Mar 2016

PNN January–March 2016

PNN Pharmacotherapy Line
Jan. 4, 2016 * Vol. 23, No. 1
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 2 issue of Lancet (2016; 387).
Dupilumab in Atopic Dermatitis: Positive results with the monoclonal antibody dupilumab in patients with moderate-to-severe atopic dermatitis lead investigators to conclude that interleukin (IL)–4 and IL-13 “are key drivers” of the pathophysiology of the disease (pp. 40–52). The drug, which blocks both pathways, was compared with placebo in the dose-ranging phase 2b study, which was conducted in North America, Europe, and Japan. Results showed: “Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n = 63], 300 mg every 2 weeks [n = 64], 200 mg every 2 weeks [n = 61], 300 mg every 4 weeks [n = 65], 100 mg every 4 weeks [n = 65]; placebo [n = 61]). [Eczema Area and Severity Index] score improvements favoured all dupilumab regimens versus placebo (p <0.0001): 300 mg once a week (−74% [SE 5.16]), 300 mg every 2 weeks (−68% [5.12]), 200 mg every 2 weeks (−65% [5.19]), 300 mg every 4 weeks (−64% [4.94]), 100 mg every 4 weeks (−45% [4.99]); placebo (−18% [5.20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively).” (D. Thaçi, diamant.thaci@uksh.de)
Availability, Affordability of Cardiovascular Medications: The Prospective Urban Rural Epidemiology (PURE) study of pharmacies in 18 countries shows that drugs designated by the World Health Organization as key medicines are “unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines” (pp. 61–9). The 2013 analysis focused on aspirin, beta blockers, ACE inhibitors, and statins. Affordability was defined as combined cost less than 20% of household capacity to pay. Study results indicated the following: “All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0.14% of households in high-income countries (14 of 9,934 households), 25% of upper middle-income countries (6,299 of 24,776), 33% of lower middle-income countries (13,253 of 40,023), 60% of low-income countries (excluding India; 1,976 of 3,312), and 59% households in India (9,939 of 16,874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0.16, 95% CI 0.04–0.57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0.16, 0.04–0.55).” (S. Yusuf, salim.yusuf@phri.ca)

>>>PNN NewsWatch
* Efficacy and affordability of medications for hepatitis C virus (HCV) infections are topics of four research articles and an editorial in last week’s New England Journal of Medicine. “The availability of simple, safe, and curative regimens creates opportunities for improving the health of the millions of patients living with HCV infection,” editorialists conclude (pp. 2678–80). “Only through these improvements can our focus be directed to what matters most: reducing the morbidity and mortality associated with HCV infection, stopping HCV transmission, and ultimately eliminating HCV as a public health threat in the United States and worldwide.” (J. W. Ward)

>>>PNN JournalWatch
* Prescription Opioid Misuse, Abuse, and Treatment in the United States: An Update, in
American Journal of Psychiatry, 2016; 173: 18–26. (K. T. Brady)
* Medical vs Invasive Therapy in AVM-Related Epilepsy: Systematic Review and Meta-analysis, in
Neurology, 2016; 86: 64–71. (N. Jette, nathalie.jette@albertahealthservices.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 © 2016, 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
Jan. 5, 2016 * Vol. 23, No. 2
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 5 issue of the Annals of Internal Medicine (2016; 164).
Skin Lesions With Anti-TNF Therapy of IBD: Results of a retrospective cohort study of 917 consecutive patients with inflammatory bowel disease shows that skin lesions occur frequently in association with anti–tumor necrosis factor (TNF) therapy but can be managed by a “dedicated dermatologist” without discontinuation of treatment (pp. 10–22). At a single IBD tertiary referral center, these findings were recorded based on occurrence of skin lesions, patient demographic characteristics, treatments, clinical course, and serologic and genetic markers: “During a median follow-up of 3.5 years (interquartile range [IQR], 0.5 to 7.4 years), skin lesions associated with the use of anti-TNF therapy developed in 264 of 917 (29%) patients (psoriasiform eczema, 30.6%; eczema, 23.5%; xerosis cutis, 10.6%; palmoplantar pustulosis, 5.3%; psoriasis, 3.8%; other, 26.1%). Lesions typically developed at flexural regions, genitalia, and the scalp, especially the psoriasiform lesions. Thirty-one percent of women and 26% of men developed lesions. Median cumulative doses (2864 mg/y [IQR, 2203 to 3819 mg/y] and 2927 mg/y [IQR, 2377 to 3667 mg/y]) and trough levels (4.2 µg/mL [IQR, 2.6 to 5.8 µg/mL] and 4.0 µg/mL [IQR, 1.6 to 5.9 µg/mL]) of infliximab were similar in patients with and without lesions. All but 28 patients (11%) were successfully managed without needing to stop therapy because of lesions.” (S. Vermeire, severine.vermeire@uzleuven.be)
HBV Reactivation During Chemotherapy of Solid Tumors: Patients beginning chemotherapy of solid tumors should be screened for hepatitis B virus (HBV) and provided with antiviral prophylaxis when needed, according to authors of a systematic review and meta-analysis of 26 studies (pp. 30–40). Risks of HBV reactivation were similar to risks with other types of immunsuppressive therapy, the group concluded based on these findings: “Random-effects model meta-analyses were used to estimate the risk and odds ratio (OR) of reactivation with versus without antiviral prophylaxis. Reactivation in chronic HBV without prophylaxis ranged from 4% to 68% (median, 25%) with substantial heterogeneity. Prophylaxis reduced the risk for HBV reactivation (OR, 0.12 [95% CI, 0.06 to 0.22]), HBV-related hepatitis (OR, 0.18 [CI, 0.10 to 0.32]), and chemotherapy interruption (OR, 0.10 [CI, 0.04 to 0.27]). In 3 studies of patients with resolved HBV infection, none received HBV prophylaxis and reactivation risk ranged from 0.3% to 9.0%.” (S. Paul, sonali.paul2@gmail.com)
Use of Generic Medications: As reported previously (see PNN, Nov. 24), the American College of Physicians is basing a recommendation to maximize use of generic medications on the improved adherence rates seen with out-of-pocket costs for patients (pp. 41–9): “Most, but not all, studies evaluating the use of a generic rather than a brand-name drug for the treatment of chronic disease show significantly higher long-term adherence after treatment initiation. For example, Shrank and colleagues evaluated commercially insured patients initiating therapy in 6 classes of long-term medications and found that those who began therapy with a generic medication had adherence rates that were 5 to 7 percentage points higher than among comparable patients initiating therapy with a brand-name drug.…
“The most recent evidence came from Gagne and associates, who studied a cohort of more than 90,000 Medicare beneficiaries initiating a statin and compared adherence and outcomes between patients initiating a generic statin and those who initiated a brand-name version of the same statin. Patients in the former group were 6% more adherent than those in the latter group. Although this study used propensity score matching to adjust for baseline differences in a large number of patient characteristics and compared patients initiating generic statins with those initiating brand-name versions of the same drug, it is still subject to the limitations of observational studies. No randomized studies comparing the effect of generic medication use on adherence have been reported or are likely to be conducted.” (A. Qaseem,
aqaseem@acponline.org)

>>>PNN NewsWatch
* FDA warns that differences in dosing regimens between the two oral formulations of the antifungal posaconazole (Noxafil, Merck) are resulting in dosing errors.

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 © 2016, 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
Jan. 6, 2016 * Vol. 23, No. 3
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 5 issue of JAMA (2016; 315).
Oral Fluconazole During Pregnancy: “Cautious prescribing of fluconazole during pregnancy may be advisable,” conclude investigators who found a link between oral use of the drug and increased rates of spontaneous abortion in a nationwide registry-based cohort study in Denmark (pp. 58–67). From 1.4 million pregnancies, those with exposure to oral fluconazole were compared with 4 unexposed pregnancies, with these results: “Among 3,315 women exposed to oral fluconazole from 7 through 22 weeks’ gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23–1.77). Among 5,382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82–2.14]). Using topical azole exposure as the comparison, 130 of 2,823 women exposed to fluconazole vs 118 of 2,823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26–2.07]); 20 of 4,301 women exposed to fluconazole vs 22 of 4,301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64–2.16]).” (D. Mølgaard-Nielsen, dnl@ssi.dk)
Valsartan/Sacubitril for Heart Failure: Adverse effects uncovered in preclinical trials need to be investigated in human studies more quickly than FDA has required for the combination product Entresto (valsartan/sacubitril, Novartis), Viewpoint authors write (pp. 25–6). Sacubitril inhibits the plasma membrane metalloendopeptidase neprilysin, which acts not only on angiotensin but also on peptides in the eye and brain. One of those is amyloid-beta peptide, which is associated with development of Alzheimer disease. FDA has required study of possible adverse effects, but results are not due until 2022, leading the editorialists to this conclusion: “In an era when information accrual from genetic animal models can outpace the collection of data from patients enrolled in traditional clinical trials, it will be important to develop effective mechanisms for reconciling differences that emerge from these 2 sources. Although the risks of neprilysin inhibition in the brain and in the eye remain speculative, the emergence or worsening of cognitive or visual impairments would be devastating for patients with heart failure regardless of their age or prognosis. Therefore, a prudent approach would be to follow high-risk patients closely with cognitive assessments, amyloid positron emission tomography, and retinal imaging until definitive answers emerge. How physicians, investigators, the pharmaceutical industry, and federal regulators respond to this challenge can set a comforting precedent for how to reconcile similar differences between preclinical and clinical data that will likely arise in the future.” (A. M. Feldman, arthur.feldman@tuhs.temple.edu)
Electronic Clinical Communication: Reimagination of clinical communications is needed as medicine moves into a “post-pager, smartphone era,” according to a Viewpoint article, and the new system should support “a team-based culture of care through more effective, interoperable, and intelligent collaboration” (pp. 21–2): “Simply adding pager functionality to a smartphone would be like turning a paper health record into an [electronic health record] without taking advantage of discrete data capture, decision support, remote access, improved reporting, and all of the other features that distinguish its functionality from that of paper records. Experience from other industries indicates that the most striking technologically enabled gains in productivity and quality come only after the work is reimagined and the technologies are adapted to a new workflow. With a little imagination, the opportunity exists to transform the way physicians and other health care practitioners communicate with one another and with patients.” (R. R. Khanna, raman.khanna@ucsf.edu)

>>>PNN NewsWatch
* Apps are connecting smartphones to OTC products such as First Response Pregnancy Pro, Aterica’s Veta EpiPen Smart Case, and L’Oréal My UVPatch, reports this morning’s Wall Street Journal.

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 © 2016, 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
Jan. 7, 2016 * Vol. 23, No. 4
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 7 issue of the New England Journal of Medicine (2016; 374).
Treatment of Ebola Virus Disease: Two studies examine treatments for patients with suspected or confirmed Ebola virus disease (EVD).
Lower mortality resulted when an antimalarial drug combination— artesunate plus amodiaquine— was administered to patients with suspected EVD during the epidemic in West Africa, researchers report (
pp. 23–32). At one treatment center, the supply of the recommended antimalarial combination, artemether–lumefantrine, ran out for a 12-day period. Artesunate–amodiaquine was substituted, providing investigators the opportunity to compare those on the two combinations or no antimalarial drug. Results showed: “Between June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether–lumefantrine and 71 were prescribed artesunate–amodiaquine. The characteristics of the patients in the artesunate–amodiaquine group were similar to those in the artemether–lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether–lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate–amodiaquine group (50.7%). In adjusted analyses, the artesunate–amodiaquine group had a 31% lower risk of death than the artemether–lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria.” (I. Ciglenecki, iza.ciglenecki@geneva.msf.org)
Another treatment studied during the epidemic, convalescent plasma, was ineffective for improving survival in 84 patients with confirmed EVD, a second study shows (
pp. 33–42). In the nonrandomized comparison, those receiving two consecutive transfusions of ABO-compatible convalescent plasma 200–250 mL were compared with 418 control patients treated at the same center within the prior 5 months. Each unit of plasma was obtained from a separate convalescent donor, the authors note, adding these results: “At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, −7 percentage points; 95% confidence interval [CI], −18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, −3 percentage points; 95% CI, −13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.” (J. van Griensven, jvangriensven@itg.be)
Antilymphocyte Globulin for Prevention of GVHD: Antihuman T-lymphocyte immune globulin (ATG), added to a myeloablative conditioning regimen for patients with acute leukemia, was beneficial in a phase 3 study of 168 patients, reducing rates of chronic graft-versus-host disease (GVHD) (pp. 43–53): “After a median follow-up of 24 months, the cumulative incidence of GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P <0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P = 0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P = 0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD–free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P = 0.005).” (N. Kröger, nkroeger@uke.de)
Cost-Sharing Reductions Case Winding Way Through Courts: A court challenge filed by the House of Representatives questions the legality of reimbursements of insurers for reducing cost sharing by enrollees under the Affordable Care Act, writes the author of a Perspective article (pp. 5–7). While likely to fail on constitutional grounds, the case “will continue in the interim to cause uncertainty for insurers, consumers, and providers,” the writer concludes. (T. S. Jost)

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 © 2016, 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
Jan. 8, 2016 * Vol. 23, No. 5
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Jan. issue of Pediatrics (2016; 137).
Contraceptives & Adolescent Use of Teratogenic Medications: Adolescent girls and young women prescribed teratogenic medications receive inadequate contraceptives, according to a retrospective review of electronic medical records at a pediatric clinic (10.1542/peds.2015-1454). At examining visits in 2008–12, these patterns of contraceptive provision were recorded for females aged 14–25 years who were prescribed known teratogens (FDA pregnancy risk category D or X): “Within 4,172 clinic visits, 1,694 females received 4,506 prescriptions for teratogenic medications. The most commonly prescribed teratogens were topiramate, methotrexate, diazepam, isotretinoin, and enalapril. The subspecialties prescribing teratogens most frequently were neurology, hematology-oncology, and dermatology. Overall, contraceptive provision was documented in 28.6% of the visits. Whites versus nonwhites and older versus younger girls were more likely to receive contraceptive provision. The presence of a federal risk mitigation system for the teratogen also increased the likelihood of contraceptive provision.” (S. L. Stancil)
Prescription Drug Misuse & Sexual Behaviors: Nonmedical use of prescription drugs (NMUPD) among high school students is associated with risky sexual behaviors that increase individuals’ risk for sexually transmitted infections, investigators conclude based on analysis of data from the 2011 and 2013 Youth Risk Behavior Surveys (10.1542/peds.2015-2480). Logistic regression analysis of survey data showed these relationships between NMUPD and ever having sexual intercourse, current sexual activity, lifetime number of sexual partners, condom use, and alcohol or drug use before last sexual intercourse: “NMUPD was associated with ever having sexual intercourse (aPR 1.16 [95% CI 1.11–1.22]), being currently sexually active (1.26 [1.20–1.33]), having ≥4 lifetime sexual partners (1.45 [1.34–1.57]), drinking alcohol or using drugs before last sexual intercourse (1.32 [1.17–1.48]), and not using a condom at last sexual intercourse (1.14 [1.05–1.23]). As the frequency of NMUPD increased, the association between NMUPD and each of the sexual risk behaviors increased in strength, suggesting a dose–response relationship.” (H. B. Clayton)
Neonatal Tianeptine Abstinence Syndrome: Authors report a case of apparent neonatal abstinence syndrome (NAS) in an infant born to woman taking the second-generation antipsychotic agent tianeptine (10.1542/peds.2015-1414): “A female patient … presented with dependence on tianeptine, with the use of >650 mg of the drug per day. She had 2 successive pregnancies with similar doses. The state of dependence remained unidentified throughout the first pregnancy, but just after delivery, her full-term newborn exhibited unexpected … NAS. The NAS was successfully treated with morphine, although both the mother’s and newborn’s urine drug screen was negative. The causality of tianeptine in inducing NAS was retrospectively assessed as ‘probable’ by using a validated causality algorithm. During the second pregnancy, this patient sought addiction treatment and was admitted for residential detoxification treatment in her seventh month of pregnancy. Delivery occurred at full term with a low birth weight neonate. No further developmental insults or medical problems were subsequently identified in the 2 children. Maternal tianeptine dependence during pregnancy may induce a type of NAS that mimics opiate NAS. This finding appears to be consistent with a recent finding of the agonist action of tianeptine on the opiate µ-receptor.” (C. Bence)

>>>Psychiatry Report
Source:
Jan. issue of the American Journal of Psychiatry (2016; 173).
Genotypic Response Differences With Risperidone: In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), cellular electrophysiologic assays and clinical responses indicate a role for Kv11.1 channels in the therapeutic effects of antipsychotic agents and “further highlight the promise of optimizing response with genotype-guided therapy for schizophrenia patients,” researchers report (pp. 53–9): “Patients with KCNH2 risk genotypes and slow metabolizer status (approximately 7% of patients) showed marked improvement in symptoms when treated with risperidone compared with patients with fast metabolizer status or without the KCNH2 risk genotypes.” (J. Heide)

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 © 2016, 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
Jan. 11, 2016 * Vol. 23, No. 6
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 9 issue of Lancet (2016; 387).
Ranolazine After Incomplete PCI Revascularization: In patients with chronic angina and incomplete revascularization after percutaneous coronary intervention (PCI), treatment with the anti-ischemic agent ranolazine failed to reduce the incidence of a composite primary endpoint, according to findings from the RIVER-PCI trial (pp. 136–45). At 245 centers in four countries, stratified random assignment was based on presence of diabetes and acute coronary syndrome presentation. Results based on a primary endpoint of time to first occurrence of ischemia-driven revascularization or ischemia-driven hospitalization without revascularization were as follows: “Between Nov 3, 2011, and May 27, 2013, we randomly assigned 2,651 patients to receive ranolazine (n = 1,332) or placebo (n = 1,319); 2,604 (98%) patients comprised the full analysis set. After a median follow-up of 643 days (IQR 575–758), the composite primary endpoint occurred in 345 (26%) patients assigned to ranolazine and 364 (28%) patients assigned to placebo (hazard ratio 0.95, 95% CI 0.82–1.10; p = 0.48). Incidence of ischaemia-driven revascularisation and ischaemia-driven hospitalisation did not differ significantly between groups. 189 (14%) patients in the ranolazine group and 137 (11%) patients in the placebo group discontinued study drug because of an adverse event (p = 0.04).” (G. Weisz, weiszg@szmc.org.il)
Global Access to Effective Antimicrobial Agents: “The challenge of simultaneously expanding appropriate access to antimicrobials, while restricting inappropriate access, particularly to expensive, newer generation antimicrobials, is unique in global health and requires new approaches to financing and delivering health care and a one-health perspective on the connections between pathogen transmission in animals and humans,” authors write (pp. 168–75). In a Series article, the writers “describe the importance of effective antimicrobials” and “assess the disease burden caused by limited access to antimicrobials, attributable to resistance to antimicrobials, and the potential effect of vaccines in restricting the need for antibiotics.” (R. Laxminarayan, ramanan@cddep.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Oral Contraceptives Before & During Pregnancy: In a prospective observational cohort study of 880,694 live births in Denmark in 1997–2011, risk of birth defects was not increased among mothers using oral contraceptives just before or during pregnancy, researchers report (h6712). The study “conservatively assumed” use of the drugs through the most recently filled prescription, with these 1-year follow-up results: “Prevalence of major birth defects (per 1,000 births) was consistent across each oral contraceptive exposure group (25.1, never users; 25.0, use >3 months before pregnancy onset (reference group); 24.9, use 0–3 months before pregnancy onset (that is, recent use); 24.8, use after pregnancy onset). No increase in prevalence of major birth defects was seen with oral contraceptive exposure among women with recent use before pregnancy (prevalence odds ratio 0.98 (95% confidence interval 0.93 to 1.03)) or use after pregnancy onset (0.95 (0.84 to 1.08)), compared with the reference group. There was also no increase in prevalence of any birth defect subgroup (for example, limb defects). It is unknown whether women took oral contraceptives up to the date of their most recently filled prescription. Also, the rarity of birth defects made disaggregation of the results difficult. Residual confounding was possible, and the analysis lacked information on folate, one of the proposed mechanisms.” (B. M. Charlton, bcharlton@mail.harvard.edu)

>>>PNN JournalWatch
* Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report, in
Chest, 2016; 149: 27–44. (P. Gibson)
* Lactic Acidosis in Sepsis: It’s Not All Anaerobic: Implications for Diagnosis and Management, in
Chest, 2016; 149: 252–61. (K. R. Walley)
* Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise, in
Journal of the American College of Cardiology, 2016; 67: 81–99. (G. W. Stone)
* Multidisciplinary Pulmonary Embolism Response Teams, in
Circulation, 2016; 133: 98–103. (G. Piazza, gpiazza@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Jan. 12, 2016 * Vol. 23, No. 7
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. issue of JAMA Internal Medicine (2016; 176).
Rx Strategies for Acute URIs: Compared with immediate provision of antibiotic prescriptions to patients with acute uncomplicated upper respiratory infections, “delayed strategies were associated with slightly greater but clinically similar symptom burden and duration and also with substantially reduced antibiotic use,” researchers report (pp. 21–9). A total of 398 adults at 23 Spanish primary care centers were randomized to a delayed patient-led prescription strategy, a delayed strategy requiring patients to pick up prescriptions at the primary care center, an immediate prescription strategy, or a no antibiotic strategy, with these results: “136 patients (34.2%) were men; mean (SD) age, 45 (17) years. The mean severity of symptoms ranged from 1.8 to 3.5 points on the Likert scale, and mean (SD) duration of symptoms described on first visit was 6 (6) days. The mean (SD) general health status on first visit was 54 (20) based on a scale with 0 indicating worst health status; 100, best status. Overall, 314 patients (80.1%) were nonsmokers, and 372 patients (93.5%) did not have a respiratory comorbidity. The presence of symptoms on first visit was similar among the 4 groups. The mean (SD) duration of severe symptoms was 3.6 (3.3) days for the immediate prescription group and 4.7 (3.6) days for the no prescription group. The median (interquartile range [IQR]) of severe symptoms was 3 (1-4) days for the prescription collection group and 3 (2-6) days for the patient-led prescription group. The median (IQR) of the maximum severity for any symptom was 5 (3–5) for the immediate prescription group and the prescription collection group; 5 (4–5) for the patient-led prescription group; and 5 (4–6) for the no prescription group. Patients randomized to the no prescription strategy or to either of the delayed strategies used fewer antibiotics and less frequently believed in antibiotic effectiveness. Satisfaction was similar across groups.” (P. Alonso-Coello, palonso@santpau.cat)
“Delayed prescribing is not perfect,” editorialists write, but rather “is a compromise between an immediate prescription and a no prescription strategy” (
pp. 29–30). “Some patients will still receive antibiotics they do not need, but the evidence shows that delayed prescribing strategies substantially reduce antibiotic use, so we should embrace them as a simple step we can take toward reducing antibiotic resistance caused by antibiotic use in acute respiratory infections. The challenge remains for researchers to define exactly what is involved in delayed prescribing and how clinicians can use it in different practice contexts.” (A. R. McCullough, amccullo@bond.edu.au)
“Flipping the Script” on Opioid Overprescribing: Given the problems inherent in the current epidemic of opioid misuse and mortality, “physicians should adapt our prescribing habits and improve our information systems to prevent overprescribing of opioids while finding ways of working with our patients as we all try to get back on track,” authors of a Viewpoint article write (pp. 7–8): “Physicians alerted to possible misuse of opioids by their patients should be prepared with strategies that preserve the therapeutic relationship. We suggest framing conversations around safety and referring back to the original treatment goals. If the patient has an opioid use disorder, opioid therapy for pain should be discontinued but the addiction caringly and effectively treated. One treatment—the combination of buprenorphine and naloxone—can be administered in office-based settings. In our view, reflexively ending a relationship with a patient or abruptly discontinuing opioid treatment without offering a feasible plan for addiction treatment is an abrogation of the prescriber’s duty to help fix a problem he or she may have had a role in creating. Such approaches rarely solve the problem. Patients can obtain medications from unlicensed sources and switch to more dangerous methods of self-medication, such as heroin.” (A. P. Wright, aileen.wright@yale.edu)
Untapped Potential of Pharmacy Leaflets: Viewpoint authors support “resuscitating pharmacy leaflets” through provision to patients of “trustworthy, plainly worded information about drug benefits and risks” (pp. 11–2): “There is no reason why pharmacy leaflets could not include quantitative summaries of the benefits and risks of individual medications” based on results of high-quality systematic reviews and summaries of preapproval data. (P. Doshi, pdoshi@rx.umaryland.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 © 2016, 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
Jan. 13, 2016 * Vol. 23, No. 8
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 12 issue of JAMA (2016; 315).
Frozen Fecal Microbiota Transplantation for C. difficile: Compared with fresh fecal microbiota transplantation (FMT), use of frozen-and-thawed FMT resulted in similar rates of resolution of recurrent or refractory Clostridium difficile infection (CDI) in a clinical trial, researchers report (pp. 142–9). Availability of frozen FMT would make this “promising intervention” more readily available, the authors note, adding these details about 219 patients at six Canadian centers in 20012–2014: “In the per-protocol population, the proportion of patients with clinical resolution was 83.5% for the frozen FMT group and 85.1% for the fresh FMT group (difference, −1.6% [95% CI, –10.5% to ]; P = .01 for noninferiority). In the mITT population the clinical resolution was 75.0% for the frozen FMT group and 70.3% for the fresh FMT group (difference, 4.7% [95% CI, –5.2% to ]; P < .001 for noninferiority). There were no differences in the proportion of adverse or serious adverse events between the treatment groups.” (C. H. Lee, clee@mcmaster.ca)
Prevention of CDI should continue to be the “most fundamental question about recurrent CDI,” editorialists write (
pp. 137–8). “Antibiotic use is still the strongest predictor for the development of CDI, especially with multiple agents or prolonged use. With about 50% of hospitalized adults receiving antibiotics at any given time, targeted measures to curtail antimicrobial use remain essential. Recurrent CDI is only one of many poignant reminders of the ongoing need for meaningful investment in antimicrobial stewardship and prevention of health care–associated infection.” (P. N. Malani, pmalani@umich.edu)
Treatment of Idiopathic & Opioid-Induced Constipation: A review article concludes that clinicians need for more information about integration of newer treatments into constipation therapy (pp. 185–91): “Strong evidence for efficacy has been established for stimulant and osmotic laxatives, new intestinal secretogogues, and peripherally restricted µ-opiate receptor antagonists, the latter a major advance in the treatment of opioid-induced constipation. An algorithm provided to evaluate chronic idiopathic constipation that is refractory to available laxatives focuses on the importance of defecation disorders and biofeedback therapies. When used appropriately, available stimulant laxatives such as senna and bisacodyl are both safe and effective when used long-term. There is a paucity of (and a strong desire for) studies that compare inexpensive laxatives with newer agents that work by other mechanisms.” (A. Wald, axw@medicine.wisc.edu)
Quality, Costs & Bundled Payments: Three models for bundled payments in the Medicare system are being tested by the CMS Innovations Center, write authors of a Viewpoint article (pp. 131–2). Bundled Payments for Care Improvement (BPCI), the Comprehensive Care for Joint Replacement (CJR) Model, and the Oncology Care Model (OCM) all share the common “core principle … that a single organization is accountable for most of the care a patient receives during the episode,” the authors note. “Bundled payment models could be expanded without displacing other [alternative payment models (APMs)]. Bundled payments for discrete episodes of care triggered by a hospitalization or treatment of a serious illness could be layered on top of other APMs—such as ACOs or advanced primary care medical homes—in which clinicians and health care organizations have accountability for the care of a population over a longer period.…
“Likewise, multiple bundled payment models can coexist. For example, if a patient undergoes hip replacement by a surgeon in a physician group practice participating in BPCI, but at a hospital participating in CJR, accountability for the episode lies with the physician group practice. Participation in some models, like BPCI, could remain voluntary, whereas other models may apply to all practitioners and organizations in a geographic area, like CJR. Ultimately, if both models were successful and expanded, all lower extremity joint replacements could be in a bundled payment arrangement.” (R. Rajkumar,
Rahul.Rajkumar@cms.hhs.gov)

>>>PNN NewsWatch
* The nomination of Robert Califf, MD, to head FDA moved forward yesterday with a Senate committee approving the nomination and sending it to the full Senate.

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 © 2016, 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
Jan. 14, 2016 * Vol. 23, No. 9
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 14 issue of the New England Journal of Medicine (2016; 374).
Intensified Therapy in Tuberculous Meningitis: Among adults with tuberculous meningitis, an intensified regimen during the first 8 weeks of treatment had no significant impact on 9-month rates of survival, according to data collected at two Vietnamese hospitals (pp. 124–34). The standard 9-month regimen included rifampin 10 mg/kg/d, while an intensified regimen increased that dose to 15 mg/kg/d and added levofloxacin 20 mg/kg/d for 8 weeks. Results showed: “During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P = 0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P = 0.08).” (A. D. Heemskerk, dheemskerk@oucru.org)
It’s time to remember that “the central nervous system is a ‘unique therapeutic compartment’ that requires special consideration in the treatment of tuberculous meningitis,” an editorialist writes (
pp. 179–81). “[These and other recent] results … stand in stark contrast to those of our group in treating children with tuberculous meningitis in the Western Cape Province of South Africa. For close to 30 years, we have used a pragmatic regimen that takes into account the ability of the relevant drugs to penetrate into the CSF at more efficacious concentrations and the doses of the drugs needed to achieve these concentrations without undue toxic effects. With a combination of isoniazid (15 to 20 mg per kilogram), rifampin (20 mg per kilogram), pyrazinamide (40 mg per kilogram), and ethionamide (20 mg per kilogram), all given throughout 6 months of treatment, the most recent overall mortality among 184 children, with more than 80% of the children having stage 2 or 3 tuberculous meningitis (British Medical Council Research Council classification), was 3.8% — and the mortality was concentrated among children with stage 3 meningitis.6 We also pay close attention to monitoring the presence of hydrocephalus and, depending on the type of hydrocephalus and degree of the associated raised intracranial pressure, manage this with a combination of furosemide and acetazolamide, with ventriculoperitoneal shunting in selected cases; all children also receive prednisone for the first month of treatment.” (P. R. Donald)
Nonmedical Prescription-Opioid Use & Heroin Use: Prescription opioids and heroin are “elements of a larger epidemic of opioid-related disorders and death” that needs to be viewed “from a unified perspective,” according to authors of a review article (pp. 154–63): “The transition from nonmedical use of prescription opioids to heroin use appears to be part of the progression of addiction in a subgroup of nonmedical users of prescription opioids, primarily among persons with frequent nonmedical use and those with prescription opioid abuse or dependence. Although some authors suggest that there is an association between policy-driven reductions in the availability of prescription opioids and increases in the rates of heroin use, the timing of these shifts, many of which began before policies were robustly implemented, makes a causal link unlikely.” (W. M. Compton, wcompton@nida.nih.gov)
Endorsement of Califf for FDA: After reviewing the track record of FDA nominee Robert M. Califf, MD, NEJM editors “strongly endorse his nomination and urge the Senate to act favorably on it” (pp. 176–7). Through a decade of service at the Institute of Medicine, “Califf’s primary interest was clearly in gathering and using solid information to promote the health and well-being of people suffering from disease,” an editorial notes. “Califf’s experience, his proven leadership abilities, his record of robust research to guide clinical practice, and his unwavering dedication to improving patient outcomes are unsurpassed qualifications for the post of commissioner of the FDA.” (J. M. Drazen)

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 © 2016, 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
Jan. 15, 2016 * Vol. 23, No. 10
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Jan. issue of Chest (2016; 133).
Ethnic Variation in Response to IM Triamcinolone: Seeking to eliminate adherence as an issue in ethnic differences in management of severe therapy-resistant asthma, researchers found poorer responses to I.M. triamcinolone among black versus white children (pp. 98–105). Using decrease of fractional exhaled nitric oxide to less than 24 parts per billion (ppb) as an outcome measure, results were as follows for steroid responses in white, black, Asian, and mixed white/black children: “Seventy-nine subjects were identified (white, n = 54 [68%]; black, n = 16 [20%]; Asian, n = 5 [6%]; and mixed white/black, n = 4 [5%]). After administration of triamcinolone, there was a significant drop in median Feno in white children (46.8 to 23.1 ppb; P <.001) but not in black children (52.2 to 34.5 ppb; P = .58). More black children than white children (86.7%) were Feno nonresponders (86.7% vs 45.3%; P <.05), and more black children had exacerbations compared with white children (61% vs 17%; P <.05).” (L. Fleming)
Managing Chronic Cough: Based on three systematic reviews of children 14 years or younger with chronic cough, authors conclude that “use of cough management protocols (or algorithms) improves clinical outcomes and cough management or the testing algorithm should differ depending on the associated characteristics of the cough and clinical history” (pp. 106–19): “It remains uncertain whether the management or testing algorithm should depend on the duration or severity of chronic cough. Pending new data, chronic cough in children should be defined as >4 weeks’ duration and children should be systematically evaluated with treatment targeted to the underlying cause irrespective of the cough severity.” (A. B. Chang)
Asthma–COPD Overlap Syndrome: Indicators of asthma–COPD overlap syndrome (ACOS) were found in 15% of well-characterized patients with COPD during 1 year of follow-up, a study shows (pp. 45–52). Those with ACOS had a better 1-year prognosis than others with COPD, the investigators report, adding these details: “Of 831 patients with COPD included, 125 (15%) fulfilled the criteria for ACOS, and 98.4% of them sustained these criteria after 1 year. Patients with ACOS were predominantly male (81.6%), with symptomatic mild to moderate disease (67%), who were receiving inhaled corticosteroids (63.2%). There were no significant differences in baseline characteristics, and only survival was worse in patients with non-ACOS COPD after 1 year of follow-up (P < .05).” (B. G. Cosío)
This syndrome “is a clinical reality and is important to identify,” writes an editorialist, “but more research is needed to define these overlap phenotypes, to identify them in the clinic, and to understand the best way of managing these patients” (
pp. 7–8). Diagnosis “is currently done by clinical assessment, including history, exposure, and bronchodilator reversibility, which are imprecise. Airway eosinophilia may be measured by using sputum eosinophil counts or fractional exhaled nitric oxide, but these tests are usually not available in routine clinical practice. Blood eosinophil counts are easy to perform and may reflect airway eosinophilia and predict corticosteroid responsiveness. Sputum neutrophilia is not reflected by circulating neutrophils and can only be detected by examination of induced sputum, however. A formal trial of oral corticosteroids (prednisolone or prednisone 30 mg daily for 2 weeks) may be useful for identifying an asthmatic component in patients with COPD (with improvement in FEV1 > 15% or 200 mL).” (P. J. Barnes)

>>>Circulation Report
Source:
Jan. 12 issue of Circulation (2016; 133).
Antidotes for Newer Oral Anticoagulants: A Cardiology Patient Page article provides consumers with an explanation of the challenges with reversing the bleeding effects of newer oral anticoagulants (pp. e18–9). “The development of safe, potent, and reliable antidotes is addressing [the] concern” about “lack of a specific approach to bleeding that may occur while taking [newer drugs]” such as dabigatran, apixaban, edoxaban, and rivaroxaban, the author advises. (C. V. Pollack, Jr., charles.pollack@jefferson.edu)

>>>PNN NewsWatch
* PNN will not be published on Mon., Jan. 18, M. L. King 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 © 2016, 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
Jan. 19, 2016 * Vol. 23, No. 11
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 19 issue of the Annals of Internal Medicine (2016; 164).
Osteoarthritis Intervention in Veterans: In veterans with hip or knee osteoarthritis, a combined patient/provider intervention “resulted in modest improvement in self-reported physical function,” researchers report (pp. 73–83). Using cluster randomization, the study included delivery of information to patients on weight management, physical activity, and cognitive behavioral pain management by telephone and patient-specific osteoarthritis treatment recommendations to primary care providers through electronic medical records. Results showed: “At 12 months, [Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)] scores were 4.1 points lower (indicating improvement) in the osteoarthritis intervention group versus usual care (95% CI, −7.2 to −1.1 points; P = 0.009). WOMAC function subscale scores were 3.3 points lower in the intervention group (CI, −5.7 to −1.0 points; P = 0.005). WOMAC pain subscale scores (P = 0.126), physical performance, and depressive symptoms did not differ between groups.…” (K. D. Allen, Kelli.allen@va.gov)
Hepatitis C Opt-Out Screening/Treatment in U.S. Prisons: Implementation of an opt-out screening and treatment program for hepatitis C virus (HCV) infection among U.S. prisoners could avert substantial health care costs over the next 30 years, according to a cost-effectiveness analysis (pp. 84–92). Taking a societal perspective, the analysis produced these findings based on prevention of HCV transmission in prisons and in society in general, costs, quality-adjusted life–years (QALYs), incremental cost-effectiveness ratio (ICER), and total prison budget: “Implementing risk-based and opt-out screening could diagnose 41,900 to 122,700 new HCV cases in prisons in the next 30 years. Compared with no screening, these scenarios could prevent 5,500 to 12,700 new HCV infections caused by released inmates, wherein about 90% of averted infections would have occurred outside of prisons. Screening could also prevent 4,200 to 11,700 liver-related deaths. The ICERs of screening scenarios were $19,600 to $29,200 per QALY, and the respective first-year prison budget was $900 to $1,150 million. Prisons would require an additional 12.4% of their current health care budget to implement such interventions.… Results were sensitive to the time horizon, and ICERs otherwise remained less than $50,000 per QALY.” (J. Chhatwal, jagchhatwal@mgh.harvard.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Cardiovascular Outcomes With Clarithromycin: In a population-based study of adults in Hong Kong in 2005–09, current use of clarithromycin was associated with increased short-term risks of myocardial infarction, arrhythmia, and cardiac mortality but no long-term cardiovascular risks (h6926): “The propensity score adjusted rate ratio of myocardial infarction 14 days after the start of antibiotic treatment was 3.66 (95% confidence interval 2.82 to 4.76) comparing clarithromycin use (132 events, rate 44.4 per 1,000 person years) with amoxicillin use (149 events, 19.2 per 1,000 person years), but no long term increased risk was observed. Similarly, rate ratios of secondary outcomes increased significantly only with current use of clarithromycin versus amoxicillin, except for stroke. In the self controlled case analysis, there was an association between current use of H pylori eradication treatment containing clarithromycin and cardiovascular events. The risk returned to baseline after treatment had ended. The case crossover analysis also showed an increased risk of cardiovascular events during current use of H pylori eradication treatment containing clarithromycin. The adjusted absolute risk difference for current use of clarithromycin versus amoxicillin was 1.90 excess myocardial infarction events (95% confidence interval 1.30 to 2.68) per 1,000 patients.” (I. C. K. Wong, i.wong@ucl.ac.uk)

>>>PNN JournalWatch
* Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention, in
Annals of Internal Medicine, 2016; doi: 10.7326/M15-1840. (A. Qaseem, aqaseem@acponline.org)
* Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis, in
Annals of Internal Medicine, 2016; 164: 102–13. (F. Zaccardi, fz43@le.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 © 2016, 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
Jan. 20, 2016 * Vol. 23, No. 12
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 19 issue of JAMA, a special issue on death, dying, and end of life (2016; 315).
Characteristics of End-of-Life Cancer Care in Developed Countries: Comparing end-of-life care in seven developed countries for older patients with cancer, investigators found higher rates of intensive care unit admissions in the U.S. but “more hospital-centric in Belgium, Canada, England, Germany, and Norway than in the Netherlands or the United States” (pp. 272–83). Hospital expenditures differed among the countries, as shown in these results compiled from retrospective cohort analysis of 2010 administrative and registry data: “The United States (cohort of decedents aged >65 years, N = 211,816) and the Netherlands (N = 7,216) had the lowest proportion of decedents die in acute care hospitals (22.2% and 29.4%, respectively). A higher proportion of decedents died in acute care hospitals in Belgium (N = 21,054; 51.2%), Canada (N = 20,818; 52.1%), England (N = 97,099; 41.7%), Germany (N = 24,434; 38.3%), and Norway (N = 6,636; 44.7%). In the last 180 days of life, 40.3% of US decedents had an intensive care unit admission compared with less than 18% in other reporting nations. In the last 180 days of life, mean per capita hospital expenditures were higher in Canada (US $21,840), Norway (US $19,783), and the United States (US $18,500), intermediate in Germany (US $16,221) and Belgium (US $15,699), and lower in the Netherlands (US $10,936) and England (US $9,342). Secondary analyses showed similar results.” (E. J. Emanuel, mehpchair@upenn.edu)
“Everyone dies,” an editorialist addressing the controversial topic of assisted suicide writes (
pp. 267–9). “Death is not an inherent failure. Neglect, however, is.” The writer adds: “The evidence indicates that the medical profession is harming vast numbers of patients by neglecting this goal—and that this is not just a US phenomenon but a global one. People everywhere have essential needs aside from just living longer. Medical practices, research, and policies must ensure that clinicians have the skills to understand those needs and have the capabilities to serve them for patients with life-limiting illness.” (A. Gawande, agawande@partners.org)
“Virtually every physician has emotionally painful and poignant stories about how medicine failed their own family members, friends, or colleagues during the final stages of life,” the
JAMA editor writes in a second editorial (pp. 270–1). “In some ways this is not surprising; death always engenders great emotion and recollections may not be accurate. Yet it is concerning when physicians, who know the health care system far better than most patients and can use their knowledge to improve the provision of health services, relate these stories, often describing too much medicine at the end of life, failed discussions about prognosis, or the very late involvement of palliative care. Progress with respect to dying well will be evident when these stories become less frequent and more physicians and others can report that their colleagues, their friends, and their family members had a good death.” (H. Bauchner, howard.bauchner@jamanetwork.org)
Family Perspectives on Aggressive End-of-Life Cancer Care: Interviews of bereaved family members of Medicare patients who died of advanced-stage lung or colorectal cancer indicate a preference for less aggressive end-of-life care, researchers report (pp. 284–92). “Earlier hospice enrollment, avoidance of ICU admissions within 30 days of death, and death occurring outside the hospital were associated with perceptions of better end-of-life care,” the authors conclude. “These findings are supportive of advance care planning consistent with the preferences of patients.” (A. A. Wright, alexi_wright@dfci.harvard.edu)
Policy Prescription for Hospice Care: A CMS demonstration project that allows “Medicare beneficiaries with life-limiting illness to receive hospice care along with concurrent disease-directed therapy” is a positive sign that policy changes regarding hospice care will address the “artificial dichotomy between hospice care and disease-directed care that is palliative and does not account for many treatments or procedures whose purpose is simply to help patients feel better (eg, blood transfusions, radiation, or drainage of excessive fluid from the abdomen),” a Viewpoint author writes (pp. 257–8; O. O. Odejide, reofe_odejide@dfci.harvard.edu">oreofe_odejide@dfci.harvard.edu).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Jan. 21, 2016 * Vol. 23, No. 13
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 21 issue of the New England Journal of Medicine (2016; 374).
Eluxadoline for IBS with Diarrhea: An oral agent with mixed mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist effects, eluxadoline 100 mg twice daily reduced symptoms in 2,427 adults who had irritable bowel syndrome (IBS) with diarrhea, researchers report (pp. 242–53). The 26-week trial used a primary end point of proportion of patients with a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26: “For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P = 0.01 and P = 0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P <0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P = 0.11 and P <0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P = 0.001 and P <0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1,666 patients in the safety population (0.3%).” (A. J. Lembo, alembo@bidmc.harvard.edu)
Predicting Success of Adjuvant Chemotherapy in Colon Cancer: In patients with high-risk, stage II colon cancer, lack of expression of the transcription factor CDX2 correlated with benefits from adjuvant chemotherapy, according to a study that used a “new bioinformatics approach” (pp. 211–22). Investigators searched “for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays,” with these results: “The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2,115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P = 0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein–negative colon cancers than among the 276 (87.9%) with CDX2 protein–positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P = 0.003).… Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P = 0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P = 0.004).… ” (P. Dalerba, pdd2109@columbia.edu)
Regulating Homeopathy: “Homeopathic drugs’ century-long evasion of regulatory scrutiny” may be coming to an end, Perspective authors write (pp. 201–3): “Unlike dietary supplements, which were explicitly excluded from rigorous FDA regulation in 1994, homeopathic products can actually be substantially regulated by the FDA, since the Food, Drug, and Cosmetic Act allows them to be sold as ‘therapeutic.’ We believe that, at minimum, regulators should reconsider the way homeopathic drugs are marketed, so that consumers who are seeking conventional medicines at pharmacies don’t become confused. In August, the FTC submitted comments to the FDA recommending that the agencies better harmonize their approaches to regulating homeopathic products and their advertising. Reconsidering the over-the-counter sale of homeopathic remedies entirely would be an even more drastic step and would require the FDA to take on the entire industry for propagating remedies that don’t meet the same standards of scientific proof applied to conventional medicines.” (S. H. Podolsky)

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 © 2016, 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
Jan. 22, 2016 * Vol. 23, No. 14
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Feb. 1 issue of Clinical Infectious Diseases (2016; 62).
Retreatment of Chronic HCV Genotype-1 Infection: Ledipasvir (LDV) plus sofosbuvir (SOF) therapy performed well in patients with hepatitis C virus (HCV) genotype 1 infection who failed short course of directly-acting antiviral agents (DAAs), researchers report (pp. 280–8). In an open-label phase 2a trial, those who failed 4–6 weeks of GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks, with these results: “Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 106 IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The [sustained virologic response at 12 weeks] rate was 91% (31/34; intention to treat) after retreatment. One patient relapsed.” (S. Kottilil, skottilil@ihv.umaryland.edu)
Eliminating HCV Through Enhanced Screening/Treatment: To eliminate hepatatis C virus (HCV) infections in the United States, “aggressive expansion” of HCV screening and treatment programs are needed, especially among people who inject drugs (PWIDs), a study shows (pp. 298–304). Using epidemiologic data for 1992–2014, investigators projected the impact of enhanced screening and treatment programs on a variety of outcomes for 2015 through 2040: “Increasing annual treatment of patients 4-fold—from the approximately 100,000 treated historically to 400,000—is predicted to prevent 526,084 (95% confidence interval, 466,615–593,347) cases of cirrhosis and 256,315 (201,589–316,114) HCV-associated deaths. By simultaneously increasing treatment capacity and increasing the number of HCV infections diagnosed, total HCV prevalence could fall to as low as 305,599 (222,955–422,110) infections by 2040. Complete elimination of HCV transmission in the United States through treatment with [interferon-free direct-acting antivirals] would require nearly universal screening of PWIDs, with an annual treatment rate of at least 30%.” (D. P. Durham, david.durham@yale.edu)

>>>Oncology Highlights
Source:
Jan. 20 issue of the Journal of Clinical Oncology (2016; 34).
Heart Disease in Survivors of Hodgkin Lymphoma: Management of coronary heart disease (CHD) risk factors and stimulation of exercise are important for survivors of Hodgkin lymphoma (HL) to avoid future cardiovascular problems related to radiation therapy, according to a case–control study of 2,617-patient cohort who survived HL for 5 or more years (pp. 235–43). Detailed examination of medical records of 325 cases and 1,204 matched controls showed the following: “The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing [mean heart dose (MHD)] (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy<27.5years, 20.0%; ERR/Gy27.5-36.4years, 8.8%; ERR/Gy36.5-50.9years, 4.2%; Pinteraction = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8).” (F. E. van Leeuwen, f.v.leeuwen@nki.nl)
Adjuvant Imatinib for High-Risk GIST: Extending adjuvant imatinib to 3 years increases recurrence-free survival (RFS) of patients with high-risk gastrointestinal stromal tumor (GIST), compared with 1 year, and “high 5-year survival rates are achievable,” a study concludes (pp. 244–50). Among 400 patients with high-risk GIST, “patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024).” (H. Joensuu, heikki.joensuu@hus.fin)

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 © 2016, 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
Jan. 25, 2016 * Vol. 23, No. 15
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 23 issue of Lancet (2016; 387).
REG1 Anticoagulation After PCI: Severe allergic reactions occurred in patients managed with the novel anticoagulation system REG1 after percutaneous coronary interventions, researchers report (pp. 349–56). In the REGULATE-PCI trial at 225 North American and European hospitals, participants received either pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, plus anivamersen, a complementary sequence reversal oligonucleotide, or bivalirudin, with these effects on a primary efficacy endpoint of composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularization by day 3 after randomization: “1,616 patients were allocated REG1 and 1,616 were assigned bivalirudin, of whom 1,605 and 1,601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1,605 patients receiving REG1 versus one (<1%) of 1,601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1,616 patients assigned REG1 and 103 (6%) of 1,616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1.05, 95% CI 0.80–1.39; p = 0.72). Major bleeding was similar between treatment groups (seven [<1%] of 1,605 receiving REG1 vs two [<1%] of 1,601 treated with bivalirudin; OR 3.49, 95% CI 0.73–16.82; p = 0.10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1.64, 1.19–2.25; p = 0.002).” (A. M. Lincoff, lincofa@ccf.org)
CEA of Investigational Malaria Vaccine: Despite “modest efficacy” of the RTS,S/AS01 malaria vaccine against Plasmodium falciparum in a phase 3 trial, investigators predict “a significant public health impact and high cost-effectiveness … across a wide range of settings (pp. 367–75). Cost-effectiveness analysis based on the trial data for a 15-year time horizon at a vaccine cost of $2–$10 per dose showed these results for estimates of cases, deaths, and disability-adjusted life–years (DALYs): “In regions with a [parasite prevalence in 2–10 year olds (PfPR2–10)] of 10–65%, RTS,S/AS01 is predicted to avert a median of 93,940 (range 20,490–126,540) clinical cases and 394 (127–708) deaths for the three-dose schedule, or 116,480 (31,450–160,410) clinical cases and 484 (189–859) deaths for the four-dose schedule, per 100,000 fully vaccinated children. A positive impact is also predicted at a PfPR2–10 of 5–10%, but there is little impact at a prevalence of lower than 3%. At $5 per dose and a PfPR2–10 of 10–65%, we estimated a median incremental cost-effectiveness ratio compared with current interventions of $30 (range 18–211) per clinical case averted and $80 (44–279) per DALY averted for the three-dose schedule, and of $25 (16–222) and $87 (48–244), respectively, for the four-dose schedule. Higher [incremental cost-effectiveness ratios] were estimated at low PfPR2–10 levels.” (M. A. Penny, melissa.penny@unibas.ch)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Betahistine in Meniere’s Disease: Compared with placebo, low and high doses of betahistine produced similar effects on vertigo in 221 patients with Meniere’s disease, a study shows (h6816). At 14 German tertiary referral centers, the number of attacks per 30 days at months 7 to 9 of treatment were as follows: “Incidence of attacks related to Meniere’s disease did not differ between the three treatment groups (P = 0.759). Compared with placebo, attack rate ratios were 1.036 (95% confidence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell significantly by the factor 0.758 (0.705 to 0.816; P <0.001). The population based, mean monthly incidence averaged over the assessment period was 2.722 (1.304 to 6.309), 3.204 (1.345 to 7.929), and 3.258 (1.685 to 7.266) for the placebo, low dose betahistine, and high dose betahistine groups, respectively. ” (M. Strupp, Michael.Strupp@med.uni-muenchen.de)

>>>PNN JournalWatch
* The Crossroads of Autoimmunity and Immunodeficiency: Lessons from Polygenic Traits and Monogenic Defects, in
Journal of Allergy and Clinical Immunology, 2016; 137: 3–17. (B. Grimbacher, b.grimbacher@ucl.ac.uk)
* Person-Centered Care: A Definition and Essential Elements, in
Journal of the American Geriatrics Society, 2016; 64: 15–8. (C. Goodwin, CGoodwin@americangeriatrics.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 © 2016, 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
Jan. 26, 2016 * Vol. 23, No. 16
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Jan. issue of the Journal of the American Geriatrics Society (2016; 64).
Infectious Disease–Related ED Visits by Older Adults: Among older Americans, infectious disease (ID) is a common reason for emergency department (ED) visits, with more visits than for myocardial infarction and congestive heart failure combined, researchers report (pp. 31–6). Analysis of a national sample of ED records showed a substantial public health burden for individuals 65 or older with a primary diagnosis of ID: “During 2012, a weighted estimate of 3,123,909 ED visits for IDs was calculated in elderly U.S. adults. This accounted for 13.5% (3.1 million visits) of all ED visits of elderly adults; this burden was higher than that for myocardial infarction and congestive heart failure combined. The rate of ID-related ED visits was 7,231 per 100,000 elderly adults. The most-common diagnoses were lower respiratory infections (26.2%; 95% confidence interval (CI) = 25.7–26.6%), urinary tract infections (25.3%, 95% CI = 25.0–25.7%), and septicemia (18.9%, 95% CI = 18.3–19.6%). Of all ID-related ED visits, 1,786,657 (57.2%, 95% CI = 56.6–57.7%) resulted in hospitalization. The leading cause of hospitalization was septicemia, accounting for 32.2% (95% CI = 31.1–33.3%) of all ID-related hospitalizations through EDs, followed by lower respiratory infections (27.8%, 95% CI = 27.2–28.4%). Overall, 123,894 individuals (4.0%, 95% CI = 3.8–4.1%) died during their ED visit or hospitalization. Of these, septicemia was the leading cause of mortality (74.7%, 95% CI = 73.8–75.6%), followed by lower respiratory infections (15.2%, 95% CI = 14.6–15.9%). Analysis of the 2011 data gave similar results for the burden of ID-related ED visits, hospitalizations, and mortality.” (T. Goto, qq_gto@yahoo.co.jp)
Vitamin D in Nursing Home Residents: In older residents of nursing homes, daily and weekly vitamin D3 supplements produced linear increases in serum concentrations of 25-hydroxyvitamin D [25(OH)D] without a ceiling effect, a study shows (pp. 65–72). During 16 weeks of oral vitamin D3 supplements of 800, 2,000, or 4,000 IU/d or 50,000 IU/wk, 81 residents had these changes in total and free 25(OH)D concentrations and other relevant parameters, including intact parathyroid hormone (iPTH): “25(OH)D concentrations increased with dose (P < .001) and were higher with 50,000 IU/wk (P < .001) than other doses and with 4,000 IU/d than 800 or 2,000 IU/d, but 800 IU and 2,000 IU/d did not differ. One subject receiving 800 IU/d had concentrations less than 20 ng/mL. All subjects receiving more than 2,000 IU/d had concentrations of 20 ng/mL and greater. Free 25(OH)D concentrations rose with total 25(OH) vitamin D. Total and free 25(OH)D were related to calcium concentrations; only free 25(OH)D was related to iPTH.” The authors concluded that free 25(OH)D levels should be studied to determine optimal total levels of this nutrient. (J. B. Schwartz, janice.schwartz@ucsf.edu)

>>>Health Affairs Highlights
Source:
Jan. Health Affairs, a theme issue on High-Cost Populations, Medicaid & Spending (2016; 35).
Tobacco Cessation Among Medicaid Beneficiaries: Smoking cessation should be a priority for Medicaid and public health agencies, investigators conclude, as enrollees are twice as likely to smoke as the general population (pp. 62–70). Even greater numbers of Medicaid patients smoke in states that have not implemented Medicaid expansion under the Affordable Care Act, the authors note, adding these details on effectiveness of state Medicaid tobacco cessation programs: “Every state Medicaid program covers cessation benefits, but the use of these medications varies widely, with the rate in Minnesota being thirty times higher than that in Texas. Most states could increase their efforts to help smokers quit, working with public health agencies, managed care plans, and others. In 2013 Medicaid spent $103 million on cessation medications—less than 0.25 percent of the estimated cost to Medicaid of smoking-related diseases. Additionally, states that have not expanded Medicaid eligibility in the wake of the Affordable Care Act have higher smoking prevalence and lower utilization rates of cessation medication, compared to expansion states. Given these factors, nonexpansion states will have a greater public health burden related to smoking. Medicaid and public health agencies should work together to make smoking cessation a priority for Medicaid beneficiaries.” (L. Ku, lku@gwu.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 © 2016, 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
Jan. 27, 2016 * Vol. 23, No. 17
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 26 issue of JAMA (2016; 315).
Prenatal Vitamin D for Asthma Prevention: Two research articles and an editorial examine the use of prenatal vitamin D supplements for preventing asthma in infants and children during their first 3 years of life.
Compared with offspring of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort whose mothers received vitamin D
3 of 400 IU/d during the third trimester of pregnancy, 581 children born to women receiving doses of 2400 IU/d had these outcomes (pp. 353–61): “Persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze (hazard ratio [HR], 0.76 [95% CI, 0.52–1.12], P = .16), but the number of episodes of troublesome lung symptoms was reduced (mean episodes [95% CI]: 5.9 [5.2–6.6] for the vitamin D3 group vs 7.2 [6.4–8.1] for the control group; incidence risk ratio [IRR], 0.83 [95% CI, 0.71–0.97], P = .02), and the airway immune profile was up-regulated (principal component analysis, P = .04).” (H. Bisgaard, bisgaard@copsac.com)
While “the study may have been underpowered,” researchers report that a 6.1 percentage point difference in incidence of asthma and recurrent wheezing in offspring of women at risk for having a child with asthma who took higher vitamin D doses was not statistically different from results with 400 IU daily doses (
pp. 362–70). In the Vitamin D Antenatal Asthma Reduction Trial, vitamin D3 doses of 4400 IU/d produced these outcomes in comparison with 400 IU/d: “Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%–28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%–73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6–1.0; P = .051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%–47.5%, P <.001).” (A. A. Litonjua, augusto.litonjua@channing.harvard.edu)
While “the lack of any major unwanted effects observed in either of these trials” supports clinicians “prescribing a higher than recommended vitamin D–containing supplement during pregnancy to mothers who are at high risk of having children with asthma,” editorialists emphasize the need for definitive research on the topic (
pp. 347–8): “These studies provide support for a larger adequately powered study of the role of vitamin D supplementation during pregnancy for asthma prevention that includes plans for rigorous outcome assessment and long-term follow-up. Then it may be possible to know whether maternal vitamin D supplementation can reduce the risk of childhood asthma.” (E. von Mutius, erika.von.mutius@med.lmu.de)
Lack of Effects of Smoking Cessation Drug Products: Results of an open-label comparison of three drug approaches to smoking cessation “raise questions about the relative effectiveness of intense smoking pharmacotherapies,” authors conclude (pp. 371–9). The 12-week trial tested varenicline, combination nicotine replacement therapy (C-NRT), and nicotine patches based on carbon monoxide–confirmed self-reported 7-day point-prevalence abstinence at 26 and 52 weeks: “Among 1,086 smokers randomized (52% women; 67% white; mean age, 48 years; mean of 17 cigarettes smoked per day), 917 (84%) provided 12-month follow-up data. Treatments did not differ on any abstinence outcome measure at 26 or 52 weeks, including point-prevalence abstinence at 26 weeks (nicotine patch, 22.8% [55/241]; varenicline, 23.6% [100/424]; and C-NRT, 26.8% [113/421]) or at 52 weeks (nicotine patch, 20.8% [50/241]; varenicline, 19.1% [81/424]; and C-NRT, 20.2% [85/421]). At 26 weeks, the risk differences for abstinence were, for patch vs varenicline, −0.76% (95% CI, −7.4% to 5.9%); for patch vs C-NRT, −4.0% (95% CI, −10.8% to 2.8%); and for varenicline vs C-NRT, −3.3% (95% CI, −9.1% to 2.6%). All medications were well tolerated, but varenicline produced more frequent adverse events than did the nicotine patch for vivid dreams, insomnia, nausea, constipation, sleepiness, and indigestion.” (T. B. Baker, tbb@ctri.wisc.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 © 2016, 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
Jan. 28, 2016 * Vol. 23, No. 18
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 28 New England Journal of Medicine (2016; 374).
Progress in Relapsed Chronic Lymphocytic Leukemia: Effectiveness of venetoclax and acalabrutinib in patients with chronic lymphocytic leukemia (CLL) is examined in two studies and an editorial.
Venetoclax, with the unique mechanism of action of targeting the protein BCL2, “had a manageable safety profile and induced substantial responses in patients with relapsed CLL or [small lymphocytic lymphoma], including those with poor prognostic features,” researchers report (
pp. 311–22). The study included 56 patients in a dose-escalation phase and 60 patients in an expansion cohort, with these results: “The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.” (A. W. Roberts, andrew.roberts@mh.org.au)
“The selective [Bruton’s tyrosine kinase (BTK)] inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion,” conclude authors of the second study (
pp. 323–32). The phase 1–2, uncontrolled trial included 61 patients with relapsed CLL who received oral acalabrutinib in a dose-escalation phase followed by an expansion portion of the study: “The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter’s transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred.” (J. C. Byrd, john.byrd@osumc.edu)
“The transformative characteristics of acalabrutinib and venetoclax arise from effective targeting of important survival pathways in CLL,” editorialists write (
pp. 386–8). “Indeed, BTK inhibition produces durable responses, improves survival, and selects for mutations in the BTK-binding domain. Whether better BTK occupancy as seen with acalabrutinib will reduce the emergence of resistance remains to be seen. Unfortunately, BTK inhibition rarely induces complete remission, indicating that BCR signaling is not critical for survival of all CLL cells or, alternatively, that sufficient inhibition is not achieved. BCL2 also plays an important role in CLL survival, as indicated by the activity of venetoclax, but complete remission is also infrequent, which is probably a result of the up-regulation of alternative BCL2 family members. In vitro, venetoclax and BTK inhibitors are synergistic, which suggests that this combination may further transform the targeted treatment of CLL.” (W. H. Wilson)
Belatacept in Kidney Transplantation: Significant advantages of belatacept in kidney transplantation over cyclosporine regimens are reported in a clinical trial (pp. 333–43; F. Vincenti, flavio.vincenti@ucsf.edu) and discussed in an editorial (pp. 388–9; E. Heher).

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 © 2016, 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
Jan. 29, 2016 * Vol. 23, No. 19
Providing news and information about medications and their proper use

>>>Diabetes Care Highlights
Source:
Feb. issue of Diabetes Care (2016; 39).
New Classification System for Diabetes: Authors issue “an urgent call” for review of the current diabetes mellitus (DM) classification system and consideration of a new, beta-cell–centric model (pp. 179–86): “The current schema … lacks a foundation that readily incorporates advances in our understanding of the disease and its treatment. For appropriate and coherent therapy, we propose an alternate classification system. The beta-cell–centric classification of DM is a new approach that obviates the inherent and unintended confusions of the current system. The beta-cell–centric model presupposes that all DM originates from a final common denominator—the abnormal pancreatic beta-cell. It recognizes that interactions between genetically predisposed beta-cells with a number of factors, including insulin resistance, susceptibility to environmental influences, and immune dysregulation/inflammation, lead to the range of hyperglycemic phenotypes within the spectrum of DM. Individually or in concert, and often self-perpetuating, these factors contribute to beta-cell stress, dysfunction, or loss through at least 11 distinct pathways. Available, yet underutilized, treatments provide rational choices for personalized therapies that target the individual mediating pathways of hyperglycemia at work in any given patient, without the risk of drug-related hypoglycemia or weight gain or imposing further burden on the beta-cells.” (S. S. Schwartz, stschwar@gmail.com)
Primary Glucose-Lowering Effect of Metformin: Metformin exerts its hypoglycemic effect primarily through actions in the lower gut, according to pharmacokinetic and dose-ranging studies of a delayed-release formulation (pp. 198–205). A phase 1 trial of 20 “otherwise healthy” participants compared bioavailability of immediate-release metformin (Met IR), a currently available extended-release formulation (Met XR), and a new delayed-release metformin (Met DR) designed to deliver the drug to the lower bowel. A phase 2 trial of 240 participants with type 2 diabetes examined various doses of Met DR, comparing effects with those of placebo and Met XR. Results showed: “The bioavailability of 1,000 mg Met DR b.i.d. was ~50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR q.d. produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ~40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information.” (M. Fineman, mark.fineman@gmail.com)
Reacting to this study, editorialists write that this “demonstration is clear and straightforward, and the results may have a great impact not only on our understanding of metformin mechanism in humans but also on future metformin therapy in clinic, for example, using gut-released metformin (Met DR) instead of the current formulation (Met XR)” (
pp. 187–9). “In addition, achieving low plasma exposure of metformin by using Met DR might be particularly useful in patients with conditions that increase the life-threatening risk of metformin-associated lactic acidosis, including renal impairment, cardiac dysfunction, hepatic insufficiency, or intercurrent illness such as dehydration.” (R. Song, ruisheng_song@hms.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday approved elbasvir and grazoprevir (Zepatier, Merck) with or without ribavirin for treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections in adult patients. The agency granted the product breakthrough therapy designation for treatment of chronic HCV genotype 1 infection in patients with end stage renal disease on hemodialysis and for treatment of chronic HCV genotype 4 infection.
*
FDA also approved eribulin mesylate (Halaven, Eisai) for second-line treatment of unresectable or metastatic liposarcoma in patients who have received prior chemotherapy that contained an anthracycline drug. In clinical trials, eribulin increased overall survival by approximately 7 months; it is the first drug to improve survival of patients with liposarcoma.

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 © 2016, 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
Feb. 1, 2016 * Vol. 23, No. 20
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 30 issue of Lancet (2016; 387).
Intensive Blood Pressure Lowering: Compared with standard regimens, intensive blood pressure control offers patients greater vascular protection, according to a meta-analysis of 19 trials of 44,989 participants (pp. 435–43). The “net absolute benefits … are large” in high-risk patients, the authors conclude, including advantages for those with systolic blood pressures below 140 mm Hg: “Our meta-analysis showed that after randomisation, patients in the more intensive blood pressure-lowering treatment group had mean blood pressure levels of 133/76 mm Hg, compared with 140/81 mm Hg in the less intensive treatment group. Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4–22]), myocardial infarction (13% [0–24]), stroke (22% [10–32]), albuminuria (10% [3–16]), and retinopathy progression (19% [0–34]). However, more intensive treatment had no clear effects on heart failure (15% [95% CI −11 to 34]), cardiovascular death (9% [–11 to 26]), total mortality (9% [–3 to 19]), or end-stage kidney disease (10% [–6 to 23]). The reduction in major cardiovascular events was consistent across patient groups, and additional blood pressure lowering had a clear benefit even in patients with systolic blood pressure lower than 140 mm Hg. The absolute benefits were greatest in trials in which all enrolled patients had vascular disease, renal disease, or diabetes. Serious adverse events associated with blood pressure lowering were only reported by six trials and had an event rate of 1.2% per year in intensive blood pressure-lowering group participants, compared with 0.9% in the less intensive treatment group (RR 1.35 [95% CI 0.93–1.97]). Severe hypotension was more frequent in the more intensive treatment regimen (RR 2.68 [1.21–5.89], p = 0.015), but the absolute excess was small (0.3% vs 0.1% per person-year for the duration of follow-up).” (J. Lv, jichenglv75@gmail.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
TNF Inhibitors & Skin Cancer: Patients with rheumatoid arthritis must be aware of their increased risk of basal and squamous cell skin cancer, according to a nationwide cohort study from Sweden (i262). Use of TNF-alpha inhibitors produce no further increase in risk of squamous cell carcinoma, the analysis shows, but a 30% increase in risk of basal cell carcinoma was associated with use of the drugs: “For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1,600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks.” (P. Raaschou, Pauline.raaschou@karolinska.se)
Suicidality & Aggression With Antidepressants: A systematic review and meta-analysis of controlled trials and data from the Lilly website show a doubling of risk of mortality, suicidality, aggressive behavior, and akathisia among children and adolescents taking SSRIs or serotonin–norepinephrine reuptake inhibitors (i65). No significant changes in these outcomes were found for adults. The authors conclude that availability of anonymous patient-level data is needed to further “elucidate the harms reliably.” (T. S. Nordic Cochrane Centre, ts@cochrane.dk)

>>>PNN JournalWatch
* Decreasing Duration of Antibiotic Prescribing for Uncomplicated Skin and Soft Tissue Infections, in
Pediatrics, 2016; 137: 10.1542/peds.2015-1223. (C. L. Schuler)
* Rotavirus Vaccines—OK to Mix and Match, in
Pediatrics, 2016; 137: 10.1542/peds.2015-3618. (C. L. Byington)
* Comparative Effectiveness of Clozapine and Standard Antipsychotic Treatment in Adults With Schizophrenia, in
American Journal of Psychiatry, 2016; 173: 166–73. (T. S. Stroup, stroups@nyspi.columbia.edu)
* Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder, in
American Journal of Psychiatry, 2016; 173: 174–83. (E. Jakubovski)

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 © 2016, 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
Feb. 2, 2016 * Vol. 23, No. 21
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 2 issue of the Annals of Internal Medicine (2016; 164).
Adult Immunization Schedule for 2016: The annual revisions of the adult immunization recommendations by the CDC’s Advisory Committee on Immunization Practices contain notable changes in terminology and vaccine timing and correct two items stated incorrectly in previous versions (pp. 184–94; CDC, www.cdc.gov/vaccines/schedules):
* Interval change for 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) from “6 to 12 months” to “at least 1 year” for immunocompetent adults aged ≥65 years. Adults aged ≥19 years with anatomical or functional asplenia, cerebrospinal fluid leak, or cochlear implant or who are immunocompromised should receive PPSV23 at least 8 weeks after PCV13.
* Serogroup B meningococcal (MenB) vaccine series should be administered to persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease. Those at increased risk include persons with anatomical or functional asplenia or persistent complement component deficiencies, microbiologists who are routinely exposed to isolates of
Neisseria meningitidis, and persons identified at increased risk because of a serogroup B meningococcal disease outbreak. MenB vaccine series may be administered to adolescents and young adults aged 16 through 23 years (preferred age is 16 through 18 years) to provide short-term protection against most strains of serogroup B meningococcal disease.
* Nine-valent human papillomavirus (HPV) vaccine (9vHPV) was added to the 2016 adult immunization schedule. This vaccine can be used for routine vaccination against HPV as 1 of 3 HPV vaccines (bivalent HPV vaccine [2vHPV], quadrivalent HPV vaccine [4vHPV], and 9vHPV) recommended for females and 1 of 2 HPV vaccines (4vHPV and 9vHPV) recommended for males.
* The row for “Meningococcal” was retitled to “Meningococcal 4-valent conjugate (MenACWY) or polysaccharide (MPSV4)” to indicate that there are 2 types of serogroup A, C, W, and Y meningococcal vaccines available for adults.
* A new row for “Meningococcal B (MenB)” was added.
* Additional text was added in several indication bars to describe reasons for alternate dosing schedules for vaccines where such designations were appropriate; for example, in the “Measles, mumps, and rubella (MMR)” indication bar that states “1 or 2 doses,” the clause “depending on indication” was added.
* The “Hepatitis A” indication bar was revised from “2 doses” to “2 or 3 doses depending on vaccine” to account for the hepatitis A and hepatitis B combination vaccine that is administered in a 3-dose series.
* “Adults aged ≥19 years” replaced “adults aged 19 through 64 years” as the age group for pneumococcal vaccination recommendations for persons with immunocompromising conditions, anatomical or functional asplenia, cerebrospinal fluid leak, or cochlear implant. The interval from PCV13 vaccination to PPSV23 vaccination is at least 8 weeks for adults aged ≥19 years with these conditions. For adults aged ≥65 years without these conditions, the interval from PCV13 vaccination to PPSV23 vaccination is at least 1 year.
* “Adults aged 19 through 64 years who are residents of nursing homes and other long-term care facilities” was removed from those for whom PPSV23 is recommended. These adults should be assessed for pneumococcal vaccination status and receive pneumococcal vaccines recommended based on their health condition(s) or age.
Disclosing Pleiotropic Gene Effects: In patients undergoing screening for Alzheimer disease (AD), disclosure of information about the apolipoprotein E (APOE) gene’s effects on other conditions “did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions,” researchers report (pp. 155–63). Mutations in such pleiotropic genes can affect multiple conditions; in this case, APOE can increase risk for AD, coronary artery disease (CAD), or both. Results of this randomized trial led the investigators to conclude, “Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk.” (R. C. Green, rcgreen@genetics.med.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Feb. 3, 2016 * Vol. 23, No. 22
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Feb. 2 issue of JAMA (2016; 315).
Subcutaneous Dupilumab in Chronic Sinusitis & Nasal Polyposis: In patients with symptomatic chronic sinusitis and nasal polyps refractory to intranasal corticosteroids, endoscopic nasal polyp burden was reduced after 16 weeks of subcutaneous dupilumab and mometasone furoate nasal spray, compared with mometasone alone (pp. 469–79). In a parallel-group study, these outcomes were noted for dupilumab 300 mg weekly following a 600-mg loading dose: “Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was −0.3 (95% CI, −1.0 to 0.4) with placebo and −1.9 (95% CI, −2.5 to −1.2) with dupilumab (LS mean difference, −1.6 [95% CI, −2.4 to −0.7]; P < .001). The LS mean difference between the 2 groups for the Lund–Mackay [computed tomography (CT)] total score was −8.8 (95% CI, −11.1 to −6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, −18.1 [95% CI, −25.6 to −10.6]; P < .001) and sense of smell assessed by [the University of Pennsylvania Smell Identification Test] (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).” (C. Bachert, claus.bachert@ugent.be)
Acetazolamide & Duration of Invasive Mechanical Ventilation in COPD: The randomized DIABOLO study shows acetazolamide added to therapy of intubated patients with chronic obstructive pulmonary disorder (COPD) does not reduce the duration of invasive mechanical ventilation (pp. 480–8). The drug “has been used for decades as a respiratory stimulant” in patients with COPD and metabolic alkalosis, the authors write, but no randomized, placebo-controlled evidence supported the practice. Initiated within 48 hours of ICU admission and continued for up to 28 days, I.V. acetazolamide 500–1000 mg twice daily had these effects in comparison with placebo: “Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379 [99.7%] with endotracheal intubation) completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (−16.0 hours; 95% CI, −36.5 to 4.0 hours; P = .17), duration of weaning off mechanical ventilation (−0.9 hours; 95% CI, −4.3 to 1.3 hours; P = .36), daily changes of minute-ventilation (−0.0 L/min; 95% CI, −0.2 to 0.2 L/min; P = .72), or partial carbon-dioxide pressure in arterial blood (−0.3 mm Hg; 95% CI, −0.8 to 0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference, −0.8 mEq/L; 95% CI, −1.2 to −0.5 mEq/L; P < .001) and number of days with metabolic alkalosis (between-group difference, −1; 95% CI, −2 to −1 days; P < .001) decreased significantly more in the acetazolamide group. Other secondary outcomes also did not differ significantly between groups.” (C. Faisy, christophe.faisy@egp.aphp.fr)
Using Drugs Past Expiration Dates: An article reprinted from the Medical Letter on Drugs and Therapeutics reviews the factors involved in drug degradation, including safety, heat, humidity, long-term storage, and dosage forms (pp. 510–1). “Many solid dosage formulations stored under reasonable conditions in their original unopened containers retain ≥90% of their potency for at least 5 years after the expiration date on the label, and sometimes much longer,” the article concludes. “Solutions and suspensions are generally less stable. There are no reports of toxicity from degradation products of currently available drugs.” (www.medicalletter.org)
FDA & Affordability of Off-Patent Drugs: While Congress looks at “business strategies that are distorting the market for generic drugs,” FDA should act when pharmaceutical companies raise prices of older medications by exorbitant amounts (pp. 461–2). FDA has the authority to permit compounding of alternative products, the authors write, and also to temporarily permit importation of drug products “reviewed by competent regulatory authorities and approved for sale outside the United States.” (J. A. Greene, greene@jhmi.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 © 2016, 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
Feb. 4, 2016 * Vol. 23, No. 23
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Feb. 4 issue of the Annals of Internal Medicine (2016; 374).
Antenatal Metformin in Women With Obesity: Among women with BMIs greater than 35 kg/sq m and without diabetes, metformin during pregnancy reduced maternal weight but not neonatal weight, researchers report (pp. 434–43). Study participants were randomized to metformin 3 g/d or placebo from 12–18 weeks’ gestation to delivery, with these effects on a primary outcome of reduction in the median neonatal birth-weight z score by 0.3 SD (equivalent to a 50% reduction, from 20% to 10%, in the incidence of large-for-gestational-age neonates): “A total of 50 women withdrew consent during the trial, which left 202 women in the metformin group and 198 in the placebo group. There was no significant between-group difference in the median neonatal birth-weight z score (0.05 in the metformin group [interquartile range, −0.71 to 0.92] and 0.17 in the placebo group [interquartile range, −0.62 to 0.89], P = 0.66). The median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P <0.001), as was the incidence of preeclampsia (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P = 0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.” (H. Shehata, hassan.shehata@nhs.net)
Amoxicillin for Uncomplicated Severe Acute Malnutrition: A study from Niger provides evidence that the common recommendation of administering routine amoxicillin to severely malnourished children is not effective (pp. 444–53). Authors conclude that “health care facilities could consider eliminating the routine use of antibiotics in protocols for the treatment of uncomplicated severe acute malnutrition” in “regions with adequate infrastructure for surveillance and management of complications.” Results of the double-blind trial of children aged 6–59 months showed the following: “A total of 2,412 children underwent randomization, and 2,399 children were included in the analysis. Nutritional recovery occurred in 65.9% of children in the amoxicillin group (790 of 1,199) and in 62.7% of children in the placebo group (752 of 1,200). There was no significant difference in the likelihood of nutritional recovery (risk ratio for amoxicillin vs. placebo, 1.05; 95% confidence interval [CI], 0.99 to 1.12; P = 0.10). In secondary analyses, amoxicillin decreased the risk of transfer to inpatient care by 14% (26.4% in the amoxicillin group vs. 30.7% in the placebo group; risk ratio, 0.86; 95% CI, 0.76 to 0.98; P = 0.02).” (R. F. Grais, rebecca.grais@epicentre.msf.org)

>>>Cardiology Highlights
Source:
Feb. 9 issue of the Journal of the American College of Cardiology (2016; 67).
Intentional v. Unintentional Nonadherence: In a report on secondary prevention lipid performance measures, a task force of the American College of Cardiology and the American Heart Association differentiates between intentional nonadherence and other reasons people may not take medications (pp. 558–87): “Unintentional nonadherence is thought to be a passive process on the part of the patient and may involve a lack of understanding of physical problems, resulting in an inability to follow treatment instructions, impaired manual dexterity, poor eyesight, or forgetfulness. In a recent systematic review and meta-analysis, it was noted that there is a statistically significant relationship between health literacy and medication adherence; however, the magnitude of effect was small when compared with other causes of nonadherence, such as medication beliefs and cost. One of the most important aspects of long-term medication adherence is to review the medication list; ask about adverse effects, cost, and adherence; and discuss barriers to adherence at every office visit. Finally, the shared accountability of all of those involved in the prescription process, including the patient, is critical to the success or failure of long-term medication adherence.” (www.acc.org; my.americanheart.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 © 2016, 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
Feb. 5, 2016 * Vol. 23, No. 24
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Feb. issue of Pediatrics (2016; 137).
Effectiveness of Live Attenuated & Inactivated Influenza Vaccine: The live attenuated influenza vaccine (LAIV) was less effective against influenza A/H1N1pdm09 than the inactivated influenza vaccine (IIV) among 2,703 children and adolescents during some influenza seasons, researchers report (10.1542/peds.2015-3279). Effectiveness was similar against influenza A(H3N2) and B, leading to a conclusion of “poor performance related to the LAIV A/H1N1pdm09 viral construct.” Using U.S. Influenza Vaccine Effectiveness Network data for participants aged 2–17 years in 2010–11 through 2013–14, investigators calculated these relative effectiveness values based on logistic regression: “Odds of influenza were similar for LAIV and IIV recipients during 3 seasons (2010–2011 through 2012–2013). In 2013–2014, odds of influenza were significantly higher among LAIV recipients compared with IIV recipients 2 to 8 years old (OR 5.36; 95% CI, 2.37 to 12.13). Participants vaccinated with LAIV or IIV had similar odds of illness associated with influenza A/H3N2 or B. LAIV recipients had greater odds of illness due to influenza A/H1N1pdm09 in 2010–2011 and 2013–2014.” (J. R. Chung)
Sequential Rotavirus Vaccine Schedules: Switching between approved rotavirus vaccines is safe and produces similar immune responses, according to results of an open-label study of healthy infants aged 6–14 weeks (10.1542/peds.2015-2603). Participants were randomized to receive either a single vaccine for all three rotavirus doses or one of three combinations of the products. Results showed: “Between March 2011 and September 2013, 1,393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated.” (R. Libster)
In Utero Beta-Agonist Exposure & Autism Disorders: Children exposed during pregnancy to beta-2-adrenergic receptor (B2AR) agonists had higher risks of developing autism spectrum disorders (ASD) in a case–control study from Denmark (10.1542/peds.2015-1316). Among 5,200 children born in 1997–2006, these patterns were observed for 5,200 cases of ASD and 52,000 controls: “Use of B2ARs during pregnancy was associated with increased risk of ASD, even after adjustment for maternal asthma and other covariates (OR: 1.3, 95% CI: 1.1–1.5). The elevated risk was observed with use of B2AR during preconception (OR: 1.3, 95% CI: 1.0–1.6), first trimester (OR: 1.3, 95% CI: 1.1–1.5), second trimester (OR: 1.5, 95% CI: 1.1–1.7), and the third trimester (OR: 1.4, 95% CI: 1.1–1.7). There was some evidence that longer B2AR within-pregnancy use was associated with the increased risk.” (N. B. Gidaya)

>>>Psychiatry Highlights
Source:
Feb. issue of the American Journal of Psychiatry (2016; 173).
Neurobehavioral Functioning After Drug Exposure: Potential problems with neurobehavioral development after SSRI and/or benzodiazepine exposure in utero were identified in a study of children born to 184 women with depression (pp. 147–57): “Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake.” (A. L. Salisbury)

>>>PNN NewsWatch
* The HHS National Vaccine Program Office yesterday released the final National Adult Immunization Plan. The document focuses on strengthening the adult immunization infrastructure, improving vaccine access, improving vaccine demand, and fostering innovation of vaccines and associated technologies. It will guide federal and other adult-vaccine efforts through 2020.
* Robert Califf, MD, yesterday called for a far-reaching action plan to reassess the agency’s approach to
opioid medications. Califf, currently a deputy commissioner at FDA, has been nominated but not confirmed as FDA Commissioner.

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 © 2016, 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
Feb. 8, 2016 * Vol. 23, No. 25
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 6 issue of Lancet (2016; 387).
Preexposure HIV Prophylaxis & Postnatal Transmission: In a study conducted in Africa, lopinavir–ritonavir was not superior to lamivudine alone for preventing postnatal transmission of HIV-1 among infants not infected with the virus at birth to HIV-1–infected mothers, researchers report (pp. 566–73). Infants were randomized at 7 days to one of the two regimens, and therapy continued until 1 week after complete cessation of breastfeeding or week 50. Results showed: “Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1,273 infants and analysed 1,236; 615 assigned to lopinavir–ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir–ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1.4% (95% CI 0.4–2.5) and 1.5% (0.7–2.5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio [HR] of lopinavir–ritonavir versus lamivudine of 0.90, 95% CI 0.35–2.34; p = 0.83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3–4 event in the lopinavir–ritonavir group compared with 246 (50%) in the lamivudine group.” (P. Van de Perre, p-van_de_perre@chu-montpellier.fr)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Benzodiazepine Use & Cognitive Function: Using the cognitive abilities screening instrument (CASI) administered every 2 years in an integrated health system in Seattle, investigators found that minimal exposure to benzodiazepines produced a slightly higher risk of dementia but that those with the highest exposures had no increased risk (i90). The results “do not support a causal association between benzodiazepine use and dementia,” the authors concluded, based on these findings in 3,434 participants aged 65 or older at study entry: “Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1–30 [total standardized daily doses (TSDDs)]; 1.31 (1.00 to 1.71) for 31–120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline.” (S. Gray slgray@u.washington.edu)

>>>PNN JournalWatch
* Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report, in
Chest, 2016; 149: 315–52. (E. A. Akl)
* Antimicrobial Peptides and Innate Lung Defenses: Role in Infectious and Noninfectious Lung Diseases and Therapeutic Applications, in
Chest, 2016; 149: 545–51. (P. S. Hiemstra)
* Effectiveness and Value of Treatment Options for Obesity—A Report for the California Technology Assessment Forum, in
JAMA Internal Medicine, 2016; 176: 247–8. (D. A. Ollendorf)
* Testosterone and Cardiovascular Disease, in
Journal of the American College of Cardiology, 2016; 67: 545–57. (R. A. Kloner)
* Cardiovascular Effects of Androgen Deprivation Therapy for the Treatment of Prostate Cancer: ABCDE Steps to Reduce Cardiovascular Disease in Patients With Prostate Cancer, in
Circulation, 2016; 133: 537–41. (A. K. Morgans, alicia.morgans@vanderbilt.edu)
* Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup, in
American Journal of Kidney Diseases, 2016; 67: 187–97. (T. D. Nolin, nolin@pitt.edu)
* Metabolic Acidosis of CKD: An Update, in
American Journal of Kidney Diseases, 2016; 67: 307–17. (J. A. Kraut, jkraut@ucla.edu)
* Therapeutic Advances in HCV Genotype 1 Infection: Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2016; 36: 10.1002/phar.1700. (P. Deming, pdeming@salud.unm.edu)
* Fulfilling an Unmet Need: Roles for Clinical Pharmacists in Preconception Care, in
Pharmacotherapy, 2016; 36: 10.1002/phar.1691. (N. A. DiPietro Mager, n-dipietro@onu.edu)
* Preventing Infant Mortality: Pharmacists’ Call to Action, in
Journal of the American Pharmacists Association, 2016; 56: 82–7. (N. A. DiPietro Mager, n-dipietro@onu.edu)
* ASHP Multihospital Health-System Pharmacy Executives Leadership Symposium. Forecasting the Future of Pharmacy: A Five-Year Plan, in
American Journal of Health-System Pharmacy, 2016; 73: 247–53.

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 © 2016, 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
Feb. 9, 2016 * Vol. 23, No. 26
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. issue of JAMA Internal Medicine (2016; 176).
High-Dose Vitamin D & Prevention of Functional Decline: High monthly doses of vitamin D failed to improve lower-extremity function among individuals 70 years or older and were associated with increased risks of falls, compared with low vitamin D doses, according to results of a study conducted in Zurich (pp. 175–83). For 1 year, participants received monthly vitamin D3 24,000 IU, vitamin D3 60,000 IU, or vitamin D3 24,000 IU plus calcifediol 300 mcg, with these effects on a primary end point of improving lower extremity function (on the Short Physical Performance Battery) and achieving 25-hydroxyvitamin D levels of at least 30 ng/mL at 6 and 12 months: “The study cohort comprised 200 participants (men and women ≥70 years with a prior fall). Their mean age was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Intent-to-treat analyses showed that, while 60,000 IU and 24,000 IU plus calcifediol were more likely than 24,000 IU to result in 25-hydroxyvitamin D levels of at least 30 ng/mL (P = .001), they were not more effective in improving lower extremity function, which did not differ among the treatment groups (P = .26). However, over the 12-month follow-up, the incidence of falls differed significantly among the treatment groups, with higher incidences in the 60,000 IU group (66.9%; 95% CI, 54.4% to 77.5%) and the 24,000 IU plus calcifediol group (66.1%; 95% CI, 53.5%–76.8%) group compared with the 24,000 IU group (47.9%; 95% CI, 35.8%–60.3%) (P = .048). Consistent with the incidence of falls, the mean number of falls differed marginally by treatment group. The 60,000 IU group (mean, 1.47) and the 24,000 IU plus calcifediol group (mean, 1.24) had higher mean numbers of falls compared with the 24,000 IU group (mean, 0.94) (P = .09).” (H. A. Bischoff-Ferrari, heike.bischoff@usz.ch)
“The vitamin D story seems to be following the familiar pattern observed with antioxidant vitamins,” editorialists write (
pp. 171–2). “Enthusiasm for the health benefits of vitamin supplements is coupled with the belief that ‘vitamins’ are inherently safe and reinforced by observational studies showing, essentially, that healthy people have higher vitamin levels. Then [randomized controlled trials] and meta-analyses proved that the supplements in fact increase mortality (beta-carotene, vitamin E), or have no health benefits (vitamin A, vitamin C).” (S. R. Cummings, scummings@sfcc-cpmc.net)
Mailing Nicotine Patches to Adult Smokers: Adult smokers recruited from across Canada had higher self-reported tobacco cessation rates when they received nicotine patches by mail, compared with no intervention, researchers report (pp. 184–90). The 5-week intervention provided a 3-week supply of step 1 patches, 1 week of step 2 patches, and 1 week of step 3 patches without any behavioral support. Results showed: “Of the 2,093 participants who were interviewed as part of the baseline survey (76.5% response rate), 1,000 were found eligible for the trial and randomized to a group. Analyses were conducted on 500 participants in the experimental group (mean [SD] age, 48.0 [12.8] years; 255 female [51.0%]) and 499 in the control group (mean [SD] age, 49.7 [12.7] years; 256 female [51.3%]). Self-reported abstinence rates were significantly higher among participants who were sent nicotine patches compared with the control group (30-day abstinence: 38 [7.6%] of 500 vs 15 [3.0%] of 499; odds ratio, 2.65; 95% CI, 1.44–4.89; P = .002). Usable saliva samples were returned by only 50.9% of the participants. Biochemically validated abstinence at 6 months was found in 14 (2.8%) of 500 participants in the experimental group vs 5 (1.0%) of 499 in the control group (odds ratio, 2.85; 95% CI, 1.02–7.96; P = .046).” (J. A. Cunningham, john.cunningham@camh.ca)
PPIs & CKD: Among 10,482 participants in the Atherosclerosis Risk in Communities study, use of proton pump inhibitors (PPIs) was associated with higher risk of incident chronic kidney disease (CKD) (pp. 238–46). “The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01–1.91) and with propensity score–matched nonusers (HR, 1.76; 95% CI, 1.13–2.74),” the authors added, noting consistency when the findings were replicated in a health-system cohort. (M. E. Grams, mgrams2@jhmi.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 © 2016, 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
Feb. 10, 2016 * Vol. 23, No. 27
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Feb. 9 issue of JAMA (2016; 315).
Changing Antibiotic Prescribing Behaviors: Behavioral interventions proved effective for reducing inappropriate antibiotic prescribing among primary care physicians (pp. 562–70). Over 18-month periods beginning in 2011–12, cluster-randomized primary care practices received 0, 1, 2, or 3 interventions: suggested alternatives using electronic order sets; accountable justification prompts calling for free-text justifications; and/or peer-comparison emails. Results showed: “Mean antibiotic prescribing rates decreased from 24.1% at intervention start to 13.1% at intervention month 18 (absolute difference, −11.0%) for control practices; from 22.1% to 6.1% (absolute difference, −16.0%) for suggested alternatives (difference in differences, −5.0% [95% CI, −7.8% to 0.1%]; P = .66 for differences in trajectories); from 23.2% to 5.2% (absolute difference, −18.1%) for accountable justification (difference in differences, −7.0% [95% CI, −9.1% to −2.9%]; P < .001); and from 19.9% to 3.7% (absolute difference, −16.3%) for peer comparison (difference in differences, −5.2% [95% CI, −6.9% to −1.6%]; P < .001).” (J. N. Doctor, jdoctor@usc.edu)
Further evidence for these promising results is not needed before implementation, editorialists write (
pp. 558–9): “Clinicians should be required to justify every antibiotic order by documenting an indication and should be compared with and held to the standard of ‘top-performing’ peers. With the uptake of electronic health records in the ambulatory setting, a national database could be created for benchmarking antibiotic prescribing for the most common acute respiratory tract infections, analogous to the Centers for Disease Control and Prevention Antimicrobial Use and Resistance module for acute care hospitals. This approach would provide an invaluable tool for broad dissemination of this outpatient antimicrobial stewardship intervention and for reducing the patient harm caused by the overuse of antibiotics.” (J. S. Gerber, gerberj@chop.edu)
Inpatient Antibiotic Therapy for Community-Acquired Pneumonia: Results of a systematic review show that “antibiotic therapy consisting of beta-lactam plus macrolide combination therapy or fluoroquinolone monotherapy initiated within 4 to 8 hours of hospital arrival was associated with lower adjusted short-term mortality, supported predominantly by low-quality observational studies,” for patients hospitalized with community-acquired pneumonia (pp. 593–602; M. J. Fine, michael.fine@va.gov)
VA v. Non-VA Care of AMI, HF & Pneumonia: Compared with care delivered at non–Veterans Affairs (VA) hospitals to older men with acute myocardial infarction (AMI), heart failure (HF), or pneumonia, VA hospitals had lower 30-day risk-standardized all-cause mortality rates for AMI and HF, but higher 30-day risk-standardized all-cause readmission rates for all 3 conditions, researchers report (pp. 582–92). Analysis of Medicare claims data showed these results at 104 VA and 1,513 non-VA hospitals: “Mortality rates were lower in VA hospitals than non-VA hospitals for AMI (13.5% vs 13.7%, P = .02; −0.2 percentage-point difference) and HF (11.4% vs 11.9%, P = .008; −0.5 percentage-point difference), but higher for pneumonia (12.6% vs 12.2%, P = .045; 0.4 percentage-point difference). In contrast, readmission rates were higher in VA hospitals for all 3 conditions (AMI, 17.8% vs 17.2%, 0.6 percentage-point difference; HF, 24.7% vs 23.5%, 1.2 percentage-point difference; pneumonia, 19.4% vs 18.7%, 0.7 percentage-point difference, all P < .001). In within-MSA comparisons, VA hospitals had lower mortality rates for AMI (percentage-point difference, −0.22; 95% CI, −0.40 to −0.04) and HF (−0.63; 95% CI, −0.95 to −0.31), and mortality rates for pneumonia were not significantly different (−0.03; 95% CI, −0.46 to 0.40); however, VA hospitals had higher readmission rates for AMI (0.62; 95% CI, 0.48 to 0.75), HF (0.97; 95% CI, 0.59 to 1.34), or pneumonia (0.66; 95% CI, 0.41 to 0.91).” (H. M. Krumholz, harlan.krumholz@yale.edu)
“These findings are important because they suggest that despite all of the challenges that VA hospitals have faced, they are still able to deliver high-quality care for some of the sickest, most complicated patients,” an editorialist writes (
pp. 560–1). “Taking these lessons to heart will result in the delivery of much better care.” (A. K. Jha, ajha@hsph.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Feb. 11, 2016 * Vol. 23, No. 28
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Feb. 11 issue of the New England Journal of Medicine (2016; 374).
Caplacizumab for TTP: In 75 patients with acquired thrombotic thrombocytopenic purpura (TTP), caplacizumab induced faster resolutions of acute episodes than did placebo, researchers report (pp. 511–22). The phase 2 trial of the platelet-protecting inhibitor of ultralarge von Willebrand factor multimers compared subcutaneous caplacizumab 10 mg daily and placebo during plasma exchange and for 30 days, producing these results: “The time to a response was significantly reduced with caplacizumab as compared with placebo (39% reduction in median time, P = 0.005). Three patients in the caplacizumab group had an exacerbation, as compared with 11 patients in the placebo group. Eight patients in the caplacizumab group had a relapse in the first month after stopping the study drug, of whom 7 had ADAMTS13 activity that remained below 10%, suggesting unresolved autoimmune activity. Bleeding-related adverse events, most of which were mild to moderate in severity, were more common with caplacizumab than with placebo (54% of patients vs. 38%). The frequencies of other adverse events were similar in the two groups. Two patients in the placebo group died, as compared with none in the caplacizumab group.” (F. Callewaert, filip.callewaert@ablynx.com)
“Many questions remain with regard to the optimal timing and sequencing of these therapeutic options in the management of TTP, not only in the curative treatment of patients in acute phases but also in the prevention of relapses,” concludes an editorialist (
pp. 583–5). “It is interesting to speculate that effective TTP treatment will involve a combination of interventions that target different aspects of the pathophysiology. ADAMTS13 replacement with either normal plasma or perhaps recombinant product would restore processing of von Willebrand factor multimers to the appropriate size. Formation of new microthrombi can be blocked by interfering with the binding of von Willebrand factor to platelets, as shown by the efficacy of caplacizumab. The autoantibody to ADAMTS13 can be inhibited by selective suppression of the B cells that produce the antibody — for example, with rituximab or other anti–B-cell antibodies. A remaining goal is the disaggregation of platelet-rich thrombi.” (A. Veyradier)
Dexamethasone in HIV-Associated Cryptococcal Meningitis: In a trial stopped early for safety reasons, adjunctive dexamethasone failed to reduce mortality in patients with HIV-associated cryptococcal meningitis and produced more adverse effects and disability (pp. 542–54). All participants in the study, conducted in southeast Asia and Africa, received amphotericin B and fluconazole plus with dexamethasone or placebo, with these results: “Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P = 0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P = 0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P <0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P = 0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P = 0.003), renal events (22 vs. 7, P = 0.004), and cardiac events (8 vs. 0, P = 0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites.” (J. N. Day, jday@oucru.org)
Urinary Tract Infections in Older Men: In a case vignette of a 79-year-old man with likely chronic bacterial prostatitis manifested as acute episodes of febrile urinary tract infections, authors conclude, “If the testing to localize the infection to the prostate is positive and the organism is sensitive to a fluoroquinolone or trimethoprim–sulfamethoxazole, a 30-day course of treatment is indicated” (pp. 562–71; A. J. Schaeffer, ajschaeffer@northwestern.edu).

>>>PNN NewsWatch
* Certain lots of SyrSpend SF and SyrSpend SF Grape suspending agents used in compounding of various oral liquid drug products are being recalled because of the presence of Candida galli, FDA says.

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 © 2016, 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
Feb. 12, 2016 * Vol. 23, No. 29
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
Feb. 16 issue of the Journal of the American College of Cardiology (2016; 67).
Ticagrelor in Low-Risk PCI: Compared with the conventional clopidogrel loading doses (LDs) in an open-label trial, ticagrelor LD provided “more prompt and potent platelet inhibition, and lower [high on-treatment platelet reactivity (HPR)] rates” in low-risk patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCIs) (pp. 603–13). In the Ad Hoc Percutaneous Coronary Intervention Study in Acute Coronary Syndrome Patients, 100 P2Y12 inhibitor–naive, troponin-negative patients with ACS were randomized to ticagrelor 180 mg LD or clopidogrel 600 mg LD, with these effects on platelet reactivity (P2Y12 reaction units [PRU]): “At 2 h, PRU levels were significantly lower with ticagrelor versus clopidogrel (98.4 ± 95.4 vs. 257.5 ± 74.5; p < 0.001; primary endpoint). PRU levels diverged as early as 0.5 h post-LD, with significant differences observed by the end of PCI (mean 0.6 h post-LD) and maintained up to 8 h post-LD. HPR rates were also significantly reduced with ticagrelor compared with clopidogrel at the end of PCI (p = 0.030), and at 2 h (p < 0.001) and 8 h (p < 0.001) after LD.” (D. J. Angiolillo)
“Elective PCI performed in stable [coronary artery disease] patients looks like a new potential indication for ticagrelor,” editorialists write (
pp. 614–7). “There is a medical demand from physicians for intuitive protection when complex revascularization procedures are performed, a strategy somewhat supported by guidelines. Whether a medical need exists for patients will be known only after the results of … ongoing trials are published.” (J. Silvain)
Statins for Primary Prevention in Low-Risk Population: The frequency of major adverse cardiovascular events (MACE) and mortality rates were reduced among low-risk patients aged 35–85 years who were placed on statin therapy during 2006–13 in the Catalan primary care system, researchers report (pp. 630–40). Patients included in the analysis had a low ankle-brachial index and no cardiovascular disease. Results showed absolute reductions in risk “comparable to that achieved in secondary prevention” of cardiovascular disease, the authors note, adding these details: “The matched-pair cohort included 5,480 patients (mean age 67 years; 44% women) treated/nontreated with statins. The 10-year coronary heart disease risk was low (median: 6.9%). Median follow-up was 3.6 years. Incidence of MACE was 19.7 and 24.7 events per 1,000 person–years in statin new-users and nonusers, respectively. Total mortality rates also differed: 24.8 versus 30.3 per 1,000 person–years, respectively. Hazards ratios were 0.80 for MACE and 0.81 for overall mortality. The 1-year number needed to treat was 200 for MACE and 239 for all-cause mortality.” (R. Ramos)

>>>Circulation Highlights
Source:
Feb. 9 issue of Circulation (2016; 133).
Texting for Adherence: In the SMS-Text Adherence Support (StAR) trial, automated mobile phone short message system (SMS) texts to patients with hypertension had little effect on systolic blood pressure reductions over a 12-month period (pp. 592–600). Conducted in South Africa, the pragmatic trial allocated 1,372 patients randomly to information only, interactive SMS text messaging, or usual care. Results showed: “At 12 months, the mean adjusted change in systolic blood pressure compared with usual care was −2.2 mm Hg (95% confidence interval, −4.4 to −0.04) with information-only SMS and −1.6 mm Hg (95% confidence interval, −3.7 to 0.6) with interactive SMS. Odds ratios for the proportion of participants with a blood pressure <140/90 mm Hg were 1.42 (95% confidence interval, 1.03–1.95) for information-only messaging and 1.41 (95% confidence interval, 1.02–1.95) for interactive messaging compared with usual care.” (A. J. Farmer, andrew.farmer@phc.ox.ac.uk)

>>>PNN NewsWatch
* A new standard for PGY1 Community-Based Pharmacy Residency Programs has been approved by ASHP and APhA, the groups announced last week. Associated Competencies, Goals, and Objectives and a guidance document are expected to be released later this year. Mandatory implementation of the new standard is expected by July 2017.
*
PNN will not be published on Mon., Feb. 15, Presidents 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 © 2016, 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
Feb. 16, 2016 * Vol. 23, No. 30
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-online articles in and Feb. 16 issue of the Annals of Internal Medicine (2016; 164).
ESAs in CKD: Used to treat anemia in patients with chronic kidney disease (CKD), erythropoietin-stimulating agents (ESAs) do not improve health-related quality of life (HRQOL), according to a systematic review and meta-analysis (doi:10.7326/M15-1839). Data from 36-item Short-Form Health Surveys (SF-36) and Kidney Dialysis Questionnaire (KDQ) showed: “Of 17 eligible studies, 13 reported SF-36 outcomes and 4 reported KDQ outcomes. Study populations consisted of patients not undergoing dialysis (n = 12), those undergoing dialysis (n = 4), or a mixed sample (n = 1). Only 4 studies had low risk of bias. Pooled analyses showed that higher hemoglobin targets resulted in no statistically or clinically significant differences in SF-36 or KDQ domains. Differences in HRQOL were further attenuated in studies at low risk of bias and in subgroups of dialysis recipients.” (N. Tangri, ntangri@sogh.mb.ca)
Treatment Advances & Mortality in Breast Cancer Screening Trials: Published in conjunction with updated recommendations for breast cancer screening from the U.S. Preventive Services Task Force (pp. 244–55 and 256–67; H. D. Nelson, nelsonh@ohsu.edu), a population-based simulation study of virtual screening trials finds a decrease in absolute benefits of screening for breast cancer based on advances in systemic therapies for breast cancer (pp. 236–43). Projecting data from meta-analyses of screening and treatment trials, the investigators found the following patterns in U.S. women aged 50–74 years of age at time horizons of 10 and 25 years from a population perspective: “At 10 years, screening in a 1975 trial yielded [a breast cancer mortality rate ratio (MRR] of 90% and an [absolute risk reduction (ARR)] of 5 deaths per 10,000 women. A 2015 screening trial yielded a 10-year MRR of 90% and an ARR of 3 deaths per 10,000 women.… Greater reductions in advanced-stage disease yielded a greater screening effect, but MRRs remained similar across trials. However, ARRs were consistently lower under contemporary treatments. When contemporary treatments were available only for early-stage cases, the MRR was 88%.” (R. Etzioni, retzioni@fredhutch.org)
This study “shows that changes in treatment efficiency over time cannot explain … contrasts” found in divergent levels of relative risk reduction of previously published meta-analyses (
pp. 297–8). “Hence, the factors associated with trial design (for example, the absence of blinding) and statistical analyses probably led to overestimation of the capacity of breast screening to decrease the risk for breast cancer death.” (P. Autier, philippe.autier@i-pri.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
RAS Blockers in Diabetes: “In people with diabetes, [renin angiotensin system (RAS)] blockers are not superior to other antihypertensive drug classes such as thiazides, calcium channel blockers, and beta-blockers at reducing the risk of hard cardiovascular and renal endpoints,” conclude authors of a systematic review and meta-analysis of 19 randomized controlled trials of 25,414 participants (i438): “When compared with other antihypertensive agents, RAS blockers were associated with a similar risk of death (relative risk 0.99, 95% confidence interval 0.93 to 1.05), cardiovascular death (1.02, 0.83 to 1.24), myocardial infarction (0.87, 0.64 to 1.18), angina pectoris (0.80, 0.58 to 1.11), stroke (1.04, 0.92 to 1.17), heart failure (0.90, 0.76 to 1.07), and revascularization (0.97, 0.77 to 1.22). There was also no difference in the hard renal outcome of end stage renal disease (0.99, 0.78 to 1.28) (power of 94% to show a 23% reduction in end stage renal disease).” (S. Bangalore, sripalbangalore@gmail.com)

>>>PNN JournalWatch
* Clinical Effectiveness of Mupirocin for Preventing
Staphylococcus aureus Infections in Nonsurgical Settings: A Meta-analysis, in Clinical Infectious Diseases, 2016; 62: 618–30. (M. L. Schweizer, marin-schweizer@uiowa.edu)
* Prevention of Surgical Site Infections: Decontamination With Mupirocin Based on Preoperative Screening for Staphylococcus aureus Carriers or Universal Decontamination?, in Clinical Infectious Diseases, 2016; 62: 631–6. (M. J. M. Bonten, m.j.m.bonten@umcutrecht.nl)

* When to Treat Adults Like Children: Optimizing Therapy for Lymphoblastic Lymphoma in Young Adults, in Journal of Clinical Oncology, 2016; 34: 533–8. (K. M. O’Dwyer, kristen_odwyer@urmc.rochester.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 © 2016, 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
Feb. 17, 2016 * Vol. 23, No. 31
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 16 issue of JAMA (2016; 315).
ACA-Mandated Contraceptive Coverage: An Affordable Care Act provision requiring coverage of FDA-approved contraceptive methods, sterilization procedures, and patient education and counseling without out-of-pocket costs “has already directly benefited millions of women who use contraceptives by decreasing their total out-of-pocket spending on contraceptives,” write Viewpoint authors (pp. 653–4). The guarantee is not absolute, the authors note, with Medicaid recipients exempt and supplies such as OTC emergency contraceptives not covered. “Insurance companies could do much more to conform to the law and the spirit of the contraceptive coverage guarantee and to provide clear information to clinicians and patients about this coverage and its limitations,” the writers conclude. “Health care professionals could do more to become educated and to educate their patients about insurers’ rules and procedures. They could also learn more about how to properly bill services so that patients are not inappropriately charged for care. Each of these steps could help ensure that the contraceptive coverage guarantee fully meets its potential to improve women’s health and well-being.” (M. C. Politi, mpoliti@wustl.edu)

>>>Infectious Diseases Report
Source:
Mar. 1 issue of Clinical Infectious Diseases (2016; 62).
Single-Dose Dalbavancin for Skin/Skin Structure Infection: Used for treating acute bacterial skin and skin structure infections, single-dose I.V. dalbavancin proved noninferior to a 2-dose regimen, researchers report (pp. 545–51). The single-dose infusion “has a similar safety profile and removes logistical constraints related to delivery of the second dose,” the authors conclude based on these data from a double-blind trial of 698 patients: “Demographic characteristics were similar on each regimen, although there were more patients with methicillin-resistant Staphylococcus aureus (MRSA) at baseline on the 2-dose regimen (36/210 [17.1%] vs 61/220 [27.7%]). Dalbavancin delivered as a single dose was noninferior to a 2-dose regimen (81.4% vs 84.2%; difference, −2.9% [95% CI, −8.5% to 2.8%]). Clinical outcomes were also similar at day 14 (84.0% vs 84.8%), day 28 (84.5% vs 85.1%), and day 14 in clinically evaluable patients with MRSA in a baseline culture (92.9% vs 95.3%) in the single- and 2-dose regimens, respectively. Treatment-emergent adverse events occurred in 20.1% of the single-dose patients and 19.9% on the 2-dose regimen.” (M. W. Dunne, michael.w.dunne@comcast.net)
American v. European Recommendations for I.V. Colistin: A pharmacokinetic evaluation of dose recommendations for I.V. colistin set by FDA and the European Medicines Agency shows clinically important differences that can inform “the setting of clinical breakpoints” (pp. 552–8). Data on 162 critically ill patients with various levels of kidney function were used to calculate average steady-state plasma colistin concentration (Css,avg) that would be achieved if each patient received the FDA or EMA dose: “For creatinine clearance <30 mL/min, 100% of patients receiving the EMA dose achieved a colistin Css,avg ≥1 mg/L, but the attainment rate was as low as 53.1% for patients receiving the FDA-approved dose. For colistin Css,avg ≥2 mg/L, the attainment rates were 87.5% with the EMA dose but only 6.3%–34.4% in patients receiving the FDA dose. Differences in attainment rates for a colistin Css,avg of ≥2 mg/L and ≥4 mg/L extended to patients with creatinine clearance 30 to <50 mL/min. For patients with creatinine clearance ≥80 mL/min, only approximately 65%–75% of patients achieved a colistin Css,avg of ≥1 mg/L with either set of recommendations.” (R. L. Nation, roger.nation@monash.edu)

>>>PNN NewsWatch
* FDA yesterday issued a new guidance recommending deferral of individuals from donating blood if they have been to areas with active Zika virus transmission, potentially have been exposed to the virus, or have had a confirmed Zika virus infection. In areas without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks. In areas with active Zika virus transmission, FDA recommends that whole blood and blood components for transfusion be obtained from areas of the U.S. without active transmission.

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 © 2016, 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
Feb. 18, 2016 * Vol. 23, No. 32
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Feb. 18 New England Journal of Medicine (2016; 374).
Testosterone Treatment in Older Men: In three 1-year trials of testosterone supplementation in 790 symptomatic men aged 65 years or older, benefits were limited to moderately improved sexual function, better mood, and less severe depressive symptoms, researchers report (pp. 611–24). Vitality and walking distance were unchanged. The sample size was too small to evaluate risks. At baseline participants had serum testosterone levels below 275 ng/dL and hypoandrogenic symptoms. Testosterone or placebo gel produced these results: “Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P <0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P = 0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.” (P. J. Snyder, pjs@mail.med.upenn.edu)
This report, with initial results from the NIH-sponsored Testosterone Trials, “is likely to stimulate controversy and to engender additional research questions—as did the Women’s Health Initiative with respect to estrogen-replacement therapy,” an editorialist writes (
pp. 682–3). “Nevertheless, it is a landmark study in the field of men’s health and no doubt a bellwether for additional important contributions from the Testosterone Trials.” (E. S. Orwoll)
Prasugrel in Sickle Cell Vaso-Occlusion: Compared with placebo in children and adolescents with sickle cell anemia, daily oral prasugrel for 9–24 months had no significant effect on rates of a composite outcome of painful crisis or acute chest syndrome (pp. 625–35). The international trial included 341 patients at 51 sites in 13 countries, producing these results: “The rate of vaso-occlusive crisis events per person–year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P = 0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups.” (M. M. Heeney, matthew.heeney@childrens.harvard.edu)
Ebola Virus Disease in America & Europe: Patients treated in the U.S. and Europe for Ebola virus disease (EVD) received “close monitoring and aggressive supportive care that included intravenous fluid hydration, correction of electrolyte abnormalities, nutritional support, and critical care management for respiratory and renal failure” (pp. 636–46). The result was an 81.5% survival rate for 27 patients, the authors report. (T. M. Uyeki, tuyeki@cdc.gov)
Zika Disease in America: Arboviruses, mostly RNA viruses transmitted by mosquitoes, ticks, and other arthropods, “continually evolve and adapt within ecologic niches that are increasingly being perturbed by humans,” Perspective authors explain, adding these clinical management tips for Zika disease (pp. 601–4). “The mainstays of management are bed rest and supportive care. When multiple arboviruses are cocirculating, specific viral diagnosis, if available, can be important in anticipating, preventing, and managing complications. For example, in dengue, aspirin use should be avoided and patients should be monitored for a rising hematocrit predictive of impending hemorrhagic fever, so that potentially lifesaving treatment can be instituted promptly. Patients with chikungunya virus infection should be monitored and treated for acute arthralgias and postinfectious chronic arthritis.” (A. S. Fauci)

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 © 2016, 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
Feb. 19, 2016 * Vol. 23, No. 33
Providing news and information about medications and their proper use

>>>Oncology Report
Source:
Feb. 20 issue of the Journal of Clinical Oncology (2016; 34).
Molecular Heterogeneity & Drug Response in Breast Cancer: Pathologic complete response rates (pCRs) to neoadjuvant therapy that dually targeted human epidermal growth factor receptor 2 (HER2) was no better in the CALGB 40601 trial than single HER2 targeting, probably because of intertumoral heterogeneity, researchers report (pp. 542–9). Patients with stage II to III HER2-positive breast cancer were randomly assigned to paclitaxel plus trastuzumab alone (TH) or with the addition of lapatinib (THL) for 16 weeks before surgery, with these results: “Among 305 randomly assigned patients (THL, n = 118; TH, n = 120; TL, n = 67), the pCR rate was 56% (95% CI, 47% to 65%) with THL and 46% (95% CI, 37% to 55%) with TH (P = .13), with no effect of dual therapy in the hormone receptor–positive subset but a significant increase in pCR with dual therapy in those with hormone receptor–negative disease (P = .01). The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing (mRNAseq). pCR rates significantly differed by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; P <.001). In multivariable analysis treatment arm, intrinsic subtype, HER2 amplicon gene expression, p53 mutation signature, and immune cell signatures were independently associated with pCR. Post-treatment residual disease was largely luminal A (69%).” (L. A. Carey, lisa_carey@med.unc.edu)
Pregabalin for Cancer-Induced Bone Pain: As add-on therapy to palliative radiotherapy in patients with cancer-induced bone pain (CIBP), pregabalin did not improve treatment response, a study shows (pp. 550–6). Adult patients with bone metastases and pain scores of 4 or more on a 10-point scale were randomized to pregabalin or placebo with dose escalation over 4 weeks. Based on a primary end point of treatment response (reduction of ≥2 points in worst pain by week 4, accompanied by a stable or reduced opioid dose), results showed: “A total of 233 patients were randomly assigned: 117 to placebo and 116 to pregabalin. The most common cancers were prostate (n = 88; 38%), breast (n = 77; 33%), and lung (n = 42; 18%). In the pregabalin arm, 45 patients (38.8%) achieved the primary end point, compared with 47 (40.2%) in the placebo arm (adjusted odds ratio, 1.07; 95% CI, 0.63 to 1.81; P = .816). There were no statistically significant differences in average pain, pain interference, or quality of life between arms. There were differences in mood (P = .031) and breakthrough pain duration (P = .037) between arms. Outcomes were compared at 4 weeks.” (M. Fallon, marie.fallon@ed.ac.uk)
Future studies of pregabalin will need to stratify patients by levels of neuropathic pain and better assess the impact of concomitant opioid therapy, editorialists write (
pp. 524–6): “More phase II trials are required to establish the adjunct role of pregabalin in addition to radiation therapy before conducting larger randomized trials. These phase II studies should explore the optimal dose of pregabalin and its interaction with opioids, determine the treatment effect, and allow for calculation of the required sample size in subsequent phase III studies. Excluding patients already taking neuropathic agents may be practically challenging because many patients will already be started on pregabalin or gabapentin prior to trial recruitment.” (E. Chow, edward.chow@sunnybrook.ca)

>>>Geriatrics Highlights
Source:
Feb. issue of the Journal of the American Geriatrics Society (2016; 64).
Anticholinergic Medications & Pneumonia Risk: Among patients 65 years or older enrolled in Medicare Advantage Plans, those using anticholinergic medications had an increased risk of community-acquired pneumonia (CAP), according to results of a nested case–control study that used data from 2009–10 (pp. 394–400). Patients’ anticholinergic drug exposure in the 30 days preceding CAP showed these patterns, investigators found: “After controlling for risk factors, overall use of anticholinergic medications was significantly associated with risk of pneumonia (odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.20–2.28). The risk of pneumonia remained significant across the different exposure periods, although use of higher-level (ADS Level 2 or 3) anticholinergics was not associated with pneumonia risk (OR = 1.16, 95% CI = 0.70–1.96).” (R. R. Aparasu, rraparasu@uh.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 © 2016, 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
Feb. 22, 2016 * Vol. 23, No. 34
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Incretins & Pancreatic Cancer: Incretin-based drugs were not associated with increased risk of pancreatic cancer in a cohort study in Canada, the U.S., and the U.K. (i581). Among 972,384 patients beginning antidiabetic therapy in 2007–13, these risks were noted using a nested case–control analysis: “During 2,024,441 person–years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1,221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1,000 person–years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.” (L. Azoulay, laurent.azoulay@mcgill.ca)
DPP-4 Inhibitors & Heart Failure: Use of dipeptidyl peptidase-4 (DPP-4) inhibitors for treating type 2 diabetes “may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use,” according to results of a systematic review and meta-analysis (i610): “Eligible studies included 43 trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case–control studies; n=1,777,358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15,701 v 33/12,591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1,000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18,554 v 552/18,474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.” (X. Sun, sunx26@gmail.com)

>>>Lancet Highlights
Source:
Feb. 20 issue of Lancet (2016; 387).
Isavuconazole in Invasive Fungal Disease: In the phase 3 SECURE trial, “isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease,” researchers report (pp. 760–9). Among 527 adult patients with infections of Aspergillus or other filamentous fungi, intention-to-treat (ITT) outcomes were as follows: “All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1.0% (95% CI −7.8 to 5.7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p = 0.122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]).” (A. J Ullmann, andrew.ullmann@uni-wuerzburg.de)

>>>PNN NewsWatch
* FDA on Friday approved brivaracetam (Briviact, UCB) as an add-on treatment of partial onset seizures in patients 16 years or older with epilepsy. It must be dispensed with a MedGuide detailing suicidality, agitation, new or worsening depression, aggression, and panic attacks.

>>>PNN JournalWatch
* Achieving High-Quality Multicultural Geriatric Care, in
Journal of the American Geriatrics Society, 2016; 64: 255–60. (A. Cegelka, acegelka@americangeriatrics.org)
* American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis, in
Arthritis & Rheumatology, 2016; 68: 282–98. (M. M. Ward, wardm1@mail.nih.gov)
* Sublingual or Subcutaneous Immunotherapy for Allergic Rhinitis?, in
Journal of Allergy and Clinical Immunology, 2016; 137: 339–49.e10. (S. R. Durham, s.durham@imperial.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 © 2016, 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
Feb. 23, 2016 * Vol. 23, No. 35
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Feb. issue of the Journal of Allergy and Clinical Immunology (2016; 137).
Vaccines for Immunotherapy: The availability of recombinant allergens and synthetic allergen peptides is enabling the development of vaccines for allergen-specific immunotherapy (AIT), according to a review article (pp. 351–7): “In the past, the development of more effective, safe, convenient, broadly applicable, and easy to manufacture vaccines for AIT has been limited by the poor quality of natural allergen extracts. Progress made in the field of molecular allergen characterization has now made it possible to produce defined vaccines for AIT and eventually for preventive allergy vaccination based on recombinant DNA technology and synthetic peptide chemistry. Here we review the characteristics of recombinant and synthetic allergy vaccines that have reached clinical evaluation and discuss how molecular vaccine approaches can make AIT more safe and effective and thus more convenient. Furthermore, we discuss how new technologies can facilitate the reproducible manufacturing of vaccines of pharmaceutical grade for inhalant, food, and venom allergens. Allergy vaccines in clinical trials based on recombinant allergens, recombinant allergen derivatives, and synthetic peptides allow us to target selectively different immune mechanisms, and certain of those show features that might make them applicable not only for therapeutic but also for prophylactic vaccination.” (R. Valenta, rudolf.valenta@meduniwien.ac.at)
Sublingual Grass/Ragweed Immunotherapy: Sublingual therapies for allergies to grass and ragweed have considerable real-world experience from Europe to support at-home use, authors of a review article write, and these products also offer a disease-modifying option (pp. 369–76): “Sublingual allergen immunotherapy provides a new option for patients with allergic rhinitis in the United States. The efficacy of these sublingual immunotherapy tablets in the treatment of allergic rhinitis has been firmly established in large multicenter clinical trials. In addition, the clinical benefits of sublingual immunotherapy might persist after treatment is discontinued. Local reactions, such as gastrointestinal or oropharyngeal symptoms, are common. However, severe anaphylaxis is rare, and therefore the immunotherapy tablets can be administered at home. Sublingual immunotherapy for allergic rhinitis has been used successfully for years in Europe, and these products might be appropriate for patients who do not do well with standard drug therapy or for those who prefer a disease-modifying approach.” (J. T. Li, li.james@mayo.edu)

>>>Health Affairs Report
Source:
Feb. issue of Health Affairs, a theme issue on Vaccines (2016; 35).
Parental Response to Measles Outbreak: Following the 2014–15 U.S. measles outbreak, parental awareness of vaccine-preventable diseases increased, but so did their concerns about vaccines, a study shows (pp. 334–40). Two surveys of parents of young children taken just before and in the weeks following the measles outbreak showed these results: “While most parents were aware of the outbreak, many were not, and the level of familiarity mattered, particularly on measures of confidence in vaccines and support for mandates requiring childhood vaccination. Increases in vaccine-related concerns were found as well, indicating that disease outbreaks foster not just awareness of vaccines and their potential to prevent disease but a range of parental responses.” (M. A. Cacciatore, mcacciat@uga.edu)
Economic Evaluations of Vaccines: While advocates argue for a broader view of the possible benefits of vaccines in economic evaluations, authors add that the same logic should be applied across medical interventions and in the ways in which “any kind of evidence is translated into policy” (pp. 208–11; J. L. Schwartz, jason.l.schwartz@yale.edu).

>>>PNN NewsWatch
* With an 80–6 procedural vote, the U.S. Senate yesterday advanced the nomination of Robert M. Califf, MD, for Commissioner of Food and Drugs. A final confirmation vote is expected today or tomorrow, the Wall Street Journal reports. Among the Senators who had been holding up the nomination was presidential candidate Bernie Sanders, who was concerned about Califf’s ties to the pharmaceutical industry.

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 © 2016, 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
Feb. 24, 2016 * Vol. 23, No. 36
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Feb. 23 issue of JAMA (2016; 315).
Defining Sepsis: One of several articles in this issue of JAMA on sepsis and septic shock, a special communication presents the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) (pp. 801–10). A 19-member task force recommends the following: “Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.” (C. S. Deutschman, cdeutschman@nshs.edu)
“An ongoing issue … is that sepsis is a syndrome and not a specific disease,” an editorialist adds (
pp. 757–9). “The new definitions do not alleviate this concern. Other conditions, most notably cancer, were previously described in a similar manner but are now further characterized based not just on anatomic location and cell type but most recently on expression of specific biomarkers, including cellular receptors, activation of intracellular pathways, and genomic alterations. Such characterization has enabled development of therapies targeted to specific patients, with remarkable improvements in outcome. Although the present definition for sepsis provides needed evolution in categorization of this syndrome, incorporation of more information about the molecular and cellular characterization of sepsis may have been helpful. Hopefully, the next iteration of this consensus process will take full advantage of the rapidly advancing understanding of molecular processes that lead from infection to organ failure and death so that sepsis and septic shock will no longer need to be defined as a syndrome but rather as a group of identifiable diseases, each characterized by specific cellular alterations and linked biomarkers. Such evolution will be required to truly transform care for the millions of patients worldwide who develop these life-threatening conditions.” (E. Abraham, eabraham@wakehealth.edu)

>>>Nephrology Highlights
Source:
Mar. American Journal of Kidney Diseases (2016; 67).
Vitamin C Intake & Kidney Stones: Among 156,735 women in the Nurses’ Health Study I and II and 40,536 men in the Health Professionals Follow-up Study, men with the highest total and supplemental intake of vitamin C were at higher risk of incident kidney stones (pp. 400–7). The prospective cohort analysis produced these results based on 6,245 incident kidney stones over a median of 11.3 to 11.7 years: “After multivariable adjustment, total vitamin C intake (<90 [reference], 90–249, 250–499, 500–999, and ≥1,000 mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HRs of 1.00 [reference], 1.19 [95% CI, 0.99–1.46], 1.15 [95% CI, 0.93–1.42], 1.29 [95% CI, 1.04–1.60], and 1.43 [95% CI, 1.15–1.79], respectively; P for trend = 0.005). Median total vitamin C intake for the 500- to 999-mg/d category was ~700 mg/d. Supplemental vitamin C intake (no use [reference], <500, 500–999, and ≥1,000 mg/d) was not significantly associated with risk for kidney stones among women, but was among men (HR, 1.19 [95% CI, 1.01–1.40] for ≥1,000 mg/d; P for trend = 0.001). Dietary vitamin C intake was not associated with stones among men or women, although few participants had dietary intakes > 700 mg/d.” (P. M. Ferraro, manuel.ferraro@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Feb. 25, 2016 * Vol. 23, No. 37
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Feb. 25 New England Journal of Medicine (2016; 374).
Aspirin Interruption Before Coronary Artery Surgery: Results of the aspirin arm of a 2 X 2 factorial trial of patients undergoing coronary artery surgery show that preoperative aspirin made no significant difference in reducing risks of complications or raising the risk of bleeding, compared with placebo (pp. 728–37). In the ATACAS trial, patients randomly received aspirin 100 mg or placebo before surgery, with these effects on a primary composite outcome of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery: “Among 5,784 eligible patients, 2,100 were enrolled; 1,047 were randomly assigned to receive aspirin and 1,053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P = 0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P = 0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P = 0.08).” (P. S. Myles, p.myles@alfred.org.au)
Weekly Paclitaxel for Ovarian Cancer: Compared with paclitaxel plus carboplatin administered every 3 weeks, dose-dense weekly paclitaxel and carboplatin failed to prolong progression-free survival among women with ovarian cancer (pp. 738–48): “A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P = 0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P = 0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P = 0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%).” (J. K. Chan, chanjohn@sutterhealth.org)
Eliminating Pediatric HIV-1 Infections: Highly effective antiretroviral treatments have produced “considerable progress” in preventing new pediatric HIV-1 infections, write authors of a review article (pp. 761–70):“Continued progress towards eliminating pediatric HIV-1 infection requires finding solutions to long-standing problems in maternal and child health systems in countries with limited resources so as to improve the delivery of preventive health care services at each stage of gestation, delivery, and breast-feeding during which transmission from mother to child may occur.” (K. Luzuriaga, katherine.luzuriaga@umassmed.edu)

>>>PNN NewsWatch
* The Senate yesterday confirmed Robert Califf, MD, as FDA Commissioner, the Washington Post reports, succeeding Margaret Hamburg, MD, who left the post last March. “Califf inherits an agency facing an array of new responsibilities and potential changes,” the Post reports. “The FDA is continuing a years-long effort to implement a 2010 law aimed at revamping the nation’s food safety system, in an effort to make it more proactive, rather than merely reacting to outbreaks after they happen. Federal regulators also are still figuring out how to regulate the vast tobacco industry, and the FDA is expected this year to release new regulations governing the booming market for e-cigarettes. At the same time, the FDA has been approving new drugs—many of them innovative but expensive treatments for cancer and other diseases—at a near-record pace in recent years.”

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 © 2016, 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
Feb. 26, 2016 * Vol. 23, No. 38
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (2016; 39).
Differentiating Between Types 1 and 2 Diabetes: A genetic risk score (GRS) based on 30 variants in diabetes-related alleles can assist clinicians in differentiating between types 1 and 2 diabetes (T1D, T2D) in young adults, a study shows (pp. 337–44). With the obesity epidemic, young patients are presenting more frequently who may look like those with T2D when they really have insulin-responsive T1D, the authors note. They tested GRSs based on published T1D- and T2D-associated variants using data from the 3,887-patient Wellcome Trust Case Control Consortium (WTCCC) and 223 patients presenting clinically who progressed to severe insulin deficiency within 3 years of diagnosis: “In the WTCCC, the T1D GRS, based on 30 T1D-associated risk variants, was highly discriminative of T1D and T2D (area under the curve [AUC] 0.88 [95% CI 0.87–0.89]; P < 0.0001), and the T2D GRS added little discrimination (AUC 0.89). A T1D GRS >0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (<0.234, <5th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just nine single nucleotide polymorphisms (AUC 0.87). In young adults with diabetes, T1D GRS alone predicted progression to insulin deficiency (AUC 0.87 [95% CI 0.82–0.92]; P < 0.0001). T1D GRS, autoantibody status, and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC 0.96 [95% CI 0.94–0.99]; P < 0.0001).” (M. N. Weedon, m.n.weedon@exeter.ac.uk)
“In the end, the clinician’s ability to absorb, assimilate, and translate genomic information will likely determine the extent of its impact on public health,” concludes an editorialist (
pp. 330–2). “Currently, clinicians trained in the most advanced settings are still woefully unprepared to make meaningful use of the data accumulating at a dizzying scale. Which pieces of information are clinically actionable and should be incorporated into medical practice need to be tested in a rigorous fashion, weighed rationally, acted upon, and disseminated in a didactic manner. The article … exemplifies how this can be done.” (J. C. Florez, jcflorez@partners.org)
High-Dose Vitamin D in Prediabetes: Tested in 44 patients with prediabetes, weekly doses of vitamin D3 30,000 IU for 8 weeks had no “substantial effect … in prediabetes or diet-treated type 2 diabetes on beta-cell function, insulin sensitivity, or glycemic control,” a placebo-controlled study concludes (pp. 345–52). Hyperglycemic clamp studies and oral glucose tolerance tests showed these results: “A total of 21 (vitamin D) and 22 (placebo) subjects completed the study, respectively. Season-adjusted 25-OH-vitamin D [25(OH)D] levels were doubled in the active treated group (43–82 nmol/L). No effect of vitamin D treatment, compared with placebo, was seen on first-phase or second-phase insulin secretion. There were no group differences in insulin sensitivity, [disposition index], or any measures of glycemic control. No hypercalcemia or other adverse effects of vitamin D treatment were seen compared with placebo. Subgroup analyses of those with the lowest basal and greatest increase in 25(OH)D levels did not change these results.” (H. Wagner, henrik.wagner@sodersjukhuset.se)
Canagliflozin in Drug-Naïve Type 2 Diabetes: Compared with monotherapy in drug-naïve type 2 diabetes, canagliflozin (CANA) plus metformin extended-release (MET) was more effective than either alone, researchers report (pp. 353–62). “CANA monotherapy demonstrated noninferior HbA1c lowering versus MET,” the authors added, based on these findings in a 26-week, phase 3 trial of 100- and 300-mg doses of CANA: “From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002).” (J. Rosenstock, juliorosenstock@dallasdiabetes.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 © 2016, 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
Feb. 29, 2016 * Vol. 23, No. 39
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 27 issue of Lancet (2016; 387).
Anastrozole vs. Tamoxifen in Breast Cancer: A trio of articles compare use of anastrozole and tamoxifen in women with breast cancer.
Among 3,104 women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation, anastrozole “provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age,” report researchers with the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial (
pp. 849–56). The phase 3 trial assessed oral tamoxifen 20 mg/d and oral anastrazole 1 mg/d, with these results: “In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0.73 [95% CI 0.56–0.96], p = 0.0234). A significant time-by-treatment interaction (p = 0.0410) became evident later in the study. There was also a significant interaction between treatment and age group (p = 0.0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism—a known side-effect of tamoxifen—for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group.” (R. G. Margolese, richard.margolese@mcgill.ca)
Focusing on adverse effects of the two drugs, NSABP B-35 investigators concluded in a second report that women older than 60 with ductal carcinoma in situ, “decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug” (
pp. 857–65). “For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative.” (P. A. Ganz, mailto:)
In 2,980 women with hormone-receptor-positive ductal carcinoma in situ (DCIS) in the IBIS-II DCIS trial, clear differences between anastrozole and tamoxifen were not evident, the third report concludes (
pp. 866–73): “Non-inferiority of anastrozole was established (upper 95% CI <1.25), but its superiority to tamoxifen was not (p = 0.49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0.93 [95% CI 0.58–1.50], p = 0.78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1,323 women, 91%) and tamoxifen (1,379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen.” (J. Cuzick, j.cuzick@qmul.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2016; 352).
Systolic BP Targets After Stroke, TIA: “Aiming for target below 130 mm Hg rather than 140 mm Hg for systolic blood pressure in people with cerebrovascular disease in primary care led to a small additional reduction in blood pressure,” conclude investigators of an open-label, randomized trial conducted at 99 general practices in England (i708). Intensive therapy with a target systolic level of <130 mm Hg and standard therapy with a target of <140 mm Hg produced these results among 529 participants: “Mean systolic blood pressure dropped by 16.1 mm Hg to 127.4 mm Hg in the intensive target arm and by 12.8 mm Hg to 129.4 mm Hg in the standard arm (difference between groups 2.9 (95% confidence interval 0.2 to 5.7) mm Hg; P = 0.03).” (J. Mant, jm677@medschl.cam.ac.uk)

>>>PNN JournalWatch
*8 Effect of Antihypertensive Treatment at Different Blood Pressure Levels in Patients With Diabetes Mellitus: Systematic Review and Meta-analyses, in
BMJ, 2016; 352: i717. (M. Brunström, mattias.brunstrom@umu.se)
* The Surging Tide of Diabetes: Implications for Nephrology, in
American Journal of Kidney Diseases, 2016; 67: 364–6. (I. H. de Boer, deboer@u.washington.edu)
* Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies, in
Diabetes Care, 2016; 39: 486–94. (S. Suissa, samy.suissa@mcgill.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 © 2016, 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
Mar. 1, 2016 * Vol. 23, No. 40
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 1 issue of the Annals of Internal Medicine (2016; 164).
CKD in Metabolically Healthy Obesity: Metabolically healthy obesity—obesity in people without obesity-related metabolic abnormalities—is not innocuous, conclude authors who show an increased risk of chronic kidney disease (CKD) among 62,249 metabolically healthy, young and middle-aged men and women without CKD or proteinuria (pp. 305–12). At baseline, participants had no component of the metabolic syndrome or insulin resistance. Stratified by body mass index, risks of CKD were as follows in the study population: “During 369,088 person–years of follow-up, 906 incident CKD cases were identified. The multivariable-adjusted differences in 5-year cumulative incidence of CKD in underweight, overweight, and obese participants compared with normal-weight participants were −4.0 (95% CI, −7.8 to −0.3), 3.5 (CI, 0.9 to 6.1), and 6.7 (CI, 3.0 to 10.4) cases per 1,000 persons, respectively. These associations were consistently seen in all clinically relevant subgroups.” (S. Ryu, sh703.yoo@gmail.com)
Novel HIV-1 Vaccine Platforms: Two prophylactic HIV-1 vaccines with different viral envelope A inserts “elicited significant immune responses in all populations” and boosted EnvA antibody titers with second doses (pp. 313–22). Adenovirus serotype 26 with an HIV-1 envelope A insert (Ad26.EnvA) and adenovirus serotype 35 with an HIV-1 envelope A insert (Ad35.Env) were administered at a dose of 5 × 1010 viral particles, with these results: “217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30–300 to 3000). The heterologous regimen of Ad26–Ad35 elicited significantly higher EnvA antibody titers than Ad35–Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States.” (L. R. Baden, lbaden@partners.org)
Medical Assistant–Based Care Management in Primary Care: At 115 German primary care practices, protocol-based care delivered by medical assistants “did not reduce all-cause hospitalizations but showed positive effects on quality of life at reasonable costs in high-risk multimorbid patients” with type 2 diabetes, chronic obstructive pulmonary disease, or chronic heart failure, researchers report (pp. 323–30). The low-intensity intervention improved “quality of life (differences, 1.16 [CI, 0.24 to 2.08] on SF-12 physical component and 1.68 [CI, 0.60 to 2.77] on SF-12 mental component) and general health (difference on EQ-5D, 0.03 [CI, 0.00 to 0.05]) … at 24 months” at a cost of $10 per patient per month. (T. Freund, tobias.freund@med.uni-heidelberg.de)
“We can spend more than $40,000 to bring 1 person
into the hospital, coordinating local volunteers with emergency medical services, air ambulances, and tertiary care, as in [a] case I witnessed in my rural neighborhood,” an editorialist writes (pp. 370–1). “It is past time that we invest in keeping patients out of the hospital with highly trained, well-supported primary care teams. Only when we do so will we achieve the Quadruple Aim of better patient experience, better population health, lower cost, and greater professional satisfaction.” (C. A. Sinsky, christine.sinsky@ama-assn.org)

>>>PNN NewsWatch
* FDA said yesterday it is requiring a new clinical study for Essure, a nonsurgical option for permanent contraception, to determine heightened risks for some women. FDA is also initiating changes to product labeling, including a boxed warning and a Patient Decision Checklist to help to ensure women receive and understand information regarding the benefits and risks of this type of device. Essure involves the insertion of flexible coils through the cervix and vagina into the fallopian tubes. Over a period of about 3 months, scar tissue forms around the inserts and creates a barrier that keeps sperm from reaching the eggs, thus preventing conception. While the scar tissue forms, women must use an alternative form of birth control.

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 © 2016, 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
Mar. 2, 2016 * Vol. 23, No. 41
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Mar. 1 issue of JAMA (2016; 315).
Statins & Kidney Injury in Cardiac Surgery: Short-term high-dose perioperative atorvastatin failed to reduce the risk of acute kidney injury (AKI) following cardiac surgery among any patient group tested in a study conducted in 2009–14 (pp. 877–88). Despite several potentially beneficial statin actions on kidney function, investigators found these results among 199 statin-naive and 416 statin experienced patients who were randomized to statins or placebo: “The data and safety monitoring board recommended stopping the group naive to statin treatment due to increased AKI among these participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) receiving atorvastatin. The board later recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] were women; 202 [32.8%] had diabetes) completed the study. Among all participants (n = 615), AKI occurred in 64 of 308 (20.8%) in the atorvastatin group vs 60 of 307 (19.5%) in the placebo group (relative risk [RR], 1.06 [95% CI, 0.78 to 1.46]; P = .75). Among patients naive to statin treatment (n = 199), AKI occurred in 22 of 102 (21.6%) in the atorvastatin group vs 13 of 97 (13.4%) in the placebo group (RR, 1.61 [0.86 to 3.01]; P = .15) and serum creatinine concentration increased by a median of 0.11 mg/dL (10th–90th percentile, −0.11 to 0.56 mg/dL) in the atorvastatin group vs by a median of 0.05 mg/dL (10th-90th percentile, −0.12 to 0.33 mg/dL) in the placebo group (mean difference, 0.08 mg/dL [95% CI, 0.01 to 0.15 mg/dL]; P = .007). Among patients already taking a statin (n = 416), AKI occurred in 42 of 206 (20.4%) in the atorvastatin group vs 47 of 210 (22.4%) in the placebo group (RR, 0.91 [0.63 to 1.32]; P = .63).” (F. T. Billings IV, frederic.t.billings@vanderbilt.edu)
While researchers should continue seeking ways of reducing kidney injury among those undergoing cardiac surgery, an editorialist writes that statins in drug-naive patients should not be the focus of that search (
pp. 873–4). “Even though the use of statins in cardiac surgery is likely to continue to generate interest and trials in an attempt to demonstrate other so-far unproven benefits, any use as nephroprotective agents in patients naive to statin treatment undergoing cardiac surgery should now be abandoned. The challenge of finding an adjuvant intervention capable of attenuating AKI during cardiac surgery, however, remains unmet and further exploration of promising or novel interventions and more studies aimed at understanding the pathogenesis of AKI following cardiac surgery remain a clinical priority and are certain to follow.” (R. Bellomo, rinaldo.bellomo@austin.org.au)
Insulin Degludec/Liraglutide in Uncontrolled Diabetes: In 557 patients with type 2 diabetes uncontrolled during treatment with insulin glargine and metformin, insulin degludec/liraglutide was noninferior and produced significant improvements in glycosylated hemoglobin levels, researchers report (pp. 898–907). The phase 3, 26-week trial produced these results: “Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (−1.81% for the degludec/liraglutide group vs −1.13% for the glargine group; estimated treatment difference [ETD], –0.59% [95% CI, –0.74% to –0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (–1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, –3.20 kg [95% CI, –3.77 to –2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient–year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine).” (J. B. Buse, jbuse@med.unc.edu)

>>>PNN NewsWatch
* Adding to its Feb. 16 advice about blood products, FDA yesterday issued recommendations to reduce the risk of Zika virus transmission via donated tissues and organs.

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 © 2016, 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
Mar. 3, 2016 * Vol. 23, No. 42
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Mar. 3 New England Journal of Medicine (2016; 374).
TMP-SMX for Uncomplicated Skin Abscess: In five U.S. emergency departments located in areas where methicillin-resistant Staphylococcus aureus (MRSA) is common, treatment of drained cutaneous abscesses with trimethoprim–sulfamethoxazole was significantly more effective than with placebo, researchers report (pp. 823–32). Results based on a primary outcome of clinical cure of the abscess at 7 to 14 days were as follows: “The median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim–sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P = 0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim–sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P <0.001). Trimethoprim–sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, −5.2 percentage points; 95% CI, −8.2 to −2.2), skin infections at new sites (3.1% vs. 10.3%; difference, −7.2 percentage points; 95% CI, −10.4 to −4.1), and infections in household members (1.7% vs. 4.1%; difference, −2.4 percentage points; 95% CI, −4.6 to −0.2) 7 to 14 days after the treatment period. Trimethoprim–sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim–sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim–sulfamethoxazole group.” (D. A. Talan, idnet@ucla.edu)
Authors of a case vignette reach the less-is-better conclusion (
pp. 882–4). Incision and drainage alone was curative for a 22-year-old woman with a 3-day history of thigh redness, swelling, and pain: “The patient in the vignette is typical of a previously healthy person in the community who presents with a very small abscess. She has normal vital signs (she does not feel very sick, nor does she appear to be) and has no history of an associated condition such as diabetes or obesity. The infection is not recurrent and not necrotic, and, from an immunologic standpoint, the patient is a normal host. Incision and drainage alone is the hallmark of treatment of an abscess like this without the costs of antibiotic therapy and the risks of potential drug side effects.” (M. B. Wilbur)
Late Mortality in Childhood Cancer Survivors: Life-threatening late events among survivors of childhood cancers have been reduced over the past 40 years through lowered therapeutic exposures to radiotherapy and chemotherapy, a study of 34,033 Childhood Cancer Survivor Study participants shows (pp. 833–42): “Of the 3,958 deaths that occurred during the study period, 1,618 (41%) were attributable to health-related causes, including 746 deaths from subsequent neoplasms, 241 from cardiac causes, 137 from pulmonary causes, and 494 from other causes. A reduction in 15-year mortality was observed for death from any cause (from 12.4% in the early 1970s to 6.0% in the 1990s, P <0.001 for trend) and from health-related causes (from 3.5% to 2.1%, P <0.001 for trend). These reductions were attributable to decreases in the rates of death from subsequent neoplasm (P <0.001), cardiac causes (P <0.001), and pulmonary causes (P = 0.04). Changes in therapy according to decade included reduced rates of cranial radiotherapy for acute lymphoblastic leukemia (85% in the 1970s, 51% in the 1980s, and 19% in the 1990s), of abdominal radiotherapy for Wilms’ tumor (78%, 53%, and 43%, respectively), of chest radiotherapy for Hodgkin’s lymphoma (87%, 79%, and 61%, respectively), and of anthracycline exposure. Reduction in treatment exposure was associated with reduced late mortality among survivors of acute lymphoblastic leukemia and Wilms’ tumor.” (G. T. Armstrong, greg.armstrong@stjude.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 © 2016, 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
Mar. 4, 2016 * Vol. 23, No. 43
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Mar. issue of Pediatrics (2016; 137).
Rapid Waning of Tdap Effectiveness: Major problems are evident with effectiveness of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine against pertussis in adolescents based on a report from Kaiser Permanente Northern California (10.1542/peds.2015-3326). Kaiser covers one of the areas affected by 2010 and 2014 outbreaks of the disease. “Among adolescents who have only received [diphtheria–tetanus–acellular pertussis (DTaP)] vaccines in childhood, Tdap provided moderate protection against pertussis during the first year and then waned rapidly so that litle protection remained 2–3 years after vaccination,” the authors conclude based on this regression analysis of data on adolescents starting at their 10th birthday: “On the basis of 1,207 pertussis cases, Tdap [vaccine effectiveness (VE)] during the first year after vaccination was 68.8% (95% confidence interval [CI] 59.7% to 75.9%), decreasing to 8.9% (95% CI –30.6% to 36.4%) by ≥4 years after vaccination. Adolescents who were more remote from Tdap were significantly more likely to test positive for pertussis than were those vaccinated more recently (HR per year 1.35, 95% CI 1.22 to 1.50).” (N. P. Klein)
Vaccinations & Mortality: No association of vaccinations and death within 30 days was found among children and adolescents who had reports from 2005–11 in the Vaccine Safety Datalink (VSD), a study shows (10.1542/peds.2015-2970). Using a case-centered cohort analysis, investigators found these patterns: “Of the 1,100 deaths identified during the study period, 76 (7%) occurred 0 to 30 days after vaccination. The relative risks for deaths after any vaccination and influenza vaccination were significantly lower for deaths due to nonexternal causes (RR 0.57, 95% confidence interval [CI] 0.38–0.83, and RR 0.44, 95% CI 0.24–0.80, respectively) and deaths due to all causes (RR 0.72, 95% CI 0.56–0.91, and RR 0.44, 95% CI 0.28–0.65). No other individual vaccines were significantly associated with death. Among deaths reviewed, 1 cause of death was unknown, 25 deaths were due to nonexternal causes, and 34 deaths were due to external causes. The causality assessment found no evidence of a causal association between vaccination and death.” (N. L. McCarthy)
Complete Influenza Vaccination in Infants & Young Children: In the United States in the 10-year period beginning in 2002, fewer than one half of infants and young children ages 6–23 months were fully vaccinated against influenza, researchers report (10.1542/peds.2015-3280). Kaplan–Meier analysis of data from the National Immunization Survey found the following: “Full influenza vaccination coverage among children 6 to 23 months increased from 4.8% in the 2002–2003 influenza season to 44.7% in the 2011–2012 season. In all 10 influenza seasons studied, non-Hispanic black children and Hispanic children had lower full influenza vaccination coverage than non-Hispanic white children. For all 10 influenza seasons, full influenza vaccination coverage was higher among children requiring only 1 dose compared with those requiring 2 doses.” (T. A. Santibanez)
Global Varicella Vaccine Effectiveness: Taking advantage of differences among countries on use of 1 or 2 doses of varicella vaccine, authors of a random-efeccts meta-analysis show that one dose is “moderately effective in preventing all varicella and highly effective in preventing moderate/severe varicella” and “the second dose adds improved protection against all varicella” (10.1542/peds.2015-3741): “The pooled 1-dose [vaccine effectiveness (VE)] was 81% (95% confidence interval [CI]: 78%–84%) against all varicella and 98% (95% CI: 97%–99%) against moderate/severe varicella with no significant association between VE and vaccine type or study design (P > .1). For 1 dose, median VE for prevention of severe disease was 100% (mean = 99.4%). The pooled 2-dose VE against all varicella was 92% (95% CI: 88%–95%), with similar estimates by study design.” (M. Marin)

>>>PNN NewsWatch
* The APhA House of Delegates convenes today at APhA2016 in Baltimore. Topics under discussion by the only professionwide policy-setting body include biologic, biosimilar, and interchangeable biologic drug products; point-of-care testing; and medication optimization services within the patient care process.

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 © 2016, 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
Mar. 7, 2016 * Vol. 23, No. 44
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Costs & Single-Dose Oncolytic Vials: After identifying $1.8 billion in waste of leftover oncolytic agents in unused single-dose vials, investigators call on “FDA, CDC, Centers for Medicare and Medicaid Services, and US Pharmacopeial Convention to reconcile their views on vial contents and vial sharing” (i788). The figure was calculated based on an analysis of Medicare claims for the top 20 cancer drugs, which were examined for amounts of drug that did not total the full contents of vials. “Several policy options merit exploration [to reduce or eliminate paying for leftover drug],” the authors write. “Regulators could require manufacturers to provide drugs in a reasonable set of size options to ensure the amount of wasted drug is low, say 3%. This is achievable …. If all of our suggestions were adopted, it would lower revenue from leftover drug from $1.8bn to $400m and, including the reductions to doctor and hospital mark-ups on leftover drug, would save around $2bn in total. An alternative would be to leave manufacturers free to select their vial sizes but also require them to refund the cost of leftover drug. This could be achieved through certified disposal and a virtual return.” (P. B. Bach, bachp@mskcc.org)
Primary Prevention in CHD: Disease burden and mortality from coronary heart disease can be reduced through population-based primary prevention programs, according to data from a 40-year study of 34,525 middle-aged men and women in eastern Finland (i721). Participants in the national FINRISK studies conducted in 1972–2012 show these risk patterns for predicted and observed age-standardized mortality from coronary heart disease: “Levels of the three major cardiovascular risk factors decreased except for a small increase in serum cholesterol levels between 2007 and 2012. From years 1969–1972 to 2012, coronary heart disease mortality decreased by 82% (from 643 to 118 deaths per 100,000 people) and 84% (114 to 17) among men and women aged 35–64 years, respectively. During the first 10 years of the study, changes in these three target risk factors contributed to nearly all of the observed mortality reduction. Since the mid-1980s, the observed reduction in mortality has been larger than predicted. In the last 10 years of the study, about two thirds (69% in men and 66% in women) of the reduction could be explained by changes in the three main risk factors, and the remaining third by other factors.” (P. Jousilahti, pekka.jousilahti@thl.fi)

>>>Lancet Highlights
Source:
Mar. 5 issue of Lancet (2016; 387).
Blood Pressure & CVD: Results of 123 studies of 613,815 participants “provide strong support for lowering blood pressure to systolic blood pressures less than 130 mm Hg and providing blood pressure lowering treatment to individuals with a history of cardiovascular disease, coronary heart disease, stroke, diabetes, heart failure, and chronic kidney disease,” authors of a systematic review and meta-analysis conclude (pp. 957–67): “Every 10 mm Hg reduction in systolic blood pressure significantly reduced the risk of major cardiovascular disease events (relative risk [RR] 0.80, 95% CI 0.77–0.83), coronary heart disease (0.83, 0.78–0.88), stroke (0.73, 0.68–0.77), and heart failure (0.72, 0.67–0.78), which, in the populations studied, led to a significant 13% reduction in all-cause mortality (0.87, 0.84–0.91). However, the effect on renal failure was not significant (0.95, 0.84–1.07). Similar proportional risk reductions (per 10 mm Hg lower systolic blood pressure) were noted in trials with higher mean baseline systolic blood pressure and trials with lower mean baseline systolic blood pressure (all ptrend >0.05).” (K. Rahimi, kazem.rahimi@georgeinstitute.ox.ac.uk)

>>>PNN NewsWatch
* The development of pharmacokinetics as a pharmacy-based science provided an important component in success of the budding clinical pharmacy movement at the University of California, San Francisco, Leslie Benet, PhD, said last night at APhA 2016 in Baltimore during his acceptance speech for the 2016 Remington Honor Medal.

>>>PNN JournalWatch
* Comorbidity of Fetal Alcohol Spectrum Disorder: A Systematic Review and Meta-Analysis, in
Lancet, 2016; 387: 978–87. (S. Popova, lana.popova@camh.ca)
* Potential Risks of Poorly Monitored Ketamine Use in Depression Treatment, in
American Journal of Psychiatry, 2016; 173: 215–8. (K. M. Schak)

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 © 2016, 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
Mar. 8, 2016 * Vol. 23, No. 45
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. issue of JAMA Internal Medicine (2016; 176).
Lifetime Marijuana Use and Cognitive Function in Middle Age: In the Coronary Artery Risk Development in Young Adults (CARDIA) study, verbal memory was worse among patients with past marijuana exposure, researchers report, but other domains of cognitive function were not affected (pp. 352–61). A cohort of 5,115 people 18–30 years of age at baseline were followed in 1985–86 (year 0) and for 25 years thereafter, with these results on the Rey Auditory Verbal Learning Test (verbal memory), the Digit Symbol Substitution Test (processing speed), and the Stroop Interference Test (executive function): “Among 3,385 participants with cognitive function measurements at the year 25 visit, 2,852 (84.3%) reported past marijuana use, but only 392 (11.6%) continued to use marijuana into middle age. Current use of marijuana was associated with worse verbal memory and processing speed; cumulative lifetime exposure was associated with worse performance in all 3 domains of cognitive function. After excluding current users and adjusting for potential confounders, cumulative lifetime exposure to marijuana remained significantly associated with worse verbal memory. For each 5 years of past exposure, verbal memory was 0.13 standardized units lower (95% CI, −0.24 to −0.02; P = .02), corresponding to a mean of 1 of 2 participants remembering 1 word fewer from a list of 15 words for every 5 years of use. After adjustment, we found no associations with lower executive function (–0.03 [95% CI, −0.12 to 0.07]; P = .56) or processing speed (–0.04 [95% CI, −0.16 to 0.08]; P = .51).” (R. Auer, reto.auer@hospvd.ch)
Text Messaging & Smoking Cessation: Short message service (SMS) text messaging yielded smoking cessation results comparable to traditional interventions among 1,590 Swedish college and university students, the Nicotine Exit (NEXit) study shows (pp. 321–8). Based on a primary outcome of self-reported prolonged abstinence (not more than 5 cigarettes over 8 weeks), the results showed: “At baseline, participants were smoking a median (range) of 63 (1–238) and 70 (2–280) cigarettes per week, respectively. Eight-week prolonged abstinence was reported by 203 participants (25.9%) in the intervention group and 105 (14.6%) in the control group; 4-week point prevalence of complete cessation was reported by 161 (20.6%) and 102 (14.2%) participants, respectively, a mean (SD) of 3.9 (0.37) months after the quit date. The adjusted odds ratios (95% CIs) for these findings were 2.05 (1.57–2.67) and 1.56 (1.19–2.05), respectively.” (P. Bendtsen, preben.bendtsen@liu.se)
Text Messaging & Medication Adherence: In 16 randomized clinical trials, text messaging has approximately doubled the odds of medication adherence, a systematic review and meta-analysis reports (pp. 340–9): “In the pooled analysis of 2,742 patients (median age, 39 years and 50.3% [1,380 of 2,742] female), text messaging significantly improved medication adherence (odds ratio, 2.11; 95% CI, 1.52–2.93; P < .001). The effect was not sensitive to study characteristics (intervention duration or type of disease) or text message characteristics (personalization, 2-way communication, or daily text message frequency). In a sensitivity analysis, our findings remained robust to change in inclusion criteria based on study quality (odds ratio, 1.67; 95% CI, 1.21–2.29; P = .002). There was moderate heterogeneity (I2 = 62%) across clinical trials. After adjustment for publication bias, the point estimate was reduced but remained positive for an intervention effect (odds ratio, 1.68; 95% CI, 1.18–2.39).” (J. Thakkar, jthakkar@georgeinstitute.org.au)

>>>PNN NewsWatch
* The APhA House of Delegates yesterday approved policies on biologic, biosimilar, and interchangeable biologic drug products and point-of-care testing but referred language on medication optimization services to the group’s Board of Trustees. New business items approved by the House included policies on substance-use disorder education, prevention of diversion and conversion of medications, access to medication-assisted treatment, and labeling and measurement of liquid drug products.
*
FDA last week approved the first coagulation factor-albumin fusion protein product, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (Idelvion, CSL Behring), for use in children and adults with hemophilia B.

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 © 2016, 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
Mar. 9, 2016 * Vol. 23, No. 46
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Mar. 8 issue of JAMA (2016; 315).
Naltrexone–Bupropion & Adverse Cardiovascular Events in Overweight/Obesity: Used for treating patients with overweight and obesity at increased cardiovascular risk, the combination of naltrexone and bupropion was not associated with a significantly increased risk of major adverse cardiovascular events (MACE), researchers report (pp. 990–1004). However, because the study was terminated early after the sponsor released confidential information publicly, “the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial,” LIGHT researchers conclude. The study included 8,910 patients at 266 U.S. centers, all of whom received an internet-based weight-management intervention. Comparing placebo with naltrexone 32 mg/d and bupropion 360 mg/d, the investigators found: “Mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1–40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion–treated patients (0.8%; HR, 0.59; 95% CI, 0.39–0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57–1.34). Adverse effects were more common in the naltrexone–bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001).” (S. E. Nissen, nissens@ccf.org)
REMS programs are among the options FDA has in cases of sponsor misbehavior like that seen in this instance, editorialists write (
pp. 984–6): “In the shadow of LIGHT, the FDA should review its policy of permitting approval based on interim analyses of ongoing safety studies. At a minimum, when a company violates its commitment to confidentiality and the FDA requires a new trial, the agency should delay approval at least until a viable replacement study is being conducted. If the drug has already been approved, the FDA should use its authority to require Risk Evaluation and Mitigation Strategies to counter misinformation or restrict use of the medication as appropriate. Such an approach would reestablish the balance between safety considerations and new drug approval. The FDA should pursue additional safeguards to prevent breakdowns in sponsor–investigator relationships and avoid the dissolution of future trials. For example, the agency should consider having data monitoring committees report interim results directly to the FDA, not to the sponsor.” (J. M. Sharfstein, joshua.sharfstein@jhu.edu)
Vitamin D & Symptomatic Knee Osteoarthritis: In patients with symptomatic knee osteoarthritis and low serum levels of vitamin D, supplementation with the vitamin failed to affect tibial cartilage volume or pain scores on the Western Ontario and McMaster Universities Arthritis Index (WOMAC), a study shows (pp. 1005–13). For 2 years, study participants received monthly oral doses of vitamin D3 of 50,000 IU or placebo, with these results: “Of 413 enrolled participants (mean age, 63.2 years; 50% women), 340 (82.3%) completed the study. The level of 25-hydroxyvitamin D increased more in the vitamin D group (40.6 nmol/L) than in the placebo group (6.7 nmol/L) (P < .001) over 2 years. There were no significant differences in annual change of tibial cartilage volume (−3.4% in the vitamin D group vs −4.2% in the placebo group [between-group difference, 0.8% {95% CI, −0.2% to 1.8%}]; P = .13) or WOMAC pain score (−49.9 in the vitamin D group vs −35.1 in the placebo group [between-group difference, −14.8 {95% CI, −32.5 to 2.9}]; P = .10). There were no significant differences in change of tibiofemoral cartilage defects (0.3 in the vitamin D group vs 0.5 in the placebo group [between-group difference, −0.2 {95% CI, −0.4 to 0.1}]; P = .21) or change in tibiofemoral bone marrow lesions (−0.1 in the vitamin D group vs 0.3 in the placebo group [between-group difference, −0.5 {95% CI, −0.9 to 0.0}]; P = .06). Adverse events (≥1 per patient) occurred in 56 participants in the vitamin D group and in 37 participants in the placebo group (P = .04).” (C. Ding, changhai.ding@utas.edu.au)

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 © 2016, 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
Mar. 10, 2016 * Vol. 23, No. 47
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Mar. 10 New England Journal of Medicine (2016; 374).
Treating, Preventing Malaria During Pregnancy: Two research studies and an editorial examine drug regimens for treating or preventing malaria in pregnant women.
A trial of four combination treatments of malaria in 3,428 pregnant women concludes that “artemether–lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin–piperaquine had the best efficacy and an acceptable safety profile” (
pp. 913–27). Also studied were amodiaquine–artesunate and mefloquine–artesunate. (U. D’Alessandro, udalessandro@mrc.gm)
Resistance to sulfadoxine–pyrimethamine is creating a need for alternative malarial prevention regimens in Africa, authors explain (
pp. 928–39). In 300 patients, “the burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin–piperaquine than among those who received sulfadoxine–pyrimethamine, and monthly treatment with dihydroartemisinin–piperaquine was superior to three-dose dihydroartemisinin–piperaquine with regard to several outcomes,” the authors conclude, adding these details: “The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine–pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin–piperaquine group (34.1%, P = 0.03) or the monthly dihydroartemisinin–piperaquine group (27.1%, P = 0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin–piperaquine group (9.2%) than in the sulfadoxine–pyrimethamine group (18.6%, P = 0.05) or the three-dose dihydroartemisinin–piperaquine group (21.3%, P = 0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine–pyrimethamine group (41 episodes over 43.0 person–years at risk) than in the three-dose dihydroartemisinin–piperaquine group (12 episodes over 38.2 person–years at risk, P = 0.001) or the monthly dihydroartemisinin–piperaquine group (0 episodes over 42.3 person-years at risk, P <0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine–pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin–piperaquine group [P <0.001] and 5.2% in the monthly dihydroartemisinin–piperaquine group [P <0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.” (G. Dorsey, gdorsey@medsfgh.ucsf.edu)
Pointing to reports of lower drug concentrations of these antimalarial drugs in pregnancy, an editorialist writes (
pp. 981–2): “Prospective pharmacokinetic studies involving pregnant women and nonpregnant controls are needed to characterize the pharmacologic properties of these antimalarial drugs in order to improve treatment. New drugs in development are still several years away from clinical use, and evidence-based dosing of currently available antimalarial drugs might increase their therapeutic lifespan by reducing the risk of treatment failures and the development of resistance. This might be particularly important in Southeast Asia, where acquired immunity is lower and resistance to artemisinin and its partner drugs is emerging and spreading.” (J. Tarning)
Zika Virus & Microcephaly: Following termination of a pregnancy at 29 weeks because of microcephaly, fetal autopsy confirms the growing evidence that Zika virus can be transmitted in utero and is associated with this birth defect (pp. 951–8). “The rapid spread of ZIKV around the globe will [likely] be a strong impetus for collaborative research on the biologic properties of the virus, particularly since the risk of neurotropic and teratogenic virus infections places a high emotional and economic burden on society,” the authors conclude. (A. ┼Żupanc, tatjana.avsic@mf.uni-lj.si)

>>>PNN NewsWatch
* FDA is alerting health professionals and patients not to use drug products intended to be sterile that are produced and distributed by I.V. Specialty Ltd., Austin, TX, due to lack of sterility assurance. The company has not complied with FDA requests to cease operations and recall all nonexpired products.

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 © 2016, 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
Mar. 11, 2016 * Vol. 23, No. 48
Providing news and information about medications and their proper use

>>>Cardiology Report
Source:
Mar. 15 issue of the Journal of the American College of Cardiology (2016; 67).
Metabolomic Profiling of Statins: Investigators study the molecular effects of statins on multiple metabolic pathways using techniques from the emerging field of metabolomics (pp. 1200–10). Four population-based cohorts from the U.K. and Finland provided data on at 2 time points for 716 statin users and 4,874 persistent nonusers. Mendelian randomization was used to determine effects of HMG-CoA reductase genetic variants on lipids and metabolites from 8 population-based cohorts of 27,914 individuals. Results showed: “Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03).” (P. Würtz)
This study “represents an important proof-of-concept study that observational data can be used to characterize drug responses using pharmacometabolomics by confirming these results with a ‘natural’ clinical trial using Mendelian randomization concepts,” editorialists write (
pp. 1211–3). “By linking genomic and electronic health record data, phenome-wide association studies or ‘pheWAS’ can use Mendelian randomization to identify novel diseases for drugs with known mechanisms of action and potentially rescue failed drugs by identifying novel indications. [These] studies can dissect on- and off-target drug effects to better understand variation in drug response and adverse drug effects.” (D. Voora)
Platelet Inhibition With Lower Doses of Ticagrelor: During dual therapy with aspirin, ticagrelor 60 mg twice daily produces peak and trough platelet inhibition similar to that of 90 mg twice daily, researchers report, “helping to explain the efficacy of the lower ticagrelor dose in the PEGASUS-TIMI 54” trial (pp. 1145–54). Pharmacokinetic and pharmacodynamic analysis of data from 180 patients showed these patterns before morning premaintenance doses and again 2 hours later: “Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose [P2Y12 reaction units (PRU)] values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose.” (R. F. Storey)
“These data also raise questions as to whether the 60-mg dose is the optimal dose and should be the focus of further investigation,” an editorialist writes (
pp. 1155–7). “The clinically relevant pharmacokinetics and pharmacodynamics of the 60-mg dose, as characterized in this platelet substudy, are not significantly different than the 90-mg dose of ticagrelor. There were no significant differences between doses in platelet reactivity across multiple assays. Moreover, the 60-mg dose was better tolerated, yielding greater compliance; discontinuation for dyspnea was lower for the 60-mg dose (4.55% vs. 6.5%; p < 0.001). Given a marginally lower risk of bleeding, no significant difference in platelet reactivity, better tolerability, and similar reduction in ischemic events, ticagrelor 60 mg twice daily is the preferable dose in this population. This observation alone warrants a reassessment of the preferred ticagrelor dose in other populations.” (S. S. Brar)

>>>PNN NewsWatch
* Teva Pharmaceuticals is recalling one lot of amikacin sulfate injection 1 g/4 mL (#4750915, exp. date 9/2017) because of potential presence of particulate matter, FDA 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 © 2016, 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
Mar. 14, 2016 * Vol. 23, No. 49
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 12 issue of Lancet (2016; 387).
Genetic Variants in Lithium Response: In patients with bipolar disorders, a genomewide association study of lithium response supports an “increasingly appreciated” role of two genes for long, noncoding RNAs, AL157359.3 and AL157359.4 (pp. 1085–93). At 22 International Consortium on Lithium Genetics sites, 2,563 patients were assessed for lithium response, and results were linked to genotyped single nucleotide polymorphisms (SNPs): “A single locus of four linked SNPs on chromosome 21 met genomewide significance criteria for association with lithium response (rs79663003, p = 1.37 × 10−8; rs78015114, p = 1.31 × 10−8; rs74795342, p = 3.31 × 10−9; and rs75222709, p = 3.50 × 10−9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p = 0.03268, hazard ratio 3.8, 95% CI 1.1–13.0).” (T. G. Schulze, thomas.schulze@med.uni-muenchen.de)
Fingolimod in Primary Progressive Multiple Sclerosis: The oral sphingosine 1-phosphate receptor modulator fingolimod failed to slow disease progression in a 148-center trial of 970 patients with primary progression multiple sclerosis conducted in 18 countries (pp. 1075–84). INFORMS trial investigators report these placebo-controlled results for cohorts 1 (fingolimod 1.25 mg/d) and 2 (fingolimod 0.5 mg/d): “By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan–Meier estimates of 77.2% (95% CI 71.87–82.51) of patients in the fingolimod group versus 80.3% (73.31–87.25) of patients in the placebo group (risk reduction 5.05%; hazard ratio 0.95, 95% CI 0.80–1.12; p = 0.544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%).” (F. Lublin, fred.lublin@mssm.edu)
Cediranib in Platinum-Sensitive Ovarian Cancer: In the ICON6 trial of 456 women with platinum-sensitive ovarian cancer at 63 centers in five countries, cediranib, an oral antiangiogenic vascular endothelial growth factor receptor 1–3 inhibitor, produced positive results (pp. 1066–74): “Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up.” (J. A. Ledermann, j.ledermann@ucl.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved expanded use of crizotinib (Xalkori, Pfizer) to treat metastatic nonsmall-cell lung cancer with ROS-1 gene alterations. This is the first and only FDA-approved treatment for patients with ROS-1–positive NSCLC.

>>>PNN JournalWatch
* A Cancer That Went Up in Smoke: Pulmonary Reaction to e-Cigarettes Imitating Metastatic Cancer, in
Chest, 2016; 149: e65–7. (L. R. Madsen)
* Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets?, in
Journal of the American College of Cardiology, 2016; 67: 1214–26. (R. A. Boon)
* Antibiotic-Associated Encephalopathy, in
Neurology, 2016; 86: 963–71. (S. Bhattacharyya, sbhattacharyya3@partners.org)
* The Epi-TAF for Tenofovir Disoproxil Fumarate?, in
Clinical Infectious Diseases, 2016; 62: 915–8. (R. P. Walensky, rwalensky@partners.org)
* How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World?, in
Clinical Infectious Diseases, 2016; 62: 919–26. (M. B. Klein, marina.klein@mcgill.ca)
* Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology, in
Journal of Clinical Oncology, 2016; 34: 987–1011. (L. Krilov, lada.krilov@asco.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2016, 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
Mar. 15, 2016 * Vol. 23, No. 50
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 15 issue of the Annals of Internal Medicine (2016; 164).
Antibiotics for Acute Respiratory Tract Infections: The American College of Physicians and CDC offer best practices for antibiotic use in healthy adults presenting with acute respiratory tract infections (ARTIs) (pp. 425–34). Defining “healthy adults” as “those without chronic lung disease or immunocompromising conditions,” the groups provide four points of “high-value care advice” (A. Qaseem, aqaseem@acponline.org):
* Clinicians should not perform testing or initiate antibiotic therapy in patients with bronchitis unless pneumonia is suspected.
* Clinicians should test patients with symptoms suggestive of group A streptococcal pharyngitis (for example, persistent fevers, anterior cervical adenitis, and tonsillopharyngeal exudates or other appropriate combination of symptoms) by rapid antigen detection test and/or culture for group A
Streptococcus. Clinicians should treat patients with antibiotics only if they have confirmed streptococcal pharyngitis.
* Clinicians should reserve antibiotic treatment for acute rhinosinusitis for patients with persistent symptoms for more than 10 days, onset of severe symptoms or signs of high fever (>39 °C) and purulent nasal discharge or facial pain lasting for at least 3 consecutive days, or onset of worsening symptoms following a typical viral illness that lasted 5 days that was initially improving (double sickening).
* Clinicians should not prescribe antibiotics for patients with the common cold.
Preventing Contrast-Induced Nephropathy: In a systematic review and meta-analysis, the comparative effectiveness of interventions for lowering the risk of contrast-induced nephropathy (CIN) showed the greatest reductions with N-acetylcysteine plus IV saline in patients receiving low-osmolar contrast media and with statins plus N-acetylcysteine plus IV saline (pp. 406–16): “Low-dose N-acetylcysteine plus IV saline compared with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to 0.89]; low SOE), N-acetylcysteine plus IV saline compared with IV saline in patients receiving low-osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84]; moderate SOE), and statins plus N-acetylcysteine plus IV saline versus N-acetylcysteine plus IV saline (RR, 0.52 [CI, 0.29 to 0.93]; low SOE) had clinically important and statistically significant benefits. The following 3 comparisons suggested a clinically important difference that was not statistically significant: sodium bicarbonate versus IV saline in patients receiving low-osmolar contrast media (RR, 0.65 [CI, 0.33 to 1.25]; low SOE), statins plus IV saline versus IV saline (RR, 0.68 [CI, 0.39 to 1.20]; low SOE), and ascorbic acid versus IV saline (RR, 0.72 [CI, 0.48 to 1.01]; low SOE). Strength of evidence was generally insufficient for comparisons of the need for renal replacement, cardiac events, and mortality.” (R. M. Subramaniam, rsubram4@jhmi.edu)
Iodine Contrast Media Types & Contrast-Induced Nephropathy: While iodixanol produced a “slightly lower risk” of contrast-induced nephropathy (CIN) than other types of low-osmolar contrast media (LOCM), no differences overall were found in a systematic review and meta-analysis (pp. 417–24): “None of the 5 studies that compared types of LOCM reported a statistically significant or clinically important difference among study groups, but the strength of evidence was low. Twenty-five randomized, controlled trials found a slight reduction in CIN risk with the iso-osmolar contrast media agent iodixanol compared with a diverse group of LOCM that just reached statistical significance in a meta-analysis (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P = 0.045). This comparison’s strength of evidence was moderate. In a meta regression of randomized, controlled trials of iodixanol, no relationship was found between route of administration and comparative CIN risk.” (J. Eng, jeng@jhmi.edu)
Improving Practice Feedback: Authors offer 15 suggestions for improving practice feedback interventions (pp. 435–41). Targeting “quality improvement professionals, information technology developers, educators, administrators, and practitioners,” the group concludes, “Designing interventions with these suggestions in mind should improve their effect, and studying the mechanisms underlying these suggestions will advance a stagnant literature.” (J. C. Brehaut, jbrehaut@ohri.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 © 2016, 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
Mar. 16, 2016 * Vol. 23, No. 51
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Early-online articles from and the Mar. 15 issue of JAMA (2016; 315).
CDC Opioid Prescribing Guideline: A clinical guideline released yesterday by CDC is presented; several editorials from JAMA journals analyze impact of the recommendations in various patient populations.
CDC concludes that its “guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy” (
doi: 10.1001/jama.2016.1464). Based on an updated 2014 systematic review and effectiveness and risks of opioids and a supplemental review on benefits and harms, the agency writes: “There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.” (D. Dowell, ddowell@cdc.gov)
“The CDC guideline for prescribing opioids for chronic pain is an important and essential step forward,” an editorialist writes (
doi: 10.1001/jama.2016.1910). “With support from physicians across the country, as well as from policy makers at all levels, implementation of the recommendations in this guideline has the potential to improve and save many, many lives.” (Y. Olsen, yolsen@ibrinc.org)
In a second editorial, an author notes that “pain management will never be easy or straightforward, but it is an intrinsic element of any effort to reduce patients’ suffering” (
doi: 10.1001/jama.2016.1912). “The data will never be perfect. The measures will never be perfect. The guidelines will never be perfect. And neither will clinicians and their performance. But by acknowledging these imperfections and trying to get better with the tools available, physicians can more effectively reduce the suffering of patients.” (T. H. Lee, thomas.lee@pressganey.com)
Vaccine Refusal & Vaccine-Preventable Diseases: In the period after “elimination” of measles and the nadir of pertussis cases in the U.S., vaccine refusal has been a factor in resurgence of both diseases among those refusing vaccines and in some cases among fully vaccinated individuals, a review article concludes (pp. 1149–58). Waning immunity is also linked to pertussis resurgence, the authors conclude, adding these details: “We identified 18 published measles studies (9 annual summaries and 9 outbreak reports), which described 1,416 measles cases (individual age range, 2 weeks–84 years; 178 cases younger than 12 months) and more than half (56.8%) had no history of measles vaccination. Of the 970 measles cases with detailed vaccination data, 574 cases were unvaccinated despite being vaccine eligible and 405 (70.6%) of these had nonmedical exemptions (eg, exemptions for religious or philosophical reasons, as opposed to medical contraindications; 41.8% of total). Among 32 reports of pertussis outbreaks, which included 10,609 individuals for whom vaccination status was reported (age range, 10 days–87 years), the 5 largest statewide epidemics had substantial proportions (range, 24%–45%) of unvaccinated or undervaccinated individuals. However, several pertussis outbreaks also occurred in highly vaccinated populations, indicating waning immunity. Nine reports (describing 12 outbreaks) provided detailed vaccination data on unimmunized cases; among 8 of these outbreaks from 59% through 93% of unvaccinated individuals were intentionally unvaccinated.” (S. B. Omer, somer@emory.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 © 2016, 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
Mar. 17, 2016 * Vol. 23, No. 52
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Mar. 17 New England Journal of Medicine (2016; 374).
Safer Prescribing Through Complex Interventions: In a cluster-randomized trial conducted in Scotland, a 48-week intervention lowered high-risk prescribing patterns in primary care practices, researchers report (pp. 1053–64). The intervention included professional education, informatics to facilitate review, and financial incentives for practices to review patients’ charts to assess appropriateness. Using a primary outcome of patient-level exposure to any of nine measures of high-risk prescribing of NSAIDs or selected antiplatelet agents, the investigators found: “A total of 34 practices underwent randomization, 33 of which completed the study. Data were analyzed for 33,334 patients at risk at one or more points in the preintervention period and for 33,060 at risk at one or more points in the intervention period. Targeted high-risk prescribing was significantly reduced, from a rate of 3.7% (1,102 of 29,537 patients at risk) immediately before the intervention to 2.2% (674 of 30,187) at the end of the intervention (adjusted odds ratio, 0.63; 95% confidence interval [CI], 0.57 to 0.68; P <0.001). The rate of hospital admissions for gastrointestinal ulcer or bleeding was significantly reduced from the preintervention period to the intervention period (from 55.7 to 37.0 admissions per 10,000 person–years; rate ratio, 0.66; 95% CI, 0.51 to 0.86; P = 0.002), as was the rate of admissions for heart failure (from 707.7 to 513.5 admissions per 10,000 person–years; rate ratio, 0.73; 95% CI, 0.56 to 0.95; P = 0.02), but admissions for acute kidney injury were not (101.9 and 86.0 admissions per 10,000 person–years, respectively; rate ratio, 0.84; 95% CI, 0.68 to 1.09; P = 0.19).” (B. Guthrie, b.guthrie@dundee.ac.uk)
Progress in the VA: “By rethinking our systems, working with our current partners, and exploring new public–private partnerships, the VA is transitioning from a loose federation of regional systems to a highly integrated enterprise,” writes the Veterans Affairs Undersecretary of Health in a Perspective article (pp. 1003–5). “Although we have requested and are awaiting several legislative changes to allow the VA to consolidate programs for care in the community and to have greater flexibility in spending for services provided by the private sector, much work has already begun, and we are engaged in intensive planning for the changes that require Congressional approval. Failing to execute a plan that supports strong and enhanced core services within the VA would have serious consequences for U.S. veterans. A well-run VA health system is essential to the nation and to U.S. medicine. The stakes are high, but we believe this vision is the best path toward delivering on President Abraham Lincoln’s promise to care for those who have ‘borne the battle.’” (D. J. Shulkin)

>>>Health Affairs Highlights
Source:
Mar. issue of Health Affairs, a theme issue on physicians, prescription drugs, ACOs & more (2016; 35).
Retail Clinic Visits For Low-Acuity Conditions: Analysis of insurance claims “do not support the idea that retail clinics decrease health care spending,” authors conclude based on analysis of Aetna claims for 2010–12 for 11 low-acuity conditions (pp. 449–55): “We found that 58 percent of retail clinic visits for low-acuity conditions represented new utilization and that retail clinic use was associated with a modest increase in spending, of $14 per person per year.” (A. Mehrotra, Mehrotra@hcp.med.harvard.edu)
Prescription Drug Services for Medicare Beneficiaries: Patients enrolled in Medicare Advantage (MA) plans are more satisfied with their drug benefit than those with coverage through standalone prescription plans, a study shows (pp. 456–63). Community-dwelling beneficiaries older than 64 years in 700 plans reported these reactions to Medicare prescription drug coverage for 2007–14: “Beneficiaries in standalone plans consistently reported less positive experiences with prescription drug plans (ease of getting medications, getting coverage information, and getting cost information) than their MA counterparts. Because MA plans are responsible for overall health care costs, they might have more integrated systems and greater incentives than standalone prescription drug plans to provide enrollees medications and information effectively, including, since 2010, quality bonus payments to these MA plans under provisions of the Affordable Care Act.” (M. N. Elliott, elliott@rand.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 © 2016, 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
Mar. 18, 2016 * Vol. 23, No. 53
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Apr. 1 issue of Clinical Infectious Diseases (2016; 62).
Timing of Pertussis Immunization During Pregnancy: Tetanus–diphtheria–acellular pertussis (Tdap) vaccine should be given to pregnant women early in the second trimester, according to results of a prospective observational noninferiority study showing better transfer of antibodies to the developing fetus (pp. 829–36). Comparing second-trimester ([gestational week (GW)] 13–25) with third-trimester (≥GW 26) Tdap vaccinations, the researchers showed these patterns based on a primary endpoint of geometric mean concentrations (GMCs) of cord blood antibodies to recombinant pertussis toxin (PT) and filamentous hemagglutinin (FHA): “We included 335 women (mean age, 31.0 ± 5.1 years; mean gestational age, 39.3 ± 1.3 GW) previously immunized with Tdap in the second (n = 122) or third (n = 213) trimester. Anti-PT and anti-FHA GMCs were higher following second- vs third-trimester immunization (PT: 57.1 EU/mL [95% confidence interval {CI}, 47.8–68.2] vs 31.1 EU/mL [95% CI, 25.7–37.7], P < .001; FHA: 284.4 EU/mL [95% CI, 241.3–335.2] vs 140.2 EU/mL [95% CI, 115.3–170.3], P <.001). The adjusted GMC ratios after second- vs third-trimester immunization differed significantly (PT: 1.9 [95% CI, 1.4–2.5]; FHA: 2.2 [95% CI, 1.7–3.0], P <.001). Expected infant seropositivity rates reached 80% vs 55% following second- vs third-trimester immunization (adjusted odds ratio, 3.7 [95% CI, 2.1–6.5], P <.001).” (C.-A. Siegrist, claire-anne.siegrist@unige.ch)
Streptococcal Infections & Obesity, Diabetes: Results of a study of invasive group A Streptococcus (iGAS) infections in patients with obesity and diabetes “may help target vaccines against GAS that are currently under development,” authors conclude (pp. 845–52). Multivariable logistic regression analysis of population-based surveillance data with behavioral risk factors revealed these risks in adults: “Between 2010 and 2012, 2,927 iGAS cases were identified. Diabetes was associated with an increased risk of iGAS in all racial groups (adjusted risk ratio [aRR] ranged from 2.71 to 5.08). Grade 3 obesity (body mass index [BMI] ≥40) was associated with an increased risk of iGAS for whites (aRR = 3.47; 95% confidence interval [CI], 3.00–4.01). Grades 1–2 (BMI = 30.0–<40.0) and grade 3 obesity were associated with an increased odds of death (odds ratio [OR] = 1.55, [95% CI, 1.05, 2.29] and OR = 1.62 [95% CI, 1.01, 2.61], respectively) when compared to normal weight patients.” (G. Langley, fez7@cdc.gov)

>>>Oncology Highlights
Source:
Mar. 20 issue of the Journal of Clinical Oncology (2016; 34).
Cost-Effectiveness of Pertuzumab: Using data from the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study in a Markov model, investigators determine that addition of pertuzumab to docetaxel and trastuzumab (THP) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2) overexpressing metastatic breast cancer is not likely to be cost-effective (pp. 902–9). Results of the analysis using 2014 Medicare rates show these health state utilities and outcomes: “Modeled median survival was 39.4 months for [docetaxel plus trastuzumab (TH)] and 56.9 months for THP. The addition of pertuzumab resulted in an additional 1.81 life–years gained, or 0.62 [quality-adjusted life–years (QALYs)], at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost effectiveness at a willingness to pay of $100,000 per QALY gained.” (B. Y. Durkee, bydurkee@stanford.edu)
Childhood Chemotherapy & Adult Breast Cancer Risk: Use of alkylator and anthracycline chemotherapy may increase the risk of breast cancer in survivors of childhood sarcoma and leukemia, the Childhood Cancer Survivor Study shows (pp. 910–8). Over a median of 25.5 years, “47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population.” (T. O. Henderson, thenderson@peds.bsd.uchicago.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 © 2016, 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
Mar. 21, 2016 * Vol. 23, No. 54
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 19 issue of Lancet (2016; 387).
Hormone Therapy in Prostate Cancer: Long-term hormone therapy for prostate cancer, as studied in the STAMPEDE trial, should include docetaxel (Doc) but not zoledronic acid (ZA), investigators conclude (pp. 1163–77). Standard-of-care (SOC) hormone therapy was provided for at least 2 years with optional radiotherapy for men with node-positive, nonmetastatic (N+M0) disease. Results of DOC and ZA therapy in the unblinded trial produced these results: “2,962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1,817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0.94, 95% CI 0.79–1.11; p = 0.450), 81 months (41 to not reached) for SOC + Doc (0.78, 0.66–0.93; p = 0.006), and 76 months (39 to not reached) for SOC + ZA + Doc (0.82, 0.69–0.97; p = 0.022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.” (M. R. Sydes, m.sydes@ucl.ac.uk)
Gene Therapy Calcium Upregulation in Cardiac Disease: In the largest gene transfer study conducted to date in patients with heart failure and reduced ejection fraction (CUPID 2), adeno-associated virus 1 (AAV1) gene therapy for low sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity failed to improve the clinical course of the disease (pp. 1178–86). At 67 clinical centers in the U.S., Europe, and Israel, these results were recorded in the masked-assignment, phase 2b trial: “Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n = 127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17.5 months (range 1.8–29.4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0.93, 95% CI 0.53–1.65; p = 0.81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes.” (B. Greenberg, bgreenberg@ucsd.edu)
TB Prevention in HIV-Infected Patients: Compared with isoniazid preventive therapy, empirical tuberculosis therapy failed to reduce mortality at 24 weeks in adult outpatients with advanced HIV disease, researchers report (pp. 1198–209). The open-label, randomized trial included patients with HIV infection in resource-poor countries where death in the first 6 months after initiation of antiretroviral therapy is common because of tubercular infection. Results showed: “Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9–32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3.5–7.8) for empirical group and for isoniazid preventive therapy (95% CI 3.4–7.8); absolute risk difference of −0.06% (95% CI −3.05 to 2.94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.” (M. C. Hosseinipour, mina_hosseinipour@med.unc.edu)

>>>PNN JournalWatch
* Microbes and Asthma: Opportunities for Intervention, in
Journal of Allergy and Clinical Immunology, 2016; 137: 690–7. (H. H. Smits, h.h.smits@lumc.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 © 2016, 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
Mar. 22, 2016 * Vol. 23, No. 55
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2016; 176).
Medication/Supplement Use by Older Americans: Use of prescription and over-the-counter medicines has increased among older Americans since 2005, and 15% of these patients are at risk for major drug–drug interactions based on their medication profiles, a study shows (doi: 10.1001/jamainternmed.2015.8581). In a longitudinal, nationally representative sample of community-dwelling older adults, in-home interviews with direct medication inspection showed these patterns of drug use among 62 to 85 years olds: “The study cohort comprised 2,351 participants in 2005–2006 and 2206 in 2010–2011. Their mean age was 70.9 years in 2005–2006 and 71.4 years in 2010–2011. Fifty-three percent of participants were female in 2005–2006, and 51.6% were female in 2010–2011. The use of at least 1 prescription medication slightly increased from 84.1% in 2005–2006 to 87.7% in 2010–2011 (P = .003). Concurrent use of at least 5 prescription medications increased from 30.6% to 35.8% (P = .02). While the use of over-the-counter medications declined from 44.4% to 37.9%, the use of dietary supplements increased from 51.8% to 63.7% (P <.001 for both). There were clinically significant increases in the use of statins (33.8% to 46.2%), antiplatelets (32.8% to 43.0%), and omega-3 fish oils (4.7% to 18.6%) (P <.05 for all). In 2010–2011, approximately 15.1% of older adults were at risk for a potential major drug–drug interaction compared with an estimated 8.4% in 2005–2006 (P < .001). Most of these interacting regimens involved medications and dietary supplements increasingly used in 2010–2011.” (D. M. Qato, dimaqato@uic.edu)
Nondisclosure of CAM Use: According to data from the 2012 National Health Interview Survey (NHIS), just over 40% of Americans do not disclose use of complementary and alternative medicines (CAM) to their primary care physicians (doi: 10.1001/jamainternmed.2015.8593). “Of the 34,525 adults who completed the CAM supplement to the 2012 NHIS, 10,158 (29.6%) reported using CAM at least once in the past year, and 22,765 (66.3%) had a primary care physician,” the authors wrote. “Of 7,493 respondents who fit both criteria, 3,094 (42.3%) did not disclose the use of their most used CAM modality.… Contrary to earlier findings, our results attribute most nondisclosure to physicians not asking about CAM use or to concerns about physician knowledge regarding CAM rather than to physician discouragement or negativity about the use of CAM. Consequently, physicians should consider more actively inquiring about patients’ use of CAM, especially for modalities likely to be medically relevant.” (J. Jou, jouxx008@umn.edu)

>>>Geriatrics Highlights
Source:
Mar. issue of the Journal of the American Geriatrics Society (2016; 64).
Anticholinergic Drug Burden in Dementia: Better communication among physicians caring for patients with dementia is needed to reduce the anticholinergic drug burden of these patients’ drug regimens as they begin treatment with cholinesterase inhibitors, researchers report (pp. 492–500). In a population-based cross-sectional study of 79,067 community and 12,113 long-term care patients in Ontario, these results were found using the Anticholinergic Risk Scale: “Community-dwelling participants had seen an average of eight different physicians in the prior year. The odds of high anticholinergic drug burden (Anticholinergic Risk Scale score ≥2) were 24% higher for every five additional physicians providing care to individuals in the prior year (adjusted odds ratio = 1.24, 95% confidence interval = 1.21–1.26). Female sex, low-income status, previous hospitalization, and higher comorbidity score were also associated with high anticholinergic drug burden. Long-term care facility residents had seen an average of 10 different physicians in the prior year. After a sensitivity analysis, the association between high anticholinergic burden and number of physicians was no longer statistically significant in the long-term care group.” (P. A. Rochon, paula.rochon@wchospital.ca)

>>>PNN NewsWatch
* FDA has approved obiltoxaximab injection (Anthim, Elusys Therapeutics) to treat inhalational anthrax in combination with antibiotics and to prevent inhalational anthrax when other therapies are not available or not appropriate.

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 © 2016, 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
Mar. 23, 2016 * Vol. 23, No. 56
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Mar. 22/29 issue of JAMA (2016; 315).
Early Antibiotic Exposure & Weight Gain During Childhood: A retrospective longitudinal study of singleton births and twin pairs shows no significant association between antibiotic exposure in the first 6 months of life and weight gain through age 7 (pp. 1258–65). Conducted in three mid-Atlantic states, the study showed these growth patterns among children seen at 30 pediatric primary care practices serving more than 200,000 children: “Of 38,522 singleton children (50% female; mean birth weight, 3.4 kg), 5,287 (14%) were exposed to antibiotics during the first 6 months of life (at a mean age of 4.3 months). Antibiotic exposure was not significantly associated with rate of weight change (0.7%; 95% CI, −0.1% to 1.5%; P = .07, equivalent to approximately 0.05 kg; 95% CI, −0.004 to 0.11 kg of added weight gain between age 2 years and 5 years). Among 92 twins (38% female; mean birth weight, 2.8 kg), the 46 twins who were exposed to antibiotics during the first 6 months of life received them at a mean age of 4.5 months. Antibiotic exposure was not significantly associated with a weight difference (−0.09 kg; 95% CI, −0.26 to 0.08 kg; P = .30).” (J. S. Gerber, gerberj@email.chop.edu)
Sulindac/Erlotinib for Duodenal Polyps: Among patients with familial adenomatous polyposis, sulindac plus erlotinib lowered the number of duodenal polyps present over a 6-month period, compared with placebo, researchers report (pp. 1266–75). Sulindac 150 mg twice daily/erlotinib 75 mg daily or placebo produced these outcomes: “Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped prematurely by recommendation of the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Over 6 months, the median duodenal polyp burden in the sulindac-erlotinib group decreased from 29.0 mm to 19.5 mm (median change, −8.5 mm), and in the placebo group increased from 23.0 mm to 31.0 mm (median change, 8.0 mm), for a net difference of −19.0 mm (95% CI, −32.0 to −10.9; P <.001) between the groups. The median duodenal polyp count in the sulindac-erlotinib group decreased from 13.5 to 10.0 (median change, −2.8), and in the placebo group increased from 10.5 to 17.0 (median change, 4.3), for a net difference between treatment and placebo groups of −8.0 polyps (95% CI, −12.2 to −4.7; P <.001). Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P <.001). Only 2 participants experienced grade 3 adverse events: 1 in the treatment group experienced oral mucositis and 1 receiving placebo experienced abdominal pain.” (D. W. Neklason, deb.neklason@hci.utah.edu)
Vaccines for Zika Virus: “Although there are several barriers for developing [Zika virus] vaccines and other measures for pregnant women, these barriers are surmountable with concerted efforts and leadership,” Viewpoint authors write (pp. 1227–8). “Drug and vaccine development and evaluation in children may provide some context for the current outbreak response. Pediatricians and child health researchers recognized many parallel challenges in the amount and quality of data available for the care of children. The term therapeutic orphans was coined for children, stressing the concept of the lack of information available to prevent and treat disease in children. To address these challenges, efforts were mobilized around the conceptualization and passing of legislation (Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act). These efforts have contributed to improving the quantity and quality of research that has been conducted in children. A similar approach may also be relevant to fostering research in pregnancy.” (S. B. Omer, somer@emory.edu)

>>>PNN NewsWatch
* FDA yesterday approved the humanized IgG4 monoclonal antibody ixekizumab (Taltz, Lilly) to treat adults with moderate-to-severe plaque psoriasis. The drug selectively binds with and inhibits interleukin 17A cytokine.
*
FDA has also announced mandatory classwide safety labeling changes for immediate-release opioids.

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 © 2016, 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
Mar. 24, 2016 * Vol. 23, No. 57
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Mar. 24 New England Journal of Medicine (2016; 374).
Timing of Parenteral Nutrition in Critically Ill Children: Delaying the start of parenteral nutrition in critically ill children by 1 week proved clinically superior to early parenteral nutrition in a study of 1,440 children, researchers report, a finding consistent with recent data in adults (pp. 1111–2). Based on primary end points of new infection acquired during pediatric intensive care unit (ICU) stay and the adjusted duration of ICU dependency, the study showed: “Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (± SE) duration of ICU stay was 6.5 ± 0.4 days in the group receiving late parenteral nutrition, as compared with 9.2 ± 0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P = 0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P = 0.04) and a shorter duration of hospital stay (P = 0.001). Late parenteral nutrition was also associated with lower plasma levels of gamma-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P = 0.001 and P = 0.04, respectively), as well as higher levels of bilirubin (P = 0.004) and C-reactive protein (P = 0.006).” (G. Van den Berghe, greet.vandenberghe@kuleuven.be)
“On the basis of the results of [this] PEPaNIC trial, delaying parenteral nutrition, along with early initiation and stepwise advancement of enteral nutrition, seems prudent in patients who are not severely malnourished,” an editorialist writes (
pp. 1190–2). “Patience and substantial resources will be required to systematically address unresolved questions through randomized, controlled trials. As the tapestry of evidence is gradually woven, we must be circumspect in our interpretation of study results, invest in mechanistic and hypothesis-generating studies, and explore relevant long-term outcomes. The PEPaNIC trial represents an important step forward, and its results will help to recalibrate the safe application of parenteral nutrition in critically ill children.” (N. M. Mehta)
Incretin-based Drugs & Heart Failure: Compared with commonly used combinations of oral antidiabetic drugs, incretin-based drugs were not associated with increased rates of heart failure hospitalizations in a large population-based case–control study of patients with diabetes (pp. 1145–54). While dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues are known to cause heart failure, assessment of health data from Canada, the U.S., and the U.K. showed these patterns of hospitalizations for this condition: “The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1,000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues.” (K. B. Filion, kristian.filion@mcgill.ca)
Genetics of Dyslipidemia: “Two studies that identify ANGPTL4 as a link between triglycerides and coronary heart disease not only improve our understanding of elevated triglyceride levels in heart disease but also provide a path to the development of future therapies for dyslipidemia,” an editorialist writes (pp. 1192–3) in reaction to genotyping research (pp. 1123–33 and 1134–44). (S. Kersten)

>>>PNN NewsWatch
* FDA yesterday approved reslizumab (Cinqair, Teva) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. The product is approved for patients who have a history of severe exacerbations despite use of other antiasthmatic therapies.

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 © 2016, 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
Mar. 25, 2016 * Vol. 23, No. 58
Providing news and information about medications and their proper use

>>>Neurology Report
Source:
Mar. 22 issue of Neurology (2016; 86).
Cost-effectiveness of Pharmacogenetic Epilepsy Screening: Screening patients for HLA-B*15:02 when they are beginning their first antiepileptic drug (AED) is not cost-effective, according to results when a policy in Hong Kong called for testing (pp. 1086–94). Identified retrospectively, 13,231 patients started therapy in 2005–11. Using a decision-tree model, the investigators incorporated real-world data to determine AED prescription patterns; incidences of AED-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), costs of AED treatments, SJS/TEN treatment, and HLA-B*15:02 testing; and quality of life based on current real-world screening, an “ideal” situation with full policy adherence and preferable testing practices, and an “extended” situation in which HLA-B*15:02 screening would be used for phenytoin in ideal practice: “The current screening policy was associated with an incremental cost-effectiveness ratio of US $85,697 per quality-adjusted life year (QALY) compared with no screening. The incremental cost-effectiveness ratio was estimated to be US $11,090/QALY in the ideal situation and US $197,158/QALY in the extended situation.…
“The HLA-B*15:02 screening policy, as currently practiced, is not cost-effective. Its cost-effectiveness may be improved by enhancing policy adherence and by low-cost point-of-care genotyping. Extending the screening to phenytoin would not be cost-effective because of the low incidence of phenytoin-SJS/TEN among HLA-B*15:02 carriers.” (P. Kwan,
patrick.kwan@unimelb.edu.au)
This study “highlights the fact that a regulatory recommendation does not miraculously result in the implementation of a well-organized and efficient service,” editorialists write (
pp. 1080–1). “That requires adequate planning, education, and monitoring. It may be that failure to educate physicians about the risks of adverse effects and the benefits of screening was a major factor diminishing the cost-effectiveness of the policy. In particular, risks associated with other drugs, including phenytoin, may have been overlooked. Poor adherence to the screening policy may have been caused by low confidence among clinicians and patients in the ability of genomic technology to stratify risk and help personalize treatment decisions, a problem recognized by the Food and Drug Administration.” (A. Marson)
Statin Pretreatment in Large Artery Atherosclerotic Stroke: Neurologic improvement, disability, survival, and stroke recurrence were all improved with statin pretreatment in consecutive patients with acute ischemic stroke caused by large artery atherosclerosis (LAA) at seven tertiary-care stroke centers over a 3-year period, researchers report (pp. 1103–11): “Statin pretreatment was documented in 192 (37.2%) of 516 consecutive patients with LAA (mean age: 65 ± 13 years; 60.8% men; median NIH Stroke Scale score: 9 points, interquartile range: 5–18). Statin pretreatment was associated with greater neurologic improvement during hospitalization and higher rates of 30-day [favorable functional outcome (FFO)] in unmatched and matched (odds ratio for FFO: 2.44; 95% confidence interval [CI]: 1.07–5.53) analyses. It was also related to lower risk of 1-month mortality and stroke recurrence in unmatched and matched analyses (hazard ratio for recurrent stroke: 0.11, 95% CI: 0.02–0.46; hazard ratio for death: 0.24, 95% CI: 0.08–0.75).” (G. Tsivgoulis, tsivgoulisgiorg@yahoo.gr)

>>>PNN NewsWatch
* FDA yesterday issued a draft guidance for use by industry in development of generic versions of approved opioids with abuse-deterrent formulations (ADF) while ensuring that generic ADF opioids are no less abuse-deterrent than the brand-name drug. In the guidance, FDA encourages industry efforts to develop pain medicines that are more difficult to abuse. “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products” includes recommendations about the studies that should be conducted to demonstrate that a generic opioid is no less abuse-deterrent than the brand name product, with respect to all potential routes of abuse. The draft guidance for generic abuse-deterrent opioids follows last year’s final guidance for brand name opioids, which began the process of defining a framework for what studies are needed to test a product’s ability to deter abuse.

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 © 2016, 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
Mar. 28, 2016 * Vol. 23, No. 59
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2016; 352).
Antidepressant Use & Cardiovascular Risks: A cohort study conducted at U.K. general practices does not support concerns over cardiovascular risks associated with antidepressant use (i1350). Using data from the QResearch primary care database, investigators found these potential benefits and risks associated with use of selective serotonin reuptake inhibitors and other antidepressants: “During five years of follow-up, 772 patients had a myocardial infarction, 1,106 had a stroke or transient ischaemic attack, and 1,452 were diagnosed as having arrhythmia. No significant associations were found between antidepressant class and myocardial infarction over five years’ follow-up. In the first year of follow-up, patients treated with selective serotonin reuptake inhibitors had a significantly reduced risk of myocardial infarction (adjusted hazard ratio 0.58, 95% confidence interval 0.42 to 0.79) compared with no use of antidepressants; among individual drugs, fluoxetine was associated with a significantly reduced risk (0.44, 0.27 to 0.72) and lofepramine with a significantly increased risk (3.07, 1.50 to 6.26). No significant associations were found between antidepressant class or individual drugs and risk of stroke or transient ischaemic attack. Antidepressant class was not significantly associated with arrhythmia over five years’ follow-up, although the risk was significantly increased during the first 28 days of treatment with tricyclic and related antidepressants (adjusted hazard ratio 1.99, 1.27 to 3.13). Fluoxetine was associated with a significantly reduced risk of arrhythmia (0.74, 0.59 to 0.92) over five years, but citalopram was not significantly associated with risk of arrhythmia even at high doses (1.11, 0.72 to 1.71 for doses ≥40 mg/day).” (C. Coupland, carol.coupland@nottingham.ac.uk)
Diet & Mortality in Japan: Adherence to Japanese dietary guidelines known as the “spinning top” is associated with lower risk of total mortality and cardiovascular mortality, researchers report (i1209). In 11 public health center areas across Japan, 36,624 men and 42,970 women aged 45–75 years with no history of cancer, stroke, ischemic heart disease, or chronic liver disease had these outcomes over a median of 15 years: “Higher scores on the food guide (better adherence) were associated with lower total mortality; the multivariable adjusted hazard ratios (95% confidence interval) of total mortality for the lowest through highest scores were 1.00, 0.92 (0.87 to 0.97), 0.88 (0.83 to 0.93), and 0.85 (0.79 to 0.91) (P<0.001 for trend) and the multivariable adjusted hazard ratio associated with a 10 point increase in food guide scores was 0.93 (0.91 to 0.95; P<0.001 for trend). This score was inversely associated with mortality from cardiovascular disease (hazard ratio associated with a 10 point increase 0.93, 0.89 to 0.98; P = 0.005 for trend) and particularly from cerebrovascular disease (0.89, 0.82 to 0.95; P = 0.002 for trend). There was some evidence, though not significant, of an inverse association for cancer mortality (0.96, 0.93 to 1.00; P = 0.053 for trend).” (K. Kurotani, kkurotani@ri.ncgm.go.jp)

>>>PNN JournalWatch
* Review: Preclinical Rheumatoid Arthritis Progress Toward Prevention, in
Arthritis & Rheumatism, 2016; 68: 779–88. (P. Emery, pemery@leeds.ac.uk)
* Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial, in
Arthritis & Rheumatism, 2016; 68: 577–86. (C. Charles-Schoeman, ccharles@mednet.ucla.edu)
* Parkinsonism in Older Adults and Its Association With Adverse Health Outcomes and Neuropathology, in
Journals of Gerontology Series A Biological Science Medical Science, 2016; 71: 549–56. (A. S. Buchman, Aron_S_Buchman@rush.edu)
* Understanding What Makes Americans Dissatisfied With Their Health Care System: An International Comparison, in
Health Affairs, 2016; 35: 502–9. (J. O. Hero, hero@fas.harvard.edu)
* Distinguishing Selection Bias and Confounding Bias in Comparative Effectiveness Research, in
Medical Care, 2016; 54: e23–9. (S. Haneuse)
* Novel Oral Therapies for Opioid-Induced Bowel Dysfunction in Patients with Chronic Noncancer Pain, in
Pharmacotherapy, 2016; 36: 287–99. (R. M. Holder, renee.m.holder@medstar.net)
* Panobinostat: A Histone Deacetylase Inhibitor for the Treatment of Relapsed or Refractory Multiple Myeloma, in
American Journal of Health-System Pharmacy, 2016; 73: 441–50. (K. Wahaib, kristy.wahaib@belmont.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 © 2016, 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
Mar. 29, 2016 * Vol. 23, No. 60
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Apr. issue of Diabetes Care (2016; 39).
Glucose Amplitude & Timing: Perspectives in Care authors discuss the importance of glucose variability (GV) in the physiology and pathophysiology of diabetes and how continuous glucose monitoring can be used to optimize GV (pp. 502–10): “Our primary message is that diabetes control is all about optimization and balance between two key markers—frequency of hypoglycemia and HbA1c reflecting average [blood glucose] and primarily driven by the extent of hyperglycemia. GV is a primary barrier to this optimization, including to automated technologies such as the ‘artificial pancreas.’ Thus, it is time to standardize GV measurement and thereby streamline the assessment of its two most important components—amplitude and timing.” (C. Cobelli, cobelli@dei.unipd.it)
Protein Preload & Vildagliptin Efficacy: In patients with type 2 diabetes treated with metformin, dipeptidyl peptidase-4 inhibitor vildagliptin (VILD) cotreatment can be enhanced by administration of protein preloads, a study shows, with improved gastric emptying, plasma intact incretins, and postprandial glycemia (pp. 511–7). Compared with placebo (PLBO) on the evenings before and mornings of study days, VILD 50 mg had these effects when the morning dose was followed 60 minutes later by 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13C-octanoate–labeled mashed potato meal: “Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P <0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact [glucagon-like peptide-1] and [glucose-dependent insulinotropic polypeptide], slower gastric emptying, and lower postprandial glycemia (P <0.05 each).” (T. Wu, tongzhi.wu@adelaide.edu.au)
Diabetic Ketoacidosis With Canagliflozin: In a study of 351 patients with type 1 diabetes inadequately controlled with insulin, addition of canagliflozin increased serious adverse events (AEs) of diabetic ketoacidosis (DKA) (pp. 532–8). The phase 2 study compared canagliflozin 100 or 300 mg with placebo once daily: “At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE.” (A. L. Peters, momofmax@mac.com)
Glucagon Nasal Powder in Type 1 Diabetes: In a phase 1 trial, 48 youth with type 1 diabetes provide pharmacokinetic and pharmodynamic insights into a needle-free nasal powder formulation of glucagon for use in treating severe hypoglycemia (pp. 555–62). “Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range,” the authors conclude. “All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.” (N. C. Foster, t1dstats@jaeb.org)

>>>PNN NewsWatch
* At an Atlanta summit on prescription drug abuse, President Obama today will unveil a proposal to double the number of buprenorphine doses physicians can prescribe to each patient, STAT 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 © 2016, 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
Mar. 30, 2016 * Vol. 23, No. 61
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Mar. issue of the Journal of Allergy and Clinical Immunology (2016; 137).
Anaphylaxis After Vaccination: In 2009–11, anaphylaxis following vaccination was “rare in all age groups” with a rate of 1–2 cases per million doses, according to authors who analyzed data from the Vaccine Safety Datalink (pp. 868–78). “Despite its rarity, anaphylaxis is a potentially life-threatening medical emergency that vaccine providers need to be prepared to treat,” the investigators conclude based on these findings: “We identified 33 confirmed vaccine-triggered anaphylaxis cases that occurred after 25,173,965 vaccine doses. The rate of anaphylaxis was 1.31 (95% CI, 0.90–1.84) per million vaccine doses. The incidence did not vary significantly by age, and there was a nonsignificant female predominance. Vaccine-specific rates included 1.35 (95% CI, 0.65–2.47) per million doses for inactivated trivalent influenza vaccine (10 cases, 7,434,628 doses given alone) and 1.83 (95% CI, 0.22–6.63) per million doses for inactivated monovalent influenza vaccine (2 cases, 1,090,279 doses given alone). The onset of symptoms among cases was within 30 minutes (8 cases), 30 to less than 120 minutes (8 cases), 2 to less than 4 hours (10 cases), 4 to 8 hours (2 cases), the next day (1 case), and not documented (4 cases).” (M. M. McNeil, mmm2@cdc.gov)
IgE Antibodies & Influenza Vaccine–Associated Anaphylaxis: A spike of influenza vaccine–associated anaphylaxis (IVA) in Japan in 2011–12 “was caused by specific IgE antibodies to influenza vaccine components,” researchers report (pp. 861–7). “Excipients could not be implicated, except for a modest effect of [2-phenoxyethanol (2-PE)],” the authors conclude based on analysis of 19 patients with confirmed IVA and 25 age-matched controls, 10 of whom had confirmed egg allergy and no adverse events after vaccination: “None of the patients with IVA had severe egg allergy. Levels of specific IgE antibodies to influenza vaccine antigens, whole-vaccine products from different manufacturers, and hemagglutinin proteins (A H1, H3, and B) derived from both egg and cell cultures were significantly increased in patients with IVA compared with those in control subjects. Influenza vaccine–induced CD203c expression in basophils was also highly enhanced in patients with IVA but not in control subjects. Because IVA was most frequent in patients who received [2-PE]–containing vaccine, the effect of this preservative on basophil activation was examined, and the activation was slightly enhanced by 2-PE but not thimerosal.” (T. Fujisawa, fujisawa@mie-m.hosp.go.jp)
U.S. Asthma Medication Use & FDA Actions: Warnings by FDA about adverse events with long-acting beta-2-agonists (LABAs) in 2005 and 2010 “might have contributed to reduced use of” the drugs, a study shows, but “their effect, independent of other factors, cannot be determined” (pp. 710–7). Data from rolling cohorts of pediatric and adult asthmatic patients in the Mini-Sentinel Distributed Database showed these patterns of asthmatic drug use in 2005–11: “When the 2005 regulatory activity was announced, there were statistically significant decreases in the use of fixed-dose [inhaled corticosteroid (ICS)]–LABA agents in children (−0.98 percentage points) and adults (−1.24 percentage points). Increased use of ICSs and leukotriene modifiers was observed just after the regulatory activities were announced in both children and adults. Although of smaller magnitude, continued favorable changes in the use of LABA agents were observed after the 2010 FDA regulatory activity.” (M. A. Baker, meghan_baker@harvardpilgrim.org)

>>>PNN NewsWatch
* B. Braun Medical Inc. is recalling one lot of 5% Dextrose Injection USP 100/150mL container (lot no. J5J706, catalog no. S5104-5264, NDC 0264-1510-32) to the consumer level, according to an FDA MedWatch notice posted yesterday. B. Braun recently identified an adverse quality trend in customer complaints reporting that some containers in this lot exhibited leakage and, in a few instances, visible particulate matter identified to be microbial growth.
* Following a series of
FDA onsite inspections, Reliable Drug Pharmacy is recalling all unexpired lots of compounded products due to concern of lack of quality assurance and potential mislabeling. All unexpired lots are subject to the recall; these were distributed between Sept. 24, 2015, and Mar. 24, 2016.

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 © 2016, 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
Mar. 31, 2016 * Vol. 23, No. 62
Providing news and information about medications and their proper use

>>>NEJM Report
Source:
Mar. 31 issue of the New England Journal of Medicine (2016; 374).
Extended-Release Naltrexone: Use of extended-release naltrexone in adult criminal justice offenders produced a rate of opioid relapse lower than that in offenders who received brief counseling and referrals to community treatment programs, researchers report (pp. 1232–42). In an open-label, 24-week trial, these results were associated with naltrexone versus usual care interventions: “A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P <0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P <0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P <0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P = 0.91). The rates of other prespecified secondary outcome measures — self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration — were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P = 0.02).” (J. D. Lee, joshua.lee@nyumc.org)
Postmenopausal Treatment with Estradiol: Oral estradiol therapy should be initiated within 6 years after menopause to prevent progression of subclinical atherosclerosis, a study shows (pp. 1221–31). Based on rates of change in carotid-artery intima–media thickness (CIMT) in 643 healthy postmenopausal women, the investigators found: “After a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P = 0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P = 0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P = 0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.” (H. N. Hodis, athero@usc.edu)
Longer-Term Therapy for Lyme Disease Symptoms: Reacting to a study showing no benefits of longer-term antibiotic therapy for symptoms attributed to Lyme disease (pp. 1209–20; A. Berende), editorialists write (pp. 1277–8): “Though prolonged antibiotic therapy is not the answer, we do not know what is truly helpful. Our personal approach is centered on making thorough assessments for alternative diagnoses such as sleep disorders and providing recommendations borrowed from practices in general medicine. Such a patchwork approach should make it clear that chronic health problems such as fatigue and pain that afflict millions of people worldwide urgently require answers with respect to the causal mechanisms and better approaches for a quicker recovery, regardless of whether the problems were triggered by Borrelia burgdorferi or by some other process.” (M. T. Melia)
Baricitinib in Refractory Rheumatoid Arthritis: In a phase 3 trial of 527 patients with refractory rheumatoid arthritis, the oral Janus kinase 1 and 2 inhibitor baricitinib produced clinical improvement at 12 weeks of therapy (pp. 1243–52; M. C. Genovese).

>>>PNN NewsWatch
* FDA is changing the product labeling for the abortifacient mifepristone “in a way that would effectively sidestep state laws aimed at restricting drug-induced abortion,” the Wall Street Journal reports. The window for use of the drug is being extended from 49 to 70 days after the last menstrual period, the dose is being lowered from 600 mg to 200 mg, and the second dose of the drug will not need to be administered in a medical setting.

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 © 2016, 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.