomes with ibrutinib or chlorambucil during a median of 18.4 months of follow-up: “Ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P <0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P = 0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P <0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib.…” (J. A. Burger, jaburger@mdanderson.org)

>>>PNN NewsWatch
* FDA yesterday approved the first follow-on insulin glargine product, Basaglar (Lilly). The product was tentatively approved in Aug. 2014 and has now been granted final approval. In a news release, FDA explained that Basaglar is not technically a biosimilar product: “No insulin glargine products are currently licensed under the Public Health Service Act, so there is no ‘reference product’ for a proposed biosimilar product.” However, FDA also said that the 505(b)(2) abbreviated application for Basaglar “relied, in part, on the FDA’s finding of safety and effectiveness for Lantus (insulin glargine injection) to support approval.”

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 © 2015, 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
Dec. 18, 2015 * Vol. 22, No. 242
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Jan. 1 issue of Clinical Infectious Diseases (2016; 62).
Salvage Therapy in HCV Genotype 1 Infection: In the C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy), patients infected with hepatitis C virus (HCV) genotype 1 with or without cirrhosis responded to 12 weeks of grazoprevir/elbasvir plus ribavirin therapy, researchers report, with viral suppression for at least 24 weeks after the completion of treatment (pp. 32–6). However, the authors note, “Baseline resistance-associated variants (RAVs) stably reappeared at relapse in all 3 patients with virologic failure. NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor.” Based on sustained virologic response at 24 weeks after therapy stopped (SVR24), the investigators found: “SVR24 rates were 76 of 79 (96.2%) overall, with all 3 relapses occurring by posttherapy week 8. Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period. NS3_A156T emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients. NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period.” (M. Buti, mbuti@vhebron.net)
MRSA Infection Risk Factors After Hospitalization: Prevention of methicillin-resistant Staphylococcus aureus (MRSA) infections after hospital discharge is needed in patients with certain risk factors, a study shows, including those with MRSA colonization, invasive devices, or chronic wounds at hospital discharge, and those discharged to nursing homes, according to results of a case–control study (pp. 45–52). Review of records of 194 case patients and 388 matched control patients at 15 hospitals showed the following risk patterns: “The median time between hospital discharge and positive culture was 23 days (range, 1–83 days). Factors independently associated with postdischarge MRSA infection included MRSA colonization (matched odds ratio [mOR], 7.71; 95% confidence interval [CI], 3.60–16.51), discharge to a nursing home (mOR, 2.65; 95% CI, 1.41–4.99), presence of a chronic wound during the postdischarge period (mOR, 4.41; 95% CI, 2.14–9.09), and discharge with a central venous catheter (mOR, 2.16; 95% CI, 1.13–4.99) or a different invasive device (mOR, 3.03; 95% CI, 1.24–7.39) in place.” (L. Epstein, xdd0@cdc.gov)
Short-Course TB Therapy: Health officials in New York City had better success with therapy completion in patients with tuberculosis infection (TBI) when a 3-month course of drugs was used with directly observed therapy (DOT) than with older 9-month regimens (pp. 53–9). In the first 11 months of 2013, these results were noted for 3 months of once-weekly isoniazid and rifapentine (3HP) administered under DOT: “Among 631 patients eligible for TBI treatment, 503 (80%) were offered 3HP; 302 (60%) accepted, 92 (18%) chose other treatment, and 109 (22%) refused treatment. The most common reason for refusing 3HP was the clinic-based DOT requirement. Forty (13%) patients treated with 3HP experienced side effects—9 were restarted on 3HP, 18 switched treatment regimens, and 13 discontinued. Although treatment acceptance did not differ from historical estimates (78% vs 79%, P = .75), treatment completion increased significantly (65% vs 34%, P < .01).” (N. L. Stennis, nlevy@health.nyc.gov)

>>>Allergy/Immunology Report
Source:
Dec. issue of the Journal of Allergy and Clinical Immunology (2015; 136).
Preventing Asthma & Exacerbations: Two research studies examine ways of preventing asthma and its exacerbations.
Short-term omalizumab in inner-city youth prevented asthma exacerbations upon return to school, “particularly among those with a recent exacerbation,” according to a comparison of the drug with an inhaled corticosteroid burst (
pp. 1476–85; S. J. Teach, steach@childrensnational.org)
A second study reports positive effects of allergy immunotherapy in preventing progression of allergic rhinitis to asthma among patients included in the German national health insurance database (
pp. 1511–6; J. Schmitt, jochen.schmitt@uniklinikum-dresden.de)

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 © 2015, 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
Dec. 21, 2015 * Vol. 22, No. 243
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 19 issue of Lancet (2015; 386).
Tight Control of Early Psoriatic Arthritis: “Tight control of psoriatic arthritis disease activity through a treat-to-target approach significantly improves joint outcomes for newly diagnosed patients, with no unexpected serious adverse events reported,” conclude TICOPA trial investigators (pp. 2489–968). The open-label study of 206 adults with psoriatic arthritis of less than 24 months’ symptom duration used random assignment to tight control or standard care and a primary outcome of proportion of patients achieving American College of Rheumatology (ACR) 20% (ACR20) response at week 48: “In the intention-to-treat patient population, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control group than in the standard care group (odds ratio 1.91, 95% CI 1.03–3.55; p = 0.0392). Serious adverse events were reported by 20 (10%) patients (25 events in 14 [14%] patients in the tight control group and eight events in six [6%] patients in the standard care group) during the course of the study. No unexpected serious adverse events or deaths occurred.” (P. S. Helliwell, p.helliwell@leeds.ac.uk)
Erythropoietin in Traumatic Brain Injury: Potential neurocytoprotective effects of erythropoietin in traumatic brain injury remain unclear based on equivocal results in a study of the drug in 596 patients with moderate to severe cases (pp. 2499–506). In the Erythropoietin in Traumatic Brain Injury (EPO-TBI) study, the agent produced these changes in an efficacy outcome of proportion of patients with an Extended Glasgow Outcome Scale (GOS-E) of 1–4 (death, vegetative state, and severe disability) and adverse effects: “Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS-E level of 1–4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0.99 [95% CI 0.83–1.18], p = 0.90). In terms of safety, erythropoietin did not significantly affect 6-month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0.68 [95% CI 0.44–1.03], p = 0.07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0.87 [95% CI 0.61–1.24], p = 0.44).” (C. French, mcraig.french@wh.org.au)

>>>BMJ Highlights
Source:
Early-release article from the annual Christmas issue of BMJ (2015; 351).
Horror Movies Can Curdle the Blood: Watching a frightening movie is associated with an increase in factor VIII without actual thrombin formation, conclude authors of an investigation of “whether, as has been hypothesised since medieval times, acute fear can curdle blood” (h6367). Young healthy volunteers watched two movies in crossover fashion, one a horror movie and the other an educational film, with these results based on analysis of blood coagulation factors: “The horror movie was perceived to be more frightening than the educational movie on a visual analogue fear scale (mean difference 5.4, 95% confidence interval 4.7 to 6.1). The difference in factor VIII levels before and after watching the movies was higher for the horror movie than for the educational movie (mean difference of differences 11.1 IU/dL (111 IU/L), 95% confidence interval 1.2 to 21.0 IU/dL). The effect of either movie on levels of thrombin-antithrombin complexes, D-dimer, and prothrombin fragments 1+2 did not differ.” (F. R. Rosendaal, f.r.rosendaal@lumc.nl)

>>>PNN JournalWatch
* The Critical Role of the Staff Nurse in Antimicrobial Stewardship—Unrecognized, but Already There, in
Clinical Infectious Diseases, 2016; 62: 84–9. (R. N. Olans, rolans@hallmarkhealth.org)
* Vemurafenib-Induced Disseminated Intravascular Coagulation in Metastatic Melanoma, in
Journal of Clinical Oncology, 2015; 33: e133–4. (G. A.P. Hospers, g.a.p.hospers@umcg.nl)
* Drivers of Chronic Rhinosinusitis: Inflammation Versus Infection, in
Journal of Allergy and Clinical Immunology, 2015; 136: 1454–9. (D. L. Hamilos, dhamilos@partners.org)
* Olfaction in Allergic Rhinitis: A Systematic Review, in
Journal of Allergy and Clinical Immunology, 2015; 136: 1460–70. (B. A. Stuck, boris.stuck@uk-essen.de)
* Check It Out: A Practical Tool for Improving Medication Safety, in
Journal of the American Pharmacists Association, 2015; 55: 621–5. (T. Warholak, warholak@pharmacy.arizona.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 © 2015, 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
Dec. 22, 2015 * Vol. 22, No. 244
Providing news and information about medications and their proper use

>>>Medical Care Report
Source:
Jan. issue of Medical Care (2016; 54).
Putting the ‘Patient’ in Patient-Centered Medical Homes: Problems in the implementation of patient-centered medical homes (PCMHs) are explored in several articles.
Emerging care models emphasize placing the patient at the center of care in partnership with a primary care provider who coordinates care, yet this model varies from what some patients want, writes a Special Commentary author (
pp. 3–4): “Patients may prefer to have their health assessed and supervised by a provider other than that physician, as evidenced by research demonstrating that patients prefer to have specialists address certain health conditions that could be addressed by primary care physicians and that some patients visit specialists for primary care. Remarkably, the literature is largely silent as to whether patients prefer to rely on a single or multiple providers for their diverse health care needs, what types of providers they prefer, and why. I contend that making progress in providing truly patient-centered care requires understanding the definitions of ‘usual’ and ‘[principal]’ health care provider used by patients vis-à-vis those used by providers and health systems.” (M. L. Stransky, michelle.stransky@unh.edu)
Health disparities are not being addressed sufficiently in PCMHs, yet their design has important implications, researchers report (
pp. 9–16). Interviews of key providers and administrators at six PCMHs and three health policy experts yielded these findings: “We find that disparities are not an explicit priority in PCMH initiatives. Nevertheless, many policymakers, providers, and initiative leaders believe that the model has the potential to reduce disparities. However, because of the funding structure of initiatives and the lack of adjustment of quality metrics, health policy experts do not share this optimism and safety-net providers report concerns and frustration.” (N. Reibling, reibling@soziologie.uni-siegen.de)

Reacting to these articles and an additional Special Commentary on chronic critical illness care (
pp. 5–8; N. A. Boucher, nathan.boucher@duke.edu), an editorialist writes (pp. 1–2): “Thus far, we have been discussing the role of the provider and health system in the patient-centered medical home, but patient-centered care is supposed to incorporate the patient’s perspective in the care received and the care processes by which it is delivered. So where has the patient been in the overall effort to implement a health care delivery system based on the concept of the patient-centered medical home? It appears that the patient may not have been consulted at all.…
“Hopefully, these special commentaries will stimulate the health services research community to more aggressively align its research agenda to provide evidence by which we can personalize not only the content of health care but its delivery as well. The expectation is that by personalizing health care we achieve the goal of improved health. It is an unproven but testable hypothesis.” (R. D. Horner,
hornerrd@mailbox.sc.edu)

>>>Health Affairs Highlights
Source:
Dec. issue of Health Affairs, a theme issue on “Affordability, Access, Models of Care & More” (2015; 34).
Direct Primary Care: Sometimes called “concierge care for the masses,” direct primary care “appears to be gaining traction,” according to a news report (pp. 2016–9). “For a monthly fee, generally $25 to $85, patients can get all of their primary care covered—from an annual physical to treatment for various maladies and screening tests—with little or nothing more out of pocket,” the author writes. “Neither the doctor nor the patient bills an insurer. However, direct primary care practices encourage patients to carry some kind of coverage for big-ticket items such as surgeries and cancer treatment.” (C. Huff, charlotte@charlottehuff.com)
EHR Adoption by Hospitals: Three-quarters of U.S. hospitals had at least basic electronic health record (EHR) systems in 2014, researchers report based on analysis of 2008–14 data (pp. 2174–80). More hospitals are meeting core stage 2 meaningful-use criteria (40.5% versus 5.8% in 2013), primarily the result of hospitals being able to exchange information with patients and physicians during care transitions. (J. Adler-Milstein, juliaam@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 © 2015, 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
Dec. 23, 2015 * Vol. 22, No. 245
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 22/29 issue of JAMA (2015; 314).
Ovarian Suppression With Triptorelin: Ovarian function recovered more frequently in premenopausal women when the luteinizing hormone–releasing hormone analogue (LHRHa) triptorelin was used with chemotherapy for treatment of hormone receptor–positive or –negative breast cancer, researchers report (pp. 2632–40). Among 281 premenopausal women with stage I to III disease in a Phase III, open-label superiority trial, these results were found for those randomized to adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group): “Median follow-up was 7.3 years (interquartile range, 6.3–8.2 years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% CI, 65.7%–80.3%) among the 148 patients in the LHRHa group and 64.0% (95% CI, 56.2%–72.8%) among the 133 patients in the control group (hazard ratio [HR], 1.28 [95% CI, 0.98–1.68]; P = .07; age-adjusted HR, 1.48 [95% CI, 1.12–1.95]; P = .006). Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1% [95% CI, 0.7%–6.3%]) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6% [95% CI, 0.4%–6.2%]) in the control group (HR, 2.56 [95% CI, 0.68–9.60]; P = .14; age-adjusted HR, 2.40 [95% CI, 0.62–9.22]; P = .20). Five-year [disease-free survival] was 80.5% (95% CI, 73.1%–86.1%) in the LHRHa group and 83.7% (95% CI, 76.1%–89.1%) in the control group (LHRHa vs control: HR, 1.17 [95% CI, 0.72–1.92]; P = .52).” (L. Del Mastro, lucia.delmastro@hsanmartino.it)
This report “adds long-term follow-up information to the growing literature regarding the use of LHRHa through chemotherapy for the prevention of premature menopause, a desired outcome for some patients for prevention of associated menopausal symptoms and adverse health effects,” writes an editorialist (
pp. 2625–7). “Although the findings suggest modest benefits regarding the potential prevention of treatment-associated infertility, collectively these studies reflect the emerging importance of understanding and improving such critical quality-of-life issues, offering patients new treatment and supportive care options, and ultimately providing hope regarding an issue that is highly valued by many young patients diagnosed with cancer.” (A. H. Partridge, ahpartridge@partners.org)
Opioids v. NSAIDs in Malignant Pleural Effusion: In patients with malignant pleural effusion, NSAIDs performed similarly to opioids for pain control, a Phase III study shows, but required more rescue medications (pp. 2641–53). The 2 × 2 factorial design trial of 320 patients requiring pleurodesis showed these outcomes with NSAIDs or opioids and larger (24F) or smaller (12F) chest tubes: “Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, −1.5 mm; 95% CI, −5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3–3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, −3%; 1-sided 95% CI, −10% to ; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, −6.0 mm; 95% CI, −11.7 to −0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, −6%; 1-sided 95% CI, −20% to ; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20).” (N. M. Rahman, najib.rahman@ndm.ox.ac.uk)

>>>PNN NewsWatch
* FDA has approved selexipag (Uptravi, Actelion) for treatment of adults with pulmonary arterial hypertension. The oral IP prostacyclin receptor agonist has been designated as an orphan drug.
*
FDA yesterday approved a xanthine oxidase inhibitor, lesinurad (Zurampic, AstraZeneca), for treatment of high uric acid levels associated with gout.
*
PNN will not be published on Thurs. and Fri., Dec. 24 and 25, Christmas Eve and 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 © 2015, 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
Dec. 28, 2015 * Vol. 22, No. 246
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 24 issue of the New England Journal of Medicine (2015; 373).
Treatment of Urogenital Chlamydia: Azithromycin and doxycycline were similarly effective in a study of patients with urogenital Chlamydia trachomatis infection, researchers report (pp. 2512–21). Despite recent concerns about the efficacy of azithromycin in this setting, noninferiority of the drug was not established in a comparison of the two drugs: “Among the 567 participants enrolled, 284 were randomly assigned to receive azithromycin, and 283 were randomly assigned to receive doxycycline. A total of 155 participants in each treatment group (65% male) made up the per-protocol population. There were no treatment failures in the doxycycline group. In the azithromycin group, treatment failure occurred in 5 participants (3.2%; 95% confidence interval, 0.4 to 7.4%). The observed difference in failure rates between the treatment groups was 3.2 percentage points, with an upper boundary of the 90% confidence interval of 5.9 percentage points, which exceeded the prespecified absolute 5-percentage-point cutoff for establishing the noninferiority of azithromycin.” (W. M. Geisler, wgeisler@uab.edu)
“It does not seem reasonable to recommend doxycycline over azithromycin as the preferred regimen for chlamydia treatment,” conclude editorialists after citing several caveats (
pp. 2573–5). “Because of the limitations of the study, particularly with regard to the directly observed administration of doxycycline, and because of the finding of very high efficacy (97% and 100%) for both treatments, we believe that the current CDC recommendation that either drug be used in the treatment of persons with chlamydia infection seems appropriate and remains valid. In populations in which adherence can be monitored and ensured, a 7-day course of doxycycline might be the preferred choice. In settings in which adherence is questionable, a single oral 1-g dose of azithromycin still remains an excellent option, for the ease of its use and administration.” (T. C. Quinn)
Secukinumab in Ankylosing Spondylitis: The anti–interleukin-17A monoclonal antibody secukinumab, dosed subcutaneously at 150 mg after a loading dose, significantly reduced symptoms of ankylosing spondylitis at week 16 in a comparison with placebo in two Phase III trials (pp. 2534–48). In MEASURE 1 and 2, these results were reported based on a primary end point of proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria: “In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P <0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P <0.001 for the 150-mg dose and P = 0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.” (D. Baeten, d.l.baeten@amc.uva.nl)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Treatment of Uncomplicated UTIs in Women: German women with uncomplicated urinary tract infections (UTIs) treated with ibuprofen “received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis,” compared with fosfomycin, a study shows (h6544; I. Gágyor, igagyor@gwdg.de)

>>>PNN JournalWatch
* Second Cancer Risk Up to 40 Years After Treatment for Hodgkin’s Lymphoma, in
New England Journal of Medicine, 2015; 373: 2499–511. (F. E. van Leeuwen, f.v.leeuwen@nki.nl)
* Standards of Medical Care in Diabetes, in
Diabetes Care, 2016; 39 (suppl 1).
* 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis, in
Arthritis & Rheumatology, 2016; 68: 1–26. (J. A. Singh, Jasvinder.md@gmail.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 © 2015, 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
Dec. 29, 2015 * Vol. 22, No. 247
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2015; 163).
Opioid Prescribing After Overdose: Among 2,848 adults in a commercial insurer database who had nonfatal overdoses of prescription opioid products in 2000–12, 91% continued to receive prescriptions for the drugs and 17% of those on high doses had repeat overdoses within 2 years, a study shows (10.7326/M15-0038): “Over a median follow-up of 299 days, opioids were dispensed to 91% of patients after an overdose. Seven percent of patients (n = 212) had a repeated opioid overdose. At 2 years, the cumulative incidence of repeated overdose was 17% (95% CI, 14% to 20%) for patients receiving high dosages of opioids after the index overdose, 15% (CI, 10% to 21%) for those receiving moderate dosages, 9% (CI, 6% to 14%) for those receiving low dosages, and 8% (CI, 6% to 11%) for those receiving no opioids.” (M. R. Larochelle, marc.larochelle@bmc.org)
An editorialist notes that opioid doses were often lowered following the index overdose and suggests ways “to build on moments like these” (
10.7326/M15-2687): “First, clinicians need to know when their patients overdose. These authors suggest several ways to facilitate that communication, most notably by building on existing state prescription monitoring programs. Second, once prescribers are aware that their patients have overdosed, they need sufficient knowledge and support to act on that information. For instance, prescribers need to know how to taper opioid dosages appropriately, how to use and prescribe buprenorphine, and what other resources can be reliably called on to help patients who demand opioids that their providers believe will do more harm than good.” (J. Gregg, jessica.gregg@ccconcern.org)

>>>Diabetes Report
Source:
Jan. issue of Diabetes Care (2016; 39).
Insulin Resistance & Testosterone Replacement in Diabetes: In men with type 2 diabetes, testosterone replacement therapy for hypogonadotropic hypogonadism (HH) improved insulin sensitivity, lean mass, and subcutaneous fat, researchers report (pp. 82–91). Among 50 men who were eugonadal and 44 men with HH, biweekly I.M. testosterone 250 mg or placebo for 24 weeks produced these results: “Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. [Glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp] was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (−3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P <0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-beta, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1-beta, tumor necrosis factor-alpha, and leptin (P < 0.05 for all).” (P. Dandona, pdandona@kaleidahealth.org)
Basal Insulins in Type 2 Diabetes: Efficacy results with basal insulin peglispro (BIL) were superior to those of insulin glargine in 466 patients with type 2 diabetes (pp. 92–100): “At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (−0.82% [−8.9 mmol/mol] vs. −0.29% [−3.2 mmol/mol]; least squares mean difference −0.52%, 95% CI −0.67 to −0.38 [−5.7 mmol/mol, 95% CI −7.3 to −4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content, assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks.” (A. M. Chang, chang_anne_m@lilly.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 © 2015, 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
Dec. 30, 2015 * Vol. 22, No. 248
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (2015; 35).
Pharmaceutical Care of Transgender Patients: Individuals who are transgender or transsexual have a number of drug-related clinical and psychosocial issues that should be considered by pharmacists, the author of a review article concludes (pp. 1130–9): “Transgender individuals are at an increased risk of tobacco, alcohol, and substance abuse; they have an increased lifetime suicide attempt risk; and they are more likely to experience significant stressors in their lives. Transgender patients may elect to transition their appearance to the gender with which they identify. Hormone treatment (and possibly sex reassignment surgery) is a significant part of this transition, and pharmacists must understand the pharmacotherapeutic principles involved so they can better recommend therapeutic agents, provide dosing recommendations, and anticipate and manage adverse effects. It is critical to be culturally sensitive when providing care for transgender patients including using their preferred gender identity, preferred names, and preferred pronouns. It is also essential to be able to identify transgender and transsexual patients correctly within electronic health records to ensure that appropriate care and monitoring are provided. For pharmacists, this means they should know the biologic sex for performing calculations such as creatinine clearance and to prevent teratogenic agents from reaching a transgender or transsexual man who could be pregnant or is capable of becoming pregnant. Promoting knowledge of transgender health issues will enable pharmacists to provide better, more holistic care to their transgender patients.” (B. M. Bishop, Bryan.Bishop2@utoledo.edu)
Practice Readiness of Pharmacy Graduates: While new ACPE standards for the PharmD degree “appear to reflect the input received [at a summit]” regarding practice readiness of graduates, an editorialist questions whether assessment of this competency is possible given the “variation in expectations of practice-ready that include many job functions that are not [direct patient care (DPC)]” (pp. 1091–5). “My bias is that the mission of colleges and schools of pharmacy should be to prepare students to succeed in their residency programs and careers and to begin their preparation for specialty certification as appropriate. Because the supply of residency programs is currently inadequate relative to the need, colleges and schools must dramatically step up their participation in residency training and in helping create high-quality residency programs at their affiliated sites.… I do not consider that to be an immediate problem because the bulk of pharmacy work today is still focused on the provision of medications rather than DPC, and the payment systems do not reward pharmacist provision of DPC.…” (J. E. Murphy, murphy@pharmacy.arizona.edu)
Writing in response, editorialists maintain assessment can be accomplished by addition of a skills component to the NAPLEX or another high-stakes, prelicensure examination (
pp. 1096–9): “Internal division over the adequacy of PharmD training is detrimental to the advancement of pharmacy as a profession and, more importantly, potentially undermines our ability to meet burgeoning health care needs in this country. We need to pull together as a profession to support provider status legislation locally and nationally to ensure compensation for direct patient care services and remove barriers to health information access, thus improving patient access to pharmacist-provided care.…” (D. Robinson, drobinson@westernu.edu)

>>>Geriatrics Highlights
Source:
Dec. Journal of the American Geriatrics Society (2015; 63).
Chronic Care Model for Frail Older Adults: Compared with usual care of frail older adults in primary care settings, a Geriatric Care Model (GCM) was not cost-effective, researchers report (pp. 2494–504). The GCM was based on the Chronic Care Model. It involved in-home comprehensive geriatric assessment by a practice nurse, education of practice nurses, and multidisciplinary coordination of care. Costs of care did not differ significantly for GCM and usual care, and “the probability of the intervention being cost-effective was 0.76 if decision-makers are willing to pay $30,000 per point improvement on the SF-12.…” (K. M. van Leeuwen, k.m.vanleeuwen@vu.nl)

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 © 2015, 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
Dec. 31, 2015 * Vol. 22, No. 249
Providing news and information about medications and their proper use

>>>PNN’s Top 10 for 2015
This was a year that will be remembered for worldwide terrorist attacks and near-daily mass shootings in the U.S. Drugs reportedly turned some of the Nov. 2015 Paris terrorists into “zombies,” and medications might have helped some of the mass shooters with mental disorders. All that though was beyond the lens of PNN; here’s how the world looked to pharmacists.
1 Specialty Pharmacy & Drug Pricing: Pricing practices in the pharmaceutical industry—long a black box—attracted the attention of the mass media (Aug. 5), with specialty agents for hepatitis C (May 6), two new PCSK9 inhibitors (July 27, Aug. 28) and “old neglected drugs” (Sept. 21) under scrutiny. Senate hearings looked at pricing of generic drugs (Dec. 11), just after the American College of Physicians endorsed their use when possible (Nov. 24).
2 New Drugs Galore: FDA approved a record number of new chemical and biologic entities—45, just eclipsing last year’s 44. An antidote for dabigatran (idarucizumab, Praxbind) and a controversial agent for female sexual desire disorder (filbanserin, Addyi) were notable, as were the pair of PCSK9 inhibitors (alirocumab, Paluent; evolocumab, Repatha) mentioned above and several oncologic drugs. With many new drug applications pending at FDA, 2016 promises more of the same—including the pattern of new agents falling into the specialty pharmacy category. These drugs account for 1% of prescriptions but 26% of costs in Medicare Part D (May 3), a trend that calls into question reliance on drug-use-control systems from years ago.
3 What Is Progress in Congress? Pharmacists gained state-level provider status (May 12, June 19), but Congressional hearings needed for a federal law have not happened, despite frequent blogs and announcements from pharmacy groups. Pharmacist roles developed in areas such as dabigatran management (Apr. 15) and heart failure (Oct. 6). While the American College of Cardiology strongly endorsed contributions of board-certified cardiology pharmacists (Nov. 6), the year began with an ominous article in the medical literature saying that evidence for medication therapy management is weak (Jan. 6) and closed with debates in the pharmacy literature on the “practice readiness” of new graduates (Dec. 30).
4 Medicare Part D at 10, ACA at 5: The Affordable Care Act was upheld once again by the U.S. Supreme Court (June 26), and Medicare Part D found itself “firmly established” in its 10th year of operation (Oct. 23). However, Part D was not producing anticipated improvements in outcomes and hospitalizations (June 16), and one article called for “intelligent assignment” of beneficiaries to plans (Mar. 24).
5 Opioid Epidemic Continues: While the number of Americans taking opioids and dying from them stayed unacceptably high (Oct. 23), evidence was lacking for any long-term use of the drugs in chronic pain (Jan. 13). Patients continued getting opioid prescriptions even after overdoses (Dec. 29).
6 Bugs, Drugs & Vaccines: Work continued on a better shingles vaccine (May 28)—even as the old product’s cost-effectivenss was questioned (Oct. 6)—and on a possible vaccine for Helicobacter pylori. Patients were underwhelmed, however, with adult vaccination rates stalled at levels far below Healthy People 2020 expectations (Feb. 6) and debates over Americans’ rights to refuse vaccines (Mar. 18).
7 Marijuana As You Like It: In a reversal of the usual way appropriate drug use develops, researchers looked for positives with cannabis therapy (June 12 and 24, Sept. 14) only after many states had relaxed drug laws.
8 Aging & Chronic Diseases: The Beers criteria were updated (Oct. 27), and moderate success was reported in guiding clinicians to care for the increasing number of aging patients with chronic diseases (Apr. 21, Oct. 5).
9 Precision Medicine: After Pres. Obama launched a Precision Medicine Initiative during his Jan. State of the Union address, researchers looked for ways the effort could be combined with pharmacogenomics (June 4, Aug. 6, Sept. 28) and personalized care (June 8).
10 Medication Safety: FDA issued drug warnings and alerts much more frequently during 2015 than in past years and awarded a contract to ASHP to help sort out the medication safety issue (Oct. 1).

>>>PNN NewsWatch
* PNN will not be published on Fri., Jan. 1, New Year’s 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 © 2015, 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.