Jun 2015

PNN April–June 2015

PNN Pharmacotherapy Line
Apr. 1, 2015 * Vol. 22, No. 61
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source: Apr. issue of the
American Journal of Psychiatry (2015; 172).
Cognitive Bias Modification in Alcohol Dependence: In 32 abstinent alcohol-dependent patients, cognitive bias modification affected alcohol cue-induced mesolimbic brain activity compared with sham training, researchers report (
pp. 335–43). In a double-blind trial, participants had six sessions of a joystick approach-avoidance task. Those randomized to bias-modification training pushed away 90% of alcohol cues and 10% of soft-drink cues, while those in the sham group used a 50:50 ratio. Results using functional MRIs of the brain showed: “Before training, alcohol cue-evoked activation was observed in the amygdala bilaterally, as well as in the right nucleus accumbens, although here it fell short of significance. Activation in the amygdala correlated with craving and arousal ratings of alcohol stimuli; correlations in the nucleus accumbens again fell short of significance. After training, the bias modification group showed greater reductions in cue-evoked activation in the amygdala bilaterally and in behavioral arousal ratings of alcohol pictures, compared with the sham training group. Decreases in right amygdala activity correlated with decreases in craving in the bias modification but not the sham training group.” (C. E. Wiers, corinde.wiers@nih.gov)
This report “provides the possibility for all programs treating alcohol use disorders to finally address the fundamental problem for alcohol-dependent individuals: the high rate of relapse to heavy drinking,” an editorialist writes (
pp. 305–6). “Brain reactivity to alcohol cues is a conditioned response, trained in the brain as the addiction develops. This reactivity is seen not only in those addicted to alcohol, but also in other addicts, such as tobacco smokers, heroin addicts, and cocaine addicts. These brain reactions are automatic, often outside of awareness and long-lasting, but they are virtually ignored in most treatment programs for drug addictions. Patients can understand conditioned responses, and cue responsivity can be used as a measure of progress. We now need randomized clinical trials with appropriate control groups to determine conclusively whether focusing on the brain does in fact result in improved overall outcome.” (C. O’Brien, obrien@upenn.edu)

>>>Pediatrics Report
Source: Apr. issue of
Pediatrics (2015; 135).
Pimecrolimus in Atopic Dermatitis: Use of topical pimecrolimus 1% cream (PIM) was safe, effective, and steroid sparing in 2,418 infants with mild to moderate cases of atopic dermatitis (AD) (
pp. 597–606). In a 5-year, open-label study, infants were randomized to PIM or topical corticosteroids (TCSs), with these results: “Both PIM and TCSs had a rapid onset of action with >50% of patients achieving treatment success by week 3. After 5 years, >85% and 95% of patients in each group achieved overall and facial treatment success, respectively. The PIM group required substantially fewer steroid days than the TCS group (7 vs 178). The profile and frequency of adverse events was similar in the 2 groups; in both groups, there was no evidence for impairment of humoral or cellular immunity.” (B. Sigurgeirsson)
Weight & Antibiotic Exposure in Infancy: Infants exposed to antibiotics in the first 6 months of life or repeatedly during infancy have higher body mass indices at 24 months, a study shows (
pp. 617–26). “Such effects may play a role in the worldwide childhood obesity epidemic and highlight the importance of judicious use of antibiotics during infancy, favoring narrow-spectrum antibiotics,” the authors conclude, based on these patterns among 6,114 healthy boys and 5,948 healthy girls: “[Antibiotic-exposed] children were on average heavier than unexposed children (adjusted BMI-for-age z-score difference in boys 0.13 SD [95% confidence interval 0.07 to 0.19, P < .001] and in girls 0.07 SD [0.01 to 0.13, P < .05]). The effect was most pronounced after exposure to macrolides before 6 months of age (boys 0.28 [0.11 to 0.46]; girls 0.23 [0.04 to 0.42]) or >1 exposure (boys 0.20 [0.10 to 0.30]; girls 0.13 [0.03 to 0.22]).” (A. Saari)
Inhaled Nitric Oxide in Premature Infants: Off-label use of nitric oxide in neonates—not a benign practice, authors warn—has continued to rise despite release of a 2011 statement by NIH discouraging the practice, according data for 2009–13 from the Pediatrix Medical Group Clinical Data Warehouse (
pp. 643–8; M. A. Ellsworth).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 2, 2015 * Vol. 22, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 2 issue of the
New England Journal of Medicine (2015; 372).
Early, Goal-Directed Resuscitation for Septic Shock: Outcomes were not improved with a strict protocol of early, goal-directed therapy (EGDT) in patients with septic shock in comparison with usual care, researchers report (
pp. 1301–11). Intravenous antibiotics and adequate fluid resuscitation were included in the 6-hour EGDT protocol, and this was compared with usual care in a pragmatic randomized trial with integrated cost-effectiveness analysis at 56 English hospitals. Based on a primary clinical outcome of all-cause mortality at 90 days, results showed: “We enrolled 1,260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P = 0.90), for an absolute risk reduction in the EGDT group of −0.3 percentage points (95% CI, −5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%.” (K. M. Rowan, kathy.rowan@icnarc.org)
Antibiotics in Adult CAP: In hospitalized patients with clinically suspected community-acquired pneumonia (CAP), a strategy of preferred empiric therapy with a beta-lactam antibiotic may be just as effective as care with beta-lactams combined with macrolides or with fluoroquinolone monotherapy, according to results of a cluster-randomized, crossover trial (
pp. 1312–23). In the noninferiority analysis, 90-day mortality results based on intention to treat showed these patterns: “A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam–macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], −0.6 to 4.4) with the beta-lactam–macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, −2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies.” (C. H. van Werkhoven, c.h.vanwerkhoven@umcutrecht.nl)
Emergency Contraception: The case of a 19-year-old woman nonadherent to an oral contraceptive regimen is used to illustrate decision patterns with regard to emergency contraception (
pp. 1342–8): “Because the woman described in the vignette recently had unprotected sex and does not wish to become pregnant, we would counsel her about the full range of options for emergency contraception. The copper [intrauterine device (IUD)] is the most effective method and may especially appeal to this patient because of her desire to avoid pregnancy for several years and her difficulty with adhering to a regimen of oral contraceptive pills. The IUD would almost eliminate the risk of pregnancy resulting from the recent unprotected sex act and would continue to provide protection for at least 10 years. Moreover, once the device is inserted, it requires virtually no attention. If the patient does not want or cannot obtain an IUD or if an IUD is contraindicated, she should consider oral emergency contraceptive pills.” (E. G. Raymond, eraymond@gynuity.org)

>>>PNN NewsWatch
*
FDA yesterday issued a final guidance to industry on developing opioid drug products with potentially abuse-deterrent properties.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 3, 2015 * Vol. 22, No. 63
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source: Apr. 7 issue of the
Journal of the American College of Cardiology (2015; 65).
Statins, Coronary Calcification & Atheroma: In a post-hoc patient-level analysis of eight prospective randomized trials using serial coronary intravascular ultrasound, high-intensity statin therapy (HIST) was associated with promotion of coronary atheroma calcification independent of effects on plaque regression, researchers report, compared with low-intensity statin therapy (LIST) and no-statin therapy (
pp. 1273–82). “These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression,” the authors conclude based on these serial changes in coronary percent atheroma volume (PAV) and calcium indices (CaI): “Following propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline (−0.6 ± 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 ± 0.1% and +1.0 ± 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median [interquartile range] HIST, +0.044 [0.0–0.12]; LIST, +0.038 [0.0–0.11]; no-statin, +0.020 [0.0–0.10]; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no-statin group.” (R. Puri)
Dual Antiplatelet Therapy After Stent Implantation: Following implantation of drug-eluting stents (DESs), the duration of use of dual antiplatelet therapy (DAPT) must be balanced through “careful assessment of the trade-off between ischemic and bleeding complications,” according to a systematic review and meta-analysis of 10 randomized controlled trials of 32,135 patients (
pp. 1298–310). Using a per-protocol analysis, investigators considered effects of shorter versus longer dual antiplatelet therapy (S-DAPT and L-DAPT) based on definite/probable stent thrombosis (efficacy) and clinically significant bleeding (CSB; safety) outcomes: “Compared with L-DAPT, S-DAPT had an overall higher rate of stent thrombosis (odds ratio [OR]: 1.71 [95% confidence interval (CI): 1.26 to 2.32]; p = 0.001). The effect of S-DAPT on stent thrombosis was attenuated with the use of second-generation DES (OR: 1.54 [95% CI: 0.96 to 2.47]) compared with the use of first-generation DES (OR: 3.94 [95% CI: 2.20 to 7.05]; p for interaction = 0.008). S-DAPT had an overall significantly lower risk of CSB (OR: 0.63 [95% CI: 0.52 to 0.75]; p < 0.001). Finally, a numerically lower all-cause mortality rate was observed with S-DAPT (OR: 0.87 [95% CI: 0.74 to 1.01]; p = 0.073).” (G. Giustino)

>>>Circulation Report
Source: Mar. 31 issue of
Circulation (2015; 131).
Statin Intolerance: On the journal’s Cardiology Patient Page, advice is provided to those with statin intolerance regarding benefits, risks, and potential alternatives (
pp. e389–91): For those with statin intolerance—defined as being unable to continue statin therapy because of adverse effects or elevated liver or muscle function tests—the authors recommend: “First, remember that the benefits of statins are large and potentially lifesaving and any risks are small, not life threatening, and reversible. The reduction in fatal and nonfatal heart attack and stroke by statin treatment cannot be achieved with other currently available medications, nutraceuticals, or dietary modifications.… Before considering the use of a second-line alternative drug, patients should try statin rechallenge, alternative regimens, doses, or types of statins. In most cases, rechallenge with a statin after a brief period of drug discontinuation (‘drug holiday&rsquoWinking can be successful.… Studies to date do not support the use of vitamins and minerals such as coenzyme Q10 supplements to reduce the rates of muscle side effects.” (S. Verma, vermasu@smh.ca)

>>>PNN NewsWatch
*
FDA yesterday joined the North Carolina Board of Pharmacy in warning professionals not to use products made and distributed by Fayetteville’s Prescription Center pharmacy.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 6, 2015 * Vol. 22, No. 64
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 4 issue of
Lancet (2015; 385).
Latanoprost in Open-Angle Glaucoma: Using a study design that enabled assessment of vision in a short observation period, researchers report that patients with open-angle glaucoma had preservation of visual fields when treated with latanoprost versus placebo over a 2-year period (
pp. 1295–304). At 10 U.K. centers, 516 participants with newly diagnosed open-angle glaucoma were enrolled in 2006–10. Using randomized, triple-masked, placebo-controlled design, the investigators found these results with latanoprost 0.005% or placebo once daily: “Baseline mean intraocular pressure was 19.6 mm Hg (SD 4.6) in 258 patients in the latanoprost group and 20.1 mm Hg (4.8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3.8 mm Hg (4.0) in 231 patients assessed in the latanoprost group and 0.9 mm Hg (3.8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0.44 (95% CI 0.28–0.69; p = 0.0003). We noted 18 serious adverse events, none attributable to the study drug.” (D. F. Garway–Heath, david.garway-heath@moorfields.nhs.uk)

>>>BMJ Highlights
Source: Early-release articles from
BMJ (2015; 350).
Meningococcal Conjugate Vaccine Schedules in Infants: Two priming doses of serogroup C meningococcal (MenC) conjugate vaccine can be combined into a single dose without compromising antibody titers, according to results of a trial of 509 healthy infants aged 6–12 weeks at baseline (
h1554). Followed up to 24 months of age, study participants had these responses when randomized to a single MenC-cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide–tetanus toxoid (TT) dose at 3 months; or no MenC doses: “The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA ≥1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC-TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age.” (D. Pace, dpace@go.net.mt)
Acetaminophen for Back Pain, Osteoarthritis: Acetaminophen “is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis,” conclude authors who conducted a systematic review and meta-analysis of 13 randomized trials (
h1225). High-quality evidence showed that the drug is ineffective in low back pain and produced statistically significant but clinically unimportant improvements in pain in patients with hip or knee osteoarthritis. The analysis also showed a 4-fold increase in risk of abnormal liver function tests while on acetaminophen. (G. C. Machado, gmachado@georgeinstitute.org.au)

>>>PNN JournalWatch
* State-of-the-Art Office-Based Interventions to Eliminate Youth Tobacco Use: The Past Decade, in
Pediatrics, 2015; 135: 734–47. (L. Pbert)
* Measles Imported to the United States by Children Adopted From China, in
Pediatrics, 2015; 135: e1032–e1037. (Q. Su)
* Practical Management of Anticoagulation in Patients With Atrial Fibrillation, in
Journal of the American College of Cardiology, 2015; 65: 1340–60. (R. J. Kovacs)
* Comparative Genomic Profiling of Synovium Versus Skin Lesions in Psoriatic Arthritis, in
Arthritis & Rheumatism, 2015; 67: 934–44. (J. Belasco jbelasco@rockefeller.edu)
* Successful Use of
N-Acetylcysteine to Treat Severe Hepatic Injury Caused by a Dietary Fitness Supplement, in Pharmacotherapy, 2015; 35: 10.1002/phar.1572. (C. El Rahi, Celrahi@houstonmethodist.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 7, 2015 * Vol. 22, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Apr. issue of
JAMA Internal Medicine (2015; 175).
Long-term Nicotine Replacement Therapy: While safe, long-term nicotine-replacement therapy is largely ineffective for achieving cessation, according to a study of 525 treatment-seeking smokers (
pp. 504–11). Randomized to 8 (standard), 24 (extended), and 52 (maintenance) weeks of nicotine patch treatment, participants had these cessation rates based on a primary outcome of 7-day point prevalence abstinence: “At 24 weeks, 21.7% of participants in the standard treatment arm were abstinent, compared with 27.2% of participants in the extended and maintenance treatment arms (chi-square  = 1.98; P = .17). In a multivariate model controlled for covariates, participants in the extended and maintenance treatment arms reported significantly greater abstinence rates at 24 weeks compared with participants in the standard treatment arm (odds ratio [OR], 1.70 [95% CI, 1.03–2.81]; P = .04), had a longer duration of abstinence until relapse (beta = 21.30 [95% CI, 10.30–32.25]; P < .001), reported smoking fewer cigarettes per day if not abstinent (mean [SD], 5.8 [5.3] vs 6.4 [5.1] cigarettes per day; beta = 0.43 [95% CI, 0.06–0.82]; P = .02), and reported more abstinent days (mean [SD], 80.5 [38.1] vs 68.2 [43.7] days; OR, 1.55 [95% CI, 1.06–2.26]; P = .02). At 52 weeks, participants in the maintenance treatment arm did not report significantly greater abstinence rates compared with participants in the standard and extended treatment arms (20.3% vs 23.8%; OR, 1.17 [95% CI, 0.69–1.98]; P = .57). Similarly, we found no difference in week 52 abstinence rates between participants in the extended and standard treatment arms (26.0% vs 21.7%; OR, 1.33 [95% CI, 0.72–2.45]; P = .36). Treatment duration was not associated with any adverse effects or adherence to the counseling regimen, but participants in the maintenance treatment arm reported lower adherence to the nicotine patch regimen compared with those in the standard and extended treatment arms (mean [SD], 3.94 [2.5], 4.61 [2.0], and 4.7 [2.4] patches/wk, respectively; F2,522 = 6.03; P = .003).” (R. A. Schnoll)
Duration of Opioid Action & Unintentional Overdose: Using VA data, researchers report the first evidence linking the duration of action of opioid drugs and risk of unintentional overdose (
pp. 608–15). “If replicated in other cohorts, our findings suggest that clinicians weighing the benefits and risks of initiating different opioid regimens should consider not only the daily dose prescribed but also the duration of opioid action, favoring short-acting agents whenever possible, especially during the first 2 weeks of therapy,” the authors conclude. Data from 2000 to 2009 were examined for newly prescribed opioid therapy and care coded for drug or medication poisonings, with these results: “A total of 319 unintentional overdose events were observed. Patients initiating therapy with long-acting opioids were more than twice as likely to overdose compared with persons initiating therapy with short-acting opioids. After adjustment for age, sex, opioid dose, and other clinical characteristics, patients receiving long-acting opioids had a significantly higher rate of overdose injury than did those receiving short-acting opioids (hazard ratio [HR], 2.33; 95% CI, 1.26–4.32). The risk associated with long-acting agents was particularly marked during the first 2 weeks after initiation of treatment (HR, 5.25; 1.88–14.72).” (M. Miller)
Antibiotic Prescribing &
C. diff infection: Ward-level prescribing is associated with “a statistically significant and clinically relevant increase in [Clostridium] difficile risk that persists after adjustment for differences in patient-level antibiotic use and other patient- and ward-level risk factor,” according to a 46-month retrospective cohort study of hospitalized adults (pp. 626–33): “A total of 255 of 34,298 patients developed C difficile (incidence rate, 5.95 per 10,000 patient–days; 95% CI, 5.26–6.73). Ward-level antibiotic exposure varied from 21.7 to 56.4 days of therapy per 100 patient–days. Each 10% increase in ward-level antibiotic exposure was associated with a 2.1 per 10,000 (P < .001) increase in C difficile incidence. The association between C difficile incidence and ward antibiotic exposure was the same among patients with and without recent antibiotic exposure, and C difficile risk persisted after multilevel, multivariate adjustment for differences in patient-risk factors among wards (relative risk, 1.34 per 10% increase in days of therapy; 95% CI, 1.16–1.57).” (K. Brown)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 8, 2015 * Vol. 22, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 7 issue of
JAMA (2015; 313).
Folate for Stroke Prevention: In the China Stroke Primary Prevention Trial, 20,702 adults with hypertension and no history of stroke or myocardial infarction (MI) had fewer first strokes while on enalapril 10 mg plus folic acid 0.8 ng daily, compared with enalapril alone (
pp. 1325–35). Findings “are consistent with benefits from folate use among adults with hypertension and low baseline folate levels,” authors write, adding: “During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril–folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril–folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68–0.93), first ischemic stroke (2.2% with enalapril–folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64–0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril–folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69–0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65–1.34), MI (HR, 1.04; 95% CI, 0.60–1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81–1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events.” (Y. Huo, huoyong@263.net.cn)
These results would likely “apply to normotensive persons, although the absolute effect would be smaller,” editorialists write (
pp. 1321–2). “It is possible to debate the ethics of whether a replication trial should be performed, especially because folic acid supplementation (or fortification) is safe and inexpensive, and carries other benefits. Large segments of the world’s population, potentially billions of people, including those living in northern China, Bangladesh, and Scandinavia, have low levels of folate. Individuals with the TT genotype might particularly benefit, although it seems unlikely that genotyping for that purpose would be cost-effective. Also, some persons in the United States on the low end of the distribution of folate intake may benefit; effects in this subgroup would not have been detected in previous trials. Ideally, adequate folate levels would be achieved from food sources such as vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, and peas. However, for many populations, achieving adequate levels from diet alone is difficult because of expense or availability. This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement.” (M. Stampfer, stampfer@hsph.harvard.edu)
Bivalirudin During PCI in AMI: Adverse events were reduced through use of bivalirudin rather than heparin with or without tirofiban during primary percutaneous coronary intervention (PCI) in 2,194 patients with acute myocardial infarction, according to results of the BRIGHT study (
pp. 1336–46). Medications were administered as a bolus followed by infusion beginning a median of 3 hours after PCI when clinically indicated. Aspirin 300 mg and clopidogrel 300–600 mg were administered before the procedure if patients were not already on the drugs. Based on a composite primary end point of 30-day net adverse clinical events (all-cause death, reinfarction, ischemia-driven target vessel revascularization, stroke, or bleeding), results showed: “Net adverse clinical events at 30 days occurred in 65 patients (8.8%) of 735 who were treated with bivalirudin compared with 96 patients (13.2%) of 729 treated with heparin (relative risk [RR], 0.67; 95% CI, 0.50–0.90; difference, −4.3%, 95% CI, −7.5% to −1.1%; P = .008); and 124 patients (17.0%) of 730 treated with heparin plus tirofiban (RR for bivalirudin vs heparin plus tirofiban, 0.52; 95% CI, 0.39-0.69; difference, −8.1%, 95% CI, −11.6% to −4.7%; P < .001). The 30-day bleeding rate was 4.1% for bivalirudin, 7.5% for heparin, and 12.3% for heparin plus tirofiban (P < .001). There were no statistically significant differences between treatments in the 30-day rates of major adverse cardiac or cerebral events (5.0% for bivalirudin, 5.8% for heparin, and 4.9% for heparin plus tirofiban, P = .74), stent thrombosis (0.6% vs 0.9% vs 0.7%, respectively, P = .77), acquired thrombocytopenia (0.1% vs 0.7% vs 1.1%; P = .07), or in acute (<24-hour) stent thrombosis (0.3% in each group). At the 1-year follow-up, the results remained similar.” (Y. Han, hanyaling@263.net)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 9, 2015 * Vol. 22, No. 67
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 9 issue of the
New England Journal of Medicine (2015; 372).
Ibrutinib in Waldenström’s Macroglobulinemia: In 63 previously treated patients with Waldenström’s macroglobulinemia, treatment with ibrutinib was highly active, associated with durable responses, and safe, researchers report (
pp. 1430–40). The study found these responses and effects of two common mutations on treatment: “After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P <0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88L265P CXCR4WT (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88L265PCXCR4WTIM (85.7% and 61.9%, respectively) and patients with MYD88WT CXCR4WT (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).” (S. P. Treon, steven_treon@dfci.harvard.edu)
Manual Thrombectomy During Primary PCI: In the Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI (TOTAL), routine manual thrombectomy during primary percutaneous coronary intervention (PCI) produced no objective benefits and was associated with increased stroke risk in the following 30 days, compared with PCI alone (
pp. 1389–98). A total of 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI were assigned to routine upfront manual thrombectomy versus PCI alone. Based on a primary outcome fo composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days, the investigators found: “The primary outcome occurred in 347 of 5,033 patients (6.9%) in the thrombectomy group versus 351 of 5,030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P = 0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P = 0.02).” (S. S. Jolly, sanjit.jolly@phri.ca)
An editorialist reviews pathophysiology involved in STEMI and reaches this conclusion based on TOTAL findings (
pp. 1464–5): “The prevention and treatment of coronary microvascular obstruction remains an unmet need. Four interacting mechanisms cause microvascular obstruction in humans: distal embolization, ischemia-related injury, reperfusion-related injury, and individual susceptibility of the microcirculation to injury. It is likely that the relevance of these mechanisms differs among patients. Furthermore, preexisting coronary microvascular dysfunction is emerging as a causal factor for future acute coronary events and for a worse response to reperfusion therapies. Thus, an integrated and personalized approach addressing all mechanisms in different time windows is needed in order to reduce the strikingly increased risk conferred by coronary microvascular obstruction. Although door-to-balloon times have improved significantly over the past 10 years, in-hospital mortality for STEMI has remained virtually unchanged. The time has come to turn our attention to the development of treatments that address the continuum of STEMI care, from symptom onset through return to the community.” (F. Crea)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 10, 2015 * Vol. 22, No. 68
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Apr. 15 issue of
Clinical Infectious Diseases (2015; 60).
Split-Virion v. Subunit Trivalent Influenza Vaccines in Older Adults: While confirmation is needed in other trials, researchers report that “all inactivated [influenza] vaccines may not offer similar protection” (
pp. 1170–5). Specifically, the study shows a large gap in effectiveness of split-virion versus subunit trivalent influenza vaccines among adults aged 50 years or older during the 2008–09, 2010–11, and 2011–12 influenza seasons: “Complete data were available for 539 participants, of whom 68 (12.6%) had influenza detected. Influenza-infected patients were younger (P <.001), were more likely to have received no vaccine or the subunit influenza vaccine than the split-virion vaccine (P <.001), and more likely to have sought care in either the emergency department or the acute care clinic than the hospital (P = .001). Split-virion vaccine effectiveness was 77.8% (95% confidence interval [CI], 58.5%–90.3%) compared with subunit vaccine effectiveness of 44.2% (95% CI, −11.8% to 70.9%), giving a difference in vaccine effectiveness of 33.5% (95% CI, 6.9%–86.7%).” (H. K. Talbot, keipp.talbot@vanderbilt.edu)
Earlier Treatment of Adult Bacterial Meningitis: A revision in Swedish guidelines that accelerated testing for suspected bacterial meningitis (ABM) led to earlier treatment and improved outcomes, a study shows (
pp. 1162–9). In 2009, impaired mental status was deleted as a contraindication for lumbar puncture (LB) without prior CT scan, with these improvements during the 2010–12 time period: “Adequate treatment was started 1.2 hours earlier, and significantly more patients were treated <2 hours from admission 2010–2012 than 2005–2009. Compared with CT before LP, immediate LP resulted in 1.6 hours earlier treatment, significant increase in door-to-antibiotic times of <1 and <2 hours, and a favorable outcome. In 2010–2012, mortality was lower (6.9% vs 11.7%) and the risk of sequelae at follow-up decreased (38% vs 49%) in comparison with 2005–2009. Treatment delay resulted in a significantly increased risk for fatal outcome, with a relative increase in mortality of 12.6% per hour of delay.” (M. Glimåker, martin.glimaker@karolinska.se)

>>>Oncology Highlights
Source: Apr. 10 issue of the
Journal of Clinical Oncology (2015; 33).
Genetics of Mercaptopurine Intolerance in Pediatric ALL: In children with acute lymphoblastic leukemia (ALL), genetic variations leading to mercaptopurine (MP) intolerance differ based on race and ethnicity, according to genome-wide association study (GWAS) cohorts from two prospective trials (
pp. 1235–42). The investigators found a germline variant in NUDT15 that strongly associated with MP intolerance: “MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P <.001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10−9) and rs116855232 in NUDT15 (P = 8.8 × 10−9), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.” (J. J. Yang, jun.yang@stjude.org)
This study “demonstrates the power of genome-wide association across diverse geographic heritages in the quest for better drug safety,” editorialists write (
pp. 1230–1). They conclude, “It is imperative that we be more thoughtful about the design of studies that evaluate drug safety and efficacy. Current approaches too often operate with the assumption that there is a single driving cause for one problem. Although this is an orderly principle, it is too often not true. The global nature of cancer care demands that more trials are designed in ways that generate data that will benefit all patients through the sufficient inclusion of patients from representative geographic heritages.” (H. L. McLeod, howard.mcleod@moffitt.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 13, 2015 * Vol. 22, No. 69
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 11 issue of
Lancet (2015; 385).
Gender & LDL Cholesterol–Lowering Therapy: Treatments of lowering LDL cholesterol levels are similarly effective in women as in men, according to a meta-analysis designed to address the debate over gender differences in primary prevention (
pp. 1397–405). In 22 controlled trials of statins with 134,537 participants and 5 trials of statin intensity with 39,612 participants, these results were recorded: “46,675 (27%) of 174,149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1.1 mmol/L in statin vs control trials and roughly 0.5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1.0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0.84, 99% CI 0.78–0.91) and men (RR 0.78, 99% CI 0.75–0.81, adjusted p value for heterogeneity by sex = 0.33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p = 0.11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0.91, 99% CI 0.84–0.99) and men (RR 0.90, 99% CI 0.86–0.95; adjusted heterogeneity p = 0.43).” (Cholesterol Treatment Trialists’ Collaboration)
ABVD Regimen in Hodgkin’s Lymphoma: In an open-label trial testing intensity reduction in patients with Hodgkin’s lymphoma who responded to initial therapy with the ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine), investigators determined that “dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy” and that “bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin’s lymphoma should remain ABVD followed by [30 Gy involved-field radiotherapy]” (
pp. 1418–27). In 1,502 patients, regimens without dacarbazine had 5-year efficacy figures that were 11.5% to 15.2% lower, and noninferiority of regimens without bleomycin was not detected. (A. Engert, a.engert@uni-koeln.de)

>>>BMJ Highlights
Source: Early-release article from
BMJ (2015; 350).
Dose-Reduction Strategies in Rheumatoid Arthritis: Lowered doses or discontinuance of TNF inhibitors can be achieved in about two-thirds of patients with rheumatoid arthritis, researchers report based on an open-label comparison with usual care (
h1389). The trial included 180 patients with low disease activity who were on adalimumab or etancercept. Doses were reduced stepwise based on increasing the dosing interval every 3 months until disease flared or drugs were discontinued. Compared with usual care, this approach produced these results: “Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care.” (N. van Herwaarden, n.vanherwaarden@maartenskliniek.nl)

>>>PNN JournalWatch
* Point-of-Prescription Interventions to Improve Antimicrobial Stewardship, in
Clinical Infectious Diseases, 2015; 60: 1252–8. (K. W. Hamilton, keith.hamilton@uphs.upenn.edu)
* Recommendations for Evaluation and Management of Bone Disease in HIV, in
Clinical Infectious Diseases, 2015; 60: 1242–51. (T. T. Brown, tbrown27@jhmi.edu)
* Profound Answers to Simple Questions, in
Journal of Clinical Oncology, 2015; 33: 1294–6. (C. E. Russell, ceilidh.eatonrussell@tlcpc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 14, 2015 * Vol. 22, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from the
Annals of Internal Medicine (2015; 162).
Screening for Type 2 Diabetes: In a systematic review prepared for the 2008 U.S. Preventive Services Task Force as it updates its guidelines on diabetes screening in adults, investigators find no significant changes in 10-year mortality rates in screened versus nonscreened populations (
doi: 10.7326/M14-2221). Data do support earlier treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), as “treatment … was associated with delayed progression of diabetes.” Review of available evidence yielded these results: “In 2 trials, screening for diabetes was associated with no 10-year mortality benefit versus no screening (hazard ratio, 1.06 [95% CI, 0.90 to 1.25]). Sixteen trials consistently found that treatment of IFG or IGT was associated with delayed progression to diabetes. Most trials of treatment of IFG or IGT found no effects on all-cause or cardiovascular mortality, although lifestyle modification was associated with decreased risk for both outcomes after 23 years in 1 trial. For screen-detected diabetes, 1 trial found no effect of an intensive multifactorial intervention on risk for all-cause or cardiovascular mortality versus standard control. In diabetes that was not specifically screen-detected, 9 systematic reviews found that intensive glucose control did not reduce risk for all-cause or cardiovascular mortality and results for intensive blood pressure control were inconsistent.” (S. Selph, selphs@ohsu.edu)
Editorialists describe screening as the obvious tool for making a difference in the large number of patients with undetected prediabetes and diabetes (
doi: 10.7326/M15-0798): “Evidence-based medicine is ‘a set of principles and methods intended to ensure that, to the greatest extent possible, population-based policies and individual medical decisions are consistent with evidence of effectiveness and benefit.’ To the greatest extent possible, short of a direct randomized, controlled trial testing of screening on a hard outcome, the overall body of data supports a broad policy, closer to the American Diabetes Association position, for early detection of prediabetes and diabetes. Furthermore, reliable tests exist, the risk associated with screening are small or none, and the cost-effectiveness of screening is well within the justifiable range. Detection of prediabetes and diabetes would offer a strategic window of opportunity to intervene on other [cardiovascular disease] risk factors in an integrated manner. Without screening, 90% of prediabetes cases will remain undetected, and we will continue to miss the opportunity to aggressively implement strategies to prevent diabetes and remain unable to slow the growing costs of managing diabetes and its complications.” (K. M. Venkat Narayan, knaraya@emory.edu)
“Lake Wobegon” Patients: Exploring differences in the mean versus median values in the assessment of clinical risk in populations, authors of an ideas article examine what they term the “Lake Wobegon effect” (
doi: 10.7326/M14-2767). Citing Garrison Keillor’s famous “all the women are strong, all the men are good-looking, and all the children are above average” closing to his weekly monologue, the authors conclude that “most patients are at below-average risk”: “It is clear that the Lake Wobegon effect—the apparently paradoxical finding that most patients are at below-average risk and expect to have less-than-average benefit from treatment—is a common and underappreciated phenomenon in medicine with important clinical implications. In many cases, too many patients are screened, diagnosed, and treated. A better understanding of this effect, and a better use of risk prediction in both research and clinical practice, will be essential to ensure that we focus our attention on patients who stand most to gain.” (A. J. Vickers, vickersa@mskcc.org)

>>>PNN NewsWatch
* Citing serious liver injuries,
FDA yesterday warned consumers not to use Tri-Methyl Xtreme, a product distributed by Las Vegas-based Extreme Products Group and promoted as containing anabolic steroids. It is sold on the Internet and in some retail stores and gyms, FDA said. The agency said it has received reports of adverse events from California, New Jersey, and Utah.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 15, 2015 * Vol. 22, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 14 issue of
JAMA (2015; 313).
Pharmacist-Led Dabigatran Management: Pharmacist-led patient selection and monitoring of dabigatran therapy resulted in greater patient adherence to dabigatran therapy among VA patients, according to a study that also identified site-level variability in adherence rates (
pp. 1443–50). Using mixed quantitative and qualitative methods, investigators assessed care at 67 VA sites where 20 or more patients received dabigatran prescriptions for nonvalvular atrial fibrillation in 2010–12. At 41 sites, 47 pharmacists participated in review of patient care at point of prescribing, patient education, and patient monitoring. Results showed: “The median proportion of patients adherent to dabigatran was 74% (interquartile range [IQR], 66%–80%). After multivariable adjustment, dabigatran adherence across sites varied by a median odds ratio of 1.57. Review of practices across participating sites showed that appropriate patient selection was performed at 31 sites, pharmacist-led education was provided at 30 sites, and pharmacist-led monitoring at 28 sites. The proportion of adherent patients was higher at sites performing appropriate selection (75% vs 69%), education (76% vs 66%), and monitoring (77% vs 65%). Following multivariable adjustment, association between pharmacist-led education and dabigatran adherence was not statistically significant (relative risk [RR], 0.94; 95% CI, 0.83–1.06). Appropriate patient selection (RR, 1.14; 95% CI, 1.05–1.25), and provision of pharmacist-led monitoring (RR, 1.25; 95% CI, 1.11–1.41) were associated with better patient adherence. Additionally, longer duration of monitoring and providing more intensive care to nonadherent patients in collaboration with the clinician improved adherence.” (M. P. Turakhia, mintu@stanford.edu)
Maternal Diabetes & Autism: Children born to mothers who had gestational diabetes mellitus (GDM) at 28–44 weeks’ gestation may be at higher risk of autism spectrum disorders (ASDs), researchers report (
pp. 1425–34). In a retrospective longitudinal cohort study of 322,323 singleton children born in 1995–2009 at facilities of Kaiser Permanente Southern California, these relative risks and hazard ratios were identified: “During follow-up, 3,388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at ≤26 weeks, 180 exposed to GDM at >26 weeks, and 2,963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1,000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year–adjusted HRs were 1.59 (95% CI, 1.29–1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35–1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84–1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97–1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15–1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68,512) did not affect the results.” (A. H. Xiang, anny.h.xiang@kp.org)
Acute Stroke Intervention: “Intravenous [recombinant tissue plasminogen activator] remains the standard of care for patients with moderate to severe neurological deficits who present within 4.5 hours of symptom onset,” conclude authors of a systematic review of 68 randomized clinical trials, observational studies, guideline statements, and review articles reporting results of acute stroke interventions in 108,082 patients (
pp. 1451–62). “Outcomes for some patients with acute ischemic stroke and moderate to severe neurological deficits due to proximal artery occlusion are improved with endovascular reperfusion therapy. Efforts to hasten reperfusion therapy, regardless of the mode, should be undertaken within organized stroke systems of care.” (S. Prabhakaran, shyam.prabhakaran@northwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 16, 2015 * Vol. 22, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 16 issue of the
New England Journal of Medicine (2015; 372).
PCSK9 Inhibition for Lipid Lowering: Results of two clinical trials of monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 serine protease (PCSK9) are reported, and an editorial discusses clinical implications.
Added to maximally tolerated statins, alirocumab significantly reduced concentrations of LDL cholesterol in 2,341 patients at high risk for cardiovascular events (
pp. 1489–99). ODYSSEY LONG TERM participants had LDL-C levels of 70 mg/dL or more while on statins with or without other lipid-lowering therapy. Subcutaneous alirocumab 150 mg every 2 weeks for 78 weeks produced these results: “At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points (P <0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P = 0.02).” (J. G. Robinson, jennifer-g-robinson@uiowa.edu)
A second PCSK9 inhibitor, evolocumab combined with standard therapy during a 1-year trial “significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis,” OSLER researchers report (
pp. 1500–9). Over a median treatment period of 11.1 months in two open-label, randomized trials, changes in lipid levels, safety, and adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure were as follows: “As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P <0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P = 0.003).” (M. S. Sabatine, msabatine@partners.org)
Results of these studies fit well into recent cardiovascular-risk guidelines that recommend use of “non-statins … in higher-risk patients in whom statin therapy did not lower LDL cholesterol levels sufficiently or in patients with unacceptable side effects from statin therapy,” editorialists write (
pp. 1564–5). “The evidence-driven cholesterol guidelines did not endorse the concept that lower LDL cholesterol levels are better at all costs. They emphasized that, while lower is better, it matters how you get there and whether the benefits outweigh the risks for that patient.
“Much work remains to be done, but PCSK9 inhibitors appear on track to become important arrows in our quiver for targeting reduction of cardiovascular events among higher-risk patients when statins are not enough.” (N. J. Stone)

>>>PNN NewsWatch
*
FDA yesterday approved ivabradine (Corlanor, Amgen) reducing the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction of 35% or less, who are in sinus rhythm with resting heart rate of 70 bpm or more, and either are on maximally tolerated doses of beta blockers or have a contraindication to beta-blocker use. The drug acts by blocking the hyperpolarization-activated cyclic nucleotide–gated channel responsible for the cardiac pacemaker.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 17, 2015 * Vol. 22, No. 73
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source: Apr. issue of the
Journal of Allergy and Clinical Immunology (2015; 135).
Biomarkers, Asthma Phenotypes & Corticosteroid Response: In patients with steroid-naive asthma, clinical responsiveness to inhaled corticosteroid (ICS) therapy can be predicted using a bank of noninvasive biomarkers, researchers report (
pp. 877–83.e1). Adequate response was defined as a 12% or greater increase in FEV1, improvements on an asthma-control questionnaire, and doubling or greater increase in a provocative dose. Inflammatory biomarkers were fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level. Using data from a two-phase study, the investigators found: “Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P <.01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy.” (S. A. A. Comhair, comhais@ccf.org)
“Perhaps the biggest block to biomarker-directed management is that there is little information on the feasibility, efficacy, and cost-effectiveness of this approach in nonspecialist settings, where most key management decisions are made,” editorialists write (
pp. 884–5). “This perception might change because a recent study in primary care has shown that Feno-guided management reduces the rate of asthma attacks, does not increase treatment burden, and appears to be cost-effective. In addition, nonspecialist clinicians might be more receptive to this approach than specialists think because they are less encumbered by outdated paradigms and more familiar with the use of biomarkers to profile risk and likely treatment responsiveness as a result of their work in other fields.” (I. D. Pavord, ian.pavord@ndm.ox.ac.uk)

>>>Rheumatology Highlights
Source: Apr. issue of
Arthritis & Rheumatology (2015; 67).
Adalimumab in Nonpsoriatic Peripheral Spondyloarthritis: In 165 patients with active nonpsoriatic peripheral spondyloarthritis (SpA), adalimumab 40 mg every other week for 12 weeks reduced signs and symptoms and improved physical function (
pp. 914–23). Compared with placebo, the drug produced these changes based on a primary end point of 40% improvement in disease activity in Peripheral SpA Response Criteria (PSpARC40): “At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups.” (A. L. Pangan, aileen.pangan@abbvie.com)
Genomic Profiling in Psoriatic Arthritis: “In the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in [psoriatic arthritis (PsA)],” investigators find that “PsA skin and joint disease are similarly responsive to TNF antagonists, while [interleukin-17 (IL-17)] antagonists have better results in PsA skin than in PsA joints” (
pp. 934–44). Based on gene-expression studies of 12 patients with PsA, the authors report: “Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger [IL-17] gene signature in skin than in synovium and more equivalent tumor necrosis factor and interferon-gamma gene signatures in both tissues.” (J. Belasco, jbelasco@rockefeller.edu)

>>>PNN NewsWatch
*
FDA yesterday approved the first generic glatiramer acetate injection (Sandoz), bioequivalent to Copaxone and approved for treatment of patients with relapsing forms of multiple sclerosis.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 20, 2015 * Vol. 22, No. 74
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 18 issue of
Lancet (2015; 385).
Prednisone in Community-Acquired Pneumonia: In hospitalized patients with community-acquired pneumonia, 7 days of prednisone 50 mg daily improved time to clinical stability without increased complications, researchers report (
pp. 1511–8). A study conducted at seven Swiss hospitals used block randomization with placebo controls and produced these outcomes based on a primary endpoint of time to clinical stability defined as the number of days until vital signs were stable for at least 24 h: “From Dec 1, 2009, to May 21, 2014, of 2,911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n = 392) or the placebo group (n = 393). Median time to clinical stability was shorter in the prednisone group (3.0 days, IQR 2.5–3.4) than in the placebo group (4.4 days, 4.0–5.0; hazard ratio [HR] 1.33, 95% CI 1.15–1.50, p <0.0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0.49 [95% CI 0.23–1.02]; p = 0.056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1.96, 95% CI 1.31–2.93, p = 0.0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups.” (M. Christ-Crain, mirjam.christ@usb.ch)
Preventive Antibiotics in Stroke: In the Preventive Antibiotics in Stroke Study (PASS), ceftriaxone 2 g every 24 h i.v. for 4 days had no significant effects on functional outcomes at 3 months among 2,538 adult patients with stroke (
pp. 1519–26): “Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82–1·09], p = 0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group.” (D. van de Beek, d.vandebeek@amc.uva.nl)

>>>BMJ Highlights
Source: Early-release article from
BMJ (2015; 350).
Treatment of Lumbosacral Radicular Pain: In a study of 145 adults with lumbosacral radiculopathy conducted at eight military, VA, and civilian hospitals, titrated oral gabapentin performed almost as well as for some outcome measures as epidural steroid injection, with “differences … modest and … transient for most people” (
h1748): “There were no significant differences for the primary outcome measure [of a 2-point decrease in leg pain on a 0–10 scale] at one month (mean pain score 3.3 (SD 2.6) and mean change from baseline −2.2 (SD 2.4) in epidural steroid injection group versus 3.7 (SD 2.6) and −1.7 (SD 2.6) in gabapentin group; adjusted difference 0.4, 95% confidence interval −0.3 to 1.2; P = 0.25) and three months (mean pain score 3.4 (SD 2.7) and mean change from baseline −2.0 (SD 2.6) versus 3.7 (SD 2.8) and −1.6 (SD 2.7), respectively; adjusted difference 0.3, −0.5 to 1.2; P = 0.43). Among secondary outcomes, one month after treatment those who received epidural steroid injection had greater reductions in worst leg pain (−3.0, SD 2.8) than those treated with gabapentin (−2.0, SD 2.9; P = 0.04) and were more likely to experience a positive successful outcome (66% v 46%; number needed to treat = 5.0, 95% confidence interval 2.8 to 27.0; P = 0.02). At three months, there were no significant differences between treatments.” (S. P. Cohen, scohen40@jhmi.edu)

>>>PNN JournalWatch
* The Pathophysiology of Insomnia, in
Chest, 2015; 147: 1179–92. (D. J. Buysse, buyssedj@upmc.edu)
* Drug Resistance in
Mycobacterium tuberculosis: Molecular Mechanisms Challenging Fluoroquinolones and Pyrazinamide Effectiveness, in Chest, 2015; 147: 1135–43. (G. B. Migliori, giovannibattista.migliori@fsm.it)
* Ebola in the United States, in
Journal of Allergy and Clinical Immunology, 2015; 135: 868–71. (R. Lindblad, rlindlblad@emmes.com)
* Reduced Acute Inpatient Care Was Largest Savings Component Of Geisinger Health System’s Patient-Centered Medical Home, in
Health Affairs, 2015; 34: 636–44. (D. D. Maeng, ddmaeng@geisinger.edu)
* Assessing Medicare Part D Claim Completeness Using Medication Self-Reports: The Role of Veteran Status and Generic Drug Discount Programs, in
Medical Care, 2015; 53: 463–70. (L. Zhou)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 21, 2015 * Vol. 22, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Apr. 21 issue of the
Annals of Internal Medicine (2015; 162).
Statins in Older Americans: Used for primary prevention in Americans 75 years of age or older, statins are cost-effective, a study shows, but “even a small increase in geriatric-specific adverse effects could offset the cardiovascular benefit” (
pp. 533–41). In cost-effectiveness analysis using a 10-year time horizon and the health care system’s perspective, researchers found these results with the Cardiovascular Disease Policy Model, a Markov model: “All adults aged 75 years or older in the National Health and Nutrition Examination Survey have a 10-year risk score greater than 7.5%. If statins had no effect on functional limitation or cognitive impairment, all primary prevention strategies would prevent [myocardial infarction (MI)] and [coronary heart disease (CHD)] deaths and be cost-effective. Treatment of all adults aged 75 to 94 years would result in 8 million additional users and prevent 105,000 (4.3%) incident MIs and 68,000 (2.3%) CHD deaths at an incremental cost per disability-adjusted life–year of $25,200.” (M. C. Odden)
“The key take-home message from this study is that despite low cost and high potential benefit, even very modest adverse effects attributable to statins tip the balance in the direction of harm,” writes an editorialist (
pp. 590–1). “Therefore, although the investigators have conducted an elegant series of analyses showing that cost should not be an important consideration in the decision to prescribe statins in older adults, I believe that the findings strongly support the view that when it comes to prescribing statins for primary prevention in older adults, less is more. In this context, I fully agree with the view articulated in the 2013 ACC/AHA guideline: ‘Accordingly, a discussion of the potential [atherosclerotic cardiovascular disease] risk reduction benefits, risk of adverse effects, drug–drug interactions, and consideration of patient preferences should precede the initiation of statin therapy for primary prevention in older individuals.’” (M. W. Rich, mrich@wustl.edu)
Metformin in Prediabetes: In national sample of 17,352 working-age adults, metformin was rarely prescribed for prediabetes, leading authors to conclude, “Future studies are needed to understand potential barriers to wider adoption of this safe, tolerable, evidence-based, and cost-effective prediabetes therapy” (
pp. 542–8). Using a national sample of employees in health plans, those with prediabetes who were insured for 3 continuous years in 2010–12 had these experiences: “Only 3.7% of patients with prediabetes were prescribed metformin over the 3-year study window. After adjustment for age, income, and education, the predicted probability of metformin prescription was almost 2 times higher among women and obese patients and more than 1.5 times higher among patients with 2 or more comorbid conditions.” (T. Moin, tmoin@mednet.ucla.edu)
Iron Screening & Supplementation in Pregnancy: In an updated systematic review for the U.S. Preventive Services Task Force, authors find that “there is inconclusive evidence that routine prenatal supplementation for [iron deficiency anemia (IDA)] improves maternal or infant clinical health outcomes, but supplementation may improve maternal hematologic indices” (
pp. 566–76): “No study directly compared clinical outcomes or harms of screening or not screening pregnant women for IDA. Twelve supplementation trials were included, and no controlled observational studies met inclusion criteria. On the basis of 11 trials, routine maternal iron supplementation had inconsistent effects on rates of cesarean delivery, small size for gestational age, and low birthweight and no effect on maternal quality of life, gestational age, Apgar scores, preterm birth, or infant mortality. Twelve trials reported improvements in maternal hematologic indices, although not all were statistically significant. Pooled analysis of 4 trials resulted in a statistically significant difference in IDA incidence at term, favoring supplementation (risk ratio, 0.29 [95% CI, 0.17 to 0.49]; I2 = 0%). Maternal iron supplementation did not affect infant iron status at 6 months. Harms, none of which were serious or had long-term consequences, were inconsistently reported in 10 of the trials, with most finding no difference between groups.” (A. G. Cantor)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 22, 2015 * Vol. 22, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 21
JAMA, a theme issue on Child Health (2015; 313).
Autism, MMR & Sibling Autism: In a retrospective cohort study, researchers report no association between receipt of the measles–mumps–rubella (MMR) vaccine and risk of autism spectrum disorders (ASD), “regardless of whether older siblings had ASD,” showing that even among higher-risk children, ASD is not associated with MMR vaccinations (
pp. 1534–40). Using patient experiences in a large commercial health plan, the authors looked at children who were continuously enrolled from birth to 5 years of age in 2001–12 who also had an older sibling continuously enrolled for at least 6 months in 1997–2012. Results showed: “Of 95,727 children with older siblings, 994 (1.04%) were diagnosed with ASD and 1,929 (2.01%) had an older sibling with ASD. Of those with older siblings with ASD, 134 (6.9%) had ASD, vs 860 (0.9%) children with unaffected siblings (P <.001). MMR vaccination rates (≥1 dose) were 84% (n = 78,564) at age 2 years and 92% (n = 86,063) at age 5 years for children with unaffected older siblings, vs 73% (n = 1,409) at age 2 years and 86% (n = 1,660) at age 5 years for children with affected siblings. MMR vaccine receipt was not associated with an increased risk of ASD at any age. For children with older siblings with ASD, at age 2, the adjusted relative risk (RR) of ASD for 1 dose of MMR vaccine vs no vaccine was 0.76 (95% CI, 0.49–1.18; P = .22), and at age 5, the RR of ASD for 2 doses compared with no vaccine was 0.56 (95% CI, 0.31–1.01; P = .052). For children whose older siblings did not have ASD, at age 2, the adjusted RR of ASD for 1 dose was 0.91 (95% CI, 0.67–1.20; P = .50) and at age 5, the RR of ASD for 2 doses was 1.12 (95% CI, 0.78–1.59; P = .55).” (A. Jain, anjali.jain@lewin.com)
“Some parents of children with ASD may have chosen to delay immunization in subsequent children until they were certain any risk had passed,” an editorialist writes in reaction (
pp. 1518–9). “Such behavior, which arguably could enrich the immunization rate in the nonautism subgroup relative to the group that may have been showing early atypical development, might create the impression that MMR vaccine is actually reducing risk for ASD. Indeed, Jain et al report relative risks of less than 1.0. Even so, short of arguing that MMR vaccine actually reduces the risk of ASD in those who were immunized by age 2 years, the only conclusion that can be drawn from the study is that there is no signal to suggest a relationship between MMR and the development of autism in children with or without a sibling who has autism.” (B. H. King, bryan.king@seattlechildrens.org)
Oral Insulin & Type 1 Diabetes Risk: A pilot study indicates potential benefit of high-dose oral insulin in preventing islet autoimmunity and type 1 diabetes in high-risk children (
pp. 1541–9). In the Phase I/II Pre-POINT study, 25 children were enrolled in Europe and the U.S. who were islet autoantibody–negative, 2 to 7 years, old and had a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Oral insulin or placebo once daily for 3–18 months produced these results: “Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4+ T-cell proliferative responses to insulin were observed in 2 of 10 (20% [95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7% [95% CI, 0.1%–46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[ 95% CI, 0.1%–46%]) treated with 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%–71%]) treated with 22.5 mg, and 5 of 6 (83.3% [ 95% CI, 53%–99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events).” (E. Bonifacio, ezio.bonifacio@crt-dresden.de)
“The Pre-POINT study provides additional evidence to inform trial design and increases enthusiasm for cautiously moving forward with a study of primary prevention in genetically screened children,” an editorialist writes (
pp. 1520–1). “It is now possible to identify children at increased risk for type 1 diabetes at birth, and there is an identifiable sequence of events that culminates in impaired insulin secretion and overt type 1 diabetes.” (J. S. Skyler, jskyler@miami.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 23, 2015 * Vol. 22, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 23 issue of the
New England Journal of Medicine (2015; 372).
PET-Directed Therapy in Hodgkin’s Lymphoma: In the Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (RAPID), noninferiority of no further treatment after chemotherapy was not demonstrated, but “patients in this study with early-stage Hodgkin’s lymphoma and negative [positron-emission tomography (PET)] findings after three cycles of [doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)] had a very good prognosis either with or without consolidation radiotherapy,” researchers report (
pp. 1598–607). The study included patients with newly diagnosed stage IA or stage IIA Hodgkin’s lymphoma. They received three ABVD cycles followed PET scanning. Randomization was to radiotherapy or no treatment, and 3-year progression-free survival rates were as follows: “A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin’s lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin’s lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of −3.8 percentage points (95% CI, −8.8 to 1.3).” (J. Radford, john.radford@manchester.ac.uk)
“Patients who have negative PET findings after three cycles of chemotherapy are cured approximately 9 times out of 10,” editorialists write (
pp. 1667–9). “Is a 4-percentage-point difference in the rate of relapse worth the added risk of using radiation therapy? Should 100 patients be exposed to radiation therapy to keep 4 from relapsing with no evidence of long-term survival benefit? The patient should be involved in making that decision after being fully informed of the risks and the benefits. Some patients will elect to receive additional therapy because they cannot live with the increased short-term risk of relapse. Others will elect to minimize the long-term risks and expect that they are among the 90% of patients who have already been cured by the chemotherapy.” (D. L. Longo)
Treatment of Alcoholic Hepatitis: In a head-to-head comparison in patients with alcoholic hepatitis, investigators found no survival benefit with pentoxifylline and nonsignificant reductions in 28-day mortality with prednisolone and no improvements at 90 days or 1 year (
pp. 1619–28). Among 1,053 patients with end-point data, these results were found: “Mortality at 28 days was 17% (45 of 269 patients) in the placebo–placebo group, 14% (38 of 266 patients) in the prednisolone–placebo group, 19% (50 of 258 patients) in the pentoxifylline–placebo group, and 13% (35 of 260 patients) in the prednisolone–pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P = 0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P = 0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P = 0.002).” (M. R. Thursz, m.thursz@imperial.ac.uk)
Amiodarone-Induced Vortex Keratopathy: A video demonstrates amiodarone-induced vortex keratopathy, or cornea verticillata, in a 50-year-old woman taking the the drug for atrial fibrillation (
p. 1656). The presenting complaint was halos around lights in both eyes. “The patient was reassured by the clinician and was advised to wear sunglasses for symptomatic relief, with follow-up annually,” the authors write. “At her last follow-up, at 12 months after presentation, the ocular examination was normal, apart from the presence of corneal deposits.” (V. Jhanji, vishaljhanji@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 24, 2015 * Vol. 22, No. 78
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source: Apr. issue of
Health Affairs, a theme issue on Cost & Quality Of Cancer Care (2015; 34).
Quality-Adjusted Cost Of Care: Introducing a “a meaningful way to measure growth in innovation cost versus the value of health gains,” authors examine three situations in which costs rose in recent years (
pp. 555–61): “Technology drives both health care spending and health improvement. Yet policy makers rarely see measures of cost growth that account for both effects. To fill this gap, we present the quality-adjusted cost of care, which illustrates cost growth net of growth in the value of health improvements, measured as survival gains multiplied by the value of survival. We applied the quality-adjusted cost of care to two cases. For colorectal cancer, drug cost per patient increased by $34,493 between 1998 and 2005 as a result of new drug launches, but value from offsetting health improvements netted a modest $1,377 increase in quality-adjusted cost of care. For multiple myeloma, new therapies increased treatment cost by $72,937 between 2004 and 2009, but offsetting health benefits lowered overall quality-adjusted cost of care by $67,863. However, patients with multiple myeloma on established first-line therapies saw costs rise without corresponding benefits. All three examples document rapid cost growth, but they provide starkly different answers to the question of whether society got what it paid for.” (D. Lakdawalla, dlakdawa@usc.edu)
Reasons FDA Requires Multiple Preapproval Reviews: Using qualitative methods, researchers report that safety concerns often accounted for multiple rounds of review for new drugs awaiting approval at FDA in 2001–11 (
pp. 681–8): “Among ninety-six applications approved between 2001 and 2011 that required multiple review cycles, safety concerns contributed to seventy-four (77.1 percent) and efficacy concerns to forty-three (44.8 percent). Our study suggests that multiple review cycles appear to play an important role in allowing the FDA to protect public health and in ensuring adequate understanding of clinical benefits and risks prior to approval.” (J. S. Ross, joseph.ross@yale.edu)

>>>Medical Care Report
Source: May issue of
Medical Care (2015; 53).
Clinical Performance in PCMHs: “Mixed results” from an analysis of clinical performance in patient-centered medical homes (PCMHs) “highlight the importance of examining relationships between specific PCMH domains and specific clinical quality measures, in addition to analyzing overall PCMH scores which could yield distorted findings,” authors conclude (
pp. 389–95). Regression analysis of data from the Health Resources and Services Administration’s 2009 Uniform Data System and the 2009 Commonwealth Fund National Survey of Federally Qualified Health Centers show these results for two process measures (childhood immunization and cervical cancer screening) and two outcome measures (hypertension control and diabetes control): “The findings showed different directional relationships, with some PCMH domains (care management, test/referral tracking, quality improvement, and external coordination) showing little or no effect on outcome measures of interest, 1 domain (access/communication) associated with improved outcomes, and 1 domain (patient tracking/registry) associated with worse outcomes.” (L. Shi)

>>>Geriatrics Highlights
Source: Apr. issue of the
Journal of the American Geriatrics Society (2015; 63).
Pain Management in NHs: The Minimum Data Set 2.0 for 2006–07 shows that “untreated pain is still common” among U.S. nursing home (NH) residents (
pp. 633–41): “More than 65% of NH residents with cancer had any pain (28.3% daily, 37.3% Camilla.Pimentel@umassmed.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 27, 2015 * Vol. 22, No. 79
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Apr. 25 issue of
Lancet (2015; 385).
Rituximab in Adult Immune Thrombocytopenia: Compared with placebo in 112 patients with adult immune thrombocytopenia, rituximab produced no significant change in long-term treatment failure rates, RITP researchers report, but “a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab” (
pp. 1653–61). Participants had platelet counts of less than 30 x 109/L. Four weekly rituximab 375 mg/sq m infusions produced these outcomes: “32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan–Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio [HR] 0.89, 95% CI 0.55–1.45; p = 0.65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p = 0.15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p = 0.12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p = 0.01) but not complete response (76 vs 49 weeks; p = 0.19). Rates of bleeding were similar in the two groups (21 [38%] in the rituximab group vs 27 [50%] in the placebo group; p = 0.08) as were rates of infection (22 [40%] vs 13 [24%]; p = 0.09).” (W. Ghanima, waleed.ghanima@so-hf.no)

>>>BMJ Highlights
Source: Early-release articles from
BMJ (2015; 350).
GI Bleeding With Oral Anticoagulants: Rates of gastrointestinal bleeding were similar among patients taking warfarin, dabigatran, or rivaroxaban in a retrospective cohort study, but investigators conclude, “We cannot rule out as much as a 50% increase in the risk of gastrointestinal bleeding with dabigatran compared with warfarin or a more than twofold higher risk of bleeding with rivaroxaban compared with warfarin” (
h1585). Using data on commericially insured Americans in 2010–12, these experiences were identified for 46,163 patients: “Dabigatran users tended to be older (dabigatran v rivaroxaban v warfarin: 62.0 v 57.6 v 57.4 years) and more likely to be male (69% v 49% v 53%). The rate of gastrointestinal bleeding was highest among dabigatran users and lowest among rivaroxaban users (dabigatran v rivaroxaban v warfarin: 9.01 v 3.41 v 7.02 cases per 100 person years). After adjustment for potentially confounding covariates, there was no evidence of a statistically significant difference in the risk of gastrointestinal bleeding between dabigatran and warfarin users (adjusted hazard ratio 1.21, 95% confidence interval 0.96 to 1.53) or between rivaroxaban and warfarin users (0.98, 0.36 to 2.69).” (H. Chang, hchang24@jhmi.edu)
Smoking Cessation in Older Adults: Confirming and expanding on previous findings, a meta-analysis of 25 cohorts in the CHANCES consortium demonstrates benefits of smoking cessation among older adults, with reduced cardiovascular events and mortality when patients stopped using tobacco (
h1551): “Overall, 503,905 participants aged 60 and older were included in this study, of whom 37,952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose–response manner, and decreased continuously with time since smoking cessation in former smokers.” (U. Mons, u.mons@dkfz.de)

>>>PNN JournalWatch
* Surge in Newly Identified Diabetes Among Medicaid Patients in 2014 Within Medicaid Expansion States Under the Affordable Care Act, in
Diabetes Care, 2015; 38: 833–7. (Harvey W. Kaufman, harvey.w.kaufman@questdiagnostics.com)
* Niacin and Progression of CKD, in
American Journal of Kidney Diseases, 2015; 65: 785–98. (E. Streja, estreja@uci.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 28, 2015 * Vol. 22, No. 80
Providing news and information about medications and their proper use

>>>Nephrology Report
Source: May issue of the
American Journal of Kidney Diseases (2015; 65).
Kidney Function & Warfarin Bleeding: When patients with compromised kidney function have elevated INRs during warfarin therapy, they have higher risks of bleeding and prolonged duration of hemorrhage, researchers report (
pp. 701–9). Comparing a warfarin pharmacogenetics cohort of 1,273 long-term warfarin users with 74 warfarin users admited for reversal because of INRs of 4 or more, the authors found these results: “In the pharmacogenetics cohort, 454 (35.7%) had eGFRs < 60 mL/min/1.73 m2. There were 137 hemorrhages in 119 patients over 1,802 person–years of follow-up (incidence rate, 7.6 [95% CI, 6.4–8.9]/100 person–years). Patients with lower eGFRs had a higher frequency of INR ≥ 4 (P < 0.001). Risk of hemorrhage was affected significantly by eGFR–INR interaction. At INR < 4, there was no difference in hemorrhage risk by eGFR (all P ≥ 0.4). At INR ≥ 4, patients with eGFRs of 30 to 44 and <30 mL/min/1.73 m2 had 2.2-fold (95% CI, 0.8–6.1; P = 0.1) and 5.8-fold (95% CI, 2.9–11.4; P < 0.001) higher hemorrhage risks, respectively, versus those with eGFRs ≥ 60 mL/min/1.73 m2. In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m2. Patients with eGFRs < 45 mL/min/1.73 m2 experienced slower anticoagulation reversal as assessed by INR (P = 0.04) and PIVKA-II level (P = 0.008) than those with eGFRs ≥ 45 mL/min/1.73 m2.” (N. A. Limdi, nlimdi@uab.edu)

>>>Diabetes Highlights
Source: May issue of
Diabetes Care (2015; 38).
Hyperglycemic Crisis Episodes in Older Patients: Older patients with diabetes who have hyperglycemic crisis epidoses (HCEs) have higher mortality risks during at least 6 years, according to a retrospective analysis of data from the Taiwanese health insurance system (
pp. 746–51). Among 13,551 older patients with new-onset diabetes in 2000–02, these outcomes were found for 4,517 case participants with HCE and 9,034 control participants: “One thousand six hundred thirty-four (36.17%) case and 1,692 (18.73%) control subjects died (P <0.0001) during follow-up. Incidence rate ratios (IRRs) of death were 2.82 times higher in case subjects (P <0.0001). The mortality risk was highest in the first month (IRR 26.56; 95% CI 17.97–39.27) and remained higher until 4–6 years after the HCE (IRR 1.49; 95% CI 1.23–1.81). After adjustment for age, sex, selected comorbidities, and monthly income, the mortality hazard ratio was still 2.848 and 4.525 times higher in case subjects with one episode and two or more episodes of hyperglycemic crisis, respectively. Older age, male sex, renal disease, stroke, cancer, chronic obstructive pulmonary disease, and congestive heart failure were independent mortality predictors.” (H-R Guo, hrguo@mail.ncku.edu.tw)
CBT v. Sertraline in Depression Plus Poorly Controlled Diabetes: Sertraline performed better than cognitive behavioral therapy (CBT) in patients with major depressive disorder and type 1 or 2 diabetes with poor control, a study shows, but neither therapy alone was sufficient for achieving both depression and glycemic control endpoints (
pp. 767–75). At 70 secondary care centers in Germany, 251 study participants received both sertraline and CBT; those responding were randomized to CBT or sertraline. Results based on glycemic control (primary outcome) and scores on the Hamilton Depression Rating Scale (HAMD-17) showed the following: “After 12 weeks, 45.8% of patients responded to antidepressant treatment and were included in the 1-year study phase. Adjusted HbA1c mean score changes from baseline to the end of the long-term phase (−0.27, 95% CI −0.62 to 0.08) revealed no significant difference between interventions. Depression improved in both groups, with a significant advantage for sertraline (HAMD-17 change: −2.59, 95% CI 1.15–4.04, P <0.05).” (F. Petrak, mail@dr-frank-petrak.de)

>>>PNN NewsWatch
*
FDA announced yesterday filing of a consent decree against Medtronic and two of its officers “for repeatedly failing to correct violations, related to the manufacture of Synchromed II Implantable Infusion Pump Systems.” The company is required to stop manufacturing, designing, and distributing new Synchromed II Implantable Infusion Pump Systems except in very limited cases and to retain a third party to assist with developing corrective plans.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 29, 2015 * Vol. 22, No. 81
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Apr. 28 issue of
JAMA (2015; 313).
Initiating Buprenorphine/Naloxone Treatment in the ED: While requiring confirmation in future trials, study results show that initiation of buprenorphine/naloxone therapy in the emergency department (ED) “significantly increased engagement in addiction treatment, reduced self-reported illicit opioid use, and decreased use of inpatient addiction treatment services,” researchers report (
pp. 1636–44). At an urban teaching hospital ED in 2009–13, 329 opioid-dependent patients were randomized to screening and referral treatment; screening, brief intervention, and facilitated referral; or screening, brief intervention, ED-initiated buprenorphine/naloxone, and referral to primary care for a 10-week follow-up visit.
Results showed: “Seventy-eight percent of patients in the buprenorphine group (89 of 114 [95% CI, 70%–85%]) vs 37% in the referral group (38 of 102 [95% CI, 28%–47%]) and 45% in the brief intervention group (50 of 111 [95% CI, 36%–54%]) were engaged in addiction treatment on the 30th day after randomization (P < .001). The buprenorphine group reduced the number of days of illicit opioid use per week from 5.4 days (95% CI, 5.1–5.7) to 0.9 days (95% CI, 0.5–1.3) vs a reduction from 5.4 days (95% CI, 5.1–5.7) to 2.3 days (95% CI, 1.7–3.0) in the referral group and from 5.6 days (95% CI, 5.3–5.9) to 2.4 days (95% CI, 1.8–3.0) in the brief intervention group (P < .001 for both time and intervention effects; P = .02 for the interaction effect). The rates of urine samples that tested negative for opioids did not differ statistically across groups, with 53.8% (95% CI, 42%–65%) in the referral group, 42.9% (95% CI, 31%–55%) in the brief intervention group, and 57.6% (95% CI, 47%–68%) in the buprenorphine group (P = .17). There were no statistically significant differences in HIV risk across groups (P = .66). Eleven percent of patients in the buprenorphine group (95% CI, 6%–19%) used inpatient addiction treatment services, whereas 37% in the referral group (95% CI, 27%–48%) and 35% in the brief intervention group (95% CI, 25%–37%) used inpatient addiction treatment services (P < .001).” (G. D’Onofrio,
gail.donofrio@yale.edu)
Genetics of Rheumatoid Arthritis: Reacting to a study that associates genotypes of the HLA-DRB1 locus with disease susceptibility, radiological severity, mortality, and treatment response (
pp. 1645–56; A. Barton, anne.barton@manchester.ac.uk), editorialists provide this assessment of the implications of these insights (pp. 1623–4): “Although [these] findings … may not have immediate clinical implications, identification of the precise HLA variants that influence disease course is of great interest. These observations open the door to further research, including replication for this haplotype and discovery related to its combination with other determinants of disease development and progression. Such discoveries will prove helpful both to understand and predict the variable disease course and response to therapy that occurs in patients with rheumatoid arthritis.” (D. T. Felson, dfelson@bu.edu)
Preventing Hepatitis B Reactivation During Immunosuppression: The increased availability of novel biologic therapies that are immunosuppressive “underscores the importance” of taking steps to prevent reactivation of hepatitis B virus (HBV) infections in patients receiving these drugs, write authors of a Viewpoint article (
pp. 1617–8). “Screening for HBV markers is the first critical step toward prevention, but ambiguity in practice guidelines may be limiting the implementation of preventive measures on a broader scale,” the authors note. “HBV screening and antiviral therapy for those at risk has the potential to prevent HBV reactivation and the associated risks of liver failure and death. However, important questions remain regarding how to most efficiently accomplish this.” Targeted screening in populations with less than a 2% prevalence is a reasonable alternative to universal screening, the authors write. (A. S. Lok, aslok@umich.edu)

>>>PNN NewsWatch
*
FDA yesterday approved the first generic versions of aripiprazole, equivalent to Otsuka America’s Abilify. Alembic Pharmaceuticals., Hetero Labs, Teva Pharmaceuticals, and Torrent Pharmaceuticals received FDA approval to market the drug in multiple strengths and dosage forms.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
Apr. 30, 2015 * Vol. 22, No. 82
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Apr. 30 issue of the
New England Journal of Medicine (2015; 372).
Targeted Therapy in Resistant Lung Cancer: Two studies and an editorial explore new approaches to therapy of non-small–cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor mutations.
The EGFR inhibitor AZD9291, active against both sensitive and resistant tumors, showed activity in 253 patients with advanced lung cancer that had progressed during prior therapy with other EGFR tyrosine kinase inhibitors, researchers report (
pp. 1689–99): “Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M–positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M–negative patients.” (P. A. Jänne, pasi_janne@dfci.harvard.edu)
In a Phase I/II study of 130 patients with EGFR-mutated NSCLC associated with the T790M resistance mutation, the EGFR inhibitor rociletinib produced objective response rates in the 20%–60% range (
pp. 1700–9): “The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).” (L. V. Sequist, lvsequist@partners.org)
“The recent progress made in the treatment of NSCLC is heartening,” editorialists write (
pp. 1760–1). “Large-scale genomic studies conducted by the Cancer Genome Atlas project and others have identified a number of actionable targets. However, more tumor specimens need to be studied to uncover rare oncogenic events. Comprehensive genomic analyses performed on serial biopsy specimens will enable us to more fully understand the process of clonal evolution and the molecular mechanisms that underlie metastases and treatment resistance. Immune checkpoint inhibitors have shown promise in the treatment of lung cancer, including EGFR-mutated NSCLC. Genome sequencing of tumor cells to identify highly antigenic neoepitopes may enable the development of customized immune therapies to augment targeted therapies and immune checkpoint blockade. With such advances on the horizon, there is every reason to be cautiously optimistic about the future of lung-cancer treatment.” (R. Govindan)
Intensive Therapy & Ocular Surgery in Type 1 Diabetes: Participants in the Diabetes Control and Complications Trial (DCCT) treated with intensive therapy had less need for ocular therapy over a median follow-up of 23 years, an analysis indicates (
pp. 1722–33). “Intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P <0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P = 0.01),” the authors write. (J. M. Lachin, jml@bsc.gwu.edu)

>>>PNN NewsWatch
*
FDA has approved deoxycholic acid (Kybella, Kythera Biopharmaceuticals) for treatment of adults with moderate-to-severe submental (below the chin) fat.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 1, 2015 * Vol. 22, No. 83
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source: May issue of
Pediatrics (2015; 135).
Early Benefits of HPV Vaccine: A program in Ontario to vaccinate eighth grade girls with the quadrivalent human papillomavirus (qHPV) product is resulting in reduced numbers of cases of cervical dysplasia and anogenital warts (AGW), a study shows (
pp. e1131–40). Provincial health databases show these patterns in a population-based retrospective cohort analysis for girls in eighth grade before and after program implementation: “The cohort comprised 131,781 ineligible and 128,712 eligible girls (n = 260,493). We identified 2,436 cases of dysplasia and 400 cases of AGW. Vaccination significantly reduced the incidence of dysplasia by 5.70 per 1,000 girls (95% CI −9.91 to −1.50), corresponding to a relative reduction of 44% (RR 0.56; 95% CI 0.36 to 0.87). Program eligibility also had a significant protective effect on dysplasia: [absolute risk differences(RD)] −2.32/1,000 (95% CI −4.02 to −0.61); RR 0.79 (95% CI 0.66 to 0.94). Results suggested decreases in AGW attributable to vaccination (RD −0.83/1,000, 95% CI −2.54 to 0.88; RR 0.57, 95% CI 0.20 to 1.58) and program eligibility (RD −0.34/1,000, 95% CI −1.03 to 0.36; RR 0.81, 95% CI 0.52 to 1.25).” (L. M. Smith)
Serogroup B Meningococcal Vaccine in University Outbreak: Results from the first use in the U.S. of a serogroup B meningococcal (MenB) vaccine shows that one or two doses protected university students against infections but not carriage of the organism, researchers report (
pp. 798–804). With FDA’s permission, the unlicensed vaccine was used at a New Jersey university, designated as “A” in this report, during a 2013–14 outbreak of meningococcal disease. Results showed the following: “Between March 25, 2013, and March 10, 2014, 9 cases of serogroup B meningococcal disease occurred in persons linked to University A. Laboratory typing results were identical for all 8 isolates available. Through May 14, 2014, 89.1% coverage with the 2-dose vaccination series was achieved in the target population. From the initiation of MenB vaccination through February 1, 2015, no additional cases of serogroup B meningococcal disease occurred in University A students. However, the ninth case occurred in March 2014 in an unvaccinated close contact of University A students.” (L. A. McNamara)

>>>Psychiatry Report
Source: May issue of the
American Journal of Psychiatry (2015; 172).
Maternal Depression, Medications & Effects on Children: In a 12-week trial of escitalopram and bupropion used individually and together, drug therapy that decreased “high anxious distress and irritability” in depressed mothers was needed to find significant improvements in their children’s symptoms (
pp. 450–9). The trial included 76 mothers and 135 of their children aged 7 to 17 years. Results of monotherapy and combination therapy showed these results: “There were no significant treatment differences in mothers’ depressive symptoms or remission. Children’s depressive symptoms and functioning improved significantly among those whose mothers were in the escitalopram group (compared with those whose mothers were in the bupropion and combination treatment groups). Only in the escitalopram group was significant improvement of mother’s depression associated with improvement in the child’s symptoms. Exploratory analyses suggested that this may be due to changes in parental functioning: Mothers in the escitalopram group reported significantly greater improvement, compared with the other groups, in their ability to listen and talk to their children, who as a group reported that their mothers were more caring over the 12 weeks. Maternal baseline negative affectivity appeared to moderate the effect of maternal treatment on children, although the effect was not statistically significant. Children of mothers with low negative affectivity improved in all treatment groups. Children of mothers with high negative affectivity improved significantly only for those whose mothers were in the escitalopram group.” (M. M. Weissman)

>>>PNN NewsWatch
* Specialty pharmaceuticals for diseases such as multiple sclerosis and cancer account for 1% of Medicare Part D claims but 26% of spending, the
Wall Street Journal reports today in a front-page story.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 4, 2015 * Vol. 22, No. 84
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 2 issue of
Lancet (2015; 385).
Oseltamivir for Influenza: Used for treatment of influenza infection in adults, oseltamivir 75 mg twice daily “accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting,” according to findings of a meta-analysis of randomized controlled trials (
pp. 1729–37). The authors included all Roche-sponsored trials of the drug at this dosage level, published or unpublished, and other articles found in database searches. Results showed: “We included data from nine trials including 4,328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0.79, 95% CI 0.74–0.85; p <0.0001). The median times to alleviation were 97.5 h for oseltamivir and 122.7 h for placebo groups (difference −25.2 h, 95% CI −36.2 to −16.0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0.85) but remained highly significant (median difference −17.8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomisation (risk ratio [RR] 0.56, 95% CI 0.42–0.75; p = 0.0001; 4.9% oseltamivir vs 8.7% placebo, risk difference −3.8%, 95% CI −5.0 to −2.2) and also fewer admittances to hospital for any cause (RR 0.37, 95% CI 0.17–0.81; p = 0.013; 0.6% oseltamivir, 1.7% placebo, risk difference −1.1%, 95% CI −1.4 to −0.3). Regarding safety, oseltamivir increased the risk of nausea (RR 1.60, 95% CI 1.29–1.99; p <0.0001; 9.9% oseltamivir vs 6.2% placebo, risk difference 3.7%, 95% CI 1.8–6.1) and vomiting (RR 2.43, 95% CI 1.83–3.23; p <0.0001; 8.0% oseltamivir vs 3.3% placebo, risk difference 4.7%, 95% CI 2.7–7.3). We recorded no effect on neurological or psychiatric disorders or serious adverse events.” (A. S. Monto, asmonto@umich.edu)
Idebenone in Duchenne Muscular Dystrophy: In a Phase III trial, the antioxidant idebenone reduced loss of respiratory function in patients with Duchenne muscular dystrophy, researchers report (
pp. 1748–57). In nine European countries and the U.S., 64 intention-to-treat (ITT) and 57 modified ITT patients aged 10–18 years had these responses to idebenone 300 mg or placebo three times daily for 52 weeks based on peak expiratory flow (PEF) as percentage predicted (PEF%p): “Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (−3.05%p [95% CI −7.08 to 0.97], p = 0.134, vs placebo −9.01%p [–13.18 to −4.84], p = 0.0001; difference 5.96%p [0.16 to 11.76], p = 0.044) and ITT populations (−2.57%p [–6.68 to 1.54], p = 0.215, vs −8.84%p [–12.73 to −4.95], p <0.0001; difference 6.27%p [0.61 to 11.93], p = 0.031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients).” (G. M. Buyse, gunnar.buyse@uzleuven.be)

>>>PNN JournalWatch
* Effectiveness of Pediatric Pill Swallowing Interventions: A Systematic Review, in
Pediatrics, 2015; 135: 883–9. (A. Patel)
* The Medical Home and Integrated Behavioral Health: Advancing the Policy Agenda, in
Pediatrics, 2015; 135: 909–17. (J. Ader)
* Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Cardiovascular Disease, in
Pharmacotherapy, 2015; 35: 10.1002/phar.1584. (I. M. Danelich, danelich.ilya@mayo.edu)
* Pharmacotherapy for Leishmaniasis in the United States: Focus on Miltefosine, in
Pharmacotherapy, 2015; 35: 10.1002/phar.1585. (N. H. Vakil, niyati.vakil@cshs.org)
* A Pharmacist’s Contribution Within a Patient-Centered Medical Home, in
Journal of the American Pharmacists Association, 2015; 55: e311–5. (J. L. McConaha, mcconahaj@duq.edu)
*The Clinical Discovery of Imipramine, in
American Journal of Psychiatry, 2015; 172: 426–9. (W. A. Brown)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 5, 2015 * Vol. 22, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: May 5 issue of the
Annals of Internal Medicine (2015; 162).
LMWHs in Women with Unexplained Pregnancy Loss: Pregnancy and live-birth rates were not improved with daily injections of dalteparin sodium 5,000 IU, researchers report (
pp. 601–9). Evidence had suggested a possible benefit from use of low-molecular-weight heparin (LMWH) in women with unexplained recurrent pregnancy loss (RPL), prompting this study of 449 participants at 14 university hospitals in Germany and Austria. Administered up to 24 weeks’ gestation, daily dalteparin or placebo showed these outcomes: “At 24 weeks’ gestation, 191 of 220 pregnancies (86.8%) and 188 of 214 pregnancies (87.9%) were intact in the intervention and control groups, respectively (absolute difference, −1.1 percentage points [95% CI, −7.4 to 5.3 percentage points]). The live-birth rates were 86.0% (185 of 215 women) and 86.7% (183 of 211 women) in the intervention and control groups, respectively (absolute difference, −0.7 percentage point [CI, −7.3 to 5.9 percentage points]). There were 3 intrauterine fetal deaths (1 woman had used LMWH); 9 cases of preeclampsia or the hemolysis, elevated liver enzyme level, and low platelet count (HELLP) syndrome (3 women had used LMWH); and 11 cases of intrauterine growth restriction or placental insufficiency (5 women had used LMWH).” (D. Petroff, david.petroff@zks.uni-leipzig.de)
LMWHs may have some role in management of women with RPL, an editorialist writes while listing these concerns (
pp. 658–9): “First, definitive evidence about the effectiveness of LMWH in women with a history of late miscarriage and constitutive thrombophilia, the most plausible group for LMWH to have an effect, remains lacking. Observational studies show that women treated with LMWH who have thrombophilic factors and a history of late miscarriage have a better prognosis of pregnancy than untreated women without thrombophilic factors. Second, RPL is a syndrome, not a molecularly defined disease. It is thus not surprising that a treatment, regardless of a precise individual justification, may be disappointing. As we move toward precision medicine, which defines disease through its molecular determinants, we should seek to understand the pathophysiologic molecular backbone of this syndrome. This may enable relevant and targeted therapeutic interventions. It is now time to begin characterizing the various molecular mechanisms behind RPL. We can then start new therapeutic trials focused on homogeneous subcategories of patients who may have the most promising benefits. Maybe then LMWH and other treatments will find a clearly defined role in the treatment of some women with RPL.” (J-C Gris, jean.christophe.gris@chu-nimes.fr)
Cost-Effectiveness of Sofosbuvir-Based Regimens in Genotypes 2 & 3: While sofosbuvir “provides good value for money for treatment-experienced patients with HCV genotype 2 or 3 infection and those with cirrhosis,” the current costs of the regimens “for treatment-naive noncirrhotic patients exceed willingness-to-pay thresholds commonly cited in the United States,” a cost-effectiveness study concludes (
pp. 619–29). Using a lifetime horizon and payer perspective, investigators made these calculations for discounted quality-adjusted life–years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs): “The ICER of sofosbuvir-based treatment was less than $100,000 per QALY in cirrhotic patients (genotype 2 or 3 and treatment-naive or treatment-experienced) and in treatment-experienced noncirrhotic patients but was greater than $200,000 per QALY in treatment-naive noncirrhotic patients.” Sensitivity analysis showed: “The ICER of sofosbuvir-based therapy for treatment-naive noncirrhotic patients with genotype 2 or 3 infection was less than $100,000 per QALY when the cost of sofosbuvir was reduced by approximately 40% and 60%, respectively. In probabilistic sensitivity analyses, cost-effectiveness conclusions were robust to uncertainty in treatment efficacy.” (B. P. Linas, Benjamin.Linas@BMC.org)
Obesity Paradox in Diabetes: Patients with type 2 diabetes who are overweight but not obese live longer than those who are underweight or normal weight, an effect termed the “obesity paradox” (
pp. 610–8). In a prospective cohort study of 10,568 patients with type 2 diabetes, those who were overweight had more hospitalizations but the greatest longevity of any group. (P. Costanzo, pierluigicostanzo83@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 6, 2015 * Vol. 22, No. 86
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Early-release articles from and May 5 issue of
JAMA (2015; 313).
Costs, Utilization with Pioneer ACOs: In 2012–13, Medicare beneficiaries enrolled in Pioneer accountable care organizations (ACOs) had smaller increases in total Medicare expenditures, less utilization of health services, and similarly satisfactory experiences with the health care system, compared with patients in fee-for-service (FFS) plans, researchers report (
doi: 10.1001/jama.2015.4930). Pioneer ACOs were launched in 2012 by CMS with the Medicare Saved Sharings Program as efforts to improve cost and quality outcomes. FFS beneficiaries were “attributed to ACOs based on their historical utilization patterns,” the authors write, but could visit any providers participating in the Medicare program.
Comparing outcomes for 32 Pioneer ACOs with alignment-eligible beneficiaries in the same markets and, for some comparisons with those in Medicare Advantage (MA) programs, the researchers identified these results: “Total spending for beneficiaries aligned with Pioneer ACOs in 2012 or 2013 increased from baseline to a lesser degree relative to comparison populations. Differential changes in spending were approximately −$35.62 (95% CI, −$40.12 to −$31.12) per-beneficiary-per-month (PBPM) in 2012 and -$11.18 (95% CI, −$15.84 to −$6.51) PBPM in 2013, which amounted to aggregate reductions in increases of approximately −$280 (95% CI, −$315 to −$244) million in 2012 and −$105 (95% CI, −$148 to −$61) million in 2013. Inpatient spending showed the largest differential change of any spending category (−$14.40 [95% CI, −$17.31 to −$11.49] PBPM in 2012; −$6.46 [95% CI, −$9.26 to −$3.66] PBPM in 2013). Changes in utilization of physician services, emergency department, and postacute care followed a similar pattern. Compared with other Medicare beneficiaries, ACO-aligned beneficiaries reported higher mean scores for timely care (77.2 [ACO] vs 71.2 [FFS] vs 72.7 [MA]) and for clinician communication (91.9 [ACO] vs 88.3 [FFS] vs 88.7 [MA]).” (R. Rajkumar,
rahul.rajkumar@cms.hhs.gov)
In one of two accompanying editorials, a writer is impressed by the initial results but uncertain that the trend can be maintained over the long run and replicated in larger numbers of health systems (
doi: 10.1001/jama.2015.5086). “There is rough traveling ahead for Pioneer ACOs and the ACOs that follow them,” the editorialist notes, adding: “The Pioneer ACOs produced savings in year 2 that were one-third of year 1 savings. It is possible that during the first year these ACOs were able to ‘grasp the low-hanging fruit’—to address relatively easy ways to control costs—and that the savings they generate will be much smaller, at best, in subsequent years. Alternatively, it may be that it will take time for ACOs to develop better processes to improve the care of their patients and that they will be able continue to lower costs for years to come.” (L. P. Casalino, lac2021@med.cornell.edu)
Progress Against Hepatitis C Virus: Commenting on two studies of investigational drug regimens for patients with hepatitis C virus (HCV) infections (
pp. 1728–35, F. Poordad, poordad@uthscsa.edu; pp. 1736–44, A. J. Muir, andrew.muir@duke.edu), an editorialist focuses on the overriding challenge in costs of these agents (pp. 1716–7): “One of the most important factors that warrants discussion is the cost that these all-oral regimens bring to society at large—even if the high costs of these drugs were to be covered by insurance companies in countries. In the United States, the cost for a 12-week course is as follows: for sofosbuvir, $84,000; ledipasvir/sofosbuvir combination, $94,500; paritaprevir-ritonavir/ombitasvir/dasubuvir combination, $83,000; and simeprevir/sofosbuvir combination, $150,000. Equally important is the concern that cost should not limit use of these medications only to patients with more advanced fibrosis, considering that until recently, the practice has been to care for all patients infected with hepatitis C. In 2 studies that addressed cost-effectiveness of HCV oral regimens in the United States from a societal perspective, it was reported that even though these novel treatments were cost-effective compared with usual care, the concern remains that increased demand for treatment may create substantial economic challenges to society.” (H. Conjeevaram, omsairam@umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 7, 2015 * Vol. 22, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 7 issue of the
New England Journal of Medicine (2015; 372).
Long-Term Ticagrelor Following Myocardial Infarction: Patients who had had myocardial infarction 1–3 years previously benefited from ticagrelor therapy in a randomized controlled trial, with reduced risk of a primary efficacy end point of cardiovascular death, myocardial infarction, or stroke but increased risk of major bleeding (
pp. 1791–800). PEGASUS-TIMI 54 investigators report these results for 21,162 patients who received low-dose aspirin plus ticagrelor 60 mg or 90 mg twice daily or placebo for a median of 33 months: “The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P = 0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P = 0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P <0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.” (M. P. Bonaca, mbonaca@partners.org)
“An important calculus for any treatment strategy is the long-term potential for harm,” an editorialist writes (
pp. 1854–6). “[A previous] study … was characterized by excess mortality with the administration of clopidogrel or prasugrel, largely due to bleeding and cancer, a finding that was not seen with long-term use of clopidogrel in [another] previous trial. In the study by Bonaca et al., ticagrelor did not significantly affect overall mortality, and the numerical excess of deaths from noncardiovascular causes appeared to be related to cancer, a feature not seen in the Study of Platelet Inhibition and Patient Outcomes (PLATO). Collectively, these data do not support a unified concern with respect to excess mortality with dual antiplatelet therapy, but they do remind us of the fragile balance between efficacy and adverse events.” (J. F. Keaney, Jr.)
Iron-Deficiency Anemia: In a review of iron-deficiency anemia, authors make these overall recommendations for use of iron replacements with special attention to malaria-endemic areas (
pp. 1832–43): “Patients with iron-deficiency anemia should receive iron supplementation. Caution must be used in areas in which malaria is endemic because supplementation may reverse the potentially protective effects of iron deficiency or increase the susceptibility to coinfections. In vitro studies have shown that the malaria parasite Plasmodium falciparum is less efficient in infecting iron-deficient erythrocytes than in infecting iron-replete erythrocytes, a protection that is reversed with iron supplementation. Some studies support the view that measurement of hepcidin levels could help to determine the best time (e.g., the end of malaria season) to provide children in these regions with iron supplementation. Emerging data suggest that nonabsorbed iron could be harmful to patients because it might modify the gut microbiota, increasing the concentration of intestinal pathogens.” (C. Camaschella, camaschella.clara@hsr.it)
Hospice Care in Nursing Homes: The increased use of hospice care by nursing home residents is “associated with less aggressive care near death but at an overall increase in Medicare expenditures” in a study of hospice users in 2009 and nonhospice users in 2004 (
pp. 1823–31): “Of 786,328 nursing home decedents, 27.6% in 2004 and 39.8% in 2009 elected to use hospice.… The increase in hospice use was associated with significant decreases in the rates of hospital transfers (2.4 percentage-point reduction), feeding-tube use (1.2 percentage-point reduction), and ICU use (7.1 percentage-point reduction). The mean length of stay in hospice increased from 72.1 days in 2004 to 92.6 days in 2009. Between 2004 and 2009, the expansion of hospice was associated with a mean net increase in Medicare expenditures of $6,761 (95% confidence interval, 6,335 to 7,186), reflecting greater additional spending on hospice care ($10,191) than reduced spending on hospital and other care ($3,430).” (P. Gozalo, pedro_gozalo@brown.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 8, 2015 * Vol. 22, No. 88
Providing news and information about medications and their proper use

>>>Chest Highlights
Source: May issue of
Chest (2015; 147).
Reasons for Readmission in Patients With COPD: A study of Medicare claims data for patients with chronic obstructive pulmonary disorder (COPD) finds potential flaws in the Hospital Readmissions Reduction Program that penalizes hospitals for 30-day readmissions (
pp. 1219–26). Based on nearly 27 million inpatient admissions—3.5% of them index admissions for COPD—the researchers found a 20.2% readmission rate in the subgroup. However, most readmissions were not for COPD, the authors show, and reasons for readmissions varied based on whether patients were discharged with postacute care or without home care. “Readmitted patients are more likely to be dually enrolled in Medicare and Medicaid, suggesting that the [Oct. 2014] addition of COPD to the readmissions penalty may further worsen the disproportionately high penalties seen in safety net hospitals,” the authors conclude. (T. Shah, tina.shah@uchospitals.edu)
Reflecting on this and a second study that showed no impact on readmissions of an intervention program that focused on smoking cessation, screenings, and inhaler education (
pp. 1227–34; J. H. Jennings, jjennin2@hfhs.org), editorialists conclude (pp. 1199–201): “With comorbidity and social factors being main drivers of rehospitalizations, prevention strategies may have to look well beyond the traditional factors addressed. For example, being hospitalized for any condition can result in impaired sleep, high levels of stress, deconditioning, and poor nutrition. Thus, one strategy to decrease rehospitalization is to change the actual hospitalization process itself by incorporating early rehabilitation, more patient-friendly medication strategies, and improved nutrition.” (D. M. Mannino, dmannino@uky.edu)
Adherence to Inhaled Asthma Controller Medications Among Older Adults: Among patients aged 60 or older with asthma, “interventions to promote proper medication use should simplify tasks and patient roles to overcome cognitive load and suboptimal performance in self-care,” shows a study of health literacy, cognitive function, and proper use and adherence of asthma controller medications (pp. 1307–15; R. O’Conor, r-oconor@northwestern.edu).

>>>Cardiology Report
Source: May 12 issue of the Journal of the American College of Cardiology (2015; 65).
EHRs & Quality of Stroke Care: In a study of Get With the Guidelines–Stroke (GWTG-Stroke) hospitals in 2007–10, use of electronic health records (EHRs) was not associated with improved care or better outcomes among patients with stroke, researchers report (pp. 1964–72). “Although EHRs may be necessary for an increasingly high-tech, transparent healthcare system, as currently implemented, they do not appear to be sufficient to improve outcomes for this important disease,” the group concludes. Using data from annual American Heart Association surveys, investigators used patient-level regression analyses to make these findings in 1,236 hospitals and 626,473 patients: “A total of 511 hospitals had EHRs by the end of the study period. Hospitals with EHRs were larger and were more often teaching hospitals and stroke centers. After controlling for patient and hospital characteristics, patients admitted to hospitals with EHRs had similar odds of receiving ‘all-or-none’ care (odds ratio [OR]: 1.03; 95% CI: 0.99 to 1.06; p = 0.12), of discharge home (OR: 1.02; 95% CI: 0.99 to 1.04; p = 0.15), and of in-hospital mortality (OR: 1.01; 95% CI: 0.96 to 1.05; p = 0.82). The odds of having a length of stay >4 days was slightly lower at hospitals with EHRs (OR: 0.97; 95% CI: 0.95 to 0.99; p = 0.01).” (K. E. Joynt)

>>>PNN NewsWatch
* Many adults in the U.S. are not getting recommended screening tests for colorectal, breast and cervical cancers, according to data published yesterday in the CDC’s Morbidity and Mortality Weekly Report. For 2013, screening for these types of cancers either fell behind previous rates or showed no improvement. Among adults in the age groups recommended for screening, about 1 in 5 women reported not being up-to-date with cervical cancer screening, about 1 in 4 women reported not being up-to-date with breast cancer screening, and about 2 in 5 adults reported not being up-to-date with colorectal cancer screening.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 11, 2015 * Vol. 22, No. 89
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 9 issue of Lancet (2015; 385).
Menopausal Hormone Use & Ovarian Cancer: A small but significantly increased risk of ovarian cancer is identified among women who used menopausal hormone therapy, researchers report (pp. 1835–42). Combining data from 52 epidemiologic studies and focusing on prospective studies, the investigators identified these results before concluding that the increased risk “may well be largely or wholly causal”: “During prospective follow-up, 12,110 postmenopausal women, 55% (6,601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1.43, 95% CI 1.31–1.56; p <0.0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1.37 (95% CI 1.29–1.46; p <0.0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p <0.0001), being definitely increased only for the two most common types, serous (RR 1.53, 95% CI 1.40–1.66; p <0.0001) and endometrioid (1.42, 1.20–1.67; p <0.0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1.25, 95% CI 1.07–1.46, p = 0.005).” (Collaborative Group on Epidemiological Studies of Ovarian Cancer, collaborations@ceu.ox.ac.uk)
Dose-Dense Adjuvant Chemotherapy in Early-Stage Breast Cancer: Compared with standard interval chemotherapy, dose-dense chemotherapy improved disease-free survival among 2,091 patients with node-positive, early-stage breast cancer, a study shows (pp. 1863–72). Addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) did not improve disease-free survival, authors add, providing these details about the open-label, Phase III comparison of dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P: “After a median follow-up of 7.0 years (interquartile range [IQR] 4.5–6.3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79–84) in patients treated every 2 weeks and 76% (74–79) in patients treated every 3 weeks (HR 0.77, 95% CI 0.65–0.92; p = 0.004); overall survival rates at 5 years were 94% (93–96) and 89% (87–91; HR 0.65, 0.51–0.84; p = 0.001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75–81) in the FEC-P groups and 79% (76–82) in the EC-P groups (HR 1.06, 0.89–1.25; p = 0.561); overall survival rates at 5 years were 91% (89–93) and 92% (90–94; 1.16, 0.91–1.46; p = 0.234).” (L. Del Mastro, lucia.delmastro@hsanmartino.it)

>>>PNN NewsWatch
* Using animal-study data since the disease is so rare in people, FDA on Friday approved moxifloxacin (Avelox, Bayer) for treatment of plague.
* FDA also approved on Friday the Senza spinal cord stimulation system (Nevro Corp.) as an aid in management of chronic intractable pain of the trunk and/or limbs, including pain associated with failed back surgery syndrome, low back pain, and leg pain.

>>>PNN JournalWatch
* Treatment of Hypertension in Patients With Coronary Artery Disease: A Scientific Statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension, in Journal of the American College of Cardiology, 2015; 65: 1998–2038. (my.americanheart.org; reprints@elsevier.com)
* Antimicrobial Resistance in Hospital-Acquired Gram-Negative Bacterial Infections, in Chest, 2015; 147: 1413–21. (J. P. Lynch III, jplynch@mednet.ucla.edu)
* Celiac Disease, in Journal of the Allergy and Clinical Immunology, 2015; 135: 1099–106. (P. H. R. Green, pg11@columbia.edu)
* Review of Twitter for Infectious Diseases Clinicians: Useful or a Waste of Time?, in Clinical Infectious Diseases, 2015; 60: 1533–40. (D A. Goff; debbie.goff@osumc.edu, twitter@idpharmd)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 12, 2015 * Vol. 22, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: May issue of JAMA Internal Medicine (2015; 175).
Stepped Care for Chronic Pain: A stepped-care approach to chronic pain—one combining analgesics, self-management, and cognitive-behavioral therapy—proved effective in veterans of the Iraq and Afghanistan conflicts (pp. 682–9). Compared with usual care in a randomized trial, stepped care yielded these results in 241 veterans: “At 9 months, the mean decrease from baseline in the Roland Morris Disability Scale score was 1.7 (95% CI, −2.6 to −0.9) points in the usual care group and 3.7 (95% CI, −4.5 to −2.8) points in the intervention group (between-group difference, −1.9 [95% CI, −3.2 to −0.7] points; P = .002). The mean decrease from baseline in the Pain Interference subscale score of the Brief Pain Inventory was 0.9 points in the usual care group and 1.7 points in the intervention group (between-group difference, −0.8 [95% CI, −1.3 to −0.3] points; P = .003). The Graded Chronic Pain Scale severity score was reduced by 4.5 points in the usual care group and 11.1 points in the intervention group (between-group difference, −6.6 [95% CI, −10.5 to −2.7] points; P = .001).” (M. J. Bair, mbair@iupui.edu)
“Although this intervention may not be entirely generalizable, much can be learned from [this] approach,” according to an editor’s note published with this study (p. 690). “Several aspects can be integrated into any primary care practice, including the deliberate analgesic treatment algorithm that requires patients to try several different types of medication therapy before using opiates, the use of nurses rather than physicians to direct and advance treatment, and the importance of treating accompanying mental health symptoms, such as depression, all of which can improve musculoskeletal pain management in primary care.” (J. S. Ross)
Discontinuing Statin Therapy in Life-Limiting Illness: Several benefits, including unexpected ones, are identified in a pragmatic trial of statin discontinuation in patients with limited life expectancy (pp. 691–700). The study included 381 patients with estimated life expectancy of 1 month to 1 year who had been taking statins for at least 3 months for primary or secondary prevention of cardiovascular disease. Monitored monthly for 1 year, the participants had these outcomes: “Mean (SD) age was 74.1 (11.6) years, 22.0% of the participants were cognitively impaired, and 48.8% had cancer. The proportion of participants in the discontinuation vs continuation groups who died within 60 days was not significantly different (23.8% vs 20.3%; 90% CI, −3.5% to 10.5%; P = .36) and did not meet the noninferiority end point. Total [quality of life (QOL)] was better for the group discontinuing statin therapy (mean McGill QOL score, 7.11 vs 6.85; P = .04). Few participants experienced cardiovascular events (13 in the discontinuation group vs 11 in the continuation group). Mean cost savings were $3.37 per day and $716 per patient.” (A. P. Abernethy, amy.abernethy@duke.edu)
Exercise, Vitamin D & Training in Fall Prevention: Strength and balance training proved effective for fall prevention among 409 home-dwelling women aged 70–80 years, researchers report, while exercise and vitamin D intervention had no significant effect (pp. 703–11). “Fall rates per 100 person–years were 118.2, 132.1, 120.7, and 113.1 in the placebo without exercise, vitamin D without exercise, placebo and exercise, and vitamin D and exercise study groups, respectively; however, injurious fall rates were 13.2, 12.9, 6.5, and 5.0, respectively,” the report states. “Hazard ratios for injured fallers were significantly lower among exercisers with vitamin D (0.38; 95% CI, 0.17–0.83) and without vitamin D (0.47; 95% CI, 0.23–0.99). Vitamin D maintained femoral neck bone mineral density and increased tibial trabecular density slightly. However, only exercise improved muscle strength and balance. Vitamin D did not enhance exercise effects on physical functioning.” (K. Uusi-Rasi, kirsti.uusi-rasi@uta.fi)

>>>PNN NewsWatch
* Washington Gov. Jay Inslee yesterday signed into law a bill that requires health insurance carriers to include pharmacists as network providers. The law—passed with “overwhelming bipartisan support” as well as that of medicine, hospitals, and patients—will increase patient access to medical care from pharmacists practicing within their scope of practice, according to the Washington State Pharmacy Association.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 13, 2015 * Vol. 22, No. 91
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: May 15 issue of Clinical Infectious Diseases (2015; 60).
Treating Complicated Intra-abdominal Infections: In the ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) trial, ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with complicated intra-abdominal infections (cIAIs), including those caused by multidrug-resistant organisms, researchers report (pp. 1462–71). The Phase III trial included hospitalized patients with cIAI who were treated for 4–14 days. Results showed: “Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, −4.2%; 95% confidence interval [CI], −8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, −1.0%; 95% CI, −4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with [extended-spectrum beta-lactamase]-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea.” (J. Solomkin, solomkjs@ucmail.uc.edu)
23-Valent Pneumococcal Polysaccharide Vaccine Efficacy in Older Adults: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) “is effective against the most severe invasive forms of pneumococcal disease, but the lack of effectiveness of PPSV23 in protecting against all-cause [hospital-treated pneumonia (HTP)] should be considered for future vaccine policies,” according to authors who conducted a retrospective case–control study (pp. 1472–80). Records from the Clalit Health Services database showed these patterns of protection by the vaccine: “A total of 470,070 individuals aged ≥65 years were members of Clalit Health Services during the study period (1 January 2007 through 31 December 2010). The case cohort consisted of 212 participants with [invasive pneumococcal disease (IPD)] and 23,441 with HTP. The adjusted association between vaccination and IPD was protective (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.41–0.81), whereas there was no demonstrated protective effect between vaccination and HTP (OR, 1.01; 95% CI, 0.97–1.04). The sensitivity analysis and all but 1 subgroup analysis provided consistent results to the base case.” (M. Leventer-Roberts, maya.roberts@gmail.com)

>>>Oncology Highlights
Source: May 10 issue of the Journal of Clinical Oncology (2015; 33).
Regression of Cervical Cancer After T-Cell Treatment: Complete remission of metastatic cervical cancer was achieved after a single infusion of tumor-infiltrating T cells selected for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs) in two patients in a small study (pp. 1543–50). All patients had been previously treated with chemotherapy or chemoradiotherapy. Provision of lymphocyte-depleting chemotherapy, administration of aldesleukin, and a single HPV-TIL infusion yielded these results: “Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238).” (C. S. Hinrichs, hinrichs@nih.gov)

>>>PNN NewsWatch
* An FDA advisory panel yesterday recommended approval of Orkambi (Vertex), a combination of Vertex’s ivacaftor and a new drug, lumacaftor, for improving lung function in patients 12 years or older with cystic fibrosis who are homozygous for the F508del mutation in the CFTR gene. The vote was 12–1 for approval, the Wall Street Journal reports, and came despite uncertainty about the benefits of adding lumacaftor.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 14, 2015 * Vol. 22, No. 92
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Early-release articles from and May 14 issue of New England Journal of Medicine (2015; 372).
TAS-102 in Refractory Metastatic Colorectal Cancer: In a Phase III trial of 800 patients with refractory colorectal cancer, TAS-102 significantly improved overall survival in comparison with placebo, researchers report (pp. 1909–19). The drug—an orally administered combination of the thymidine-based nucleic acid analogue trifluridine and tipiracil hydrochloride, a thymidine phosphorylase inhibitor—produced these results based on a primary end point of overall survival: “The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P <0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P <0.001).” (R. J. Mayer)
Financial Incentives for Smoking Cessation: CVS Caremark 2,538 employees and their relatives and friends responded better to reward-based smoking cessation programs than ones based on deposits, a study shows (doi: 10.1056/NEJMoa1414293). Incentive programs were tested individuals as well as in groups of six participants. Those achieving cessation could earn either $800 or receive refundable deposits of $150 plus $650 in reward payments. Results showed: “Rates of sustained abstinence from smoking through 6 months were higher with each of the four incentive programs (range, 9.4 to 16.0%) than with usual care (6.0%) (P<0.05 for all comparisons); the superiority of reward-based programs was sustained through 12 months. Group-oriented and individual-oriented programs were associated with similar 6-month abstinence rates (13.7% and 12.1%, respectively; P=0.29). Reward-based programs were associated with higher abstinence rates than deposit-based programs (15.7% vs. 10.2%, P<0.001). However, in instrumental-variable analyses that accounted for differential acceptance, the rate of abstinence at 6 months was 13.2 percentage points (95% confidence interval, 3.1 to 22.8) higher in the deposit-based programs than in the reward-based programs among the estimated 13.7% of the participants who would accept participation in either type of program.” (S. D. Halpern, shalpern@exchange.upenn.edu)
Gene Therapy in Childhood Blindness: Long-term follow-up in three patients treated with gene therapy for Leber’s congenital amaurosis show “progressive diminution of the areas of improved vision,” confounding investigators searching for a cure of this form of childhood blindness (pp. 1920–6): “Retinal gene therapy for Leber’s congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision.” (S. G. Jacobson, jacobsos@mail.med.upenn.edu)
Commenting on this and another study of gene therapy in Leber’s congenital amaurosis (pp. 1887–97; J. W. B. Bainbridge, j.bainbridge@ucl.ac.uk), an editorialist discusses possible approaches to improving treatment (pp. 1954–5): “Human disease may necessitate more efficient RPE65 delivery, perhaps with the use of a lentiviral vector or one of the newer [recombinant adeno-associated virus] vectors.… Without a highly efficient vector delivery system and sufficient surviving retinal pigment epithelium and photoreceptors, treatment success will be transient.” (A. F. Wright)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 15, 2015 * Vol. 22, No. 93
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source: May issue of the Journal of Allergy and Clinical Immunology (2015; 135).
Anaphylaxis in Infants & Young Children: Monitoring and home use of age-appropriate epinephrine autoinjectors are among the key interventions needed in infants and children who have had anaphylactic reactions before age 2, according to authors of a Rostrum article (pp.1125–31): “Anaphylaxis is increasingly reported in this age group. Foods are the most common triggers. Presentation typically involves the skin (generalized urticaria), the respiratory tract (cough, wheeze, stridor, and dyspnea), and/or the gastrointestinal tract (persistent vomiting). Tryptase levels are seldom increased because of infant anaphylaxis, although baseline tryptase levels can be increased in the first few months of life, reflecting mast cell burden in the developing immune system. The differential diagnosis of infant anaphylaxis includes consideration of age-unique entities, such as food protein–induced enterocolitis syndrome with acute presentation. Epinephrine (adrenaline) treatment is underused in health care and community settings. No epinephrine autoinjectors contain an optimal dose for infants weighing 10 kg or less. After treatment of an anaphylactic episode, follow-up with a physician, preferably an allergy/immunology specialist, is important for confirmation of anaphylaxis triggers and prevention of recurrences through avoidance of confirmed specific triggers. Natural desensitization to milk and egg can occur. Future research should include validation of the clinical criteria for anaphylaxis diagnosis in infants, prospective longitudinal monitoring of baseline serum tryptase levels in healthy and atopic infants during the first year of life, studies of infant comorbidities and cofactors that increase the risk of severe anaphylaxis, development of autoinjectors containing a 0.1-mg epinephrine dose suitable for infants, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis recurrences.” (F. E. R. Simons, lmcniven@hsc.mb.ca)
Peer Coaching of Parents of Children With Asthma: Compared with usual care in a cluster-randomized trial, a telephone-based, peer-coaching intervention with parents reduced asthma impairment among children with the disease, researchers report (pp. 1163–870.e2). Asthma risk was also reduced among children with Medicaid insurance whose parents received the intervention, which included a median of 18 telephone calls over a 12-month period. Among 948 families at 22 pediatric practices, these outcomes were identified based on interviews at 12 and 24 months: “After 12 months, intervention participation resulted in 20.9 (95% CI, 9.1–32.7) more symptom-free days per child than in the control group, and there was no difference in emergency department (ED) visits. After 24 months, ED visits were reduced (difference in mean visits/child, −0.28; 95% CI, −0.5 to −0.02), indicating a delayed intervention effect. In the Medicaid subgroup, after 12 months, intervention participation resulted in 42% fewer ED visits (difference in mean visits/child, −0.50; 95% CI, −0.81 to −0.18) and 62% fewer hospitalizations (difference in mean hospitalizations/child, −0.16; 95% CI, −0.30 to −0.014). Reductions in health care use endured through 24 months.” (J. M. Garbutt, jgarbutt@dom.wustl.edu)

>>>Rheumatology Highlights
Source: May issue of Arthritis & Rheumatology (2015; 67).
CBT for Insomnia in Patients With Osteoarthritis: In 100 patients with osteoarthritis (OA) of the knee, cognitive–behavioral therapy for insomnia (CBT-I) proved a significantly better intervention than the active placebo of behavioral desensitization (pp. 1221–33): “Intent-to-treat analyses demonstrated substantial improvement in sleep in both groups of patients. Patients in the CBT-I group had significantly greater reductions in wake after sleep onset (WASO), as measured by patient diary and [in-home polysomnography]. Patients in both groups reported significant and comparable reductions in pain over 6 months, with one-third reporting a 30% reduction in pain severity. Baseline-to-posttreatment reductions in WASO as measured by diary and PSG predicted subsequent decreases in clinical pain. This effect was significantly greater for CBT-I compared with behavioral desensitization. No significant changes in laboratory measures of pain modulation were observed.” (M. T. Smith, msmith62@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 © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 18, 2015 * Vol. 22, No. 94
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 16 issue of Lancet (2015; 385).
Treatment of Complicated UTIs: In the ASPECT-cUTI trial, ceftolozane–tazobactam produced better responses than high-dose levofloxacin in 1,083 patients with complicated lower-urinary-tract infections or pyelonephritis, researchers report (pp. 1949–56). For 7 days, adult patients hospitalized for one of these conditions received I.V. ceftolozane 1.5 g with tazobactam every 8 h or I.V. levofloxacin 750 mg once daily, with these results: “Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76.9%] of 398 vs 275 [68.4%] of 402, 95% CI 2.3–14.6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious.” (F. M. Wagenlehner, florian.wagenlehner@chiru.med.uni-giessen.de)
Renal Denervation for Resistant Hypertension: Renal denervation added to a standardized stepped-care antihypertensive treatment (SSAHT) lowered ambulatory pressures over a 6-month period more than SSAHT alone in patients with well-defined resistant hypertension, according to results of the Renal Denervation for Hypertension (DENERHTN) trial (pp. 1957–65). Patients aged 18–75 years received triple antihypertensive therapy for 4 weeks to confirm resistance, with 106 of 1,416 patients proceeding to randomization. Renal denervation plus an SSAHT regimen (spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were added sequentially in months 2–5) or SSAHT alone produced these results: “The mean change in daytime ambulatory systolic blood pressure at 6 months was −15.8 mm Hg (95% CI −19.7 to −11.9) in the renal denervation group and −9.9 mm Hg (−13.6 to −6.2) in the group receiving SSAHT alone, a baseline-adjusted difference of −5.9 mm Hg (−11.3 to −0.5; p = 0.0329). The number of antihypertensive drugs and drug-adherence at 6 months were similar between the two groups. Three minor renal denervation-related adverse events were noted (lumbar pain in two patients and mild groin haematoma in one patient). A mild and similar decrease in estimated glomerular filtration rate from baseline to 6 months was observed in both groups.” (M. Azizi, michel.azizi@egp.aphp.fr)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Neonatal Abstinence Syndrome After Opioid Exposure: Following in utero exposure to prescription opioids, neonates have a low absolute risk of developing neonatal abstinence syndrome (NAS) unless other risk factors are present, an observational cohort study shows (h2102). Using Medicaid data from 46 states, investigators found these patterns for babies born to women who filled at least one prescription for an opioid analgesic during pregnancy: “1,705 cases of NAS were identified among 290,605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1,000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use [≥30 d] during pregnancy resulted in higher absolute risk of NAS per 1,000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1,000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively).” (R. J. Desai, rdesai2@partners.org)

>>>PNN JournalWatch
* Antipsychotic Drug Use in Pregnancy, in BMJ, 2015; 350: h2298. (S. N. Vigod, simone.vigod@wchospital.ca)
* ACA Provisions Associated With Increase in Percentage of Young Adult Women Initiating and Completing the HPV Vaccine, in Health Affairs, 2015; 34: 757–64. (B. J. Lipton, BLipton@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 19, 2015 * Vol. 22, No. 95
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source: May issue of the Journal of the American Geriatrics Society (2015; 63).
Research Agenda on Delirium: In a special article, the American Geriatrics Society releases results of its seventh Bedside-to-Bench research conference, “Delirium in Older Adults: Finding Order in the Disorder’’ (pp. 843–52). Recommendations call for research on delirium and geriatric syndromes, delirium phenomenology, delirium pathophysiology and basic mechanisms, biomarkers of delirium, and measurement and quality control in delirium research. Recommendations specific to clinical care include the following (A. Mikhailovich, AMikhailovich@americangeriatrics.org):
* Strong consideration should be given to including cognitive impairment as a primary or secondary outcome of clinical interventions for delirium regardless of age or comorbidity. Similarly, functional and economic measures closely related to delirium (e.g., acute hospital length of stay) should also be strongly considered as secondary outcomes.
* Increasing the individual’s homeostatic reserve to withstand physiological stress is an emerging concept in delirium prevention. Prehabilitation and increasing resiliency may be useful to increase homeostatic reserve.
* There is an ongoing need to investigate the role of anesthetics in modulating the perioperative acute stress response and other potentially modifiable risk factors for delirium in the perioperative setting.
* The creation of a delirium research consortium for leveraging existing data to advance the study of delirium would be extremely useful.
Pneumonia in New Users of Cholinesterase Inhibitors: Interesting differences among cholinesterase inhibitors and their routes of administration are uncovered in a retrospective cohort study of users of donepezil, galantamine, or rivastigmine for dementia (pp. 869–76). From a nationally representative 5% sample of Medicare beneficiaries aged 65 or older, these results are highlighted: “The mean age of 35,570 new users of cholinesterase inhibitors (30,174 users of donepezil, 1,176 users of galantamine, 4,220 users of rivastigmine) was 82; 75% were women, and 82% were white. The cumulative incidence of pneumonia was 51.9 per 1,000 person–years. The risk of pneumonia for rivastigmine users was 24% lower than that of donepezil users (hazard ratio (HR) = 0.75, 95% confidence interval (CI) = 0.60–0.93). Risk in galantamine users (HR = 0.87, 95% CI = 0.62–1.23) was not significantly different from risk in donepezil users. Results of subgroup and sensitivity analyses were similar to the primary results.” (S. Setoguchi, soko.setoguchi@duke.edu)
Newer Antidepressants in Older Adults: A systematic review and network meta-analysis presents “clear evidence of the effectiveness of sertraline, paroxetine, and duloxetine” in adults aged 60 or older, researchers report (pp. 1002–9). “There also appears to be a hierarchy of safety associated with the different antidepressants, although there appears to be a dearth of reporting of safety outcomes,” the group adds based on these findings: “Fifteen randomized controlled trials were eligible for inclusion in the analysis. Citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, fluoxetine, and sertraline were represented. Reporting on partial response and dizziness was sufficient to conduct a network meta-analysis. Reporting on other outcomes was sparse. For partial response, sertraline (RR = 1.28), paroxetine (RR = 1.48), and duloxetine (RR = 1.62) were significantly better than placebo. The remaining interventions yielded RRs lower than 1.20. For dizziness, duloxetine (RR = 3.18) and venlafaxine (RR = 2.94) were statistically significantly worse than placebo. Compared with placebo, sertraline had the lowest RR for dizziness (1.14) and fluoxetine the second lowest (1.31). Citalopram, escitalopram, and paroxetine all had RRs between 1.4 and 1.7.” (E. Mills, emills@redwoodoutcomes.com)

>>>PNN NewsWatch
* FDA yesterday released a draft “Guidance for Industry (GFI) #230, Compounding Animal Drugs from Bulk Drug Substances.” The document outlines specific conditions under which the agency generally does not intend to take action against state-licensed pharmacies, veterinarians, and facilities registered as outsourcing facilities when drugs are compounded for animals from bulk drug substances.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 20, 2015 * Vol. 22, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: May 20 issue of JAMA (2015; 313).
Oral Steroids in Herniated Lumbar Disk: Tapering 15-day courses of oral corticosteroids produced modestly improved function but no relief from pain among 269 adult patients with radicular pain secondary to herniated lumbar disk, researchers report (pp. 1915–23). Study participants had had acute sciatica for less than 3 months on study admission. The steroid regimen was oral prednisone 600 mg divided into 5 days each of 60, 40, and 20 mg. Compared with placebo, oral steroids produced these effects: “Observed baseline and 3-week mean [Oswestry Disability Index (ODI)] scores were 51.2 and 32.2 for the prednisone group and 51.1 and 37.5 for the placebo group, respectively. The prednisone-treated group showed an adjusted mean 6.4-point (95% CI, 1.9–10.9; P = .006) greater improvement in ODI scores at 3 weeks than the placebo group and a mean 7.4-point (95% CI, 2.2–12.5; P = .005) greater improvement at 52 weeks. Compared with the placebo group, the prednisone group showed an adjusted mean 0.3-point (95% CI, −0.4 to 1.0; P = .34) greater reduction in pain at 3 weeks and a mean 0.6-point (95% CI, −0.2 to 1.3; P = .15) greater reduction at 52 weeks. The prednisone group showed an adjusted mean 3.3-point (95% CI, 1.3–5.2; P = .001) greater improvement in the [Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS)] score at 3 weeks, no difference in the SF-36 PCS score at 52 weeks (mean, 2.5; 95% CI, −0.3 to 5.4; P = .08), no change in the SF-36 [Mental Component Summary (MCS)] score at 3 weeks (mean, 2.2; 95% CI, −0.4 to 4.8; P = .10), and an adjusted 3.6-point (95% CI, 0.6-6.7; P = .02) greater improvement in the SF-36 MCS score at 52 weeks. There were no differences in surgery rates at 52-week follow-up. Having 1 or more adverse events at 3-week follow-up was more common in the prednisone group than in the placebo group (49.2% vs 23.9%; P < .001).” (H. Goldberg, harley.goldberg@kp.org)
Stroke Prevention in AF: Authors of a review article examine current evidence on stroke prevention in patients with atrial fibrillation (AF) (pp. 1950–62): “The risk of stroke in AF is reduced by anticoagulant therapy. Thromboprophylaxis can be obtained with vitamin K antagonists (VKA, eg, warfarin) or a non-VKA oral anticoagulant (NOAC). Major guidelines emphasize the important role of oral anticoagulation (OAC) for effective stroke prevention in AF. Initially, clinicians should identify low-risk AF patients who do not require antithrombotic therapy (ie, CHA2DS2-VASc score, 0 for men; 1 for women). Subsequently, patients with at least 1 stroke risk factor (except when the only risk is being a woman) should be offered OAC. A patient’s individual risk of bleeding from antithrombotic therapy should be assessed, and modifiable risk factors for bleeding should be addressed (blood pressure control, discontinuing unnecessary medications such as aspirin or nonsteroidal anti-inflammatory drugs). The international normalized ratio should be tightly controlled for patients receiving VKAs.” (G. Y. H. Lip, g.y.h.lip@bham.ac.uk)
Hospital Quality Reporting: Reacting to a Viewpoint that describes coverage of hospital quality in U.S. News & World Reports (pp. 1903–4; B. Harder, bharder@usnews.com), an editorialist provides a series of questions and answers to help clinicians talk with patients concerned about what they have read (pp. 1911–2): “One reasonable approach might be first to point out that any highly touted institution—be it a restaurant, a college, or a hospital—may deliver a disastrous experience, whereas a less prestigious choice sometimes provides exactly what is needed. A discussion of the strengths and limitations of quality data might follow. Finally, patients and clinicians should turn to the particulars: does the patient need primarily a superb physician, superb nursing care, a superb hospice program? Is continuity of inpatient and outpatient care essential? Is hospital location close to home, family, and friends more important than anything else? Where would the patient feel most comfortable? To date, hospital rating systems incorporate only a few of these concerns, but a conversation between patient and physician may clarify them all.” (A. Zuger, abzug@panix.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 21, 2015 * Vol. 22, No. 97
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 21 issue of the New England Journal of Medicine (2015; 372).
Short Antimicrobial Course for Intraabdominal Infection: With appropriate management of the microbial source, patients with intra-abdominal infections have similar outcomes from shorter, fixed-duration antimicrobial courses (4 days) as from antibiotics given until 2 days after resolution of fever, leukocytosis, and ileus, the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial shows (pp. 1996–2005). Among 517 patients with complicated intraabdominal infection and adequate source control, these outcomes were noted from short-course therapy (experimental group) and up to 10 days of therapy (control group): “Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, −0.5 percentage point; 95% confidence interval [CI], −7.0 to 8.0; P = 0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, −4.0 days; 95% CI, −4.7 to −3.3; P <0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes.” (R. G. Sawyer, rws2k@virginia.edu)
While shorter antibiotic courses “would be desirable to minimize drug-related adverse events, the selection of antibiotic resistance, and costs,” editorialists are troubled by the sizable fraction of patients (20%) with complications in both treatment groups (pp. 2062–3): “Early in the 21st century, it seems likely that source control remains a considerable problem in treating abdominal sepsis. Nevertheless, a contrarian might argue that patients in both study groups needed more, not fewer, days of antibiotics. However, to support the latter argument, we would have expected still more complications after treatment in the short-course therapy group. In the future, there may be improved approaches to source control in abdominal sepsis and safer antibiotics for limiting microbial growth. In the meantime, we have encouraging data from the STOP-IT trial that suggest cost savings and improved safety.” (R. P. Wenzel)
Nivolumab in Untreated Melanoma: In 142 patients with advanced, untreated melanoma, nivolumab plus ipilimumab improved objective-response rates and progression-free survival, compared with ipilimumab monotherapy, researchers report (pp. 2006–17). Based on a primary end point of rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors, results showed the following: “Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P <0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P <0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation–positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.” (F. S. Hodi, stephen_hodi@dfci.harvard.edu)

>>>PNN NewsWatch
* The drug strength stated on vial and carton labeling is causing confusion and leading to medication errors with ceftolozane–tazobactam (Zerbaxa, Cubist), FDA warned yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 22, 2015 * Vol. 22, No. 98
Providing news and information about medications and their proper use

>>>Medical Care Report
Source: June issue of Medical Care (2015; 53).
Drug Adherence & Payer Costs: Among insured patients with chronic diseases, improved medication adherence does lower costs, a study that accounts for healthy patients who take their medications properly (pp. 517–23). The article is titled “Does Good Medication Adherence Really Save Payers Money?”; it concludes, “These results buttress the economic case for action by health care payers to improve medication adherence among insured persons with chronic disease.” Survey and claims data for 1,273 Medicare Part D beneficiaries with diabetes in 2006–09 were assessed while controlling for healthy adherer bias (HAB) Results showed: “We found consistent evidence that controlling for HAB reduces estimated savings in medical costs from better adherence, and likewise, reduces estimates of additional adherence-related drug spending. For ACE inhibitors/ARBs we estimate that controlling for HAB reduced adherence-related medical cost offsets from $6,389 to $4,920 per person (P <0.05). Estimates of additional adherence-related drug costs were 26% and 14% lower in HAB-controlled models (P <0.05).” (B. C. Stuart)
Evidence-Based Management: In an editorial that describes the difficulties with using health services research in day-to-day management of health systems, a writer calls for researchers to “demonstrate our value” (pp. 477–9). “If health services research is to be more than an esoteric pursuit for ivory tower researchers, this question of usefulness of the research needs to be addressed head on. It is better that we take the initiative than having solutions dictated or funding eliminated. There are many impediments such as the requirements for successful academic careers, ‘peer’ review, and our notions of research and its underlying philosophical assumptions. To take that initiative, we will have to examine our own mental models, recognize their limitations, and move out of our comfort zones. Managers will need to change as well. [Evidence-based management (EBMgt)] will have to address all the issues faced by evidence-based medicine (EBM), only more so and in a more complex context. In health care, EBM and EBMgt go hand in hand. As health services researchers, we should play our part in generating useful knowledge. We must demonstrate our value, recognizing that value is determined not by us, but by those who utilize the knowledge in the world of practice.” (D. C. Aron, david.aron@va.gov)

>>>Health Affairs Highlights
Source: May issue of Health Affairs (2015; 34).
Addiction Treatment Programs: State agencies that oversee addiction-treatment programs are doing little with the expanded funding provided through the Affordable Care Act (ACA), researchers report based on a national survey (pp. 828–35). Despite dramatic expansion of health insurance for addiction treatment and “unprecedented opportunities for service growth and delivery model reform,” the authors “found that most Single State Agencies provide little assistance to addiction treatment programs. Most agencies are helping programs develop collaborations with other health service programs. However, fewer than half reported providing help in modernizing systems to support insurance participation, and only one in three provided assistance with enrollment outreach. In the absence of technical assistance, it is unlikely that addiction treatment programs will fully realize the ACA’s promise to improve access to and quality of addiction treatment.” (C. Andrews, candrews@mailbox.sc.edu)

>>>PNN NewsWatch
* “Permanent interruption of global poliovirus transmission appears possible in the near future,” according to an article in this week’s Morbidity and Mortality Weekly Report (pp. 527–31; J. E. Hagan, jehagan@cdc.gov), adding that this goal depends on progress in Afghanistan and Pakistan. “The recent gains in control and elimination of poliovirus transmission globally must be maintained and built upon through innovative strategies to access populations during [supplementary immunization activities] in areas with complex security and political challenges, improve [acute flaccid paralysis] surveillance, and strengthen routine immunization,” the article notes.
* PNN will not be published on Mon., May 25, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 26, 2015 * Vol. 22, No. 99
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 23 issue of Lancet (2015; 385).
Hypotensive Agents in Diabetes & Kidney Disease: In adults with diabetes and kidney disease, no drug therapy aimed at reducing blood pressure prolonged survival compared with placebo, according to results of a network meta-analysis of 157 studies of 43,256 participants (pp. 2047–56). Based on primary outcomes of all-cause mortality and end-stage kidney disease, the analysis showed: “No drug regimen was more effective than placebo for reducing all-cause mortality. However, compared with placebo, end-stage renal disease was significantly less likely after dual treatment with an angiotensin-receptor blocker (ARB) and an angiotensin-converting-enzyme (ACE) inhibitor (odds ratio 0.62, 95% CI 0.43–0.90) and after ARB monotherapy (0.77, 0.65–0.92). No regimen significantly increased hyperkalaemia or acute kidney injury, although combined ACE inhibitor and ARB treatment had the lowest rank among all interventions because of borderline increases in estimated risks of these harms (odds ratio 2.69, 95% CI 0.97–7.47 for hyperkalaemia; 2.69, 0.98–7.38 for acute kidney injury).” (G. F. M. Strippoli, gfmstrippoli@gmail.com)
Once-Weekly Dulaglutide vs. Bedtime Insulin Glargine: For patients with type 2 diabetes that is not controlled with conventional insulin therapy, once-weekly dulaglutide provides a new alternative, one that performed significantly better than bedtime insultin glargine in the AWARD-4 study (pp. 2057–66). The noninferiority Phase III trial, conducted open label in 15 countries, provided these results for 884 adult patients who were assigned to one of two doses of once-weekly dulaglutide or daily bedtime insulin glargine: “At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1.5 mg (−1.64% [95% CI −1.78 to −1.50], −17.93 mmol/mol [−19.44 to −16.42]) and dulaglutide 0.75 mg (−1.59% [−1.73 to −1.45], −17.38 mmol/mol [−18.89 to −15.87]) than in those receiving glargine (−1.41% [−1.55 to −1.27], −15.41 mmol/mol [−16.92 to −13.90]). The adjusted mean difference versus glargine was −0.22% (95% CI −0.38 to −0.07, −2.40 mmol/mol [–4.15 to −0.77]; p=0.005) for dulaglutide 1.5 mg and −0.17% (–0.33 to −0.02, −1.86 mmol/mol [–3.61 to −0.22]; p=0.015) for dulaglutide 0.75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1.5 mg group); pneumonia (n=1 in the dulaglutide 0.75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1.5 mg group, 44 (15%) patients in the dulaglutide 0.75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting.” (Z. Milicevic, milicevic_zvonko@lilly.com)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Lipid Lowering & Vascular Events in Older People: The risk of stroke was reduced by 30% among 7,484 older community-dwelling men and women with no history of vascular events when they were treated with statins or fibrates, according to a prospective, population-based cohort study from France (h2335). These risks and outcomes were observed: “Lipid lowering drug users were at decreased risk of stroke compared with non-users (hazard ratio 0.66, 95% confidence interval 0.49 to 0.90); hazard ratios for stroke were similar for statin (0.68, 0.45 to1.01) and fibrate (0.66, 0.44 to 0.98). No association was found between lipid lowering drug use and coronary heart disease (hazard ratio 1.12, 0.90 to 1.40). Analyses stratified by age, sex, body mass index, hypertension, systolic blood pressure, triglyceride concentrations, and propensity score did not show any effect modification by these variables, either for stroke or for coronary heart disease.” (C. Tzourio, Ichristophe.tzourio@u-bordeaux.fr)

>>>PNN JournalWatch
* Comparative Efficacy and Safety of Selective Serotonin Reuptake Inhibitors and Serotonin-Norepinephrine Reuptake Inhibitors in Older Adults: A Network Meta-Analysis, in Journal of the American Geriatrics Society, 2015; 63: 1002–9. (E. Mills, emills@redwoodoutcomes.com)
* Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment, in Diabetes Care, 2015; 38: 1161–72. (L. Van Gaal, luc.van.gaal@uza.be)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 27, 2015 * Vol. 22, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from JAMA Internal Medicine (2015; 175).
Risks of Bridge Therapy: A retrospective cohort study of members of Kaiser Permanente Colorado identifies increased risk of bleeding with bridge therapy in patients undergoing invasive procedures (doi: 10.1001/jamainternmed.2015.1843). The authors conclude that bridge therapy “is likely unnecessary for most of these patients,” referring to those with recurrent venous thromboembolism (VTE). In 2006–12, 1,178 patients who underwent 1,812 procedures had these outcomes with bridge or no bridge therapy: “Among the 1,178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1,431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians [(ACCP)]. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non–bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non–bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group.” (T. Delate, tom.delate@kp.org)
This study “is not without its limitations, particularly the lack of discrimination between full-dose and prophylactic-dose parenteral anticoagulants used as bridge therapy and the absence of information on the timing of anticoagulation therapy,” editorialists write (doi: 10.1001/jamainternmed.2015.1858). “Nevertheless, it is likely that the imbalance between bleeding and thrombotic events between subgroups would have been even more dramatic had all patients in the bridge therapy group received full-dose parenteral anticoagulants in the immediate postoperative setting. As such, we support the authors’ contention that the majority—indeed the vast majority—of patients receiving anticoagulants for a history of VTE should not be given therapeutic-dose bridge therapy, and that revision of the ACCP risk-stratification recommendations is warranted. There are undoubtedly some patients at such high risk for recurrent VTE that bridge therapy is a necessary evil, such as those with acute VTE in the preceding month and those with a prior pattern of brisk VTE recurrence during short-term interruption of anticoagulation therapy. However, for the vast majority of patients receiving oral anticoagulants for VTE, it is probably safer to simply allow the oral anticoagulant to wash out before the procedure and, if indicated based on the type of surgery, to use routine prophylactic-dose anticoagulation therapy afterward. Parenteral anticoagulants are inherently high-risk medications that should be used with great caution, particularly in the postoperative setting: first, do no harm.” (D. J. Brotman, brotman@jhmi.edu)

>>>JAMA Highlights
Source: May 26 issue of JAMA (2015; 313).
Soy Isoflavone Supplement in Asthma: Lung function was not improved in adults or adolescents with asthma through addition of soy isoflavone supplements to controller medications, researchers report (pp. 2033–43). Study participants received placebo or soy isoflavone supplement (total isoflavones, 100 mg) in two divided daily doses for 24 weeks. Results showed: “Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement.” (L. J. Smith, ljsmith@northwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 28, 2015 * Vol. 22, No. 101
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: May 28 issue of the New England Journal of Medicine (2015; 372).
Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults: In a Phase III trial of a new subunit vaccine containing varicella–zoster virus (VSV) glycoprotein E and the AS01B adjuvant system (HZ/su), immunized adults aged 50 years or older had lower risk of herpes zoster and those 70 or older had efficacy rates similar to younger age groups, researchers report (pp. 2087–96). Compared with placebo at centers in 18 countries, HZ/su was administered in two intramuscular doses 2 months apart, with these results: “A total of 15,411 participants who could be evaluated received either the vaccine (7,698 participants) or placebo (7,713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1,000 person–years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P <0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups.” (T. C. Heineman, thomas.c.heineman@gsk.com)
An editorialist discusses the relative advantages of HZ/su over the currently licensed live attenuated vaccine (pp. 2149–50): “The current live attenuated vaccine is contraindicated in persons with impaired cellular immunity, which includes persons who are at highest risk for herpes zoster, such as patients undergoing hematopoietic-cell transplantation, those with HIV who have a CD4+ cell count of 200 per cubic millimeter or less, and those receiving high doses of immunosuppressive medications. Since the HZ/su vaccine contains only a single virus protein and therefore cannot replicate, it will probably be safer in such patients, although it is unclear whether the vaccine will elicit a sufficiently protective immune response. A phase 1–2 trial of the HZ/su vaccine involving patients who had undergone autologous hematopoietic-cell transplantation showed that it induced VSV-specific CD4+ T cells that persisted for up to 1 year. A heat-inactivated live attenuated vaccine reduced the incidence of herpes zoster in adults who had undergone autologous hematopoietic-cell transplantation.” (J. I. Cohen)
Neonatal Abstinence Syndrome in U.S. NICUs: Drug withdrawal increased in American neonatal intensive care units (NICUs) from 2004 to 2013, consuming “a substantial and growing portion of resources,” a study shows (pp. 2118–26). Using multiple cross-sectional analysis of a deidentified dataset, investigators found these patterns in 299 NICUs: “Among 674,845 infants admitted to NICUs, we identified 10,327 with the neonatal abstinence syndrome. From 2004 through 2013, the rate of NICU admissions for the neonatal abstinence syndrome increased from 7 cases per 1,000 admissions to 27 cases per 1,000 admissions; the median length of stay increased from 13 days to 19 days (P <0.001 for both trends). The total percentage of NICU days nationwide that were attributed to the neonatal abstinence syndrome increased from 0.6% to 4.0% (P <0.001 for trend), with eight centers reporting that more than 20% of all NICU days were attributed to the care of these infants in 2013. Infants increasingly received pharmacotherapy (74% in 2004–2005 vs. 87% in 2012–2013, P <0.001 for trend), with morphine the most commonly used drug (49% in 2004 vs. 72% in 2013, P <0.001 for trend).” (V. N. Tolia, veeral.tolia@baylorhealth.edu)

>>>PNN NewsWatch
* FDA yesterday approved two drug products for treatment of irritable bowel syndrome with diarrhea (IBS-D) in adult men and women. Eluxadoline (Viberzi, Patheon) is a new controlled substance that will be marketed by Forest Pharmaceuticals. Rifaximin (Xifaxan, Salix) was originally approved in 2004 for treatment of travelers’ diarrhea caused by noninvasive Escherichia coli and later for reduction in risk in adult patients of recurring overt hepatic encephalopathy.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
May 29, 2015 * Vol. 22, No. 102
Providing news and information about medications and their proper use

>>>Diabetes Report
Source: June issue of Diabetes Care (2015; 38).
Pancreatic Events With Liraglutide: In two articles and a commentary, authors explore aspects of adverse pancreatic events in patients on liraglutide.
While more patients on liraglutide in Phase II and III trials had pancreatic events than did those on comparator drugs, confounding variables and cases not fulfilling diagnostic criteria complicate the analysis, researchers report (pp. 1058–66). Trials sponsored by Novo-Nordisk and completed by Apr. 2013 show these patterns: “Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient–years, respectively (n = 6,345 and 1,846, respectively). Eight cases of acute pancreatitis (AP) with liraglutide and one with any comparator (glimepiride) were found. The incidence of AP was 1.6 cases/1,000 patient–years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for total active comparators. One of the eight AP cases reported with liraglutide did not meet diagnostic criteria for AP. In six of these eight cases, recognized risk factors for AP were present and/or the onset of AP occurred >6 months after liraglutide initiation. All patients were receiving multiple medications. Four cases of chronic pancreatitis (CP) with liraglutide and none with comparators were found. One of these four cases fulfilled diagnostic criteria for CP; these criteria were not met or information was missing in the remaining three.” (T. M. Jensen, toej@novonordisk.com)
No association between acute pancreatitis and use of incretin-based drugs was found in a nationwide population-based case–control study from Denmark (pp. 1089–98). Between 2005 and 2012, 12,868 patients were hospitalized for the first time for acute pancreatitis. Compared with 128,680 matched controls, these results were generated: “A total of 89 pancreatitis patients (0.69%) and 684 control subjects (0.53%) were ever users of incretins. The crude OR for acute pancreatitis among incretin users was 1.36 (95% CI 1.08–1.69), while it was 1.44 (95% CI 1.34–1.54) among users of other antihyperglycemic drugs. After confounder adjustment, the risk of acute pancreatitis was not increased among incretin users (OR 0.95 [95% CI 0.75–1.21]), including DPP4 inhibitor users (OR 1.04 [95% CI 0.80–1.37]) or GLP-1 receptor agonist users (OR 0.82 [95% CI 0.54–1.23]), or among nonincretin antihyperglycemic drug users (OR 1.05 [95% CI 0.98–1.13]), compared with nonusers of any antihyperglycemic drugs. Findings were similar in current versus ever drug users and in patients with pancreatitis risk factors. The adjusted OR comparing incretin-based therapy with other antihyperglycemic therapy internally while also adjusting for diabetes duration and complications was 0.97 (95% CI 0.76–1.23).” (R. W. Thomsen, rwt@dce.au.dk)
The author of a Commentary calls for prompt resolution of the safety questions about incretin-based antidiabetic drugs (pp. 951–3): “Compared with other antidiabetes therapies, incretin-based drugs have been shown to decrease hemoglobin A1c levels, lower the risk of hypoglycemia, and have favorable effects on body weight. As a result, they have become attractive treatment options for patients with type 2 diabetes. However, there remains a cloud of uncertainty regarding their safety, and additional, well-conducted studies using real-world data are urgently needed to determine whether these concerns are substantiated.” (L. Azoulay, laurent.azoulay@mcgill.ca)
Glycemic Control & Antipsychotic Drugs: Patients with type 1 diabetes under 25 years of age often have worse glycemic control and more acute complications when they are on first- or second-generation antipsychotic agents, according to the German/Austrian Diabetes Survey (pp. 1051–7). Those on the drugs also had higher BMIs and greater frequencies of severe hypoglycemia and diabetic ketoacidosis. (A. Galler, angela.galler@charite.de)

>>>PNN NewsWatch
* FDA yesterday approved the first drug treatment for lymphangioleiomyomatosis (LAM), a very rare, progressive lung disease that primarily affects women of childbearing age. Sirolimus (Rapamune, Wyeth) received the additional indication based on a 12-month study of 89 patients with LAM. Lung function declined at a slower rate in patients taking sirolimus, compared with placebo, and resumed a higher rate of decline upon drug discontinuation.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 1, 2015 * Vol. 22, No. 103
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: May 30 issue of Lancet (2015; 385).
Anacetrapib in Familial Hypercholesterolemia: In a Phase III trial of adult patients with familial hypercholesterolemia, anacetrapib “was well tolerated and resulted in substantial reductions in LDL-C concentration,” report REALIZE investigators (pp. 2153–61). An outcomes study will determine whether the lowered lipid levels result in reduced cardiovascular events. Oral anacetrapib 100 mg or placebo for 52 weeks produced these results in the current study: “Between Feb. 10, 2012, and Feb. 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3.3 mmol/L (SD 0.8) to 2.1 mmol/L (0.8; percentage change 36.0% [95% CI −39.5 to −32.5] compared with an increase with placebo from 3.4 mmol/L (1.2) to 3.5 mmol/L (1.6; percentage change 3.7% [–1.2 to 8.6], with a difference in percentage change between anacetrapib and placebo of −39.7% (95% CI −45.7 to −33.7; p <0.0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p = 0.1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102).” (J. J. P. Kastelein, j.j.kastelein@amc.uva.nl)
ART Adherence Support: In Africa, mortality was reduced with cryptococcal screening and a short initial period of medication adherence support when antiretroviral therapy (ART) was started in patients with HIV infection (pp. 2173–82): “At 12 months, 25 (2%) of 1,001 participants in the clinic plus community support group and 24 (2%) of 998 participants in the standard care group had been lost to follow-up, and were censored at their last visit for the primary analysis. At 12 months, 134 (13%) of 1,001 participants in the clinic plus community support group had died compared with 180 (18%) of 998 in the standard care group. Mortality was 28% (95% CI 10–43) lower in the clinic plus community support group than in standard care group (p = 0·004).” (S. Jaffar, shabbar.jaffar@lshtm.ac.uk)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Combined Oral Contraceptives & Venous Thromboembolism: The risk of venous thromboembolism is higher with newer combined oral contraceptive products than with those in the second-generation category, according to findings from two nested case–control studies of large U.K. research/practice databases (h2135). Newer preparations containing drospirenone have in particular not been assessed on a long-term bases, the authors note, adding these details from assessment of the Clinical Practice Research Datalink (CPRD; 618 practices) and QResearch primary care database (722 practices): “5,062 cases of venous thromboembolism from CPRD and 5,500 from QResearch were analysed. Current exposure to any combined oral contraceptive was associated with an increased risk of venous thromboembolism (adjusted odds ratio 2.97, 95% confidence interval 2.78 to 3.17) compared with no exposure in the previous year. Corresponding risks associated with current exposure to desogestrel (4.28, 3.66 to 5.01), gestodene (3.64, 3.00 to 4.43), drospirenone (4.12, 3.43 to 4.96), and cyproterone (4.27, 3.57 to 5.11) were significantly higher than those for second generation contraceptives levonorgestrel (2.38, 2.18 to 2.59) and norethisterone (2.56, 2.15 to 3.06), and for norgestimate (2.53, 2.17 to 2.96). The number of extra cases of venous thromboembolism per year per 10,000 treated women was lowest for levonorgestrel (6, 95% confidence interval 5 to 7) and norgestimate (6, 5 to 8), and highest for desogestrel (14, 11 to 17) and cyproterone (14, 11 to 17).” (Y. Vinogradova, yana.vinogradova@nottingham.ac.uk)

>>>PNN JournalWatch
* Glycerin Enemas and Suppositories in Premature Infants: A Meta-analysis, in Pediatrics, 2015; 135: 1093–106. (M. H. Livingston)
* Strategies to Decrease Pertussis Transmission to Infants, in Pediatrics, 2015; 135: e1475–82. (K. Forsyth)
* Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Diagnosis, Management, and Prevention in Critically Ill Patients, in Pharmacotherapy, 2015; 35: 10.1002/phar.1599. (D. Dixit, ddixit@rci.rutgers.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 2, 2015 * Vol. 22, No. 104
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: June 2 issue of the Annals of Internal Medicine (2015; 162).
Early v. Late Readmissions: Patients readmitted early versus late in the important 30-day period following discharge have differing reasons for returning to the hospital, a study shows, and readmission prevention strategies may also need to vary (pp. 741–9). In a retrospective cohort study for 2009–10 admissions at an academic medical center, investigators found these relationships among the index hospitalization (acute illness burden, inpatient care process factors, clinical indicators of instability at discharge), unrelated factors (chronic illness burden, social determinants of health), and early (0–7 days after discharge) versus late (8–30 days) readmissions: “13,334 admissions, representing 8,078 patients, were included in the analysis. Early readmissions were associated with markers of acute illness burden, including length of hospital stay (odds ratio [OR], 1.02 [95% CI, 1.00 to 1.03]) and whether a rapid response team was called for assessment (OR, 1.48 [CI, 1.15 to 1.89]); markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.19 [CI, 1.02 to 1.40]); and social determinants of health, including barriers to learning (OR, 1.18 [CI, 1.01 to 1.38]). Early readmissions were less likely if a patient was discharged between 8:00 a.m. and 12:59 p.m. (OR, 0.76 [CI, 0.58 to 0.99]). Late readmissions were associated with markers of chronic illness burden, including receiving a medication indicating organ failure (OR, 1.24 [CI, 1.08 to 1.41]) or hemodialysis (OR, 1.61 [CI, 1.12 to 2.17]), and social determinants of health, including barriers to learning (OR, 1.24 [CI, 1.09 to 1.42]) and having unsupplemented Medicare or Medicaid (OR, 1.16 [CI, 1.01 to 1.33]).” (K. L. Graham, kgraham@bidmc.harvard.edu)
ED Revisit Rates: Patients return to emergency departments (EDs) more frequently than previously believed, researchers report (pp. 750–6). Revisits are often to different EDs, a possibility not anticipated in previous studies, the authors report, adding these results for adult visits to EDs in six U.S. states based on data from the Healthcare Cost and Utilization Project: “Within 3 days of an index ED visit, 8.2% of patients had a revisit; 32% of those revisits occurred at a different institution. Revisit rates varied by diagnosis, with skin infections having the highest rate (23.1% [95% CI, 22.3% to 23.9%]). Revisit rates also varied by state. For skin infections, Florida had higher risk-adjusted revisit rates (24.8% [CI, 23.5% to 26.2%]) than Nebraska (10.6% [CI, 9.2% to 12.1%]). In Florida, the only state with complete cost data, total revisit costs for the 19.8% of patients with a revisit within 30 days were 118% of total index ED visit costs for all patients (including those with and without a revisit).” (R. Duseja, reena.duseja@emergency.ucsf.edu)
Type 2 Diabetes Mellitus Screening: In a review conducted for purposing of updating the 2008 U.S. Preventive Services Task Force review on diabetes screening in adults, investigators find that screening for type 2 diabetes did not improve 10-year mortality rates but that treatment of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) delayed progression to diabetes (pp. 765–76): “In 2 trials, screening for diabetes was associated with no 10-year mortality benefit versus no screening (hazard ratio, 1.06 [95% CI, 0.90 to 1.25]). Sixteen trials consistently found that treatment of IFG or IGT was associated with delayed progression to diabetes. Most trials of treatment of IFG or IGT found no effects on all-cause or cardiovascular mortality, although lifestyle modification was associated with decreased risk for both outcomes after 23 years in 1 trial. For screen-detected diabetes, 1 trial found no effect of an intensive multifactorial intervention on risk for all-cause or cardiovascular mortality versus standard control. In diabetes that was not specifically screen-detected, systematic reviews found that intensive glucose control did not reduce risk for all-cause or cardiovascular mortality and results for intensive blood pressure control were inconsistent.” (S. Selph, selphs@ohsu.edu)

>>>PNN NewsWatch
* The White House Forum on Antibiotic Stewardship is livestreaming today, according to an information page on the CDC website. “Antibiotic stewardship does not mean stopping the use of antibiotics; it means using antibiotics when necessary and appropriate,” CDC said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 3, 2015 * Vol. 22, No. 105
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: June 2 issue of JAMA (2015; 313).
Maternal Antidepressant Use & Neonatal Persistent Pulmonary Hypertension: While the absolute risk was small, a cohort study shows that maternal use of selective serotonin reuptake inhibitor (SSRI) antidepressants late in pregnancy may be associated with a significant increase in risk of persistent pulmonary hypertension of the newborn (PPHN) (pp. 2142–51). The topic of a 2006 FDA public health advisory, PPHN occurred at these rates among the babies born to 3.8 million women enrolled in Medicaid in 2000–10 in 46 U.S. states and the District of Columbia: “A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7,630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4–21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3–35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3–36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35–1.69) unadjusted and 1.10 (95% CI, 0.94–1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12–1.75) and 1.02 (95% CI, 0.77–1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01–1.64) and for non-SSRIs 1.14 (95% CI, 0.74–1.74).” (K. F. Huybrechts, khuybrechts@partners.org)
Pioneer ACO Performance: Compared with Medicare fee-for-service (FFS) beneficiaries, those cared for in the Pioneer Accountable Care Organization (ACO) Model in 2012 and 2013 had “smaller increases in total Medicare expenditures and differential reductions in utilization of different health services, with little difference in patient experience,” researchers report (pp. 2152–61). As reported in the May 6 PNN, Pioneer ACOs were launched in 2012 by CMS with the Medicare Saved Sharings Program as efforts to improve cost and quality outcomes. FFS beneficiaries were “attributed to ACOs based on their historical utilization patterns,” the authors write, but could visit any providers participating in the Medicare program.
Comparing outcomes for 32 Pioneer ACOs with alignment-eligible beneficiaries in the same markets and for some comparisons, with those in Medicare Advantage (MA) programs, the researchers identified these results: “Total spending for beneficiaries aligned with Pioneer ACOs in 2012 or 2013 increased from baseline to a lesser degree relative to comparison populations. Differential changes in spending were approximately −$35.62 (95% CI, −$40.12 to −$31.12) per-beneficiary-per-month (PBPM) in 2012 and -$11.18 (95% CI, −$15.84 to −$6.51) PBPM in 2013, which amounted to aggregate reductions in increases of approximately −$280 (95% CI, −$315 to −$244) million in 2012 and −$105 (95% CI, −$148 to −$61) million in 2013. Inpatient spending showed the largest differential change of any spending category (−$14.40 [95% CI, −$17.31 to −$11.49] PBPM in 2012; −$6.46 [95% CI, −$9.26 to −$3.66] PBPM in 2013). Changes in utilization of physician services, emergency department, and postacute care followed a similar pattern. Compared with other Medicare beneficiaries, ACO-aligned beneficiaries reported higher mean scores for timely care (77.2 [ACO] vs 71.2 [FFS] vs 72.7 [MA]) and for clinician communication (91.9 [ACO] vs 88.3 [FFS] vs 88.7 [MA]).” (R. Rajkumar, rahul.rajkumar@cms.hhs.gov)
An editorialist predicts “rough traveling ahead” for Pioneer ACOs, as they may have relied on “low-hanging fruit” for initial gains (pp. 2126–7; L. P. Casalino).

>>>PNN NewsWatch
* FDA issued a final veterinary rule yesterday that promotes “the judicious use of antimicrobials in food-producing animals” by bringing their use under veterinary supervision. The veterinary feed directive (VFD) outlines the process for authorizing use of VFD drugs (animal drugs intended for use in or on animal feed that require the supervision of a licensed veterinarian) and provides veterinarians in all states with a framework for authorizing the use of medically important antimicrobials in feed when needed for specific animal health purposes.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 4, 2015 * Vol. 22, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: June 4 issue of the New England Journal of Medicine (2015; 372).
Type 2 Diabetes Glycemic Control & Cardiovascular Outcomes: In the Veterans Affairs Diabetes Trial, participants assigned to intensive glucose control for 5.6 years had fewer major cardiovascular events but no change in overall survival at 10 years, compared with those on standard therapy (pp. 2197–206). Based on a primary outcomes of time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death), investigators found these effects using annual surveys and periodic chart reviews: “The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P = 0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1,000 person–years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P = 0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P = 0.54; median follow-up, 11.8 years).” (R. A. Hayward, rhayward@umich.edu)
Vasopressin Antagonists: Availability of vasopressin antagonists such as conivaptan and tolvaptan has led to changes in practice guidelines for treatment of hyponatremia, according to a review article (pp. 2207–16): “The advent of the use of vasopressin antagonists has provided physicians with a new means of increasing the plasma sodium level in patients with hyponatremia. These agents appear to offer substantial advantages over previously available therapies that have been shown to have limited efficacy, an unacceptable side-effect profile, or both. To ascertain whether such increases in the plasma sodium level have an effect on mortality and morbidity associated with hyponatremia is a challenge for the next decade.” (T. Berl, tomas.berl@ucdenver.edu)
Precision Medicine: “Precision medicine [is] treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations,” authors of a Sounding Board article write (pp. 2229–34). This differentiates the concept from individualized or personalized medicine, they note, which many clinicians “contend they have always practiced.” In the article, the authors highlight “the convergence of a variety of technological breakthroughs that are accelerating the field of precision medicine. The extent to which these advances are constructive or disruptive depends on our ability to harness vast amounts of new knowledge and treatment options within the framework of everyday clinical practice. Changes that occur will require reengineering and adaptations by multiple stakeholders. Medical school curricula will need to focus even more on information management. Physicians will require informatics support and algorithms that work in the background to assist with information management and decision making. Health systems will need to design pathways that facilitate ready access to specialists when appropriate. Regulatory agencies and payers will need to evaluate and support, when appropriate, advances in precision medicine if patients are to receive maximum benefit. When the term precision medicine disappears from our lexicon, we will know that a revised disease classification with more targeted treatment options has become the norm.” (J. L. Jameson)
Clinical Genome Resource Program: A publicly accessible database created by the collaborative Clinical Genome Resource (ClinGen) program can provide clinicians and patients with important, current information about genetic variants and risks of clinical diseases, authors write (pp. 2235–42). The system is accessed more than 5,000 times each day, FDA is considering using its data for clinical interpretation of genetic variation, and ClinGen could “shepherd in a new era of transparency and advancement in genomic science.” (H. L. Rehm, hrehm@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 © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 5, 2015 * Vol. 22, No. 107
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source: June issue of the American Journal of Psychiatry (2015; 172).
Citalopram, Methylphenidate in Geriatric Depression: Citalopram plus methylphenidate was more effective than either drug alone for relief of symptoms of depression in older adults, researchers report (pp. 561–9). In a 16-week randomized controlled trial, 143 older outpatients had these responses to the drugs, with remission defined as a score of 6 or less on the Hamilton Depression Rating Scale: “Daily doses ranged from 20 mg to 60 mg for citalopram (mean = 32 mg) and from 5 mg to 40 mg for methylphenidate (mean = 16 mg). All groups showed significant improvement in depression severity and in cognitive performance. However, the improvement in depression severity and the Clinical Global Impressions improvement score was more prominent in the citalopram plus methylphenidate group compared with the other two groups. Additionally, the rate of improvement in the citalopram plus methylphenidate group was significantly higher than that in the citalopram plus placebo group in the first 4 weeks of the trial. The groups did not differ in cognitive improvement or number of side effects.” (H. Lavretsky)

>>>Pediatrics Report
Source: June issue of Pediatrics (2015; 135).
Tdap Vaccine Effectiveness: “Lack of long-term protection after vaccination is likely contributing to increases in pertussis among adolescents,” according to investigators who found waning of protection 2–4 years after administration of a sixth dose of pertussis-containing vaccine, tetanus toxoid, reduced diphtheria toxoid, or acellular pertussis, adsorbed (Tdap) (pp. 981–9). A case–control study of adolescents during the 2012 pertussis epidemic in Washington State showed these results for vaccine effectiveness (VE): “Among adolescents who received all acellular vaccines (450 cases, 1,246 controls), overall Tdap VE was 63.9% (95% confidence interval [CI]: 50% to 74%). VE within 1 year of vaccination was 73% (95% CI: 60% to 82%). At 2 to 4 years postvaccination, VE declined to 34% (95% CI: −0.03% to 58%).” (A. M. Acosta)
First Pertussis Vaccine Dose & Infant Mortality: “The first pertussis vaccine dose and antibiotic treatment protect against death, hospitalization, and pneumonia,” conclude authors who analyzed national data from 1991 to 2008 (pp. 990–9). Using a variable of receipt of a first pertussis vaccine dose at age 6 weeks, logistic regression analysis showed these results: “Pertussis-related deaths occurred among 258 of 45,404 cases. Fatal and nonfatal cases were confirmed by culture (54% vs 49%) and polymerase chain reaction (31% vs 27%). All deaths occurred before age 34 weeks at illness onset; 64% occurred before age 6 weeks. Among infants aged ≥42 days, receiving ≥1 doses of vaccine protected against death (adjusted odds ratio [aOR]: 0.28; 95% confidence interval [CI]: 0.11–0.74), hospitalization (aOR: 0.69; 95% CI: 0.63–0.77), and pneumonia (aOR: 0.80; 95% CI: 0.68–0.95). Risk was elevated for Hispanic ethnicity (aOR: 2.28; 95% CI: 1.36–3.83) and American Indian/Alaska Native race (aOR: 5.15; 95% CI: 2.37–11.2) and lower for recommended antibiotic treatment (aOR: 0.28; 95% CI: 0.16–0.47). Among infants aged <42 days, risk was elevated for Hispanic ethnicity and lower with recommended antibiotic use.” (T. S. P. Tiwari)
Pharmacy-Level Asthma Medication Ratio (Ph-AMR): Patterns of fills and refills of controller and rescue asthma medications may provide “a community-based leverage point for improving population-level asthma control through targeted interventions,” concludes a retrospective, ecological study of a 27-unit chain pharmacy (pp. 1009–17): “The median utilization rate across included census tracts was 22.4 visits per 1,000 child–years (range 1.3–60.9). Tracts with Ph-AMR <0.5 had significantly higher utilization rates than those with Ph-AMR ≥0.5 (26.1 vs 9.9; P = .001). For every 0.1 increase in Ph-AMR, utilization rates decreased by 9.5 (P = .03), after adjustment for underlying poverty and access. Seasonal variation in fills was evident, but pharmacies in high-utilizing tracts filled more rescue than controller medications at nearly every point during the study period.” (Andrew F. Beck)

>>>PNN NewsWatch
* An FDA advisory panel yesterday recommended that flibanserin be approved for treatment of low libido in healthy women, the Washington Post reports.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 8, 2015 * Vol. 22, No. 108
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: June 6 issue of Lancet (2015; 385).
Genetic Risks & Statins: Patients with the highest genetic risk for new and recurrent coronary heart disease events derive the greatest relative and absolute clinical benefits from statin therapy, according to stratification of data on 48,421 people with 3,477 events (pp. 2264–71). Investigators compiled figures from four randomized controlled trials and a community-based cohort study to calculate a genetic risk score based on 27 genetic variants, with these results: “When individuals were divided into low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1.34 (95% CI 1.22–1.47, p <0.0001) and that for the high genetic risk category was 1.72 (1.55–1.92, p <0.0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p = 0.0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p = 0.0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT.” (J. L Mega, jmega@partners.org)

>>>BMJ Highlights
Source: Early-release articles from BMJ (2015; 350).
TNF Inhibitors & Serious Infections in IBD: In patients with inflammatory bowel disease, the risk of serious infections is greatest in the first 90 days of therapy with tumor necrosis factor–alpha (TNF-alpha) inhibitors, a nationwide study from Denmark shows (h2809). Subsequent risk declines, according to these results for 52,392 people with the disease, 4,300 of whom were treated with TNF-alpha inhibitors: “Within the 90 days risk period, 51 cases of infection were observed in users of TNF-alpha inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12).” (N. Nyboe Andersen, nyna@ssi.dk)
Varenicline & Psychiatric Conditions: Use of varenicline was not associated with suicidality, accidents, or many other adverse outcomes in a study of the nearly 8 million residents of Sweden (h2388). In 2006–09, 69,757 people were treated with varenicline, with these effects on incidence of adverse outcomes: “In the whole population, 337,393 new psychiatric conditions were diagnosed during follow-up. In addition, 507,823 suspected and 338,608 convicted crimes, 40,595 suicidal events, 124,445 transport accidents, and 99,895 suspected and 57,068 convicted traffic crimes were recorded. Within person analyses showed that varenicline was not associated with significant hazards of suicidal behaviour, criminal offending, transport accidents, traffic offences, or psychoses. However, varenicline was associated with a small increase in the risk of anxiety conditions (hazard ratio 1.23, 95% confidence interval 1.01 to 1.51) and mood conditions (1.31, 1.06 to 1.63), which was only seen in people with pre-existing psychiatric disorders.” (S. Fazel, seena.fazel@psych.ox.ac.uk)

>>>PNN JournalWatch
* Are at Least 12 Months of Dual Antiplatelet Therapy Needed for All Patients With Drug-Eluting Stents [point–counterpoint]?, in Circulation, 2015; 131: 2001–9 (S. J. Brener, sjb9005@nyp.org); 2010–9 (R. C. Becker, richard.becker@uc.edu)
* Cardio-Pulmonary-Renal Interactions: A Multidisciplinary Approach, in Journal of the American College of Cardiology, 2015; 65: 2433–48. (F. Husain-Syed)
* The Use of Inhaled Prostaglandins in Patients With ARDS: A Systematic Review and Meta-analysis, in Chest, 2015; 147: 1510–22. (B. M. Fuller, fullerb@wusm.wustl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 9, 2015 * Vol. 22, No. 109
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: June issue of JAMA Internal Medicine (2015; 175).
Zoledronic Acid for Osteoporosis: In frail older women with osteoporosis, a single dose of zoledronic acid improved bone mineral density (BMD) over a 2-year period, suggesting the need for further study of lack of nursing home treatment of this condition (pp. 913–21). In 2007–12, investigators randomized 181 women aged 65 years or older to a single dose of zoledronic acid 5 mg or placebo I.V. plus daily calcium/vitamin D, with these results: “There were no baseline differences in mean (SE) age (85.4 [0.6] years), BMD, or functional or cognitive status, but the treatment group included more participants with frailty, falls history, diabetes, and anticonvulsant medication use. Values for BMD were available for 87% of participants at 12 months and 73% at 24 months. Mean (SE) BMD changes were greater in the treatment group: 3.2 (0.7) and 3.9 (0.7) percentage-point differences in the total hip at 12 and 24 months, respectively (P < .01 for both comparisons), and 1.8 (0.7) and 3.6 (0.7) percentage-point differences at the spine (P < .01); adjusted analyses were similar. The treatment and placebo groups’ fracture rates were 20% and 16%, respectively (OR, 1.30; 95% CI, 0.61–2.78); mortality rates were 16% and 13% (OR, 1.24; 95% CI, 0.54–2.86). Groups did not differ in the proportion of single fallers (28% vs 24%; OR, 1.24; 95% CI, 0.64–2.42; P = .52), but more participants in the treatment group had multiple falls (49% vs 35%; OR, 1.83; 95% CI, 1.01–3.33; P = .047); however, this difference was no longer significant when adjusted for baseline frailty.” (S. L. Greenspan)
An editorialist lists these lessons from this study (pp. 921–2): “It would be premature to use this study to immediately modify our clinical use of potent bone-active agents in the nursing home population with documented osteoporosis (i.e. those who have a low BMD as a major risk factor for fracture). … This study draws attention to the need for large controlled clinical trials to determine if a combination of fall prevention strategies and treatment with bone-active drugs might produce additive benefits on fractures, especially in high-risk populations such as those living in nursing homes. These studies will be difficult, and Greenspan and her colleagues are to be congratulated on beginning to fill this void.” (R. Lindsay)
Corticosteroid Injection & Exercise in Knee Osteoarthritis: In 100 patients with osteoarthritis of the knee who were undergoing exercise therapy, intra-articular methylprednisolone acetate 40 mg yielded no significant benefits over placebo, researchers report (pp. 923–30). Using a primary outcome of change in the Pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire (range, 0–100; higher scores indicate greater improvement) at week 14, the investigators report these results: “The mean (SE) changes in the KOOS Pain subscale score at week 14 were 13.6 (1.8) and 14.8 (1.8) points in the corticosteroid and placebo groups, respectively, corresponding to a statistically insignificant mean difference of 1.2 points (95% CI, −3.8 to 6.2; P = .64). We found no statistically significant group differences in any of the secondary outcomes at any time point.” (M. Henriksen)
Abuse-Deterrent Opioids, Propoxyphene Withdrawal & Opioid Dispensing Rates: The impact of introduction of abuse-deterrent opioids and withdrawal of propoxyphene in late 2010 had noticeable effects on opioid dispensing and prescription opioid overdoses, according to a study of insurance claims for adults 18–64 years (pp. 978–87): “Two years after the opioid market changes, total opioid dispensing decreased by 19% from the expected rate (absolute change, −32.2 mg morphine-equivalent dose per member per quarter [95% CI, −38.1 to −26.3]). By opioid subtype, the absolute change in dispensing by milligrams of morphine-equivalent dose per member per quarter at 2 years was −11.3 (95% CI, −12.4 to −10.1) for extended-release oxycodone, 3.26 (95% CI, 1.40 to 5.12) for other long-acting opioids, −8.19 (95% CI, −9.30 to −7.08) for propoxyphene, and −16.2 (95% CI, −18.8 to −13.5) for other immediate-release opioids. Two years after the market changes, the estimated overdose rate attributed to prescription opioids decreased by 20% (absolute change, −1.10 per 100,000 members per quarter [95% CI, −1.47 to −0.74]), but heroin overdose increased by 23% (absolute change, 0.26 per 100,000 members per quarter [95% CI, −0.01 to 0.53]).” (M. R. Larochelle)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 10, 2015 * Vol. 22, No. 110
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: June 10 issue of JAMA (2015; 313).
Acute Gastroenteritis Hospitalizations After Marketing of Rotavirus Vaccine: Following implementation of rotavirus vaccination in 2006, all-cause acute gastroenteritis hospitalization rates among U.S. children younger than 5 years of age declined by 31%–55% in each of the postvaccine years from 2008 through 2012, a study shows (pp. 2282–4). Investigators analyzed the State Inpatient Databases of the Healthcare Cost and Utilization Project for the 26 states that consistently reported discharges during this time period. The researchers found that compared with the prevaccine average annual acute gastroenteritis hospitalization rate of 76 per 10,000 among children younger than 5 years, postvaccine introduction rates declined by 31% in 2008, 33% in 2009, 48% in 2010, 47% in 2011, and 55% in 2012. Similar rate declines were noted in both boys and girls, all race/ethnicity groups, and all age groups, with the greatest reductions among children age 6–23 months. Compared with the prevaccine average annual rotavirus-coded hospitalization rate of 16 per 10,000 among children younger than 5 years, rates of rotavirus--coded hospitalizations postvaccine introduction declined by 70% in 2008, 63% in 2009, 90% percent in 2010, 79% in 2011, and 94% in 2012. (E. Leshem)
Nonalcoholic Fatty Liver Disease: Some 75–100 million Americans have nonalcoholic fatty liver disease, according to a review article on the topic (pp. 2263–73). “Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis,” the author writes. “Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The incidence of nonalcoholic fatty liver disease–related hepatocellular carcinoma is increasing and up to 50% of cases may occur in the absence of cirrhosis.” (M. E. Rinella)
NSAIDs in Acute Gout: In a JAMA Clinical Evidence Synopsis, authors recommend against use of NSAIDs for treatment of acute gout (pp. 2276–7): “NSAIDs are not significantly associated with a difference in pain reduction compared with cyclooxygenase inhibitors and glucocorticoids for treating acute gout. However, NSAIDs are associated with higher rates of adverse events and higher rates of withdrawal due to adverse events compared with cyclooxygenase inhibitors.” (C. M. P. G. van Durme)
ADA at 25: An editorial (pp. 2231–5) and several related Viewpoints examine the impact of the American With Disabilities Act, passed and signed into law in 1990. “As a civil rights law coming in the wake of racial and gender equality legislation, the ADA has had profound symbolic meaning and real-world effects,” the editorialist writes. “Its promise of full participation in life stood in marked contrast to the often-impenetrable social and physical barriers that individuals with disabilities faced regarding inclusion in the workplace and public spaces. In sponsoring the ADA, Senator Edward Kennedy described life for persons with disabilities as an ‘American apartheid.’ The ADA embodies the highest values of the United States—a compassionate nation with the vision to unleash the vast potential of persons with disabilities and to inspire global social change.” The editorialist, in print and a podcast, reviews the limitations placed on interpretation of ADA by the U.S. Supreme Court and revisited by Congress in 2008. (L. O. Gostin)

>>>PNN NewsWatch
* Alirocumab (Praluent; Sanofi, Regeneron) should be approved by FDA for treating dyslipidemias, an FDA advisory panel voted 13–3 yesterday. Panelists expressed concerns about the injectable PCSK9 inhibitor, the Wall Street Journal reports, with some recommending restricting use to conditions such as familial hypercholesterolemia. The panel today considers a second new agent in this category, this one from Amgen.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 11, 2015 * Vol. 22, No. 111
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source: June 16 issue of the Journal of the American College of Cardiology (2015; 65).
Warfarin & Renal Decline in Atrial Fibrillation: In the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial, “patients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus [dabigatran], and it was amplified by diabetes and previous vitamin K antagonist use,” investigators conclude (pp. 2481–93). A total of 18,113 patients received warfarin or dabigatran etexilate (DE) 110 or 150 mg twice daily, with this impact on changes in glomerular filtration rate (GFR): “GFR declined in all treatment groups. After an average of 30 months, the mean ± SE decline in GFR was significantly greater with warfarin (–3.68 ± 0.24 ml/min) compared with DE 110 mg (–2.57 ± 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (–2.46 ± 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR >25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period >18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range <65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes.” (M. Böhm)
“Clinicians now find themselves in the relatively uncomfortable position of having to choose the ‘best’ option among anticoagulants for their patients,” editorialists write (pp. 2494–5). “The selection of the most appropriate oral anticoagulant can be a complex, multistep process that is based on the consideration of several clinical variables including, importantly, the assessment of renal function.” (R. W. Asinger)
Cardiac Dysfunction in Childhood Cancer Survivors: St. Jude Lifetime Cohort Study data “may identify a subset of [childhood cancer] survivors at higher risk for poor clinical cardiac outcomes who may benefit from early medical intervention (pp. 2511–22). In 1,820 adults with a median age of 31 years, echocardiographic assessment with 3-dimensional (3D) left ventricular ejection fraction (LVEF) showed these outcomes: “Only 5.8% of survivors had abnormal 3D LVEFs (<50%). However, 32.1% of survivors with normal 3D LVEFs had evidence of cardiac dysfunction by global longitudinal strain (28%), American Society of Echocardiography–graded diastolic assessment (8.7%), or both. Abnormal global longitudinal strain was associated with chest-directed radiotherapy at 1 to 19.9 Gy (rate ratio [RR]: 1.38; 95% confidence interval [CI]: 1.14 to 1.66), 20 to 29.9 Gy (RR: 1.65; 95% CI: 1.31 to 2.08), and >30 Gy (RR: 2.39; 95% CI: 1.79 to 3.18) and anthracycline dose > 300 mg/m2 (RR: 1.72; 95% CI: 1.31 to 2.26). Survivors with metabolic syndrome were twice as likely to have abnormal global longitudinal strain (RR: 1.94; 95% CI: 1.66 to 2.28) and abnormal diastolic function (RR: 1.68; 95% CI: 1.39 to 2.03) but not abnormal 3D LVEFs (RR: 1.07; 95% CI: 0.74 to 1.53).” (G. T. Armstrong)

>>>Chest Highlights
Source: June issue of Chest (2015; 147).
Weight Loss & Airway Responsiveness in Asthma: Airway responsiveness improves when adults with asthma and obesity lose weight, according to a parallel-group study of 22 participants with BMIs of 32.5 kg/m2 or more (pp. 1582–90): “At study entry, participant mean ± SD age was 44 ± 9 years, 95% were women, and mean BMI was 45.7 ± 9.2 kg/m2. After 3 months, mean weight loss was 16.5 ± 9.9 kg in the intervention group, and the control group had a mean weight gain of 0.6 ± 2.6 kg. There were significant improvements in PC20 (P = .009), FEV1 (P = .009), FVC (P = .010), asthma control (P < .001), and asthma quality of life (P = .003) in the intervention group, but these parameters remained unchanged in the control group. Physical activity levels also increased significantly in the intervention group but not in the control group.” (S. Pakhale, spakhale@ohri.ca)

>>>PNN NewsWatch
* An FDA advisory panel yesterday voted 11–4 that benefits outweigh risks for Amgen’s evolocumab (Repatha) in treatment of patients with elevated LDL cholesterol levels, the Wall Street Journal reports.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 12, 2015 * Vol. 22, No. 112
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: July 1 issue of Clinical Infectious Diseases (2015; 61).
Pharmacodynamic Modeling in Pulmonary Tuberculosis: Pharmacodynamic modeling of bacillary elimination rates (BERs) from sputum cultures in patients with pulmonary tuberculosis can predict final clinical outcomes, researchers report (pp. 1–8). The group also found that high percentages of lipid body–positive acid-fast bacilli (%LB + AFB) on sputum smears were useful in identifying patients with infections of bacteria with a “persister phenotype.” The study included adults who were receiving standard 6-month therapy for pulmonary tuberculosis, and participants were followed for 1 year after treatment: “One hundred and thirty-three patients (56% HIV coinfected) participated, and 15 unfavorable outcomes were reported. These were inversely associated with faster sterilization phase bacillary elimination from the [serial sputum colony counting] model (odds ratio [OR], 0.39; 95% confidence interval [CI], .22–.70) and a faster BER from the [time-to positivity] model (OR, 0.71; 95% CI, .55–.94). Higher %LB + AFB counts on day 21–28 were recorded in patients who suffered unfavorable final outcomes compared with those who achieved stable cure (P = .008).” (D. J. Sloan, derek.sloan@lstmed.ac.uk)
Cannabis Use & Reduced Insulin Resistance in HIV-HCV Coinfections: “Cannabis-based pharmacotherapies” may be useful in patients with coinfections of HIV and hepatitis C virus (HCV) who have insulin resistance (IR), a study concludes (pp. 40–8). Using data from HEPAVIH, a French nationwide cohort of HIV–HCV-coinfected patients, investigators found these patterns of cannabis use and IR as measured using the homeostatic model assessment of insulin resistance (HOMA-IR): “Among the 703 patients included in the study (1,287 visits), 323 (46%) had HOMA-IR > 2.77 for at least 1 follow-up visit and 319 (45%) reported cannabis use in the 6 months before the first available visit. Cannabis users (irrespective of frequency) were less likely to have HOMA-IR > 2.77 (odds ratio [95% confidence interval], 0.4 [.2–.5]) after adjustment for known correlates/confounders. Two sensitivity analyses with HOMA-IR values as a continuous variable and a cutoff value of 3.8 confirmed the association between reduced IR risk and cannabis use.” (M. P. Carrieri, pmcarrieri@aol.com)

>>>Oncology Highlights
Source: June 10 issue of the Journal of Clinical Oncology (2015; 33).
Ipilimumab in Unresectable or Metastatic Melanoma: “Durability of long-term survival in ipilimumab-treated patients with advanced melanoma” is demonstrated in an analysis of pooled overall survival (OS) data for 1,861 patients from 10 prospective and 2 retrospective studies of the drug (pp. 1889–94): “Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3.” (D. Schadendorf, Dirk.Schadendorf@uk-essen.de)
Omega-3 Fatty Acids in Aromatase Inhibitor–Induced Musculoskeletal Pain: Among women with early-stage breast cancer who had joint pain and stiffness while receiving aromatase inhibitors (AIs), treatment with omega-3 fatty acids (O3-FAs) produced substantial and sustained improvements, compared with placebo, but authors conclude that the differences were not “meaningful” (pp. 1910–7): “Compared with baseline, the mean observed [Brief Pain Inventory–Short Form (BPI-SF)] score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein.” (D. L. Hershman, dlh23@columbia.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 15, 2015 * Vol. 22, No. 113
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: June 13 issue of Lancet (2015; 385).
Eliglustat for Gaucher’s Disease: In a Phase III, open-label, noninferiority trial, “oral eliglustat maintained haematological and organ volume stability in adults with Gaucher’s disease type 1 already controlled by intravenous [enzyme replacement therapy (ERT)] and could be a useful therapeutic option,” authors write (pp. 2355–62). Compared with imiglucerase infusions over a 12-month period, oral eliglustat produced these outcomes based on a composite primary efficacy endpoint of percentage of patients whose hematologic variables and organ volumes remained stable for 12 months: “In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference −8.8%; 95% CI −17.6 to 4.2). The lower bound of the 95% CI of −17.6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity).” (T. M. Cox, tmc12@medschl.cam.ac.uk)
Digoxin in AF: In patients with atrial fibrillation (AF) and moderate-to-high risk factors for stroke, digoxin “was associated with a significant increase in all-cause mortality, vascular death, and sudden death,” report investigators with the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (pp. 2363–70). Calling for a randomized trial of digoxin in AF, the authors report these results from a retrospective analysis of study data: “In 14,171 randomly assigned patients, digoxin was used at baseline in 5,239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p <0.0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5.41 vs 4.30 events per 100 patient–years; hazard ratio 1.17; 95% CI 1.04–1.32; p = 0.0093), vascular death (3.55 vs 2.69 per 100 patient–years; 1.19; 1.03–1.39, p = 0.0201), and sudden death (1.68 vs 1.12 events per 100 patient–years; 1.36; 1.08–1.70, p = 0.0076).” (M. R. Patel, manesh.patel@duke.edu)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Benzodiazepines & Mortality in Opioid Users: A case–cohort study of VA data from 2004 to 2009 indicates an association between receipt of benzodiazepines and mortality from drug overdose among veterans receiving opioid analgesics (h2698). In a random sample of 420,386 veterans, 2,400 died from drug overdose while receiving opioid analgesics, with these patterns of benzodiazepine use: “Risk of death from drug overdose increased with history of benzodiazepine prescription: adjusted hazard ratios were 2.33 (95% confidence interval 2.05 to 2.64) for former prescriptions versus no prescription and 3.86 (3.49 to 4.26) for current prescriptions versus no prescription. Risk of death from drug overdose increased as daily benzodiazepine dose increased. Compared with clonazepam, temazepam was associated with a decreased risk of death from drug overdose (0.63, 0.48 to 0.82).” (T. W. Park, tpark1@lifespan.org)

>>>PNN NewsWatch
* FDA on Friday approved the Brio Neurostimulation System, an implantable deep brain stimulation device to help reduce symptoms of Parkinson’s disease and essential tremor. The device is the second approved for this indication, joining Medtronic’s Activa Deep Brain Stimulation Therapy System, approved in 1997.

>>>PNN JournalWatch
* Platelets in Patients With Aspirin-Exacerbated Respiratory Disease, in Journal of Allergy and Clinical Immunology, 2015; 135: 1407–14. (T. M. Laidlaw, tlaidlaw@partners.org)
* Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT): Scoring System to Guide Use of Echocardiography in the Management of Staphylococcus aureus Bacteremia, in Clinical Infectious Diseases, 2015; 61: 18–28. (M. R. Sohail, sohail.muhammad@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 16, 2015 * Vol. 22, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: June 16 issue of the Annals of Internal Medicine (2015; 162).
Medicare Part D & Health Outcomes, Hospitalizations: In 5 years after implementation, Medicare Part D had no significant effects on “a range of population-level health indicators among Medicare enrollees” and did not produce “gains in medical care efficiencies,” according to a population-level longitudinal time-series analysis (pp. 825–33). A nationally representative sample of 59,293 Medicare beneficiaries showed these patterns of self-reported health status, limitations in activities of daily living (ADLs) (ADLs and instrumental ADLs), emergency department visits and hospital admissions (prevalence, counts, and spending), and mortality in 2000 through 2010: “Five years after Part D implementation, no clinically or statistically significant reductions in the prevalence of fair or poor health status or limitations in ADLs or instrumental ADLs, relative to historical trends, were detected. Compared with trends before Part D, no changes in emergency department visits, hospital admissions or days, inpatient costs, or mortality after Part D were seen. Confirmatory analyses [using Medicare claims data] were consistent.” (B. A. Briesacher, b.briesacher@neu.edu)
Vitamin D/Calcium at Start of Antiretroviral Therapy: In patients starting antiretroviral therapy with efavirenz/emtricitabine/tenofovir disoproxil fumarate, administration of vitamin D plus calcium attenuates bone loss, a study shows (pp. 815–24). At 39 AIDS Clinical Trials Group units, adult patients with antiretroviral therapy–naive HIV had these outcomes with 48 weeks of active or placebo treatment: “165 eligible patients were randomly assigned (79 received vitamin D3 plus calcium and 86 received placebo). The study groups were well-balanced at baseline: 90% were men, 33% were non-Hispanic black, and the median CD4 count was 0.341 × 109 cells/L. At 48 weeks, the percentage of decline in total hip BMD was smaller in the vitamin D3 plus calcium group than in the placebo group: Medians were −1.36% (interquartile range [IQR], −3.43% to 0.50%) and −3.22% (IQR, −5.56% to −0.88%), respectively (P = 0.004). Similar results were seen at the lumbar spine. At 48 weeks, 90% of patients achieved HIV-1 RNA levels less than 50 copies/mL. Levels of 25-hydroxyvitamin D3 increased with vitamin D3 plus calcium but not with placebo: Median change was 61.2 nmol/L (IQR, 36.4 to 94.3) versus 1.7 nmol/L (IQR, −13.2 to 10.7) (P < 0.001). Overall, 103 patients (62%) reported 1 or more adverse event, with similar distribution between groups; no cases of hypercalcemia and 1 case of nephrolithiasis were reported in the placebo group.” (E. T. Overton, toverton@uab.edu)
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Rintatolimod, counseling therapies, and graded exercise therapy are the most promising treatments for myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), according to a systematic review conducted for an NIH Pathways to Prevention Workshop (pp. 841–50): “Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence). Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence). Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence).” (M. E. B. Smith, smithbet@ohsu.edu)
In a position paper issued in conjunction with the NIH workshop on ME/CFS, a multidisciplinary working group identifies research gaps and future research priorities (pp. 860–5). The Oxford definition of the condition should be retired in favor of a single case definition, “even if it is not perfect,” the group writes. Panelists also call on NIH to work with CMS and “the Patient-Centered Outcomes Research Institute to develop demonstration projects of patient-centered medical homes for patients with ME/CFS.” (C. R. Green)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 17, 2015 * Vol. 22, No. 115
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: June 16 issue of JAMA (2015; 313).
Antibiotics for Acute Appendicitis: While antibiotic therapy failed to meet noninferiority criteria in comparison with surgery, the Appendicitis Acuta (APPAC) randomized clinical trial shows that conservative therapy of uncomplicated acute appendicitis is a reasonable option for many patients (pp. 2340–8). “Most patients randomized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period, and those who required appendectomy did not experience significant complications,” authors write, adding these details for I.V. ertapenem 1 g/d for 3 days followed by 7 days of oral levofloxacin 500 mg once daily and metronidazole 500 mg 3 times per day: “There were 273 patients in the surgical group and 257 in the antibiotic group. Of 273 patients in the surgical group, all but 1 underwent successful appendectomy, resulting in a success rate of 99.6% (95% CI, 98.0% to 100.0%). In the antibiotic group, 70 patients (27.3%; 95% CI, 22.0% to 33.2%) underwent appendectomy within 1 year of initial presentation for appendicitis. Of the 256 patients available for follow-up in the antibiotic group, 186 (72.7%; 95% CI, 66.8% to 78.0%) did not require surgery. The intention-to-treat analysis yielded a difference in treatment efficacy between groups of −27.0% (95% CI, −31.6% to &infinWinking (P = .89). Given the prespecified noninferiority margin of 24%, we were unable to demonstrate noninferiority of antibiotic treatment relative to surgery. Of the 70 patients randomized to antibiotic treatment who subsequently underwent appendectomy, 58 (82.9%; 95% CI, 72.0% to 90.8%) had uncomplicated appendicitis, 7 (10.0%; 95% CI, 4.1% to 19.5%) had complicated acute appendicitis, and 5 (7.1%; 95% CI, 2.4% to 15.9%) did not have appendicitis but received appendectomy for suspected recurrence. There were no intra-abdominal abscesses or other major complications associated with delayed appendectomy in patients randomized to antibiotic treatment.” (P. Salminen)
“These findings suggest that for CT-diagnosed uncomplicated appendicitis, an initial trial of antibiotics is reasonable followed by elective appendectomy for patients who do not improve with antibiotics or present with recurrent appendicitis,” editorialists write (pp. 2327–8). “The time has come to consider abandoning routine appendectomy for patients with uncomplicated appendicitis. The operation served patients well for more than 100 years. With development of more precise diagnostic capabilities like CT and effective broad-spectrum antibiotics, appendectomy may be unnecessary for uncomplicated appendicitis, which now occurs in the majority of acute appendicitis cases.” (E. Livingston)
Solving the Organ Shortage: The United States should adopt a two-step process for organ donation following an “unexpected” circulatory determination of death, according to authors seeking to address the shortage of organs for transplantation and associated long wait times (pp. 2321–2): “The first step, permission for preservation, seeks permission to maintain the body for possible organ donation after unexpected death. This step requires only that families and other authorized persons are able to indicate a choice to begin organ preservation, not a full authorization for donation. For some decedents, organ donation wishes will be known, and opting to support those desires through preservation is all that is requested of authorized persons. If desires are unknown, recognition of societal and human benefit or desire to find meaning in the death might lead to preservation until a final decision about donation can be made later.…
“The second step of the proposed 2-step authorization process is authorization to donate. Family members and loved ones initially need time to process the fact that death has occurred. Later they need the opportunity to weigh the pros and cons of donation against the decedent’s and family’s values.” (S. P. Wall, Stephen.Wall@nyumc.org)

>>>PNN NewsWatch
* FDA yesterday finalized its determination that partially hydrogenated oils (PHOs), the primary dietary source of artificial trans fat in processed foods, are not “generally recognized as safe” or GRAS for use in human food. Food manufacturers will have 3 years to remove PHOs from products or petition FDA to permit specific uses of PHOs.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 18, 2015 * Vol. 22, No. 116
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: June 18 issue of the New England Journal of Medicine (2015; 372).
Ezetimibe Added to Statins in ACS: Results from the IMPROVE-IT trial of 18,144 patients hospitalized for acute coronary syndrome show improved clinical markers and cardiovascular outcomes when ezetimibe was added to statin therapy, researchers report (pp. 2387–97). “Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit,” the authors conclude based on these results for patients with ACS within the past 10 days and LDL cholesterol of 50–100 mg/dL: “The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin–ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P <0.001). The Kaplan–Meier event rate for the primary end point [cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke] at 7 years was 32.7% in the simvastatin–ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.” (C. P. Cannon, cpcannon@partners.org)
Editorialists remind readers that persistence—getting patients to stay on their medications—is the bigger problem with lipid-lowering therapy (pp. 2448–50): “A sobering observation was that 42% of the participants in IMPROVE-IT, regardless of treatment assignment, discontinued the study medication prematurely. As noted by the authors, this discontinuation rate is approximately 7% per year, which closely mirrors that seen in other trials. Since lipid-lowering is presumably intended to be a lifelong goal, this diminishment in long-term use is an important practical clinical concern, and one that suggests that treatment adherence to lipid-lowering therapy needs to be an ongoing focus of practitioner attention. It also raises questions about the practicality of long-term use of PCSK9 inhibitors, since all these agents are currently given by subcutaneous injection once every 2 to 4 weeks.” (J. A. Jarcho)
Genetic Predisposition to Early-Onset Invasive Infections: An autosomal recessive mendelian disorder may be present in children with “clinical features of combined immunodeficiencies, especially with early-onset, invasive infections” (pp. 2409–22). In five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)–cell responses, these results came from genetic and cellular immunologic studies: “We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-alpha and interferon-lambda production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2.” (L. D. Notarangelo, luigi.notarangelo@childrens.harvard.edu)
Follow-on Biologics: The advent of follow-on biologics presents opportunities but also many hurdles for those trying to achieve cost savings, authors of a Perspective author write (pp. 2380–2): “Innovative approaches will be required to ensure mandatory, rigorous postapproval research on the safety and effectiveness of biosimilars compared with their innovator predecessors in order to promote confidence in these new products. Over the long term, attention to both these areas will help ensure that U.S. patients benefit from appropriate price reductions for older biologic drugs that are essential for their clinical care. At the same time, fair but appropriately limited periods of exclusivity will reward the innovators of the original products while also spurring them to create new products rather than prolong exclusivity rights over older ones long after such monopolies should have come to a natural end.” (A. Sarpatwari)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 19, 2015 * Vol. 22, No. 117
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source: June issue of Health Affairs (2015; 34).
Buprenorphine Waivers & Opioid Agonist Treatment: Increased access to opioid agonist treatment with buprenorphine, methadone, or both has been facilitated by a dramatic increase in the number of physicians with buprenorphine waivers from DEA, researchers report (pp. 1028–34). Using county-level data for 2002 to 2011, these patterns of waivered physicians were identified: “We found that the percentage of counties with a shortage of waivered physicians fell sharply, from 98.9 percent in 2002 to 46.8 percent in 2011. As a result, the percentage of the US population residing in what we classified as opioid treatment shortage counties declined from 48.6 percent in 2002 to 10.4 percent in 2011. These findings suggest that the increase in waivered physicians has dramatically increased potential access to opioid agonist treatment. Policy makers should focus their efforts on further increasing the number and geographical distribution of physicians, particularly in more rural counties, where prescription opioid misuse is rapidly growing.” (B. D. Stein, stein@rand.org)
Medication Use Among Marketplace Enrollees: Express Scripts data for 1 million of the 7.3 million Americans who enrolled in insurance plans through Marketplaces established under the Affordable Care Act in 2014 show medication-use differences between early and late enrollees (pp. 1049–56): “Among Marketplace enrollees, we found that those who enrolled earlier (October 2013–February 2014) were older and used more medication than later enrollees. Marketplace enrollees, as a whole, had lower average drug spending and were less likely to use most medication classes than the employer-sponsored comparison group. However, Marketplace enrollees were more likely to use medicines for hepatitis C and particularly for HIV.” (J. M. Donohue, jdonohue@pitt.edu)

>>>Medical Care Report
Source: July issue of Medical Care (2015; 53).
Role of Long-term Acute Care Hospitals: The place of long-term acute care hospitals (LTCHs) is emerging in the American health care system, an article explains, and for some patients, outcomes are improved (pp. 582–90). A retrospective cohort study of Medicare beneficiaries in LTCHs shows these 1-year mortality rates and 6-month Medicare payment amounts: “LTCH care is associated with increases in Medicare payments ranging from $3,146 to $17,589 (P <0.01) with no mortality benefit for 3 categories and payment reductions of $5419 and $5,962 (P <0.01) at lower or similar mortality for 2 categories. LTCH patients with multiple organ failure experience lower mortality at similar or lower payments (3 categories) or similar mortality at lower payments (1 category) compared with patients in other settings, with mortality benefits between 5.4 and 9.7 percentage points (P <0.05) and payment reductions between $13,806 and $20,809 (P <0.01). For 1 category, we found no difference in mortality or payments between LTCH and non-LTCH patients with multiple organ failure. For patients with ≥3 days in intensive care, LTCH care is associated with improved mortality and lower payments in 4 and 3 categories, respectively.” (L. Koenig, lane.koenig@knghealth.com)

>>>PNN NewsWatch
* A pharmacist provider status bill is now law in Oregon, pharmacist.com reports. “The Oregon provider status law clarifies that pharmacists can be paid for clinical services, expands existing laws related to collaborative drug therapy management (referred to as clinical pharmacy agreements in the legislation), and authorizes the Oregon Health Authority to work with the state Board of Pharmacy to establish statewide protocols, primarily for postdiagnostic clinical services such as smoking cessation and travel medicine, according to Gary DeLander, BSPharm, PhD, OSPA President,” according to the site.
* FDA, in partnership with international regulatory and law enforcement agencies, took action this week against more than 1,050 websites that illegally sell potentially dangerous, unapproved prescription medicines and medical devices to consumers. These actions include the issuance of regulatory warnings to the operators of offending websites and seizure of illegal medicines and medical devices worldwide.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 22, 2015 * Vol. 22, No. 118
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: June 20 issue of Lancet (2015; 385).
Interferon-Free Treatment of Genotype 4 HCV Infection: In noncirrhotic previously untreated and previously treated patients with hepatitis C virus (HCV) genotype 4 infection, an “interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation,” PEARL-I researchers report (pp. 2502–9): “Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, [sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12)] rates were 100% (42/42 [95% CI 91.6–100]) in the ribavirin-containing regimen and 90.9% (40/44 [95% CI 78.3–97.5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference −9.16% [95% CI −19.61 to 1.29]; p = 0.086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92.7–100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia.” (C. Hézode, christophe.hezode@hmn.aphp.fr)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Insulin Pump Therapy in Type 1 Diabetes: Based on data from the Swedish National Diabetes Register for 2005–12, patients with type 1 diabetes had lower cardiovascular mortality when using insulin pump therapy than with multiple daily insulin injections (h3234). The registry included 18,168 people with type 1 diabetes, 2,441 using insulin pump therapy and 15,727 using multiple daily insulin injections; results during a mean of 6.8 years showed: “With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1,000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association.” (I. Steineck, isabelle.steineck@iname.com)

>>>PNN JournalWatch
* CKD in HIV-Infected Patients: From the New Plague to Chronic Care Management, in American Journal of Kidney Diseases, 2015; 65: 823–5. (J. A. Vassalotti, joseph.vassalotti@mssm.edu)
* Self-Management in Chronic Disease: Clear Benefits for Blood Pressure Control in CKD, in American Journal of Kidney Diseases, 2015; 66: 12–4. (T. W. R. Doulton, tdoulton@nhs.net)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 23, 2015 * Vol. 22, No. 119
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Early-release article from the New England Journal of Medicine (2015; 372).
Idarucizumab for Dabigatran Reversal: Released in conjunction with presentation at the International Society on Thrombosis and Haemostasis 2015 Congress in Toronto, a study shows complete, rapid reversal of the anticoagulant effects of dabigatran by idarucizumab, an antibody fragment (10.1056/NEJMoa1502000). Participants had serious bleeding (group A) or needed an urgent procedure (group B). Intravenous infusions of idarucizumab 5 g produced these effects: “This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.” (C. V. Pollack, Jr., charles.pollack@jefferson.edu)
“Without a control group, it is difficult to assess the clinical benefit that is conferred by the administration of idarucizumab in patients with dabigatran-related bleeding,” an editorialist writes (10.1056/NEJMe1506600). “The mortality in the study population was high at 20%; half the deaths occurred more than 96 hours after the administration of the antidote and were attributable to coexisting illness. Given that the half-life of dabigatran is 12 to 14 hours if renal function is normal, how important is it to be able to neutralize the anticoagulant activity of dabigatran rapidly in addition to providing supportive care measures? Major bleeding events in patients taking anticoagulants originate from anatomical lesions, and anticoagulation can lead to a rapid loss of blood from these sites. Thus, the location and size of the lesion along with the coexisting conditions of the patient may have a greater effect on prognosis than the ability to rapidly neutralize an anticoagulant that the patient is taking.” (K. A. Bauer)

>>>Geriatrics Highlights
Source: June issue of the Journal of the American Geriatrics Society (2015; 63).
GI Antispasmodic and Anticholinergic Medications: Use of gastrointestinal (GI) antispasmodic and anticholinergic medications by older adults is associated with greater risk of injury, researchers report (pp. 1197–202). Among 54,152 cases and 205,858 control patients in an integrated health care system, these results were identified by a retrospective case–control study: “Of the total population, 1,068 (0.4%) had current exposure to a GI antispasmodic or anticholinergic (302 (0.6%) cases, 766 (0.4%) controls). Current users had a small but significantly greater risk of injury than nonusers (OR = 1.16, 95% CI = 1.01–1.34, P = .03). Past use was not significantly different from no use. Short-term users had a significantly greater risk of injury (OR = 1.31, 95% CI = 1.01–1.70, P = .04) than nonusers. Long-term use was associated with greater risk, but the difference was not statistically significant.” (M. M. Spence, Michele.M.Spence@kp.org)
Homocysteine, B Vitamins & Cognition: At an Italian memory clinic, patients older than 65 with hyperhomocysteinemia had worse cognitive and functional status and dementia, regardless of B group vitamin (BGV) status (pp. 1158–63). Those with elevated homocysteine levels and normal BGV status had the worst functional status and highest prevalence of dementia, investigators found. (F. Bonetti, francesco_bonetti1@virgilio.it)

>>>PNN NewsWatch
* FDA yesterday approved cangrelor (Kengreal, The Medicines Company) for preventing thrombus formation in coronary arteries of adults undergoing percutaneous coronary intervention.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 24, 2015 * Vol. 22, No. 120
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: June 23/30 issue of JAMA (2015; 313).
Cannabinoids for Medical Use: Based on a systematic review of 79 trials of 6,462 participants, investigators find “moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity” and “low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome” (pp. 2456–73). Four of the trials had low risk of bias, the authors note, adding these details based on their review: “Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55–9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99–2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0–10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.36 [95% CI, −0.69 to −0.05]; 7 trials). There was an increased risk of short-term [adverse events (AEs)] with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.” (P. F. Whiting)
“If the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized,” editorialists write in reaction to this article (pp. 2431–2). “Conversely, if the goal is to make marijuana available for medical purposes, then it is unclear why the approval process should be different from that used for other medications. Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, double-blind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety. The federal government and states should support medical marijuana research. Since medical marijuana is not a life-saving intervention, it may be prudent to wait before widely adopting its use until high-quality evidence is available to guide the development of a rational approval process.” (D. C. D’Souza)
Medical Marijuana for Chronic Pain: While “medical marijuana is used to treat a host of indications,” authors of a Clinical Crossroads article write that only “a few of [these] have evidence to support treatment with marijuana and many … do not” (pp. 2474–83). Focusing on 28 clinical trials of cannabinoids for indications other than those approved by FDA for dronabinol and nabilone, the investigators find: “Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1,600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications.” (K. P. Hill)
PDE5 Inhibitors & Malignant Melanoma: Use of oral phosphodiesterase type 5 (PDE5) inhibitors was more common among Swedish men who developed malignant melanoma than in nonusers of the erectile-dysfunction drugs, researchers report (pp. 2449–55). “However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal,” the group concludes. Using the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other databases, the authors find: “Of 4,065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1,713 men of 20,325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls).” (S. Loeb)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 25, 2015 * Vol. 22, No. 121
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: June 25 issue of the New England Journal of Medicine (2015; 372).
Pembrolizumab in Metastatic Carcinoma: Mismatch-repair status of tumors predicted clinical benefits of use of an anti–programmed death 1 immune checkpoint inhibitor in a Phase II study of 41 patients (pp. 2509–20). I.V. pembrolizumab 10 mg/kg every 14 days was administered to patients with mismatch repair–deficient colorectal cancers, mismatch repair–proficient colorectal cancers, or mismatch repair–deficient cancers that were not colorectal, with these results: “The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P <0.001], and hazard ratio for death, 0.22 [P = 0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1,782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P = 0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P = 0.02).” (L. A. Diaz, Jr., ldiaz1@jhmi.edu)
Pembrolizumab in Advanced Melanoma: Compared with ipilimumab in 834 patients with advanced melanoma in a Phase III study, pembrolizumab prolonged progression-free survival and overall survival and produced less high-grade toxicity, researchers report (pp. 2521–32). Pembrolizumab 10 mg/kg every 2 or 3 weeks or four doses of ipilimumab 3 mg/kg every 3 weeks produced these changes: “The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P <0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P <0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).” (C. Robert, caroline.robert@gustaveroussy.fr)
21st Century Cures Act: If enacted into law, the 21st Century Cures Act could “take us back in time” with regard to the evidence needed for FDA drug approvals, according to authors of a Perspective article (pp. 2473–5). “Embedded in the language of the 21st Century Cures Act are some good ideas that could streamline the development and evaluation of new drugs and devices; its call for increased NIH funding may prove to be its most useful component,” the authors write. But by instructing “FDA to consider nontraditional study designs and methods of data analysis to further speed approvals,” the bill could have unintended adverse impact: “Over the past 80 years, this country’s regulatory approach has embraced steadily improving criteria for accurately assessing therapeutic efficacy and risk. Patients and physicians would not benefit from legislation that instead of catapulting us into the future, could actually bring back some of the problems we thought we had left behind in the 20th century.” (J. Avorn)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 26, 2015 * Vol. 22, No. 122
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source: July issue of Diabetes Care (2015; 38).
Sotagliflozin in Type 1 Diabetes: Given as an adjunct to insulin in a placebo-controlled study of 33 patients with type 1 diabetes, the dual sodium–glucose cotransporter (SGLT) 1 and SGLT2 inhibitor sotagliflozin “improved glycemic control and [the continuous glucose monitoring (CGM)] profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes,” a study shows (pp. 1181–8): “In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by … CGM of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70–180 mg/dL (3.9–10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group.” (A. T. Sands, arthur.sands@bcm.edu)
Ranolazine Monotherapy in Type 2 Diabetes: The antianginal drug ranolazine improves glycemic parameters in patients with poorly controlled type 2 diabetes, researchers report (pp. 1189–96). Among 465 participants in a multicountry study, baseline glycosylated hemoglobin was 7%–10% and fasting serum glucose levels were 130–240 mg/dL. Randomization to ranolazine or placebo produced these changes in study end points: “Compared with placebo, there was a greater decline in HbA1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA1c <7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated.” (R. H. Eckel, robert.eckel@ucdenver.edu)
Dapagliflozin in Type 2 Diabetes: Compared with placebo in 922 patients with type 2 diabetes, the selective sodium–glucose cotransporter 2 inhibitor dapagliflozin produced significantly improved glycosylated hemoglobin, body weight (BW), and systolic blood pressure (SBP) (pp. 1218–27). During 24 weeks of drug/placebo administration and 28 weeks of follow-up, these changes were noted in co-primary end points of a change from baseline inHbA1c and the proportion of patients achieving a combined reduction in HbA1c of ≥0.5%, BW of ≥3%, and SBP of ≥3 mm Hg: “At 24 weeks, dapagliflozin significantly reduced HbA1c (−0.38% [−4.2 mmol/mol]) from baseline (8.18%) compared with a slight increase with placebo from baseline (8.08%) (0.08% [0.9 mmol/mol]). Significantly more patients met the three-item end point with treatment with dapagliflozin than with placebo (11.7% vs. 0.9%, respectively). Changes were maintained over 52 weeks. Although ~42% of patients were ≥65 years old, similar results were observed in both age-stratified groups. Serious adverse events, hypoglycemia, urinary tract infections, and cardiac disorders were similar between groups. Adverse events of hypotension, dehydration, hypovolemia, genital infection, and renal failure or impairment occurred more often with dapagliflozin treatment.” (W. T. Cefalu, william.cefalu@pbrc.edu)

>>>PNN NewsWatch
* “APhA and our nation’s more than 300,000 pharmacists are committed to finding ways to increase patient access to quality care and improve their health outcomes,” APhA CEO Thomas E. Menighan said in reaction to yesterday’s Supreme Court ruling on the Affordable Care Act, according to a news story posted on pharmacist.com.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 29, 2015 * Vol. 22, No. 123
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: June 27 issue of Lancet (2015; 385).
Reduced Adverse Effects With Tenofovir Alafenamide: Compared with tenofovir disoproxil fumarate in highly active antiretroviral regimens, the novel prodrug tenofovir alafenamide produced similar virologic results and significantly reduced renal and bone effects, researchers report (pp. 2606–15). In two Phase III studies, participants received once-daily oral tablets containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (E/C/F/tenofovir alafenamide) or tenofovir disoproxil fumarate 300 mg (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Results were as follows based on main outcomes of proportion of patients with plasma HIV-1 RNA less than 50 copies/mL at week 48 (with a prespecified noninferiority margin of 12%) and prespecified renal and bone endpoints at 48 weeks: “We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2,175 screened and 1,744 randomly assigned), and gave treatment to 1,733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2.0%, 95% CI −0.7 to 4.7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0.08 vs 0.12 mg/dL; p <0.0001), significantly less proteinuria (median % change −3 vs 20; p <0.0001), and a significantly smaller decrease in bone mineral density at spine (mean % change −1.30 vs –2.86; p <0.0001) and hip (−0.66 vs –2.95; p <0.0001) at 48 weeks.” (P. E. Sax, psax@partners.org)

>>>BMJ Highlights
Source: Early-release article from BMJ (2015; 350).
Risks to Healthy Volunteers in Phase I Nononcology Trials: Serious adverse events are rare in Phase I trials of nononcology investigational drugs, according to results of a meta-analysis of individual-level data (h3271). A total of 11,028 participants were included in the analysis of 394 distinct nononcology Phase I trials conducted at Pfizer’s three dedicated Phase I testing sites in Belgium, Singapore, and the U.S.; 2,460 of 4,620 participants were included in only one trial, while the remainder participated in multiple trials. As defined by FDA, serious adverse events were those resulting in death, a life-threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. Results showed: “Overall, 4,000 (36.3%) participants who received the study drug experienced no adverse events and 7,028 (63.7%) experienced 24,643 adverse events. Overall, 84.6% (n = 20,840) of adverse events were mild and 1.0% (n = 255) were severe. 34 (0.31%) serious adverse events occurred among the 11,028 participants who received the study agent, with no deaths or life threatening events. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, whereas 16 were unrelated to a study drug or procedure, including four that occurred when the participant was receiving a placebo. Overall, 24.1% (n = 5,947) of adverse events were deemed to be unrelated to the study drug. With a total of 143 (36%) studies involving placebo, 10.3% (n = 2,528) of all adverse events occurred among participants receiving placebo. The most common adverse events were headache (12.2%, n = 3,017), drowsiness (9.8%, n = 2,410), and diarrhea (6.9%, n = 1,698). Research on drugs for neuropsychiatric indications had the highest frequency of adverse events (3,015 per 1,000 participants).” (E. J. Emanuel, vp-global@upenn.edu)

>>>PNN JournalWatch
* Diabetes Self-management Education and Support in Type 2 Diabetes: A Joint Position Statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics, in Diabetes Care, 2015; 38: 1372–82. (M. A. Powers, margaret.powers@parknicollet.com)
* International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease, in Arthritis & Rheumatology, 2015; 67: 1688–99. (T. Chiba, chiba@kuhp.kyoto-u.ac.jp)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.


PNN Pharmacotherapy Line
June 30, 2015 * Vol. 22, No. 124
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source: July issue of the American Journal of Kidney Diseases (2015; 66).
Mortality With Hematopoietic Agents: The long-term safety of epoetin alfa (EPO) and darbepoetin alfa (DPO) requires study using either adequately powered randomized trials or observational postmarketing comparative effectiveness studies, conclude authors of a systematic review and meta-analysis (pp. 69–74). Looking for trials of these agents lasting 3 months or more, the investigators found: “We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic = 4.60; P = 0.8).” The group concluded, “Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO.” (W. C. Winkelmayer, winkelma@bcm.edu)
Rivaroxaban in Patients on Hemodialysis: In 18 patients on maintenance hemodialysis without residual kidney function, a 10-mg dose of rivaroxaban yielded pharmacodynamic and pharmacokinetic effects similar to those of 20-mg doses reported previously in healthy volunteers (pp. 91–8). Researchers also found that rivaroxaban was not removed by hemodialysis and that no accumulation occurred with multiple daily doses. Concluding that a large randomized trial is needed to confirm these findings, the authors report these results for rivaroxaban 10 mg dosed at the end of each of three consecutive dialysis sessions: “Mean AUC0–44 of rivaroxaban plasma concentrations after a single dose of 10 mg was 2,072 µg/L/h, mean maximum concentration was 172.6 µg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10 mg was 20.2 µg/L.” (A. S. De Vriese, an.devriese@azsintjan.be)
I.V. Solutions for Volume Depletion & Electrolyte Abnormalities: A teaching case provides this summary of the use of I.V. solutions in the care of patients with volume depletion and electrolyte abnormalities (pp. 147–53): “Infusion fluids are often given to restore blood pressure (volume resuscitation), but may also be administered to replace ongoing losses, match insensible losses, correct electrolyte or acid-base disorders, or provide glucose. The development of new infusion fluids has provided clinicians with a wide range of products. Although the choice for a certain infusion fluid is often driven more by habit than by careful consideration, we believe it is useful to approach infusion fluids as drugs and consider their pharmacokinetic and pharmacodynamic characteristics. This approach not only explains why infusion fluids may cause electrolyte and acid–base disturbances, but also why they may compromise kidney function or coagulation. In this teaching case, we present a 19-year-old patient in whom severe hypernatremia developed as a result of normal saline solution infusion and explore the pharmacokinetic and pharmacodynamic effects of frequently used infusion fluids. We review clinical evidence to guide the selection of the optimal infusion fluid.” (D. Severs, d.severs@erasmusmc.nl)

>>>PNN NewsWatch
* The U.S. Supreme Court yesterday upheld the use of midazolam as a substitute for pentobarbital in lethal injection, according to a report on pharmacist.com. The need for an alternative arose based on the unavailability of the barbiturate for this purpose. An amicus brief filed by pharmacologists explained “why midazolam cannot induce unconsciousness at any dose, and why it is not an appropriate substitute for either thiopental or pentobarbital as the first drug in a three-drug lethal injection protocol.” In a 5–4 decision, the majority of the Court disagreed, ruling that midazolam sufficiently avoids the possibility for pain from the second and third drugs used in the procedure and therefore does not violate the Eighth Amendment’s proscription against cruel and unusual punishment.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2015, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.