Sep 2015

PNN July–September 2015

PNN Pharmacotherapy Line
July 1, 2015 * Vol. 22, No. 125
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
July issue of Pediatrics (2015; 136).
Guideline Adherence in Pneumonia Care: Antibiotics used for children with community-acquired pneumonia (CAP) changed in appropriate ways following dissemination of new national guidelines in 2011, a study shows, with less third-generation cephalosporin use and more penicillin/ampicillin (pp. 44–52). The report is based on data from three U.S. children’s hospitals for 2010–12. Antibiotic prescribing before and after the guidelines were published was as follows: “Overall, 2,121 children were included. During the preguideline period, 52.8% (interquartile range 47.8–56.6) of children with CAP received third-generation cephalosporins, whereas 2.7% (2.1, 7.0) received penicillin/ampicillin. By 9 months postguidelines, third-generation cephalosporin use declined (absolute difference −12.4% [95% confidence interval −19.8% to −5.1%]), whereas penicillin/ampicillin use increased (absolute difference 11.3% [4.3%–18.3%]). The most substantial changes were noted at those institutions that implemented guideline-related dissemination activities.” (D. J. Williams)
Mycophenolate in Refractory Nephrotic Syndrome: Based on a study of 24 children with steroid-resistant nephrotic syndrome, mycophenolate mofetil “may be an effective and safe maintenance therapy to consider as an additive immunosuppressant after induction with rituximab in maintaining remission,” researchers report (e132–9; B. Basu).

>>>Psychiatry Report
Source:
July issue of the American Journal of Psychiatry (2015; 172).
Predicting Improvement With Antipsychotics Based on Early Response: “Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change,” conclude authors of a review article (pp. 617–29). Using a main outcome of prediction of nonresponse—defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4–12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2—the investigators report these results from evaluations of available studies: “In 34 studies (N = 9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity = 86%, PPV=85%) or lack of remission (specificity = 77%, PPV = 88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity = 70%, PPV = 55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration.” (M. T. Samara)
Genetics & Anxiety: Environment plays a bigger role in “transmission” of anxiety disorders from parents to children than do genes, a study of twins shows (pp. 630–7). “No evidence of significant genetic transmission” was found among 385 monozygotic and 486 dizygotic same-sex twin families, the authors report. They reach this conclusion: “The association between parental and offspring anxiety largely arises because of a direct association between parents and their children independent of genetic confounds. The lack of genetic transmission may reflect there being different genetic effects on these traits in adolescence and adulthood. Direct environmental transmission is in line with developmental theories of anxiety suggesting that children and adolescents learn anxious behaviors from their parents through a number of pathways such as modeling. Future analyses should combine children-of-twins data with child twin data in order to examine whether this direct effect solely represents parental influences on the offspring or whether it also includes child/adolescent anxiety evoking parental anxiety.” (T. C. Eley)

>>>PNN NewsWatch
* FDA yesterday extended the deadline for drug dispensers’ compliance with track-and-trace requirements to Nov. 1 of this year, pharmacist.com reports. Several pharmacy groups had recently told the agency that the July 1 deadline would result in disruptions in the pharmaceutical supply chain.

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
July 2, 2015 * Vol. 22, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 2 issue of the New England Journal of Medicine (2015; 373).
Liraglutide in Weight Management: In a 56-week, double-blind trial of 3,731 patients without diabetes, subcutaneous liraglutide 3 mg administered weekly reduced body weight and improved metabolic control, researchers report (pp. 11–22). Used as an adjunct to diet and exercise in patients with BMIs of 30 kg/sq m (or 27 if they also had dyslipidemia or hypertension), liraglutide produced these changes body weight and weight loss in comparison with placebo: “At baseline, the mean (± SD) age of the patients was 45.1 ± 12.0 years, the mean weight was 106.2 ± 21.4 kg, and the mean BMI was 38.3 ± 6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4 ± 7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8 ± 6.5 kg (a difference of −5.6 kg; 95% confidence interval, −6.0 to −5.1; P <0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P <0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P <0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group.” (X. Pi-Sunyer, fxp1@cumc.columbia.edu)
This study shows that liraglutide may make modest weight loss easier to achieve, editorialists write (
pp. 82–3). The results need to be confirmed in longer-term studies, the pair note: “Given previous disappointments with various weight-loss strategies, these are welcome findings. Still, liraglutide is no cure. Most obese participants stayed obese, reversal of the metabolic syndrome was not quantified, and liraglutide may be required indefinitely, like statins, but with delivery by injection and at a nontrivial cost.” (E. S. Siraj)
Nivolumab/Ipilimumab in Untreated Melanoma: Nivolumab alone or combined with ipilimumab significantly increased progression-free survival in patients with untreated metastatic melanoma, compared with ipilimumab alone, a study shows (pp. 23–4). Participants (n = 945) had unresectable stage III or IV melanoma. Based on coprimary end points of progression-free and overall survival, results for monotherapy and combination therapy showed: “The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P <0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P <0.001). In patients with tumors positive for the [programmed death]-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.” (S. Hodi, stephen_hodi@dfci.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday announced enforcement actions against companies that manufacture and/or distribute certain unapproved otic products labeled to relieve ear pain, infection, and inflammation. The products typically contain benzocaine, hydrocortisone, antipyrine, zinc acetate, chloroxylenol, or pramoxine. The agency said it is notifying companies to stop marketing 16 unapproved prescription drugs.
* A federal judge has entered a consent decree of permanent injunction between the U.S. and
Acino Products and the company’s president for marketing unapproved and misbranded prescription drugs, FDA said yesterday.
*
PNN will not be published on Fri., July 3, Independence Day (celebrated).

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
July 6, 2015 * Vol. 22, No. 127
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 4 issue of Lancet (2015; 386).
Cognitive v. Antidepressant Therapy in Depression: As an alternative to drug therapy, mindfulness-based cognitive therapy (MBCT) is not superior to maintenance antidepressant therapy, researchers report, but both interventions improve relapse or recurrence, residual depressive symptoms, and quality of life (pp. 63–73). In the PREVENT trial, adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants at U.K. private practices were randomized to nonblinded MBCT-TS or maintenance antidepressants, with these effects on time to relapse or recurrence of depression over a 24-month period: “Between March 23, 2010, and Oct 21, 2011, we assessed 2,188 participants for eligibility and recruited 424 patients from 95 general practices. 212 patients were randomly assigned to MBCT-TS and 212 to maintenance antidepressants. The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months (hazard ratio 0.89, 95% CI 0.67–1.18; p = 0.43), nor did the number of serious adverse events. Five adverse events were reported, including two deaths, in each of the MBCT-TS and maintenance antidepressants groups. No adverse events were attributable to the interventions or the trial.” (W. Kuyken, willem.kuyken@psych.ox.ac.uk)
Malaria Vaccine in Pediatrics: In a Phase III trial of the RTS,S/AS01 candidate malaria vaccine, a “substantial number of cases of clinical malaria [were prevented] over a 3–4 year period in young infants and children” when the product was administered with or without a booster dose (pp. 31–45). Previously studied for 18 months, the vaccine produced these longer-term vaccine efficacy (VE) and serious adverse event (SAE) figures in 8,922 children and 6,537 young infants followed for a median of 48 and 38 months, respectively, following dose 1: “From month 0 until study end, compared with 9,585 episodes of clinical malaria that met the primary case definition in children in the [control] C3C group, 6,616 episodes occurred in the [booster] R3R group (VE 36.3%, 95% CI 31.8–40.5) and 7,396 occurred in the [nonbooster] R3C group (28.3%, 23.3–32.9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32.2%, 13.7 to 46.9) and 169 in the R3C group (1.1%, −23.0 to 20.5). In young infants, compared with 6,170 episodes of clinical malaria that met the primary case definition in the C3C group, 4,993 episodes occurred in the R3R group (VE 25.9%, 95% CI 19.9–31.5) and 5,444 occurred in the R3C group (18.3%, 11.7–24.4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17.3%, 95% CI −9.4 to 37.5) and 104 in the R3C group (10.3%, −17.9 to 31.8). In children, 1,774 cases of clinical malaria were averted per 1,000 children (95% CI 1387–2186) in the R3R group and 1,363 per 1,000 children (995–1797) in the R3C group. The numbers of cases averted per 1,000 young infants were 983 (95% CI 592–1337) in the R3R group and 558 (158–926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2.2 per 1,000 doses in young infants and 2.5 per 1,000 doses in children.” (RTS,S Clinical Trials Partnership)

>>>PNN NewsWatch
* FDA has approved lumacaftor 200 mg/ivacaftor 125 mg (Orkambi, Vertex) for treatment of cystic fibrosis in patients aged 12 years or older who have the F508del mutation in the CFTR gene. In clinical trials, lung function was significantly improved with the orphan drug.

>>>PNN JournalWatch
* Systematic Review on Intensive Interdisciplinary Pain Treatment of Children With Chronic Pain, in
Pediatrics, 2015; 136: 115–27. (T. Hechler)
* Distinguishing Adolescents With ADHD From Their Unaffected Siblings and Healthy Comparison Subjects by Neural Activation Patterns During Response Inhibition, in
American Journal of Psychiatry, 2015; 172: 674–83. (D. van Rooij)

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
July 7, 2015 * Vol. 22, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 7 issue of the Annals of Internal Medicine (2015; 163).
PCSK9 Antibodies in Dyslipidemias: Used in adults with elevated lipid levels, proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies “seem to be safe and effective,” authors of a review article conclude (pp. 40–51). Focusing on 24 randomized controlled Phase II and III trials of 10,159 participants, the authors found: “Compared with no antibody, treatment with PCSK9 antibodies led to marked reductions in low-density lipoprotein cholesterol levels (mean difference, −47.49% [95% CI, −69.64% to −25.35%]; P < 0.001] and other atherogenic lipid fractions, and it reduced all-cause mortality (odds ratio [OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%). The rate of myocardial infarction was significantly reduced with use of PCSK9 antibodies (OR, 0.49 [CI, 0.26 to 0.93]; P = 0.030; heterogeneity P = 0.45; I2 = 0%), and increases in the serum creatine kinase level were reduced (OR, 0.72 [CI, 0.54 to 0.96]; P = 0.026; heterogeneity P = 0.65; I2 = 0%). Serious adverse events did not increase with administration of PCSK9 antibodies.” (E. P. Navarese, eliano.navarese@med.uni-duesseldorf.de)
Asking whether the new agents will usher in “a new era in lipid-lowering treatment,” editorialists write (
pp. 64–5): “The current 2013 American College of Cardiology/American Heart Association cholesterol guideline focuses largely on statin therapy and does not establish specific treatment goals. If the efficacy and safety profile of PCSK9 inhibitors is confirmed in long-term trials with a larger number of clinical events and if costs are not prohibitive, clinicians will be able to add PCSK9 inhibitors or ezetimibe to statin therapy and achieve additional LDL cholesterol reductions. Furthermore, with multiple evidence-based safe therapeutic options, it will be critical to establish the optimal sequence and combination of drugs as well as the LDL cholesterol goals that minimize long-term risk in different patient populations. Studies assessing CVD outcomes and cost-effectiveness of different lipid-lowering strategies in populations at different risks for CVD will provide answers to these questions.” (E. Guallar, eguallar@jhu.edu)
Timing of Antiretroviral Therapy Initiation: Survival figures from clinical trials support early antiretroviral therapy (ART) during tuberculosis (TB) treatment in those with low CD4+ T-cell counts, according to a review article, but with increased incidence of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) (pp. 32–9): “The 8 included trials (n = 4,568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I2 = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4+ T-cell counts less than 0.050 × 109 cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I2 = 0%). However, a mortality benefit from early ART was not found among those with CD4+ T-cell counts greater than 0.050 × 109 cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I2 = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I2 = 19%).” (O. A. Uthman, lalekan.uthman@warwick.ac.uk">olalekan.uthman@warwick.ac.uk)
Grazoprevir–Elbasvir for HCV Infections: In 421 treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection, the NS3/4A inhibitor grazoprevir and the NS5A inhibitor elbasvir produced high rates of sustained virologic response at week 12 of therapy (SVR12), a study shows (pp. 1–13). Used in an oral once-daily, fixed-dose combination, grazoprevir 100 mg/elbasvir 50 mg produced these results with immediate or deferred therapy: “Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, −5.4 to 3.1 percentage points]); none were considered drug related….” (S. Zeuzem, zeuzem@em.uni-frankfurt.de)

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


PNN Pharmacotherapy Line
July 8, 2015 * Vol. 22, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 7 issue of JAMA (2015; 314).
Duration of Anticoagulation After Pulmonary Embolism: In patients with a first episode of unprovoked pulmonary embolism, adding 12 months of anticoagulant treatment to an initial 6 months of therapy lowered rates of recurrent venous thrombosis, researchers report, and major bleeding occurred in only 4 of nearly 200 patients on active drug (pp. 31–40). Benefits did not continue after the end of the study, which was conducted at 14 French centers. Based on a composite of recurrent venous thromboembolism or major bleeding, the investigators report: “After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09–0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05–0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups.” (F. Couturaud, francis.couturaud@chu-brest.fr)
Duration of Anticoagulation for Symptomatic Venous Thromboembolism: Vitamin K antagonists (VKAs) administered for more than 3 months produce additional clinical benefits in patients with symptomatic venous thromboembolism (VTE), compared with short-term therapy, but major bleeding rates are increased and mortality is unchanged (pp. 72–3). Authors of a JAMA Clinical Evidence Symposium add these details about the optimal duration of VKA therapy in this patient population: “Long-term VKA therapy was associated with lower rates of thromboembolic events compared with short-term VKA therapy (30 of 1,771 patients [1.7%] for long-term therapy vs 155 of 1,765 patients [8.8%] for short-term therapy; relative risk [RR], 0.20 [95% CI, 0.11–0.38]).…
“Long-term VKA therapy was associated with a higher rate of major bleedings compared with patients with short-term VKA therapy (14 of 675 patients [2.1%] for long-term therapy vs 3 of 675 patients [0.4%] for short-term therapy; RR, 3.44 [95% CI, 1.22–9.74]). Long-term VKA therapy was not associated with reduced mortality compared with short-term VKA therapy (75 of 1,753 patients [4.3%] for long-term therapy vs 83 of 1,749 patients [4.7%] for short-term therapy; RR, 0.89 [95% CI, 0.66–1.21]).” (B. A. Hutten,
b.a.hutten@amc.uva.nl)
Ideology & Needle-Exchange Programs: Politics and ideology are complicating efforts to reduce HIV transmission by establishing and funding needle and syringe exchange programs (NSEPs), according to authors of a Viewpoint article (pp. 23–4). Citing “lessons from the Indiana HIV outbreak,” the authors discuss the conflict between the view of NSEPs as interfering with the “war on drugs” and the need to address HIV epidemics as public health emergencies. (J. D. Rich)

>>>PNN NewsWatch
* Acting 6 weeks before its review action date, FDA yesterday approved sacubitril/valsartan (Entresto, Novartis) for reducing the risk of cardiovascular death and heart failure hospitalization in patients with NYHA Class II–IV heart failure (reduced ejection fraction). Approval was based on results from the 8,442-patient PARADIGM-HF study, which was stopped early when it was shown sacubitril/valsartan significantly reduced the risk of cardiovascular death versus enalapril. Compared with enalapril, patients with reduced ejection fraction who were given sacubitril/valsartan had higher survival rates and lower rates of hospitalization for heart failure. Analysis of safety data showed that sacubitril/valsartan had a similar tolerability profile to enalapril. The most common adverse effects of the product have been hypotension, hyperkalemia, and renal impairment.

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
July 9, 2015 * Vol. 22, No. 130
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 9 issue of the New England Journal of Medicine (2015; 373).
Nivolumab in Advanced Squamous-Cell Non–Small-Cell Lung Cancer: Nivolumab outperformed docetaxel in patients with advanced squamous-cell non–small-cell lung cancer (NSCLC), and study results held regardless of the programmed death 1 (PD-1) ligand status of the tumor, report researchers (pp. 123–35). Nivolumab, a fully human IgG4 PD-1 immune-checkpoint–inhibitor antibody, or docetaxel was administered to 272 participants, with these effects on a primary end point of overall survival: “The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P <0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P <0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.” (J. Brahmer, brahmju@jhmi.edu)
Guselkumab for Plaque Psoriasis: Guselkumab (CNTO 1959), an anti–interleukin-23 monoclonal antibody, achieved control of plaque psoriasis in a Phase II trial of 293 patients, a study shows (pp. 136–44). Using a dose-ranging design and a primary end point of proportion of patients with a Physician’s Global Assessment (PGA) score of 0 (cleared psoriasis) or 1 (minimal psoriasis) at week 16, investigators identified these results with guselkumab or adalimumab: “At week 16, the proportion of patients with a PGA score of 0 or 1 was significantly higher in each guselkumab group than in the placebo group: 34% in the 5-mg group, 61% in the 15-mg group, 79% in the 50-mg group, 86% in the 100-mg group, and 83% in the 200-mg group, as compared with 7% in the placebo group (P ≤0.002 for all comparisons). Moreover, the proportion was significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (58%) (P <0.05 for all comparisons). At week 16, the proportion of patients with at least a 75% improvement in Psoriasis Area and Severity Index scores was significantly higher in each guselkumab group than in the placebo group (P <0.001 for all comparisons). At week 40, the proportion of patients with a PGA score of 0 or 1 remained significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (71%, 77%, and 81%, respectively, vs. 49%) (P <0.05 for all comparisons). Between week 0 and week 16, infections were observed in 20% of the patients in the guselkumab groups, 12% in the adalimumab group, and 14% in the placebo group.” (K. Reich, kreich@dermatologikum.de)
Synthetic Cannabinoid Morbidity & Mortality: Estimating the scope of adverse effects associated with use of synthetic cannabinoids (SCs) is difficult because of “underreporting by clinicians and public health practitioners, limited availability of laboratory testing to confirm exposures, delays in the availability of analytical laboratory standards for the newest compounds, and frequent product changes,” authors of a Perspective article write (pp. 103–7). “To address these challenges, clusters of adverse health effects potentially related to SC-product use can be reported to either local poison centers or local public health departments. Cases of severe SC intoxication, unusual toxic effects, death, or multiple patients presenting with SC intoxication clustered in time and space may reflect the appearance of a novel SC compound or toxicity of a contaminated or poorly manufactured product; rapid identification of these events will allow public health officials to better support local practitioners. Collaboration between forensic and toxicology laboratories and legitimate suppliers of analytical standards may result in better preparation and a more timely response to future outbreaks. Increased recognition and reporting by clinicians and public health personnel may aid federal and state regulatory efforts in combating this ongoing SC epidemic.” (J. Trecki)

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
July 10, 2015 * Vol. 22, No. 131
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
July 7 issue of Circulation (2015; 132).
Cinacalcet in Hemodialysis: In a secondary analysis of data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, investigators found that treatment with cinacalcet significantly lowered serum fibroblast growth factor-23 (FGF23) concentrations and that this was associated with lower rates of cardiovascular death and major cardiovascular events (pp. 27–39). The trial compared cinacalcet, a calimimetic agent, with placebo in patients who were also receiving standard therapy with phosphate binders and vitamin D. Results showed: “This analysis included 2,985 patients (77% of randomized) with serum samples at baseline and 2,602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69–0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50–0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37–0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48–0.99).” (S. M. Moe, smoe@iupui.edu)
Clopidogrel–Aspirin After Stroke: Patients with minor stroke or high-risk transient ischemic attacks benefited from 90 days of therapy with clopidogrel plus aspirin for up to 1 year after treatment, researchers report (pp. 40–6). The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial, conducted at 114 centers in China, included 5,170 patients who received drug treatment within 24 hours of symptoms. Participants received clopidogrel for 90 days plus aspirin for the first 21 days or aspirin only for 90 days, with these results: “The primary outcome was stroke event (ischemic or hemorrhagic) during 1-year follow-up. Differences in outcomes between groups were assessed by using the Cox proportional hazards model. Stroke occurred in 275 (10.6%) patients in the clopidogrel–aspirin group, in comparison with 362 (14.0%) patients in the aspirin group (hazard ratio, 0.78; 95% confidence interval, 0.65–0.93; P = 0.006). Moderate or severe hemorrhage occurred in 7 (0.3%) patients in the clopidogrel–aspirin group and in 9 (0.4%) patients in the aspirin group (P = 0.44).” (Y. Wang, yongjunwang1962@gmail.com)

>>>Cardiology Highlights
Source:
July 14 issue of the Journal of the American College of Cardiology (2015; 66).
Lipid-Lowering Therapy After ACS: “Durable strategies to address gaps in lipid lowering for secondary prevention are essential to maximize reduction in cardiovascular disease risk,” write authors of a review article on use of guidelines in managing lipid-lowering therapy after acute coronary syndromes (pp. 184–92). The article assesses health system factors, provider behaviors, and patient factors involved in adherence to guideline-recommended therapies, concluding: “In addition to aggressive lifestyle and nonlipid risk factor modification, statin therapy improves cardiovascular disease outcomes following acute coronary syndromes. Despite established benefits of treatment, contemporary registries reveal substantial underutilization of and nonadherence to statin therapy for secondary prevention. In randomized controlled trials investigating statin therapy, including moderate-intensity statin plus ezetimibe therapy, rates of nonadherence are reported in up to 40% of subjects.” (B. J. Hirsh)

>>>PNN NewsWatch
* FDA yesterday said it is strengthening an existing label warning that nonaspirin NSAIDs increase the chance of a heart attack or stroke. OTC NSAIDs already carry the warning; it will now be revised for prescription products to include information about onset (as early as the first weeks of use), dose (greater risk with higher doses), differences between agents (risks differ with the agents but not sufficiently so that FDA can determine which drugs are safer), and differences between patients (those with heart disease or risk factors have greater likelihood of heart attack or stroke).

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
July 13, 2015 * Vol. 22, No. 132
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2015; 351).
SSRIs & Birth Defects: While providing “reassuring evidence for some SSRIs,” authors report that “some birth defects occur 2–3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy” (h3190). Using an expanded dataset from the National Birth Defects Prevention Study, the group analyzed outcomes for 17,952 mothers of infants with birth defects and 9,857 mothers of infants without birth defects, with these drug-specific results for SSRIs used in the month before through the third month of pregnancy: “Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0).” (J. Reefhuis, NZR5@cdc.gov)
Symptom Checkers for Self Diagnosis: Used for triage or diagnosis, online symptom checkers had deficits, researchers report (h3480). “Triage advice from symptom checkers is generally risk averse, encouraging users to seek care for conditions where self care is reasonable,” the group concludes based on these data for 45 patient vignettes used to test the systems: “The 23 symptom checkers provided the correct diagnosis first in 34% (95% confidence interval 31% to 37%) of standardized patient evaluations, listed the correct diagnosis within the top 20 diagnoses given in 58% (55% to 62%) of standardized patient evaluations, and provided the appropriate triage advice in 57% (52% to 61%) of standardized patient evaluations. Triage performance varied by urgency of condition, with appropriate triage advice provided in 80% (95% confidence interval 75% to 86%) of emergent cases, 55% (47% to 63%) of non-emergent cases, and 33% (26% to 40%) of self care cases (P <0.001). Performance on appropriate triage advice across the 23 individual symptom checkers ranged from 33% (95% confidence interval 19% to 48%) to 78% (64% to 91%) of standardized patient evaluations.” (A. Mehrotra, mehrotra@hcp.med.harvard.edu)

>>>Lancet Highlights
Source:
July 11 issue of Lancet (2015; 386).
50-Year Trends in AF: Enhanced surveillance may explain an upswing in diagnoses of atrial fibrillation over the past 50 years, according to an analysis of Framingham data for 9,511 participants (pp. 154–62): “During 50 years of observation (202,417 person–years), 1,544 cases of new-onset atrial fibrillation occurred (of whom 723 [47%] were women). Between 1958–67 and 1998–2007, age-adjusted prevalence of atrial fibrillation quadrupled from 20.4 to 96.2 cases per 1,000 person–years in men and from 13.7 to 49.4 cases per 1,000 person–years in women; age-adjusted incidence increased from 3.7 to 13.4 new cases per 1,000 person–years in men and from 2.5 to 8.6 new cases per 1,000 person–years in women (ptrend <0.0001 for all comparisons). For atrial fibrillation diagnosed by electrocardiograph (ECG) during routine Framingham examinations, age-adjusted prevalence per 1,000 person–years increased (12.6 in 1958–67 to 25.7 in 1998–2007 in men, ptrend = 0.0007; 8.1 to 11.8 in women, ptrend = 0.009). However, age-adjusted incidence of atrial fibrillation by Framingham Heart Study ECGs did not change significantly with time. Although the prevalence of most risk factors changed over time, their associated hazards for atrial fibrillation changed little.…” (R. B Schnabel, r.schnabel@uke.de)

>>>PNN JournalWatch
* Economic Evaluation of Bevacizumab for the First-Line Treatment of Newly Diagnosed Glioblastoma Multiforme, in
Journal of Clinical Oncology, 2015; 33: 2296–302. (F. Xie, fengxie@mcmaster.ca)
* In Utero Exposure to Zidovudine and Heart Anomalies in the ANRS French Perinatal Cohort and the Nested PRIMEVA Randomized Trial, in
Clinical Infectious Diseases, 2015; 61: 270–80. (J. Sibiude, jeannesibiude@yahoo.fr)

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
July 14, 2015 * Vol. 22, No. 133
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July issue of JAMA Internal Medicine (2015; 175).
Antimicrobial Stewardship & Urinary Catheter–Associated Asymptomatic Bacteriuria: In VA health systems in 2010–13, stewardship efforts helped reduced inappropriate use of urinary catheters for asymptomatic bacteriuria (ASB), researchers report, with effects most pronounced in long-term care settings (pp. 1120–7). On acute medicine wards and long-term care units, primary outcomes were urine cultures ordered per 1,000 bed–days and cases of ASB receiving antibiotics during intervention and maintenance periods compared with baseline. Results showed: “The overall rate of urine culture ordering decreased significantly during the intervention period (from 41.2 to 23.3 per 1,000 bed–days; incidence rate ratio [IRR], 0.57; 95% CI, 0.53–0.61) and further during the maintenance period (to 12.0 per 1,000 bed–days; IRR, 0.29; 95% CI, 0.26–0.32) (P < .001 for both). At the comparison site, urine cultures ordered did not change significantly across all 3 periods. There was a significant difference in the number of urine cultures ordered per month over time when comparing the 2 sites using longitudinal linear regression (P < .001). Overtreatment of ASB at the intervention site fell significantly during the intervention period (from 1.6 to 0.6 per 1,000 bed–days; IRR, 0.35; 95% CI, 0.22–0.55), and these reductions persisted during the maintenance period (to 0.4 per 1,000 bed–days; IRR, 0.24; 95% CI, 0.13–0.42) (P < .001 for both). Overtreatment of ASB at the comparison site was similar across all periods (odds ratio, 1.32; 95% CI, 0.69–2.52). When analyzed by type of ward, the decrease in ASB overtreatment was significant in long-term care. (B. W. Trautner, trautner@bcm.edu)
Elimination of reimbursement by CMS for catheter-associated urinary tract infection (CAUTI) has prompted health facilities to emphasize stewardship efforts, an editorialist writes (
pp. 1127–9). The intervention described in this article “provides one additional method to potentially reduce CAUTI rates. It can be adapted to determine if it is effective in individual institutions. Based on the findings of the study by Trautner and colleagues, this intervention would seem to be most effective in acute care facilities with hospitalist services or long-term care facilities with high rates of urine culture ordering, high rates of ASB treatment at baseline, and established clinicians who can be trained to use the algorithm. As audit and feedback have been successfully incorporated into antimicrobial stewardship programs, this algorithm for inappropriate urine culture ordering can be built into existing stewardship and infection control programs. In doing so, there is the potential to further reduce urine cultures ordered, reduce rates of CAUTI, reduce inappropriate antimicrobial use, and improve care of patients. Despite the difficulties involved with changing clinicians’ behaviors, there is hope that they can be trained not to order urine cultures when they are not indicated.” (M. Juthani-Mehta)
Costs & CFC Ban: Out-of-pocket costs for albuterol inhalers increased greatly following the ban on chlorofluorocarbon (CFC) inhalers at the end of 2008, and this has been associated with decreases in utilization, a study shows (pp. 1171–9; A. B. Jena, jena@hcp.med.harvard.edu).

>>>PNN NewsWatch
* FDA yesterday approved gefitinib (Iressa, AstraZeneca) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by an FDA-approved test, therascreen EGFR RGQ PCR Kit (Qiagen).
*
FDA also yesterday approved brexpiprazole (Rexulti, Otsuka) tablets to treat adults with schizophrenia and as an add-on treatment to an antidepressant medication to treat adults with major depressive disorder (MDD). Like other agents approved for treatment of schizophrenia, brexpiprazole carries a boxed warning alerting health care professionals about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. In a news release, FDA emphasized that no drug in this class is approved to treat patients with dementia-related psychosis. The boxed warning also notes increased risk of suicidal ideation with brexpiprazole when used as an antidepressant.

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
July 15, 2015 * Vol. 22, No. 134
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 14 issue of JAMA (2015; 314).
Comparison of Lipid Guidelines: Two studies and an editorial examine lipid treatments and costs.
Guidelines adopted in 2013 by the American College of Cardiology/American Heart Association (ACC/AHA) performed better than older national guidelines in a community-based, primary prevention cohort study (
pp. 134–41). Compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines, the ACC/AHA risk-based approach yielded these results based on a primary outcome of incident cardiovascular disease (CVD) (myocardial infarction, death due to coronary heart disease [CHD], or ischemic stroke): “Among 2,435 statin-naive participants (mean age, 51.3 [SD, 8.6] years; 56% female), 39% (941/2,435) were statin eligible by ACC/AHA compared with 14% (348/2,435) by ATP III (P <.001). There were 74 incident CVD events (40 nonfatal myocardial infarctions, 31 nonfatal ischemic strokes, and 3 fatal CHD events). Participants who were statin eligible by ACC/AHA had increased hazard ratios for incident CVD compared with those eligible by ATP III: 6.8 (95% CI, 3.8–11.9) vs 3.1 (95% CI, 1.9–5.0), respectively (P <.001). Similar results were seen for CVD in participants with intermediate Framingham Risk Scores and for CHD. Participants who were newly statin eligible (n = 593 [24%]) had an incident CVD rate of 5.7%, yielding a number needed to treat of 39 to 58. Participants with [coronary artery calcification (CAC)] were more likely to be statin eligible by ACC/AHA than by ATP III: CAC score >0 (n = 1,015): 63% vs 23%; CAC score >100 (n = 376): 80% vs 32%; and CAC score >300 (n = 186): 85% vs 34% (all P < .001). A CAC score of 0 identified a low-risk group among ACC/AHA statin-eligible participants (306/941 [33%]) with a CVD rate of 1.6%.” (U. Hoffmann, uhoffmann@mgh.harvard.edu)
In a microsimulation model of Americans aged 45–70 years, treatment based on the ACC/AHA guidelines were cost-effective at the recommended risk threshold of 7.5% over 10 years, researchers report (
pp. 142–50). Using a lifetime horizon and societal perspective, the cost-effectiveness study produced these results based on hypothetical individuals who took statins for primary prevention, developed atherosclerotic cardiovascular disease (ASCVD), and died from related or unrelated causes: “In the base-case scenario, the current ASCVD threshold of 7.5% or higher, which was estimated to be associated with 48% of adults treated with statins, had an incremental cost-effectiveness ratio (ICER) of $37,000/[quality-adjusted life-year (QALY)] compared with a 10% or higher threshold. More lenient ASCVD thresholds of 4.0% or higher (61% of adults treated) and 3.0% or higher (67% of adults treated) had ICERs of $81,000/QALY and $140,000/QALY, respectively. Shifting from a 7.5% or higher ASCVD risk threshold to a 3.0% or higher ASCVD risk threshold was estimated to be associated with an additional 161,560 cardiovascular disease events averted. Cost-effectiveness results were sensitive to changes in the disutility associated with taking a pill daily, statin price, and the risk of statin-induced diabetes. In probabilistic sensitivity analysis, there was a higher than 93% chance that the optimal ASCVD threshold was 5.0% or lower using a cost-effectiveness threshold of $100,000/QALY.” (A. Pandya, anpandya@hsph.harvard.edu)
These studies provide clarity to the “questions of in whom and how regarding cholesterol lowering,” editorialists write (
pp. 127–8). “Available evidence indicates that statins are both effective and cost-effective for primary prevention even among low-risk individuals. Although lifestyle interventions must be employed across all segments of the population, for many people a statin drug will also be required to minimize risk. Where to set the treatment threshold and how to determine the individual’s level of risk are also becoming progressively clarified. The 2013 Pooled Cohort Equation, despite its flaws, identifies more high-risk individuals than the previously used Framingham Risk Score. The Pooled Cohort Equation appears to be a justifiable approach to risk assessment as a replacement for the older Framingham Risk Score, and the recommended threshold of 7.5% is also justifiable; in fact, it may even be too conservative.” (P. Greenland, p-greenland@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
July 16, 2015 * Vol. 22, No. 135
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 16 issue of the New England Journal of Medicine (2015; 373).
Palbociclib in Advanced Breast Cancer: An inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), palbociclib plus fulvestrant extended progression-free survival in 521 patients with hormone-receptor–positive metastatic breast cancer who had progression of disease during prior endocrine therapy, researchers report (pp. 209–19). In a Phase III trial, participants received the two drugs together or fulvestrant alone; premenopausal and perimenopausal women received goserelin. Results showed: “The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib–fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo–fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P <0.001). The most common grade 3 or 4 adverse events in the palbociclib–fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo–fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo.” (N. C. Turner, nicholas.turner@icr.ac.uk)
“We have many treatment options for estrogen-receptor–positive, HER2-negative metastatic breast cancer, including two drugs—everolimus and palbociclib—that augment progression-free survival when added to conventional endocrine therapies,” editorialists write, “What we don’t yet have is a strategy and a target population in whom to use these drugs most effectively” (
pp. 273–4). “This is important now but will have even greater implications if CDK4 and CDK6 inhibition lives up to its promise in the adjuvant setting, in which endocrine therapy is currently recommended to nearly 150,000 women in the United States per year. In that setting, it will be crucial to identify patient populations and tumor features predictive of benefit and, at the same time, to identify persons who would do well with endocrine therapy alone.” (L. A. Carey)
Lumacaftor–Ivacaftor in Homozygous Cystic Fibrosis: In 1,108 patients with cystic fibrosis homozygous for the Phe508del mutation in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, lumacaftor in combination with ivacaftor improved outcomes based on a primary end point of absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24 (pp. 220–31). The drugs, a CFTR corrector and potentiator, respectively, were used in combination in patients aged 12 years or older, with these results: “The mean baseline FEV1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0 percentage points (P <0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P <0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–ivacaftor versus 1.6% among those who received placebo.” (C. E. Wainwright, claire.wainwright@health.qld.gov.au)
Cardiovascular Outcomes With Sitagliptin in Type 2 Diabetes: In a Merck-funded randomized, double-blind study, sitagliptin “did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events” (pp. 232–42). The drug or placebo was added usual care in 14,671 patients over a median of 3.0 years without significant changes in a composite primary cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. (R. R. Holman, rury.holman@dtu.ox.ac.uk)

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


PNN Pharmacotherapy Line
July 17, 2015 * Vol. 22, No. 136
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
July issue of the Journal of Allergy and Clinical Immunology (2015; 136).
Allergy Epidemics in Recent Times: While the recent shift in population from farms to towns can be associated with an increase in hay fever and asthma among humans, the epidemiologic trends are more complicated than that, according to a review of allergy epidemics between 1870 and 2010 (pp. 3–13): “Before the first description of hay fever in 1870, there was very little awareness of allergic disease, which is actually similar to the situation in prehygiene villages in Africa today. The best explanation for the appearance and subsequent increase in hay fever at that time is the combination of hygiene and increased pollen secondary to changes in agriculture. However, it is important to remember that the major changes in hygiene in Northern Europe and the United States were complete by 1920. Asthma in children did not start to increase until 1960, but by 1990, it had clearly increased to epidemic numbers in all countries where children had adopted an indoor lifestyle. There are many features of the move indoors that could have played a role; these include increased sensitization to indoor allergens, diet, and decreased physical activity, as well as the effects of prolonged periods of shallow breathing. Since 1990, there has been a remarkable increase in food allergy, which has now reached epidemic numbers. Peanut has played a major role in the food epidemic, and there is increasing evidence that sensitization to peanut can occur through the skin. This suggests the possibility that changes in lifestyle in the last 20 years could have influenced the permeability of the skin. Overall, the important conclusion is that sequential changes in lifestyle have led to increases in different forms of allergic disease. Equally, it is clear that the consequences of hygiene, indoor entertainment, and changes in diet or physical activity have never been predicted.” (T. A. E. Platts-Mills, tap2z@virginia.edu)

>>>Rheumatology Highlights
Source:
July issue of Arthritis & Rheumatology (2015; 67).
Apremilast in Rheumatoid Arthritis: Efficacy of the oral phosphodiesterase 4 inhibitor apremilast “was not demonstrated in patients who had active [rheumatoid arthritis (RA)] despite stable [methotrexate (MTX)] therapy,” researchers conclude (pp. 1703–10). Study participants (n = 237) initially received placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily. At week 16, nonresponders were shifted to an early-escape option, and at week 24, those on placebo began taking blinded apremilast 20 mg twice daily. All patients were receiving stable MTX doses (7.5–25 mg/wk). Results showed: “At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In [a magnetic resonance imaging] substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated.” (M. C. Genovese, genovese@stanford.edu)
Rosuvastatin-Induced Carotid Plaque Regression: In the ROsuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases (RORA-AS) study, 86 participants on intensive lipid-lowering treatment had atherosclerotic regression and lowered LDL cholesterol levels (pp. 1718–28). “The mean ± SD LDL cholesterol level during the 18 months of rosuvastatin treatment was 1.7 ± 0.4 mmoles/liter (area under the curve)…,” the authors write. “Attainment of the LDL cholesterol goal of ≤1.8 mmoles/liter (≤70 mg/dl) or the amount of change in the LDL cholesterol level during the study period did not influence the degree of carotid plaque height reduction.” (S. Rollefstad, s-rollef@diakonsyk.no)

>>>PNN NewsWatch
* Used for treating hypoglycemia, diazoxide has been associated with development of pulmonary hypertension in neonates and infants, FDA said yesterday. Eleven cases have been reported since the drug’s approval in 1973.

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
July 20, 2015 * Vol. 22, No. 137
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 18 issue of Lancet (2015; 386).
Primary Chemotherapy in Advanced Ovarian Cancer: Among 552 women with suspected stage III or IV ovarian cancer, platinum-based primary chemotherapy followed by surgery was noninferior to primary surgery, according to findings of the CHORUS study (pp. 249–57). The Phase III trial assigned participants to primary surgery followed by six cycles of chemotherapy, or to three cycles of primary chemotherapy, then surgery, followed by three more cycles of completion chemotherapy, with these results: “As of May 31, 2014, 451 deaths had occurred: 231 in the primary-surgery group versus 220 in the primary-chemotherapy group. Median overall survival was 22.6 months in the primary-surgery group versus 24.1 months in primary chemotherapy. The HR for death was 0.87 in favour of primary chemotherapy, with the upper bound of the one-sided 90% CI 0.98 (95% CI 0.72–1.05). Grade 3 or 4 postoperative adverse events and deaths within 28 days after surgery were more common in the primary-surgery group than in the primary-chemotherapy group (60 [24%] of 252 women vs 30 [14%] of 209, p = 0.0007, and 14 women [6%] vs 1 woman [<1%], p = 0.001). The most common grade 3 or 4 postoperative adverse event was haemorrhage in both groups (8 women [3%] in the primary-surgery group vs 14 [6%] in the primary-chemotherapy group). 110 (49%) of 225 women receiving primary surgery and 102 (40%) of 253 receiving primary chemotherapy had a grade 3 or 4 chemotherapy related toxic effect (p = 0.0654), mostly uncomplicated neutropenia (20% and 16%, respectively). One fatal toxic effect, neutropenic sepsis, occurred in the primary-chemotherapy group.” (M. Nankivell, m.nankivell@ucl.ac.uk)
Serious Infection With Biological Agents in Rheumatoid Arthritis: Compared with traditional disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis, standard- and high-dose biological agents are associated with an increase in serious infections, according to a systematic review and meta-analysis of 106 trials (pp. 258–65): “Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09–1.58) and high-dose biological drugs (1.90, 1.50–2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65–1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug–experienced patients. The absolute increase in the number of serious infections per 1,000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs.” (J. A. Singh, jasvinder.md@gmail.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Intracranial Hemorrhage With Antidepressants/NSAIDs: Combined use of antidepressants and NSAIDs produced increased risk of intracranial hemorrhage within 30 days, conclude authors who analyzed a nationwide health insurance database from Korea (h3517). Among patients with no history of cerebrovascular diseases or antidepressant use within the year before the date of hospital admission for intracranial hemorrhage, results showed: “After propensity score estimation and matching in a 1:1 ratio, the cohort used in the analysis included 4,145,226 people. The 30 day risk of intracranial haemorrhage during the entire study period was higher for combined use of antidepressants and NSAIDs than for use of antidepressants without NSAIDs (hazard ratio 1.6, 95% confidence interval 1.32 to 1.85). No statistically meaningful differences were found in risk of intracranial haemorrhage between the antidepressant drug classes.” (B-J Park, bjpark@snu.ac.kr)

>>>PNN JournalWatch
* 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)
* Failing to Focus on Healthy Aging: A Frailty of Our Discipline?, in
Journal of the American Geriatrics Society, 2015; 63: 1459–62. (S. M. Friedman, Susan_Friedman@urmc.rochester.edu)
* Antiepileptic Drugs and Intrauterine Death: A Prospective Observational Study From EURAP, in
Neurology, 2015; 10.1212/WNL.0000000000001840. (T. Tomson, torbjorn.tomson@karolinska.se)

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
July 21, 2015 * Vol. 22, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 21 issue of the Annals of Internal Medicine (2015; 163).
Outpatient Antibiotics for Acute Respiratory Infections: In the VA health system, veterans often receive antibiotics for acute respiratory infections (ARIs), and macrolide use is increasing, a study shows (pp. 73–80). Retrospective analysis of all patient visits for ARIs in 2005–12 showed these patterns of antibiotic use and characteristics of patients, providers, and settings: “The proportion of 1 million visits with ARI diagnoses that resulted in antibiotic prescriptions increased from 67.5% in 2005 to 69.2% in 2012 (P < 0.001). The proportion of macrolide antibiotics prescribed increased from 36.8% to 47.0% (P < 0.001). Antibiotic prescribing was highest for sinusitis (adjusted proportion, 86%) and bronchitis (85%) and varied little according to fever, age, setting, or comorbid conditions. Substantial variation was identified in prescribing at the provider level: The 10% of providers who prescribed the most antibiotics did so during at least 95% of their ARI visits, and the 10% who prescribed the least did so during 40% or fewer of their ARI visits.” (B. E. Jones, barbara.jones@hsc.utah.edu)
Dual-Antiplatelet Therapy Duration After Drug-Eluting Stent Placement: Patients’ values and preferences are key when deciding how long to use dual-antiplatelet therapy (DAPT) after placement of drug-eluting stents (DESs), according to authors of a review article showing equivocal clinical results with longer- versus shorter-duration DAPT (pp. 118–26). “Extended DAPT is associated with approximately 8 fewer myocardial infarctions per 1,000 treated patients per year but 6 more major bleeding events than shorter-duration DAPT.” the article concludes. “Because absolute effects are very small and closely balanced, decisions regarding the duration of DAPT therapy must take into account patients’ values and preference.” (F. A. Spencer, fspence@mcmaster.ca)
Sexual Orientation & HPV Vaccine Acceptance: The human papillomavirus (HPV) vaccine is accepted less often by adolescent and young adult lesbians than heterosexual girls and women, researchers report (pp. 99–106). “Programs should facilitate access to HPV vaccination services among young lesbians,” the authors advise based on these findings from the 2006–10 National Survey of Family Growth: “Among U.S. women and girls aged 15 to 25 years, 84.4% reported having heard of the HPV vaccine; of these, 28.5% had initiated HPV vaccination. The adjusted prevalence of vaccine awareness was similar among heterosexual, bisexual, and lesbian respondents. After adjustment for covariates, 8.5% (P = 0.007) of lesbians and 33.2% (P = 0.33) of bisexual women and girls who had heard of the vaccine had initiated vaccination compared with 28.4% of their heterosexual counterparts.” (M. Agénor, magenor@mail.harvard.edu)
Cognitive Outcomes After Cardiovascular Procedures: Among older adults undergoing cardiovascular procedures, intermediate- or long-term cognitive impairment is rare, according to results of a review article (pp. 107–17). While the strength of evidence (SOE) was “mostly low to insufficient,” the authors found these risks in published literature: “17 trials and 4 cohort studies were included; 80% of patients were men, and mean age was 68 years. Cognitive function did not differ after the procedure between on- and off-pump coronary artery bypass grafting (CABG) (n = 6; low SOE), hypothermic and normothermic CABG (n = 3; moderate to low SOE), or CABG and medical management (n = 1; insufficient SOE). One trial reported lower risk for incident cognitive impairment with minimal versus conventional extracorporeal CABG (risk ratio, 0.34 [95% CI, 0.16 to 0.73]; low SOE). Two trials found no difference between surgical carotid revascularization and carotid stenting or angioplasty (low and insufficient SOE, respectively). One cohort study reported increased cognitive decline after transcatheter versus surgical aortic valve replacement but had large selection and outcome measurement biases (insufficient SOE).” (H. A. Fink, Howard.fink@va.gov)

>>>PNN NewsWatch
* The Pharmacy Health Information Technology Collaborative has released a draft guidance document designed to promote the development of pharmacogenomics coding, APhA CEO Tom Menighan blogs 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
July 22, 2015 * Vol. 22, No. 139
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 22 issue of JAMA (2015; 314).
Adjuvants & Influenza Vaccine: A key to influenza pandemic preparedness programs could be on-site addition of adjuvants to vaccines, according to a study demonstrating highest titers with product containing the AS03 adjuvant (pp. 237–46). In a double-blind, Phase II trial, research pharmacists at each of five U.S. sites added AS03 or MF59 adjuvants to a monovalent, inactivated, subvirion, preservative-free vaccine prepared with influenza A/Shanghai/2/2013(H7N9) virus. The vaccine was given on days 0 and 21 at four doses with or without adjuvants, with these results: “Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving [a hemagglutination inhibition antibody] titer of 40 or higher was 2% (95% CI, 0%–7%) without adjuvant (n = 94), 84% (95% CI, 76%–91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%–68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7–54.4]; n = 92) and (58.6 [95% CI, 44.3–77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7–135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4–37.6]; P < .001).” (L. A. Jackson, jackson.l@ghc.org)
Pioglitazone & Bladder Cancer: In large cohort and nested case–control analyses of patients with diabetes, pioglitazone use was not associated with increased risk of bladder cancer, but links to prostate and pancreatic cancer were uncovered (pp. 265–77). From a dataset on 193,099 people with bladder cancer, 464 case patients were identified for comparison with 464 matched controls. Ten additional cancers were also studied using data on 236,507 people aged 40 years or older in 1997–2005 who were followed until mid-2012. Results showed: “Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2–13.2 years) and 1,261 had incident bladder cancer. Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person–years, respectively. Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89–1.26). Results were similar in case–control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78–1.80). In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02–1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16–1.71). Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person–years, respectively. No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.” (A. Ferrara, assiamira.ferrara@kp.org)
Arguing that “an essential quality of FDA decision making in the setting of uncertainty is credibility,” editorialists assess potential responses to the pioglitazone data (
pp. 233–4): “That these data … shed new light on the safety of pioglitazone reflects the dynamic nature of many drug safety questions. As in this case, caution and further review are the appropriate responses to many safety signals. But when emerging available data—clinical, laboratory, observational, and even population-based studies—create a compelling picture of risk in excess of potential benefit to patients, the FDA should act to protect the public. Such was the case for rosiglitazone, even though subsequent data comparing the drug’s risk to alternatives has led the FDA to revise its recommendations. Establishing guideposts for how to tell the difference between ‘wait and see’ and ‘act now’ will help prevent every safety issue from reopening core questions about the agency’s approach. No framework will be perfect, but it can be assessed and improved over time.” (J. M. Sharfstein, joshua.sharfstein@jhu.edu)

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


PNN Pharmacotherapy Line
July 23, 2015 * Vol. 22, No. 140
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 23 issue of the New England Journal of Medicine (2015; 373).
Nodal Irradiation in Early-Stage Breast Cancer: Among 1,832 women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy, “addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence,” researchers report (pp. 307–16). Study participants were receiving hormonal therapy, chemotherapy, or neither when they were randomized to whole-breast irradiation plus regional nodal irradiation or the control condition of whole-breast irradiation alone, with these results: “The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P = 0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P = 0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P = 0.01) and lymphedema (8.4% vs. 4.5%, P = 0.001).” (T. J. Whelan, twhelan@hhsc.ca)
Based on this and another irradiation study in this issue (
pp. 317–27; P. M. Poortmans, philip.poortmans@radboudumc.nl), editorialists conclude that these studies “show the possibilities and the limits of more extensive regional treatment of breast cancer in an unselected population and frame the discussion for the next generation of individualized treatment programs, built largely on genomic characterization of tumor biology” (pp. 379–81; H. J. Burstein).
Retail-Based Ambulatory Care Clinics: Two articles explore the impact of ambulatory care clinics based in pharmacies, other retail settings, and urgent care centers.
Three trends are relevant as policy is formulated regarding retail clinics and urgent care centers, authors of a Health Policy Report write (
pp. 382–8): “First, patients face increasing challenges in navigating to the right care setting, owing in part to wide variations in services and staffing levels across the ambulatory care sector. States can aid patients in making informed choices by developing common definitions and naming standards for retail clinics and urgent care centers. Individual states may also consider enforcing licensure and accreditation requirements on the basis of common definitions to ensure minimum service standards. Second, adoption of electronic tools and partnerships with health systems make it easier for providers of convenient ambulatory care to support continuity of care. Policymakers can further encourage continuity of care by mandating or incentivizing connectivity to health information exchanges and supporting referral of patients back to more permanent sources of care. Third, there is a need to ensure that routine efforts to collect quality or safety data from convenient ambulatory care sites are integrated into existing quality frameworks. For example, the National Quality Forum could drive consensus on the quality and safety measures that are most germane to convenient ambulatory care.” (J. E. Chang)
The rapid expansion of clinics by CVS and a change in Walmart’s approach to in-store clinics represent a development with which “traditional medical centers must reckon,” writes the author of a Perspective article, “given that the clinics are meeting patients’ demands for greater convenience, their quality is withstanding peer-reviewed scrutiny, and their numbers are growing” (
pp. 301–3): “[American Academy of Family Physicians] President Robert Wergin has cautiously expressed this sentiment, saying, ‘The AAFP recognizes the growing presence of retail clinics in the health care marketplace.… We recognize that many patients currently lack a primary care physician and we are optimistic that retail clinics can play an important role in connecting such patients with a primary care physician in their community.’ Similarly, Steven Weinberger, chief executive officer of the American College of Physicians, has said, ‘The ACP recognizes there is a role for retail health clinics but stresses that such care—minor and self-limited—should complement and not replace the longitudinal relationship with a physician.’” (J. K. Iglehart)

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
July 24, 2015 * Vol. 22, No. 141
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
July issue of Health Affairs, a theme issue on Medicaid’s Evolving Delivery Systems (2015; 34).
Contraceptive Cost After Health Care Reform: Out-of-pocket costs for prescription contraceptives dropped 20% or more following implementation of the Affordable Care Act, a study shows (pp. 1204–11). Based on analysis of a national insurer’s administrative claims data set, researchers report these results: “We found that mean and median per prescription out-of-pocket expenses have decreased for almost all reversible contraceptive methods on the market. The average percentages of out-of-pocket spending for oral contraceptive pill prescriptions and intrauterine device insertions by women using those methods both dropped by 20 percentage points after implementation of the ACA mandate. We estimated average out-of-pocket savings per contraceptive user to be $248 for the intrauterine device and $255 annually for the oral contraceptive pill. Our results suggest that the mandate has led to large reductions in total out-of-pocket spending on contraceptives and that these price changes are likely to be salient for women with private health insurance.” (N. V. Becker, norab@wharton.upenn.edu)

>>>Medical Care Report
Source:
Aug. issue of Medical Care (2015; 53).
Opioid Poisonings in Washington State: Based on data showing opioid poisonings among Medicaid beneficiaries in Washington State who are prescribed relatively low doses for acute or intermittent use, authors conclude that a state guideline needs to be revised (pp. 679–85). Included in the study were patients in the state’s Medicaid fee-for-service system in Apr. 2006 through Dec. 2010, dates that bookend implementation of the Washington (WA) State Opioid Guideline in 2007. Participants had at least one paid claim for an opioid prescription and had an emergency department or inpatient hospital claim for opioid poisoning. Results showed: “Methadone poisonings occurred at 10 times the rate of other prescription opioid poisonings and increased between 2006 and 2010. Rates of other prescription opioid poisonings appeared to level off after implementation of the WA opioid guideline in 2007. Among individuals with nonmethadone opioid poisonings, only 44% had chronic opioid use, 17% had prescribed doses in the week before the poisoning >120 mg/d morphine-equivalent dose (MED), 28% had doses <50 mg/d MED, and 48% had concurrent sedative prescriptions.” (D. Fulton-Kehoe)
“Machine Learning” for Examining Adherence, Hospitalizations: Using a “machine learning” approach to develop a predictive algorithm for the Pennsylvania Medicaid database, researchers find widely varying medication adherence rates among patients with type 2 diabetes that were associated with increased hospitalization risk (pp. 720–8). Rather than the 80% proportion of days covered (PDC) generally considered as adequate in quality-improvement efforts, the study reports these results for 33,130 non-dual-eligible enrollees: “The [predictive algorithm] training and testing samples had similar characteristics (mean age, 48 y; 67% female; mean PDC = 0.65). We identified 8 important predictors of all-cause hospitalizations (rank in order): prior hospitalizations/emergency department visit, number of prescriptions, diabetes complications, insulin use, PDC, number of prescribers, Elixhauser index, and eligibility category. The adherence thresholds most discriminating for risk of all-cause hospitalization varied from 46% to 94% according to patient health and medication complexity. PDC was not predictive of hospitalizations in the healthiest or most complex patient subgroups.” (W-H Lo-Ciganic, lociganic@pharmacy.arizona.edu)

>>>PNN NewsWatch
* FDA yesterday approved the Bio-Rad BioPlex 2200 HIV Ag-Ab assay, the first FDA-approved diagnostic that differentiates between HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen in human serum or plasma specimens. It may be used in adults, children 2 years of age and older, as well as in pregnant women. The assay may also be used to screen organ donors for HIV-1/2 when the blood specimen is collected while the donor’s heart is still beating. However, the assay is not approved for use in screening blood or plasma donors, except in urgent situations where traditional licensed blood donor screening tests are unavailable or their use is impractical.

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
July 27, 2015 * Vol. 22, No. 142
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 25 issue of Lancet (2015; 386).
Methadone Policies in Jails: “Forced withdrawal from methadone on incarceration reduced the likelihood of prisoners re-engaging in methadone maintenance after their release,” conclude investigators who compared this approach with continued methadone treatment (pp. 350–9). In Rhode Island correctional facilities, 283 prisoners had these outcomes: “Participants assigned to continued methadone were more than twice as likely than forced-withdrawal participants to return to a community methadone clinic within 1 month of release (106 [96%] of 110 in the continued-methadone group compared with 68 [78%] of 87 in the forced-withdrawal group; adjusted hazard ratio [HR] 2.04, 95% CI 1.48–2.80). We noted no differences in serious adverse events between groups. For the continued-methadone and forced-withdrawal groups, the number of deaths were one and zero, non-fatal overdoses were one and two, admissions to hospital were one and four; and emergency-room visits were 11 and 16, respectively.” (J. D. Rich, jrich@lifespan.org)

>>>PNN NewsWatch
* FDA on Friday approved the first agent in the highly anticipated class of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. Indicated for use with diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, alirocumab (Praluent) will be marketed by Sanofi-Aventis U.S. and Regeneron Pharmaceuticals. With a price tag of $14,600 per year but a larger potential market than most other marketed injectable antibodies, alirocumab and soon-to-come agents in this class could propel them to the top of expenditure charts, the Wall Street Journal reports. In clinical trials of patients with HeFH or otherwise at high risk for heart attack or stroke, and taking maximally tolerated doses of a statin, those on alirocumab had mean reductions in LDL cholesterol ranging from 36% to 59%, compared with placebo. A trial evaluating the drug’s effectiveness in reducing cardiovascular risk is ongoing. Common adverse effects of alirocumab include itching, swelling, pain, or bruising where injection is given, nasopharyngitis, and symptoms of the common cold and flu or flu-like symptoms. Educational information, clinical support for health professionals, and reimbursement services, including copayment support for eligible patients and information about insurance eligibility support, are available from the manufacturers at 1-844-PRALUENT (1-844-772-5836).
* Two hepatitis C virus (HCV) treatments were approved on Friday by FDA, one for genotype 3 and another for genotype 4.
Daclatasvir (Daklinza, Bristol-Myers Squibb) is approved for use with sofosbuvir to treat HCV genotype 3 infections. Daclatasvir is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for coadministration of interferon or ribavirin, FDA said. In clinical trials of 152 patients, 98% of treatment-naive participants with no cirrhosis and 58% of the treatment-naive participants with cirrhosis achieved sustained virologic response. Among treatment-experienced patients, 92% of those with no cirrhosis and 69% of those with cirrhosis achieved sustained virologic response. FDA also approved Technivie (AbbVie), a combination product containing ombitasvir, paritaprevir, and ritonavir for use in combination with ribavirin for the treatment of HCV genotype 4 infections in patients without cirrhosis. Abbvie uses the same three drugs are used in its Viekira Pak, used for treating HCV genotype 1.
*
FDA wrapped up a busy Friday with approval of sonidegib (Odomzo) to treat patients with locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or who are not candidates for surgery or radiation therapy. The product carries a boxed warning about death or severe birth defects in the developing fetus when the once-daily oral product is administered to pregnant women.

>>>PNN JournalWatch
* Minimizing Hypoglycemia in Diabetes, in
Diabetes Care, 2015; 38: 1583–91. (P. E. Cryer, pcryer@wustl.edu)
* Interventions That Restore Awareness of Hypoglycemia in Adults With Type 1 Diabetes: A Systematic Review and Meta-analysis, in
Diabetes Care, 2015; 38: 1592–609. (E. Yeoh, esteryeoh@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
July 28, 2015 * Vol. 22, No. 143
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
July issue of the Journal of the American Geriatrics Society (2015; 63).
Evidence-Based Antipsychotic Prescribing Guidelines: While dissemination of evidence-based antipsychotic prescribing guidelines was successful in Connecticut nursing homes (NHs), prescribing of the drugs did not measurably change, researchers report (pp. 1289–98). Using cluster randomization, 42 NHs received mailed toolkits (minimal intensity); mailed toolkits with quarterly audits and feedback reports about facility-level antipsychotic prescribing (moderate intensity); and in-person toolkit delivery with academic detailing, on-site behavioral management training, and quarterly audit and feedback reports (high intensity). Results showed: “Toolkit awareness of 30% (7/23) of leadership of low-intensity NHs, 54% (19/35) of moderate-intensity NHs, and 82% (18/22) of high-intensity NHs reflected adoption and implementation of the intervention. Highest levels of use and knowledge among direct care staff were reported in high-intensity NHs. Antipsychotic prescribing levels declined during the study period, but there were no statistically significant differences between study arms or from secular trends.” (J. Tjia, jennifer.tjia@umassmed.edu)
Statins in High Noncardiovascular Mortality Risk: Patients’ cardiovascular (CV) and non-CV mortality risks affect the benefits they receive from statins, according to results of a meta-analysis and meta-regression of 16 trials of 59,707 individuals aged 55–75 years (pp. 1413–9): “Every 1% increase in 5-year non-CV mortality risk of the study population was associated with a 3.7% (95% confidence interval (CI) = 1.2 to 6.3%) greater RR of major CV events and a 4.4% (95% CI = 2.1 to 6.9%) greater RR of total mortality. (Higher RRs indicate smaller benefits.) CV mortality was not associated with statin effects (P > .05). In stratified analysis according to CV (≥5.3% vs <5.3%) and non-CV mortality (≥3.8% vs <3.8%) of the study population, statins had little mortality benefit in populations with high non-CV mortality, regardless of CV mortality (random-effects pooled RR = 0.81, 95% CI = 0.72 to 0.91, for low CV and low non-CV mortality; random-effects pooled RR = 0.90, 95% CI = 0.76 to 1.06 for low CV and high non-CV mortality; random-effects pooled RR = 0.79, 95% CI = 0.72 to 0.87 for high CV and low non-CV mortality; random-effects pooled RR = 0.94, 95% CI = 0.87 to 1.02 for high CV and high non-CV mortality). The CV event reduction was also attenuated in populations with high non-CV mortality (random-effects pooled RR = 0.67, 95% CI = 0.60 to 0.75, for low CV and low non-CV mortality; random-effects pooled RR = 0.73, 95% CI = 0.66 to 0.81 for low CV and high non-CV mortality; random-effects pooled RR = 0.77, 95% CI = 0.69 to 0.87 for high CV and low non-CV mortality; random-effects pooled RR = 0.83, 95% CI = 0.74 to 0.92 for high CV and high non-CV mortality).” (D. H. Kim, dkim2@bidmc.harvard.edu)

>>>Infectious Disease Report
Source:
Aug. 1 issue of Clinical Infectious Diseases (2015; 61).
Pneumococcal Vaccine in Stem Cell Transplant: To prevent life-threatening Streptococcus pneumoniae infections in patients after hematopoietic stem cell transplant (HSCT), a five-dose regimen of two pneumococcal vaccines may be needed, a study shows (pp. 313–23). An open-label study of 216 patients shows these results for 3 doses of 13-valent pneumococcal conjugate vaccine (PCV13) at 1-month intervals, a fourth dose 6 months later, and 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) 1 month later: “Geometric mean fold rises (GMFRs) of immunoglobulin G geometric mean concentrations from baseline to postdose 3 showed significant increases in antibody levels across all PCV13 serotypes (GMFR range, 2.99–23.85; 95% confidence interval lower limit, >1); there were significant declines over the next 6 months, significant increases from predose 4 to postdose 4 (GMFR range, 3.00–6.97), and little change after PPSV23 (GMFR range, 0.86–1.12). Local and systemic reactions were more frequent after dose 4. Six patients experienced serious adverse events possibly related to PCV13 (facial diplegia, injection-site erythema and pyrexia, autoimmune hemolytic anemia, and suspected lack of vaccine efficacy after dose 3 leading to pneumococcal infection), PCV13 and PPSV23 (Guillain-Barré syndrome), or PPSV23 (cellulitis).” (C. Cordonnier, catherine.cordonnier@hmn.aphp.fr)

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
July 29, 2015 * Vol. 22, No. 144
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 28 issue of JAMA (2015; 314).
Medicare & Medicaid at 50: Marking tomorrow’s 50th anniversary of the creation of the Medicare and Medicaid programs, authors project further growth of enrollments but complicated efforts to make changes (pp. 384–95): “Together, Medicare and Medicaid serve 111 million beneficiaries and account for $1 trillion in total spending, generating 43% of hospital revenue and representing 39% of national health spending. The median income for Medicare beneficiaries is $23,500 and the median income for Medicaid beneficiaries is $15,000. Future issues confronting both programs include whether they will remain open-ended entitlements, the degree to which the programs may be privatized, the scope of their cost-sharing structures for beneficiaries, and the roles the programs will play in payment and delivery reform.” (D. Altman, daltman@kff.org)
Medicaid’s New Role: The nation’s largest insurer, Medicaid now covers 71.1 million Americans and is expected to account for $343 billion in spending in 2015, authors of a Viewpoint write (pp. 343–4). Since expansion of Medicaid under the Affordable Care Act, 12.3 million people have been added to the program’s roles. Age and disability account for a disproportionate share of costs: “It is impossible to contemplate Medicaid’s future without noting the cost pressures associated with new treatments and an aging population. The 22% of Medicaid enrollees who qualify based on age or disability account for more than half (56%) of Medicaid expenditures. Much of the attention to delivery and payment reform is focused on these high-need individuals; increased cost pressures add to the imperative to improve care and avoid preventable and inefficient costs.
“Medicaid has regularly been reinvented to meet the needs of a new time, a new population, or a new health care crisis. Reinvention is under way yet again, and if past is prologue, the path will not be easy, but the program will continue to move forward.” (C. Mann,
cmann@manatt.com)
Managing Medicaid’s Future: By learning from state variation in costs and outcomes, the Medicaid system can “continue to play a critical role in improving the health of the country’s most vulnerable populations,” a Viewpoint author writes (pp. 345–6): “Within limits, the federal government is likely to grant states the flexibility they request to manage their programs, while nudging them toward greater fiscal and performance accountability. Some states, including New York and Oregon, have taken the bold step of placing at risk funds that they might obtain through a Medicaid waiver, based on whether or not they achieve prespecified improvements in health outcomes and reductions in costs. This approach to shared savings could become a model for the federal government to encourage states to redirect their efforts away from destructive cost-saving practices and toward approaches that are beneficial for the patient population.…” (A. B. Bindman, andrew.bindman@ucsf.edu)
Outpatient Pharmacy Expenditures for Pediatric Illness: In the California Children’s Services system, antihemophilic factor accounted for about 40% of expenditures for children with serious chronic illnesses in 2010–12 (pp. 405–7). Analysis of unique pharmacy paid claims showed these patterns for 34,330 children: “Outpatient pharmacy expenditures totaled $475,718,130 (20% of total health care expenditures); per-child pharmacy expenditures ranged from $0.16 to $56,849,034, and mean and median per-child expenditures were $13,857 (SD, $349,782) and $791 (IQR, $127–$5,873), respectively.
“The product class of blood formation, coagulation, and thrombosis agents accounted for the greatest share (41.9%) of outpatient pharmacy expenditures, and antihemophilic factor represented 98% of this class’s expenditures or 40.9% of total pharmacy expenditures. All children with an antihemophilic factor paid claim (0.4% of cohort) had International Classification of Diseases, Ninth Revision, diagnostic codes for coagulation and hemorrhagic disorders or hemophilia carrier. The mean per-child expenditure for antihemophilic factor was $1,343,262. Among children with antihemophilic factor claims and enrolled for all 3 years, the mean and median per-child annualized expenditures were $634,054 (SD, $2,159,355) and $152,280 (IQR, $19,434–$393,000), respectively.” (S. M. Swenson,
sonjas1@stanford.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
July 30, 2015 * Vol. 22, No. 145
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 30 New England Journal of Medicine (2015; 373).
PLX3397 in Tenosynovial Giant-Cell Tumor: In a Phase I trial of patients with tenosynovial giant-cell and other tumors, the selective colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 produced prolonged regression in tumor volume in most patients, researchers report (pp. 428–37). A dose-escalation phase of the study in patients with solid tumors was followed by an extension phase testing PLX3397 in patients with tenosynovial giant-cell tumors. Results showed: “A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1,000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment.” (W. D. Tap, tapw@mskcc.org)
Antisense Inhibition of Apolipoprotein C-III: ISIS 304801, a selective antisense inhibitor of apolipoprotein C-III (APOC3), significantly reduced triglyceride levels in a Phase II trial (pp. 438–47). At study entry, patients either had untreated elevations of triglycerides (350–2,000 mg/dL) or were on stable doses of fibrates and had triglyceride levels of 225–2,000 mg/dL. ISIS 304081 in doses of 100 or 300 mg produced these results in comparison with placebo: “A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801–fibrate cohort (20 received active agent, and 8 received placebo). The mean (± SD) baseline triglyceride levels in the two cohorts were 581 ± 291 mg per deciliter (6.6 ± 3.3 mmol per liter) and 376 ± 188 mg per deciliter (4.2 ± 2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0 ± 32.0% in the 100-mg group, 63.8 ± 22.3% in the 200-mg group, and 79.6 ± 9.3% in the 300-mg group, vs. an increase of 4.2 ± 41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2 ± 12.5% in the 200-mg group and 70.9 ± 13.0% in the 300-mg group, vs. a decrease of 2.2 ± 25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.” (J. J. P. Kastelein, j.j.kastelein@amc.uva.nl)
Needle-Exchange Programs for Injection Drug Users: To stop HIV outbreaks such as the recent one in rural Indiana, changes in laws are needed that will permit more needle-exchange programs to operate legally, write authors of a Perspective article (pp. 397–9): “Permanently lifting the ban on using federal funds to support needle-exchange programs will be a critical component of HIV prevention, since these programs reduce HIV incidence and front-line exchange workers are often the first people injection-drug users reach out to for help. There are currently 228 known needle-exchange programs in 35 U.S. states, the District of Columbia, the Commonwealth of Puerto Rico, and Indian Nations. However, the federal funding ban limits their scalability and quality of services, including their ability to provide critical ancillary services (e.g., on-site HIV and HCV testing and referrals for drug treatment). States can adapt prescription-drug monitoring programs so they are secure, enable searches in real time, and are used as clinical and public health tools rather than law-enforcement weapons. But such supply-reduction measures will work best when complemented by the harm reduction achievable with opioid-agonist therapy and needle-exchange programs.” (S. A. Strathdee)
Health Systems & Older Americans: Marking the 50th anniversary of the Older Americans Act, Perspective authors conclude that health systems need to shift care from institutions to homes and communities of seniors as value-driven care takes hold (pp. 399–401): “Health systems can build on … successes through innovative partnerships and more comprehensive delivery models.” (R. B. Parikh)

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
July 31, 2015 * Vol. 22, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2015; 38).
Screening for Type 2 Diabetes: Time of initiation of treatment after diagnosis of type 2 diabetes is more important than intensity of therapy, a study shows, emphasizing the need for early detection of the condition (pp. 1449–55). Using a validated computer simulation model (the Michigan Model), investigators analyzed “data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors,” with these results: “When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors.” (W. H. Herman, wherman@umich.edu)
Evidence from this and other studies tips the scale in favor of screening for and early detection of hyperglycemia, editorialists write (
pp. 1399–401): “Considerable evidence exists for type 2 diabetes prevention among people with prediabetes, and screening for hyperglycemia is the first step toward delivering interventions to this subpopulation (over 90% of whom remain undetected). Safe and reliable tests are available for hyperglycemia screening, and evidence suggests that screening for hyperglycemia is cost-effective and causes little harm. Of course, follow-up of newly detected prediabetes and type 2 diabetes requires sufficient infrastructure to deliver effective lifestyle intervention and high-quality care. The totality of evidence supporting screening for hyperglycemia is strong and should persuade the [U.S. Preventive Services Task Force] to adopt its new set of recommendations for type 2 diabetes and prediabetes screening.” (K. M. Venkat Narayan, knaraya@emory.edu)
Vitamin D Supplementation & Glycemic Control: In the SUNNY trial of 275 adult patients with type 2 diabetes without insulin treatment, intermittent high-dose vitamin D supplementation had no significant effect on glycemic control, researchers report (pp. 1420–6). Participants received either vitamin D3 (50,000 IU/month) or placebo for 6 months. Linear regression analysis of glycosylated hemoglobin levels revealed these associations: “Mean baseline serum 25-hydroxyvitamin D [25(OH)D] increased from 60.6 ± 23.3 to 101.4 ± 27.6 nmol/L and 59.1 ± 23.2 to 59.8 ± 23.2 nmol/L in the vitamin D and placebo group, respectively. Mean baseline HbA1c was 6.8 ± 0.5% (51 ± 6 mmol/mol) in both groups. After 6 months, no effect was seen on HbA1c (mean difference: beta = 0.4 [95% CI −0.6 to 1.5]; P = 0.42) and other indicators of glycemic control (HOMA of insulin resistance, fasting insulin, and glucose) in the entire study population. Subgroup analysis in patients with a serum 25(OH)D <50 nmol/L or an HbA1c level >7% (53 mmol/mol) did not differ the results.” (S. Simsek, s.simsek@mca.nl)
Awareness of Hypoglycemia: A systematic review and meta-analysis of 43 studies supports a stepped-care approach for managing impaired awareness of hypoglycemia (IAH) through structured diabetes education about flexible insulin therapy (pp. 1592–609): “Educational interventions included structured diabetes education on flexible insulin therapy, including psychotherapeutic and behavioral techniques. These were able to reduce [severe hypoglycemia (SH)] and improve glycemic control, with greater benefit from the latter two techniques in improving IAH. Technological interventions (insulin pump therapy, continuous glucose monitoring, and sensor-augmented pump) reduced SH, improved glycemic control, and restored awareness when used in combination with structured education and frequent contact. Pharmacological studies included four insulin studies and one noninsulin study, but with low background SH prevalence rates.” (E. Yeoh, esteryeoh@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
Aug. 3, 2015 * Vol. 22, No. 147
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Real-World Warfarin in Atrial Fibrillation: At 1,487 U.S. hospitals participating in the Get With The Guidelines (GWTG)-Stroke program in 2009–11, patients with ischemic stroke secondary to atrial fibrillation had improved long-term clinical outcomes and more days at home when on warfarin therapy, researchers report (h3786). Data came from Medicare claims for longitudinal outcomes following an initial hospitalization for ischemic stroke. Comparing those treated with warfarin or no oral anticoagulant, the study shows these results for major adverse cardiovascular events (MACE): “Among 12,552 survivors of stroke, 11,039 (88%) were treated with warfarin at discharge. Warfarin treated patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease but had similar severity of stroke as measured by the National Institutes of Health Stroke Scale. Relative to those not treated, patients treated with warfarin had more days at home (as opposed to institutional care) during the two years after discharge (adjusted home time difference 47.6 days, 99% confidence interval 26.9 to 68.2). Patients discharged on warfarin treatment also had a reduced risk of MACE (adjusted hazard ratio 0.87, 99% confidence interval 0.78 to 0.98), all cause mortality (0.72, 0.63 to 0.84), and recurrent ischemic stroke (0.63, 0.48 to 0.83). These differences were consistent among clinically relevant subgroups by age, sex, stroke severity, and history of previous coronary artery disease and stroke.” (Y. Xian, ying.xian@duke.edu)

>>>Lancet Highlights
Source:
Aug. 1 issue of Lancet (2015; 386).
CETP Inhibition in Mild Dyslipidemia: In a Phase II trial, the new cholesterol esterase transfer protein (CETP) inhibitor TA-8995 was well tolerated and improved lipid and apolipoprotein levels in patients with mild dyslipidemia (pp. 452–60). Adults were allocated to one of four daily doses of the drug or placebo, or to TA-8995 10 mg plus atorvastatin 20 mg or rosuvastatin 10 mg, or to one of the latter statins alone. Results showed: “Between Aug 15, 2013, and Jan 10, 2014, 364 patients were enrolled. At week 12, LDL cholesterol levels were reduced by 27.4% in patients assigned to the 1 mg dose, 32.7% in patients given the 2.5 mg dose, 45.3% in those given the 5 mg dose, and 45.3% in those given the 10 mg dose (p <0.0001). LDL cholesterol levels were reduced by 68.2% in patients given 10 mg TA-8995 plus atorvastatin, and by 63.3% in patients given rosuvastatin plus 10 mg TA-8995 (p <0.0001). A daily dose of 1 mg TA-8995 increased HDL cholesterol levels by 75.8%, 2.5 mg by 124.3%, 5 mg by 157.1%, and 10 mg dose by 179.0% (p <0.0001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin HDL cholesterol levels increased by 152.1% and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 157.5%. We recorded no serious adverse events or signs of liver or muscle toxic effects.” (G. K. Hovingh, j.s.jansen@amc.nl)
Long-Term Lithium: “Lithium treatment is associated with a decline in renal function, hypothyroidism, and hypercalcaemia,” concludes a study of laboratory data from Oxford U. Hosp., with “women younger than 60 years and people with lithium concentrations higher than median … at greatest risk” (pp. 461–8; R. F. McKnight, Rebecca.mcknight@psych.ox.ac.uk).

>>>PNN JournalWatch
* Adjuvant Denosumab in Breast Cancer (ABCSG-18): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial, in
Lancet, 2015; 386: 433–43. (M. Gnant, michael.gnant@meduniwien.ac.at)
* Dabrafenib and Trametinib Versus Dabrafenib and Placebo for Val600 BRAF-Mutant Melanoma: A Multicentre, Double-Blind, Phase 3 Randomised Controlled Trial, in
Lancet, 2015; 386: 444–51. (G. V. Long, georgina.long@sydney.edu.au)
* Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis, in
American Journal of Psychiatry, 2015; 172: 731–42. (C. Stinton)
* Pediatric Psychopharmacology for Treatment of ADHD, Depression, and Anxiety, in
Pediatrics, 2015; 136: 351–9. (C. Southammakosane)
* Choosing Wisely in Newborn Medicine: Five Opportunities to Increase Value, in
Pediatrics, 2015; 136: e482–9. (T. Ho)
* Fluoroquinolone Sequential Therapy for
Helicobacter pylori: A Meta-analysis, in Pharmacotherapy, 2015; 35: 10.1002/phar.1614. (S. M. Wilhelm, swilhelm@wayne.edu)
* Liposomal Bupivacaine for Total Knee Arthroplasty, in
Pharmacotherapy, 2015; 35: 10.1002/phar.1620. (B. Faley, bfaley@hackensackumc.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
Aug. 4, 2015 * Vol. 22, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 4 issue of the Annals of Internal Medicine (2015; 163).
Electronic Interventions for Alcohol Use Disorders: Electronic interventions (e-interventions) have some positive but short-term effects on alcohol consumption in adults with alcohol-related impairment, according to findings of a systematic review of studies (pp. 205–14). Studies had at least 50 participants, compared e-interventions with controls, and reported outcomes from 6 months or longer. Concluding that “future e-interventions could provide more intensive treatment and possibly human support to assist persons in meeting recommended drinking limits,” the authors found: “In 28 unique trials, the modal e-intervention was brief feedback on alcohol consumption. Available data suggested a small reduction in consumption (approximately 1 drink per week) in adults and college students at 6 months but not at 12 months. There was no statistically significant effect on meeting drinking limit guidelines in adults or on binge-drinking episodes or social consequences of alcohol in college students.” (E. Dedert, eric.dedert@duke.edu)
CBT in Insomnia: Now typically used as first-line therapy, cognitive behavioral therapy for insomnia (CBT-i) “is an effective treatment for adults with chronic insomnia, with clinically meaningful effect sizes,” conclude authors of a systematic review (pp. 191–204): “Among 292 citations and 91 full-text articles reviewed, 20 studies (1,162 participants [64% female; mean age, 56 years]) were included. Approaches to CBT-i incorporated at least 3 of the following: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the posttreatment time point, [sleep onset latency] improved by 19.03 (95% CI, 14.12 to 23.93) minutes, [wake after sleep onset] improved by 26.00 (CI, 15.48 to 36.52) minutes, [total sleep time] improved by 7.61 (CI, −0.51 to 15.74) minutes, and [sleep efficiency] improved by 9.91% (CI, 8.09% to 11.73%). Changes seemed to be sustained at later time points. No adverse outcomes were reported.” (J. M. Trauer)
Restrictions on Medicaid Access to Sofosbuvir: An analysis of information available on state Medicaid websites indicates that many programs are violating federal law by restricting access to the new, expensive oral therapies for hepatitis C virus (HCV), researchers report (pp. 215–23). Websites found these policies during the latter half of 2014: “Of the 42 states with known Medicaid reimbursement criteria for sofosbuvir, 74% limit sofosbuvir access to persons with advanced fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis [METAVIR] fibrosis stage F3) or cirrhosis (F4). One quarter of states require persons co-infected with HCV and HIV to be receiving antiretroviral therapy or to have suppressed HIV RNA levels. Two thirds of states have restrictions based on prescriber type, and 88% include drug or alcohol use in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence and 64% requiring urine drug screening. Heterogeneity is present in Medicaid reimbursement criteria for sofosbuvir with respect to liver disease staging, HIV co-infection, prescriber type, and drug or alcohol use across the United States. Restrictions do not seem to conform with recommendations from professional organizations, such as the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. Food and Drug Administration labels.” (L. E. Taylor, LTaylor@Lifespan.org)

>>>PNN NewsWatch
* FDA strongly encourages health care facilities using the Symbiq Infusion System to begin transitioning to alternative infusion systems as soon as possible, the agency said on Friday. In what appears to be the first cybersecurity problem with such devices, FDA said the U.S. Department of Homeland Security’s Industrial Control Systems Cyber Emergency Response Team and Hospira are aware of cybersecurity vulnerabilities associated with this system.
* The brand names of
vortioxetine (Brintellix) and ticagrelor (Brilinta) are being confused by prescribers and dispensers, FDA has warned. The agency suggests inclusion of the generic names of drugs and the indication for use on prescriptions to avoid the problem.

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
Aug. 5, 2015 * Vol. 22, No. 149
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 4 issue of JAMA, a theme issue on Violence/Human Rights (2015; 314).
Treatments for Posttraumatic Stress Disorder: Reflecting on three research articles in this issue on mindfulness-based and other innovative therapies for posttraumatic stress disorder (PTSD), editorialists call for “broadening the approach” to treatment of this condition and other “consequences of trauma” (pp. 453–5): “It has … been suggested that available PTSD therapies focus too narrowly on the remission of symptoms such as intrusion, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity. Posttraumatic stress disorder and its initiating traumatic events can affect multiple domains of health. Although many trials of PTSD treatments have included quality-of-life assessments, little attention has been paid to quality of life as a therapeutic goal for patients with PTSD. From a patient’s point of view, an improvement in quality of life is likely to be clinically meaningful, especially for those whose posttreatment symptom scores remain at or above the threshold criteria for PTSD. A potentially advantageous aspect of mindfulness-based interventions is that they may provide benefit for domains of health beyond PTSD symptomatology. A recent VA Evidence-based Synthesis Program report indicated a benefit of [mindfulness-based stress reduction] for overall health status, depression, chronic illness, and possibly pain—conditions that commonly accompany PTSD.” (D. J. Kearney, david.kearney@va.gov)
Prescription Drug Costs: The “chorus of concern over the cost of prescription drugs” provides fodder for a JAMA Forum article that focuses on specialty drugs and the role of third-party payers in “getting the pricing ‘right’” (pp. 440–1): “Discussions of trying to provide information about approximate value of new oncology drugs to patients, even explicitly discussing the concept of value in oncology, are receiving increased attention. For example, the American Society for Clinical Oncology (ASCO) recently published a conceptual value framework to help physicians and patients better assess the value of new cancer treatment options based on clinical benefit, adverse effects, and cost (http://bit.ly/1GxpfMJ). All of this was unimaginable just a few years ago.
“It remains to be seen whether clinicians and patients will be comfortable using concepts of value when choosing among oncologic drugs or when weighing other therapeutic products. But the fact that these issues are even being discussed indicates a new willingness to consider concepts of value when considering competing therapies—and represents an important first step in improving the value of health care provided to even the sickest patients.” (G. Wilensky,
gwilensky@projecthope.org)

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2015; 35).
Quetiapine in Hypoactive Delirium: Supporting the need for a controlled trial, a retrospective cohort study of 113 critically ill adults with documented hypoactive delirium shows that quetiapine therapy was “safe and reduced the duration of delirium compared with standard care alone” (doi: 10.1002/phar.1619). Patients included in the analysis had lengths of stay (LOS) of at least 72 hours in an intensive-care unit (ICU). Based on screening for hypoactive delirium using the Confusion Assessment Method-ICU (CAM-ICU) and the Richmond Agitation Sedation Scale (RASS), the authors found: “Median duration of hypoactive delirium was shorter in the quetiapine-treated group compared with the no-quetiapine group (1.5 vs 2.0 days, p= 0.04), and time to extubation after screening positive for delirium trended favorably toward quetiapine-treated patients (3 vs 5 days, p = 0.08). There were no significant differences in ICU or hospital LOS, and safety outcomes were similar between groups.” (C. J. Michaud, cj.michaud@spectrumhealth.org)
Fluoroquinolone Therapy for H. pylori: In patients requiring an alternative to first-line eradication therapy for treatment of Helicobacter pylori, “treatment with fluoroquinolone-based sequential therapy” is reasonable, according to results of a meta-analysis of six randomized controlled trials (doi: 10.1002/phar.1614). Eradication rates were 87.8% with fluoroquinolones and 71.1% with standard regimens. (S. M. Wilhelm, swilhelm@wayne.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
Aug. 6, 2015 * Vol. 22, No. 150
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 6 New England Journal of Medicine (2015; 373).
Idarucizumab for Dabigatran Reversal: Released earlier in conjunction with presentation at the International Society on Thrombosis and Haemostasis 2015 Congress in Toronto (see PNN, June 23), a study shows complete, rapid reversal of the anticoagulant effects of dabigatran by idarucizumab, an antibody fragment (pp. 511–20). 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 (
pp. 569–71). “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)
Tenofovir Gel for HSV Type 2: Herpes simplex virus type 2 (HSV-2) infection was reduced in 422 women by pericoital application of tenofovir gel, researchers report (pp. 530–9). In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, participants received active gel or placebo, with these results for HSV-2 acquisition in previously negative women: “The HSV-2 incidence rate was 10.2 cases per 100 person–years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person–years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P = 0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person–years, as compared with 15.5 cases per 100 person–years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P = 0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P = 0.005).” (S. A. Karim, caprisa@caprisa.org)
Public Health & Precision Medicine: In the U.S., public health should be emphasized rather than precision medicine, Perspective authors write (pp. 499–501): “‘What is needed now’ is quite different if one views the world from the perspective of the broad pattern of morbidity and mortality, if one is concerned about why the United States has sunk to the bottom of the list of comparable countries in terms of disease experience and life expectancy, or if one is troubled by the steep social gradient that characterizes who becomes sick and who dies.” (R. Bayer)

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
Aug. 7, 2015 * Vol. 22, No. 151
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 11 issue of the Journal of the American College of Cardiology (2015; 66).
Triple Therapy in AMI & AF: Among patients aged 65 years or older, use of triple therapy for acute myocardial infarction (MI) with atrial fibrillation (AF) is common but associated with increased risks and little benefit, according to analysis of data in the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines (pp. 616–27). Triple therapy consisted of dual antiplatelet therapy (DAPT) plus warfarin. Using a primary effectiveness outcome of 2-year major adverse cardiac events (MACE; death, readmission for MI, or stroke) and a primary safety outcome of bleeding readmission, the investigators found: “Among 4,959 patients, 27.6% (n = 1,370) were discharged on triple therapy. Relative to DAPT, patients on triple therapy had a similar risk of MACE (adjusted hazard ratio [HR]: 0.99 [95% confidence interval (CI): 0.86 to 1.16]) but significantly greater risk of bleeding requiring hospitalization (adjusted HR: 1.61 [95% CI: 1.31 to 1.97]) and greater risk of intracranial hemorrhage (adjusted HR: 2.04 [95% CI: 1.25 to 3.34]). Of 1,591 Medicare Part D patients, 90-day post-discharge warfarin persistence among patients discharged on warfarin was 93.2% (n = 412). Results of 90-day landmark analyses comparing triple therapy versus DAPT in patients persistently on warfarin versus those not discharged on warfarin who had not filled a warfarin prescription were similar to our primary findings.” (C. N. Hess)

>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2015; 172).
Predicting Antidepressant Response: Two reports from the International Study to Predict Optimized Treatment for Depression (iSPOT-D) and an editorial examine antidepressant pharmacogenomics.
Among patients with melancholic, atypical, and anxious depressive subtypes, individuals responded similarly to three antidepressants, indicating that “subtypes may be of minimal value in antidepressant selection,” researchers report (
pp. 743–50). The following results were reported for 1,008 adults meeting major depressive disorder criteria and assigned to 8 weeks of therapy with escitalopram, sertraline, or extended-release venlafaxine: “Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect.” (B. A. Arnow)
Genotyping for 10
ABCB1 single-nucleotide polymorphisms (SNPs) proved more fruitful among 683 patients with major depressive disorder, with variances predicting both therapeutic responses and adverse effects (pp. 751–9). A total of 576 patients completed 8 weeks of antidepressant therapy with the P-glycoprotein substrates escitalopram, sertraline, or extended-release venlafaxine. Analysis showed: “The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.” (A. F. Schatzberg)
As with the disease itself, antidepressant response is likely “a polygenic trait,” an editorialist writes, “influenced by numerous genes, each of small effect” (
pp. 697–9). “Therefore, many more genetic markers will be needed before we can achieve clinically significant prediction. This will required much larger samples than have been studied so far. We now know that genome-wide association studies (GWAS) require very large sample sizes to identify genetic markers of polygenic traits. Samples in the tens of thousands are now routine, yet no GWAS of antidepressant outcome to date has exceeded 2,000. As pharmacogenomics begins to bear fruit in psychiatry, we can hope for renewed focus on the large sample sizes necessary for robust findings.” (F. J. McMahon)

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
Aug. 10, 2015 * Vol. 22, No. 152
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 8 issue of Lancet (2015; 386).
Monoclonal Antibodies for Psoriasis: Two research studies examine use of monoclonal antibodies for plaque psoriasis.
“Selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option,” conclude investigators who compared two doses of ixekizumab with etanercept and placebo (
pp. 541–51). In the Phase III UNCOVER-2 and -3 trials, 1,224 adult participants with chronic plaque psoriasis for at least 6 months had these outcomes based on psoriasis area and severity index (PASI) score improvements and changes in static physician global assessment (sPGA) scores: “At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89.7%; [effect size 87.4% (97.5% CI 82.9–91.8) vs placebo; 48.1% (41.2–55.0) vs etanercept]) and 336 (87.3%; [80.0% (74.4–85.7) vs placebo; 33.9% (27.0–40.7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77.5%; [75.1% (69.5–80.8) vs placebo; 35.9% (28.2–43.6) vs etanercept]) and 325 (84.2%; [76.9% (71.0–82.8) vs placebo; 30.8% (23.7–37.9) vs etanercept]) patients; in the placebo group, by four (2.4%) and 14 (7.3%) patients; and in the etanercept group by 149 (41.6%) and 204 (53.4%) patients (all p <0.0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83.2%; [effect size 80.8% (97.5% CI 75.6–86.0) vs placebo; 47.2% (39.9–54.4) vs etanercept]) and 310 (80.5%; [73.8% (67.7–79.9) vs placebo; 38.9% (31.7–46.1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72.9%; [70.5% (64.6–76.5) vs placebo; 36.9% (29.1–44.7) vs etanercept]) and 291 (75.4%; [68.7% (62.3–75.0) vs placebo; 33.8% (26.3–41.3) vs etanercept]) patients; in the placebo group by four (2.4%) and 13 (6.7%) patients; and in the etanercept group by 129 (36.0%) and 159 (41.6%) patients (all p <0.0001 vs placebo or etanercept).” (C. E. M. Griffiths, christopher.griffiths@manchester.ac.uk)
A higher dose of the oral Janus kinase inhibitor tofacitinib was more effective than etanercept in 1,106 patients with chronic stable plaque psoriasis, but a lower dose did not show noninferiority, researchers report (
pp. 552–61). Coprimary endpoints of the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of “clear” or “almost clear” (PGA response) provided these insights into drug efficacy: “At week 12, PASI75 responses were recorded in 130 (39.5%) of 329 patients in the tofacitinib 5 mg group, 210 (63.6%) of 330 in the tofacitinib 10 mg group, 197 (58.8%) of 335 in the etanercept group, and six (5.6%) of 107 in the placebo group. A PGA response was achieved by 155 (47.1%) of 329 patients in the tofacitinib 5 mg group, 225 (68.2%) of 330 in the tofacitinib 10 mg group, 222 (66.3%) of 335 in the etanercept group, and 16 (15.0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group.” (H. Bachelez, herve.bachelez@sls.aphp.fr)

>>>PNN JournalWatch
* Electrolyte and Acid–Base Disturbances in Patients With Diabetes Mellitus, in
New England Journal of Medicine, 2015; 373: 548–59. (B. F. Palmer, biff.palmer@utsouthwestern.edu)
* Comparison of Hospital Variation in Acute Myocardial Infarction Care and Outcome Between Sweden and United Kingdom: Population Based Cohort Study Using Nationwide Clinical Registries, in
BMJ, 2015; 351: h3913. (S-C Chung, s.chung@ucl.ac.uk)
* Is Cholesteryl Ester Transfer Protein Inhibition an Effective Strategy to Reduce Cardiovascular Risk? CETP as a Target to Lower CVD Risk:
The Pro Case (pp. 423–32; P. J. Barter, pbarter@ozemail.com.au) and Suspension of Disbelief (pp. 433–40; G. K. Hovingh, g.k.hovingh@amc.uva.nl)? [point–counterpoint], in Circulation, 2015; 132.
* Community-Acquired Pneumonia: Pathogenesis of Acute Cardiac Events and Potential Adjunctive Therapies, in
Chest, 2015; 148: 523–32. (C. Feldman, charles.feldman@wits.ac.za)
* Filling the Feedback Gap in Cardiovascular Education, in
Journal of the American College of Cardiology, 2015; 66: 748–53. (M. W. Cullen)

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
Aug. 11, 2015 * Vol. 22, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. issue of JAMA Internal Medicine (2015; 175).
Sublingual Tablets for Allergic Rhinoconjunctivitis: Sublingual immunotherapy (SLIT) tablets in patients with seasonal allergic rhinoconjunctivitis (SARC) provide little benefit, researchers report, calling their use into question despite convenience and easy administration (pp. 1301–9). In a systematic review and meta-analysis of 13 randomized controlled trials (RCTs) of 4,659 patients with symptom scores and 12 RCTs of 4,558 patients with medication scores, the investigators found “a small treatment benefit in the symptom score (SMD, −0.28; 95% CI, −0.37 to −0.19; P < .001) and in the medication score (SMD, −0.24; 95% CI, −0.31 to −0.17; P < .001). Adverse events were reported in 1,384 of 2,259 patients (61.3%) receiving SLIT and in 477 of 2,279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine.” (G. Di Lorenzo, gabriele.dilorenzo@unipa.it)
The benefits demonstrated in this analysis are “unimpressive,” an editor writes, but “what was impressive is the 70.0% (1,817 of 2,597 patients) proportion experiencing adverse effects (mostly mouth itching or burning and gastrointestinal tract symptoms)” (
p. 1310). “As these sublingual agents become increasingly available and heavily advertised, it will be prudent for physicians to be aware of these data, in addition to their cost (approximately $90 for a 3-month supply, plus the requirement to coprescribe an epinephrine autoinjector).” (P. G. O’Malley)
Need for Anti-infective Stewardship in Nursing Homes: All residents—not just those being treated—are harmed in nursing homes with high rates of antibiotic use, a study shows, pointing to the need for stewardship efforts (pp. 1331–9). At 607 nursing homes in Ontario, a longitudinal study revealed these patterns and outcomes based on tertiles of antibiotic use: “Antibiotics were provided on 2,783,000 of 50,953,000 resident–days in nursing homes (55 antibiotic–days per 1,000 resident–days). Antibiotic use was highly variable across homes, ranging from 20.4 to 192.9 antibiotic–days per 1,000 resident–days. Antibiotic-related adverse events were more common (13.3%) in residents of high-use homes than among residents of medium-use (12.4%) or low-use homes (11.4%) (P <.001); this trend persisted even among the residents who did not receive antibiotic treatments. The primary analysis indicated that residence in a high-use nursing home was associated with an increased risk of a resident experiencing an antibiotic-related adverse event (adjusted odds ratio, 1.24; 95% CI, 1.07–1.42; P = .003). A sensitivity analysis examining nursing home–level antibiotic use as a continuous variable confirmed an increased risk of resident-level antibiotic-related harms (adjusted odds ratio, 1.004 per additional day of nursing home antibiotic use; 95% CI, 1.001–1.006; P = .01).” (N. Daneman, nick.daneman@sunnybrook.ca)
Interdisciplinary Team Care on General Medical Wards: Traditional measures of quality do not capture benefits of team-based interdisciplinary care on general medical wards, a systematic review shows (pp. 1288–98). “Complications of care or preventable adverse events may merit inclusion as quality indicators for general medical wards,” the authors conclude. “Future study should clarify how best to implement interdisciplinary team care interventions and establish quality metrics that are credible to both health care professionals and patients in this setting.” Results of 30 articles with 66,548 patients (mean age, 63 years) showed the following: “Nineteen of 30 (63%) studies reported length of stay, readmission, or mortality rate as their primary outcome, or did not specify the primacy of their outcomes. The most commonly reported objective patient outcomes were length of stay (23 of 30 [77%]), complications of care (10 of 30 [33%]), in-hospital mortality rate (8 of 30 [27%]), and 30-day readmission rate (8 of 30 [27%]). Of 23 interventions, 16 (70%) had no effect on length of stay, 12 of 15 (80%) did not reduce readmissions, and 14 of 15 (93%) did not affect mortality. Five of 10 (50%) interventions reduced complications of care. In an exploratory quantitative analysis, the interventions did not consistently reduce the relative risk of early readmission or early mortality, or the weighted mean difference in length of stay. All studies had a medium or high risk of bias.” (S. Pannick, s.pannick@imperial.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 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
Aug. 12, 2015 * Vol. 22, No. 154
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 11 issue of JAMA (2015; 314).
Testosterone & Subclinical Atherosclerosis Progression: While a study shows no significantly increased progression of subclinical atherosclerosis in older men during 3 years of testosterone replacement therapy, investigators caution that conclusions regarding overall cardiovascular safety cannot be reached because the study was powered only to evaluate atherosclerosis progression (pp. 570–81). At three U.S. centers, 156 men with low or low-normal testosterone levels had these responses to topical 1% testosterone 7.5 g or placebo daily: “Baseline characteristics were similar between groups: patients were a mean age of 67.6 years; 42% had hypertension; 15%, diabetes; 15%, cardiovascular disease; and 27%, obesity. The rate of change in intima-media thickness was 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference adjusted for age and trial site, 0.0002 mm/year; 95% CI, −0.003 to 0.003, P = .89). The rate of change in the coronary artery calcium score was 41.4 Agatston units/year in the placebo group and 31.4 Agatston units/year in the testosterone group (adjusted mean difference, −10.8 Agatston units/year; 95% CI, −45.7 to 24.2; P = .54). Changes in intima-media thickness or calcium scores were not associated with change in testosterone levels among individuals assigned to receive testosterone. Sexual desire, erectile function, overall sexual function scores, partner intimacy, and health-related quality of life did not differ significantly between groups. Hematocrit and prostate-specific antigen levels increased more in testosterone group.” (S. Bhasin, sbhasin@partners.org)

>>>Chest Report
Source:
Aug. issue of Chest (2015; 148).
Lung Function After Steroid Withdrawal in COPD: Evidence from a 5-year follow-up of inhaled corticosteroid (ICS) discontinuance in patients with chronic obstructive pulmonary disorder (COPD) “suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation” (pp. 389–96). The drugs were discontinued at month 30 of the study, which included 114 patients with moderate to severe COPD. Fluticasone 500 mcg twice daily, fluticasone 500 mcg/salmeterol 50 mcg twice daily, or placebo produced these outcomes during the first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study (GL1) and the GLUCOLD follow-up study (GL2): “Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2–GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, −68 mL/y [−112 to −25], P = .002; 30-month treatment with fluticasone, −73 mL/y [−119 to −26], P = .002), accompanied by deterioration in [airway hyperresponsiveness] and [quality of life].” (L. I. Z. Kunz, L.I.Z.Kunz@lumc.nl)
Umeclidinium–Vilanterol in COPD: In patients with moderate to severe chronic obstructive pulmonary disorder (COPD), once-daily treatment with umeclidinium (UMEC)/vilanterol (VIL) is superior to the two drugs used alone, tiotropium, and fluticasone/combination, according to results of a systematic review (pp. 397–407): “Eleven trials from 10 studies (9,609 patients) showed that UMEV/VIL provided superior improvements in lung function compared with UMEC, VIL, tiotropium, and fluticasone propionate/salmeterol (mean trough FEV1, 60, 110, 90, and 90 mL, respectively; P < .0001). Also, UMEC/VIL had a greater likelihood of demonstrating a minimal clinically important difference on the Transition Dyspnea Index compared with UMEC and VIL (number needed to treat for benefit [NNTB] = 14 and 10, respectively). UMEC/VIL therapy significantly reduced the risk of COPD exacerbations compared with UMEC and VIL (NNTB = 42 and 41, respectively). On the contrary, we noted no significant differences between UMEC/VIL and tiotropium with respect to dyspnea, health status, or risk of COPD exacerbation. Regarding safety issues, the incidence of [adverse events] and mortality on treatment was similar across treatments, suggesting reduced safety concerns with the use of the UMEC/VIL combination.” (G. J. Rodrigo, gustavo.javier.rodrigo@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
Aug. 13, 2015 * Vol. 22, No. 155
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 13 issue of the New England Journal of Medicine (2015; 373).
Elotuzumab for Multiple Myeloma: An immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), elotuzumab reduced risk of disease progression or death by 30% when used in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma, researchers report (pp. 621–31). The Phase III study used coprimary end points of progression-free survival and overall response rate: “Overall, 321 patients were assigned to the [elotuzumab plus lenalidomide and dexamethasone] group and 325 to the [lenalidomide and dexamethasone alone] control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P <0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P <0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.” (S. Lonial, sloni01@emory.edu)
Troponin in Stable Ischemic Heart Disease, Diabetes: While elevated troponin levels are associated with higher risks of cardiovascular events in patients with stable ischemic heart disease and type 2 diabetes, a study cutoff value of 14 ng/L failed to identify a subgroup of patients who benefited from prompt coronary revascularization (pp. 610–20). The Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes trial group reports these results for association between troponin T concentration and composite cardiovascular death, myocardial infarction, or stroke: “Of the 2,285 patients, 2,277 (99.6%) had detectable (≥3 ng per liter) troponin T concentrations and 897 (39.3%) had abnormal troponin T concentrations at baseline. The 5-year rate of the composite end point was 27.1% among the patients who had had abnormal troponin T concentrations at baseline, as compared with 12.9% among those who had had normal baseline troponin T concentrations. In models that were adjusted for cardiovascular risk factors, severity of diabetes, electrocardiographic abnormalities, and coronary anatomy, the hazard ratio for the composite end point among patients with abnormal troponin T concentrations was 1.85 (95% confidence interval [CI], 1.48 to 2.32; P <0.001). Among patients with abnormal troponin T concentrations, random assignment to prompt revascularization, as compared with medical therapy alone, did not result in a significant reduction in the rate of the composite end point (hazard ratio, 0.96; 95% CI, 0.74 to 1.25).” (B. M. Everett, beverett@partners.org)
Differential Taxes for Nicotine-Yielding Products: Taxes for nicotine products should be based on how much drug they deliver, write Perspective authors (pp. 594–7): “[This] could substantially expedite the move away from cigarette smoking that has occurred during the past half-century, especially now that there are nicotine-yielding products that pose dramatically less danger than combustible tobacco products. Nearly a fifth of U.S. adults are cigarette smokers, and smoking accounts for one of every five deaths in the United States. Failure to seriously entertain a differential taxation approach may contribute to the prolongation of the epidemic of disease and death caused by smoking.” (F. J. Chaloupka)

>>>PNN NewsWatch
* The physician who cited lack of safety evidence in refusing to approve thalidomide died last week, FDA reports in a blog. “Frances Oldham Kelsey, PhD, MD, who joined FDA in 1960 as a medical officer, was known worldwide as a leader in drug safety and the protection of patients,” writes Acting FDA Commissioner Stephen M. Ostroff, MD. “She established that reputation in one of first FDA assignments: reviewing the marketing application for a drug called thalidomide, which was already available in dozens of countries around the world.”

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
Aug. 14, 2015 * Vol. 22, No. 156
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Sept. 1 issue of Clinical Infectious Diseases (2015; 61).
Long-Term Valacyclovir in Herpes Simplex Encephalitis: Among high-functioning survivors of herpes simplex encephalitis (HSE), addition of a 3-month course of oral valacyclovir (VACV) did not improve neurophysiologic outcomes 12 months later, researchers report (pp. 683–91). The study included 87 adults with HSE confirmed by polymerase chain reaction. After a standard course of I.V. acyclovir (ACV), treatment with oral VACV 2 g three times daily or placebo yielded little change in a primary endpoint of survival with no or mild neuropsychological impairment at 12 months: “The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the [Mattis Dementia Rating Scale] scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group.” (J. W. Gnann, Jr., gnann@musc.edu)
“Perhaps the easiest target of all for improving survival and outcomes [with HSE] is simply to do better with therapy that we know works,” an editorialist writes in evaluating study results (
pp. 692–4). “Many studies have suggested that we need to dramatically improve performance in the use of empiric ACV therapy in patients with suspected encephalitis, and to address factors causing delays.… Factors that can contribute to these delays include the associated presence of other severe underlying illnesses, a delay in brain imaging, and low CSF cell counts. Surprisingly, in some settings, an important factor in delay is simply the failure to consider HSE in the differential diagnosis despite compatible and suggestive clinical and laboratory features.” (K. L. Tyler, ken.tyler@ucdenver.edu)
Sustained Pseudomonal Eradication in Cystic Fibrosis: The “critical importance” of early antipseudomonal therapy in children with cystic fibrosis is demonstrated in the Early Pseudomonas Infection Control trial (pp. 707–15). The cohort study examined patients whose Pseudomonas aeruginosa (Pa) infections were successfully eradicated (Pa-negative cultures for 12 months) after initial antipseudomonal therapy: “Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17–.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25–.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline.” (N. Mayer–Hamblett, nicole.hamblett@seattlechildrens.org)
“This study … suggests the need to further improve our eradication strategies given that 1 in 3 children did not achieve sustained eradication,” editorialists write (
pp. 716–8). “Although antibiotic resistance did not emerge during this study, the increased use of anti-Pa antibiotics among those who did not achieve sustained eradication suggests that those children are at increased risk for antibiotic resistance with time. As people with CF live longer, judicious use of antibiotics will be increasingly important, and balancing this with the need to delay lung disease development will be challenging. This study supports our current clinical practice while highlighting the need for improved eradication approaches and more sensitive outcome measures in children.” (E. T. Zemanick, edith.zemanick@childrenscolorado.org)

>>>PNN NewsWatch
* Registration as outsourcing facilities under the 503B section of the compounding law is proceeding slowly, pharmacist.com reports, with just 55 companies so far.
* While
naloxone availability for use by nonmedical responders is expanding, so is price of the product, according to a news article in the American Journal of Health-System Pharmacy. Cost is forcing some community programs to use intramuscular products rather than autoinjector devices.

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
Aug. 17, 2015 * Vol. 22, No. 157
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 15 issue of Lancet (2015; 386).
Idarucizumab Reversal of Dabigatran: In a proof-of-concept Phase I trial, the monoclonal antibody fragment idarucizumab “was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing,” researchers report (pp. 680–90). A total of 47 participants received four twice-daily doses of dabigatran 220 mg. Two hours after the last dose, placebo or idarucizumab in dose-ranging infusions was administered, with these results: “Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2.5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 [area under the effect curve from 2 h to 12 h (AUEC2–12)]to day 3 AUEC2–12 for [diluted thrombin time] was 1.01 with placebo, 0.26 with 1 g idarucizumab (74% reduction), 0.06 with 2 g idarucizumab (94% reduction), 0.02 with 4 g idarucizumab (98% reduction), and 0.01 with 5 g plus 2.5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups.” (S. Glund, stephan.glund@boehringer-ingelheim.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Risks of Saturated & Trans Unsaturated Fatty Acids: In the first meta-analysis of prospective observational studies that examine associations of saturated and trans fats with all-cause mortality, results of five previous systematic reviews are confirmed: “There was no association between saturated fats and health outcomes in studies where saturated fat generally replaced refined carbohydrates, but there was a positive association between total trans fatty acids and health outcomes” (h3978): “For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501–339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), [cardiovascular disease (CVD)] mortality (0.97, 0.84 to 1.12), total [coronary heart disease (CHD)] (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P = 0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942–230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was ‘very low.’ The certainty of associations of trans fat with CHD outcomes was ‘moderate’ and ‘very low’ to ‘low’ for other associations.” (S. Anand, anands@mcmaster.ca)

>>>PNN NewsWatch
* Pediatric pain management options are discussed by an FDA physician in a Q&A about approval of OxyContin in patients aged 11–16 years.

>>>PNN JournalWatch
* American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options, in
Journal of Clinical Oncology, 2015; 33: 2563–77. (L. E. Schnipper, lschnipp@bidmc.harvard.edu)
* Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR), in
Clinical Infectious Diseases, 2015; 61: 800–6. (S. R. Evans, evans@sdac.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 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
Aug. 18, 2015 * Vol. 22, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 18 issue of the Annals of Internal Medicine (2015; 163).
Dyslipidemia—Guideline & ‘Beyond the Guidelines’: Two articles present ideas on how to manage dyslipidemias and how to balance benefits and risks of available treatments.
While advising elimination of treatment target levels for LDL cholesterol and non–HDL cholesterol in patients with dyslipidemia, a VA/Dept. of Defense clinical practice guideline notes that “clear evidence shows that moderate fixed-dose statin monotherapy improves total mortality and results in fewer [cardiovascular disease (CVD)] events” (
pp. 291–7). Making recommendations in five areas (elimination of treatment targets, additional tests for risk prediction, primary and secondary prevention, and laboratory testing), the authors provide this reason for their advice on medication use: “Because of the lack of direct evidence about target cholesterol goals, which can lead to physicians prescribing escalating doses of statins and combinations of drugs with higher rates of adverse effects without known benefit in outcomes, the VA/DoD recommends against the use of cholesterol levels as treatment targets.” (J. R. Downs, john.downs@va.gov)
A second article based on a grand rounds discussion “summarizes a discussion between a cardiologist and an internist about how each clinician would balance these factors and what treatment they would suggest for an individual patient” (
pp. 280–90). While 2013 guidelines of the American College of Cardiology and the American Heart Association are clear in their recommendations for statin therapy for four patient groups at risk for atherosclerotic cardiovascular disease, the discussion notes that their application in clinical practice might present challenges based on individual patient characteristics. (R. B. Burns, rburns@bidmc.harvard.edu)
Mortality With Medical Therapy in Ulcerative Colitis: In patients aged 50 or older with advanced ulcerative colitis (UC), medical therapy was associated with higher mortality rates than was elective colectomy in a retrospective matched cohort study (pp. 262–70). Using a primary outcome of time to death, investigators found these patterns among Medicaid, Medicare, and dual-eligible beneficiaries in various time periods between 2000 and 2011 (n = 830 patients pursuing colectomy and 7,541 matched patients pursuing medical therapy with long-term immunosuppressants): “The mortality rates associated with elective surgery and medical therapy were 34 and 54 deaths per 1,000 person–years, respectively. Elective colectomy was associated with improved survival compared with long-term medical therapy (adjusted hazard ratio [HR], 0.67 [95% CI, 0.52 to 0.87]), although this result did not remain statistically significant in all sensitivity analyses. Post hoc analysis by age group showed improved survival with surgery in patients aged 50 years or older with advanced UC (HR, 0.60 [CI, 0.45 to 0.79]; P = 0.032 for age-by-treatment interaction).” (M. Bewtra, mbewtra@upenn.edu)
“The goal of therapy is not avoiding surgery but making the patient well—not saving colons, but saving lives,” an editorialist writes in reaction to this study (
pp. 316–7). “Surgery is associated with a survival benefit, a finding previously suggested by European data.… Perhaps more important, we need to reappraise the answer to the question raised in the first sentence of this editorial: What constitutes success? Too often, we reflexively assume that the touchstone of therapeutic success is ‘sparing’ or ‘salvaging’ the patient from surgery. The measure of triumph, and indeed the end point of most clinical trials in severe UC, has traditionally been discharging the patient from the hospital without colectomy. In these scenarios, surgery has generally represented an end point of ‘failure.’ Yet, this study demonstrates that simply keeping a patient’s colon intact is not a sufficient long-term measure of therapeutic ‘success.…’ We cannot preserve quality of life unless we first save life itself.” (D. B. Sachar, david.sachar@mountsinai.org)

>>>PNN NewsWatch
* A federal judge yesterday entered a consent decree of permanent injunction against Iowa Select Herbs LLC, a manufacturer and distributor of drugs and dietary supplements, and two co-owners, FDA 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
Aug. 19, 2015 * Vol. 22, No. 159
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 18 issue of JAMA (2015; 314).
Tinzaparin in VTE With Active Cancer: In a 164-center trial conducted on five continents among 900 patients with active venous thromboembolism (VTE) and active cancer, “full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did not significantly reduce [a] composite measure of recurrent VTE and was not associated with reductions in overall mortality or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding,” researchers report (pp. 677–86). Based on a primary efficacy outcome of recurrent [proximal deep vein thrombosis (DVT)], fatal or nonfatal pulmonary embolism, and incidental VTE, the study yielded these results: “Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41–1.03]; P = .07). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89 [95% CI, 0.40–1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin; HR, 1.08 [95% CI, 0.85–1.36]; P = .54). A significant reduction in clinically relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40–0.84]; P = .004).” (A. Y. Y. Lee)
Liraglutide for Weight Loss in Type 2 Diabetes: In a 56-week trial, 846 patients with type 2 diabetes and body mass index of 27.0 kg/sq m or more, subcutaneous liraglutide 3 mg daily resulted in weight loss compared with placebo (pp. 687–99). Participants were randomized to one of two doses of liraglutide or to placebo at 126 sites in nine countries, with these results: “Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, −4.00% [95% CI, −5.10% to −2.90%]; liraglutide [1.8 mg] vs placebo, −2.71% [95% CI, −4.00% to −1.42%]; P < .001 for both). Weight loss of 5% or greater occurred in 54.3% with liraglutide (3.0 mg) and 40.4% with liraglutide (1.8 mg) vs 21.4% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 32.9% [95% CI, 24.6% to 41.2%]; for liraglutide [1.8 mg] vs placebo, 19.0% [95% CI, 9.1% to 28.8%]; P < .001 for both). Weight loss greater than 10% occurred in 25.2% with liraglutide (3.0 mg) and 15.9% with liraglutide (1.8 mg) vs 6.7% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 18.5% [95% CI, 12.7% to 24.4%], P < .001; for liraglutide [1.8 mg] vs placebo, 9.3% [95% CI, 2.7% to 15.8%], P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported.” (M. J. Davies, melanie.davies@uhl-tr.nhs.uk)
E-cigarette Use & Tobacco Initiation: Based on a study showing that high school students who use electronic cigarettes were more likely to begin using combustible tobacco products (pp. 700–7; A. M. Leventhal, adam.leventhal@usc.edu), an editorialist calls for “prompt, effective action … to protect youth and reduce the demand for e-cigarettes by nonsmokers of all ages” (pp. 673–4). “A rational approach is to extend to e-cigarettes the same sales, marketing, and use restrictions that apply to combustible cigarettes.… To support future actions, researchers must seek to understand how to balance the benefits and risks of e-cigarettes and thereby to maximize public health and reduce the enormous toll of tobacco-related disease.” (N. A. Rigotti, nrigotti@partners.org)

>>>PNN NewsWatch
* In a controversial decision, FDA yesterday approved flibanserin (Addyi, Sprout Pharmaceuticals) for treatment of acquired, generalized hypoactive sexual desire disorder in premenopausal women. This is the first approval for this indication. Flibanserin is a serotonin 1A receptor agonist/serotonin 2A receptor antagonist that is taken at bedtime to reduce the incidence of several adverse effects—hypotension, syncope, and sleepiness, sedation, and other CNS depressive symptoms.

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
Aug. 20, 2015 * Vol. 22, No. 160
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 20 issue of the New England Journal of Medicine (2015; 373).
Treating HCV/HIV-1 Coinfections: Two studies examine regimens of the nucleotide polymerase inhibitor sofosbuvir in patients with hepatitis C virus (HCV) coinfected with human immunodeficiency virus type 1 (HIV-1).
In patients with HIV-1 and HCV genotypes 1 or 4, 12 weeks of treatment with a combination of the NS5A inhibitor ledipasvir and sofosbuvir “provided high rates of sustained virologic response,” researchers report (
pp. 705–13): “Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events.” (S. Naggie, susanna.naggie@duke.edu)
A second study examined effects of daclatasvir, also an NS5A inhibitor, with sofosbuvir in 151 previously untreated and 52 previously treated patients with HCV and HIV-1 (
pp. 714–25). Across all HCV genotypes, the 12-week rate of sustained virologic response was 97.0%, the study shows: “Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised.” (D. L. Wyles, dwyles@ucsd.edu)
Chemohormonal Therapy in Prostate Cancer: Among 790 men with metastatic, hormone-sensitive prostate cancer placed on androgen-deprivation therapy (ADT), addition of docetaxel increased overall survival, a study shows (pp. 737–46). Participants received ADT with or without six cycles of docetaxel at the beginning of therapy, with these results: “After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P <0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P <0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P <0.001).” (C. J. Sweeney, christopher_sweeney@dfci.harvard.edu)

>>>PNN NewsWatch
* Compounded or repackaged drugs should not be stored in 3-mL and 5-mL Becton–Dickinson syringes unless no suitable alternatives are available, FDA warned this week. Preliminary information indicates that drugs stored in these syringes may lose potency over a period of time due to a possible interaction with the rubber stopper in the syringe, FDA said. This issue may extend to other general-use syringes made by other manufacturers that were not cleared for the purpose of closed-container storage usage. Products approved by FDA for marketing as prefilled syringes are unaffected, as they will maintain stability through their expiration dates.

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
Aug. 21, 2015 * Vol. 22, No. 161
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept issue of Diabetes Care (2015; 38).
Euglycemic Diabetic Ketoacidosis With SGLT2 Inhibitors: Two studies and a commentary examine the increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium–glucose cotransporter 2 (SGLT2) inhibitors.
In 17,596 patients with type 2 diabetes who participated in randomized trials of canagliflozin, “DKA and related events occurred at a low frequency…, with an incidence consistent with limited existing observational data in the general population with type 2 diabetes.” researchers report (
pp. 1680–6): “Serious adverse events of DKA and related events were reported in 12 patients (0.07%), including 4 (0.07%), 6 (0.11%), and 2 (0.03%) treated with canagliflozin 100 and 300 mg and comparator, respectively; corresponding incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient–years, respectively. Most patients with DKA and related events had a blood glucose >300 mg/dL (16.7 mmol/L) at presentation of DKA, were on insulin, and had DKA-precipitating factors, including some with type 1 diabetes/latent autoimmune diabetes of adulthood.” (G. Meininger, gmeining@its.jnj.com)
Based on 13 episodes of SGLT-2 inhibitor–associated euDKA or ketosis in nine individuals with type 1 or type 2 diabetes, authors reach this conclusion in a second report (
pp. 1687–93): “SGLT-2 inhibitors seem to be associated with euglycemic DKA and ketosis, perhaps as a consequence of their noninsulin-dependent glucose clearance, hyperglucagonemia, and volume depletion. Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for the presence of urine and/or serum ketones. SGLT-2 inhibitors should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes.” (A. L. Peters, momofmax@mac.com)
Through ongoing, long-term trials of SGLT-2 inhibitors, safety and efficacy will be further elucidated in both type 1 and insulin-treated type 2 diabetes, conclude the commentary authors (
pp. 1638–42): “Regulatory scrutiny of these compounds will balance their beneficial impact on overall glycemic control, glycemic variability, and weight management against the risk of hypoglycemia and overall safety, including risk of euDKA. A reduction in insulin dose should not be regarded as a positive outcome in itself and should be achieved by slow, gentle decrements simultaneously to avoid hypoglycemia and sliding toward euDKA. Hopefully, these clinical development programs will quickly expand so as to offer to patients and physicians a potential adjunct against the day-to-day management challenges of such a demanding disease.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
Energy Balance in SGLT-2 Inhibition: An “adaptive intake” of calories prevents major weight loss that is expected secondary to glycosuria in patients treated with sodium–glucose cotransporter 2 (SGLT2) inhibitors, a study shows (pp. 1730–5). In 86 patients with type 2 diabetes, the predicted caloric deficit averaged 206 kcal/d, which should have produced mean weight loss of 11.3 kg over 90 weeks. Instead, patients averaged a 3.2 kg weight loss, just 29% of expected. Patients had increased caloric intake that was inversely related to their baseline body mass index, thus minimizing the weight loss associated with the drug. (E. Ferrannini, ferranni@ifc.cnr.it)
Alcohol & Type 2 Diabetes Risk: Reductions in risk of type 2 diabetes associated with moderate alcohol intake may be limited to women and non–Asian populations, according to a systematic review and meta-analysis of data from 38 observational studies involving 1.9 million people (pp. 1804–12): “Relative to combined abstainers, reductions in the risk of type 2 diabetes were present at all levels of alcohol intake <63 g/day, with risks increasing above this threshold. Peak risk reduction was present between 10–14 g/day at an 18% decrease in hazards. Stratification of available data revealed that reductions in risk may be specific to women only and absent in studies that adopted a never-drinking abstention category or sampled an Asian population region.” (C. Knott, craig.knott.10@ucl.ac.uk)

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


PNN Pharmacotherapy Line
Aug. 24, 2015 * Vol. 22, No. 162
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2015; 351).
Treatments for H. pylori: Data on dozens of possible combinations of treatments for Helicobacter pylori identify several optimal regimens for efficacy and safety: 7–14 days of concomitant therapies, 10–14 days of probiotic-supplemented triple treatment, 10–14 days of levofloxacin-based triple treatment, 14 days of hybrid treatment, and 10 or 14 days of sequential treatment (h4052). A systematic review and network meta-analysis of 143 studies found that 14 treatments had been studied. Of the 91 possible combinations of these treatments, 34 had been compared directly: “The following treatments performed better: seven days of concomitant treatment (proton pump inhibitor and three kinds of antibiotics administered together), 10 or 14 days of concomitant treatment, 10 or 14 days of probiotic supplemented triple treatment (standard triple treatment which is probiotic supplemented), 10 or 14 days of levofloxacin based triple treatment (proton pump inhibitor, levofloxacin, and antibiotic administered together), 14 days of hybrid treatment (proton pump inhibitor and amoxicillin used for seven days, followed by a proton pump inhibitor, amoxicillin, clarithromycin, and 5-nitroimidazole for another seven days), and 10 or 14 days of sequential treatment (five or seven days of a proton pump inhibitor plus amoxicillin, followed by five or seven additional days of a proton pump inhibitor plus clarithromycin and 5-nitroimidazole or amoxicillin). In terms of tolerance, all treatments were considered tolerable, but seven days of probiotic supplemented triple treatment and seven days of levofloxacin based triple treatment ranked best in terms of the proportion of adverse events reported.” (D-Q Ye, ydq@ahmu.edu.cn)
Alcohol & Cancer: In studies of U.S. health professionals, consumption of as little as one drink per day was associated with a slightly increased risk of cancer in women, researchers report (h4238). Men who had never smoked had no increased risk with up to two drinks per day, according to 3.1 million person–years of experiences recorded in the Nurses’ Health Study and Health Professionals Follow-up Study: “Compared with non-drinkers, light to moderate drinkers had relative risks of total cancer of 1.02 (95% confidence interval 0.98 to 1.06) and 1.04 (1.00 to 1.09; Ptrend=0.12) for alcohol intake of 0.1–4.9 and 5–14.9 g/day among women, respectively. Corresponding values for men were 1.03 (0.96 to 1.11), 1.05 (0.97 to 1.12), and 1.06 (0.98 to 1.15; Ptrend=0.31) for alcohol intake of 0.1–4.9, 5–14.9, and 15–29.9 g/day, respectively. Associations for light to moderate drinking and total cancer were similar among ever or never smokers, although alcohol consumption above moderate levels (in particular ≥30 g/day) was more strongly associated with risk of total cancer among ever smokers than never smokers. For a priori defined alcohol related cancers in men, risk was not appreciably increased for light and moderate drinkers who never smoked (Ptrend=0.18). However, for women, even an alcohol consumption of 5–14.9 g/day was associated with increased risk of alcohol related cancer (relative risk 1.13 (95% confidence interval 1.06 to 1.20)), driven by breast cancer. More frequent and heavy episodic drinking was not further associated with risk of total cancer after adjusting for total alcohol intake.” (E. L. Giovannucci, egiovann@hsph.harvard.edu)

>>>PNN JournalWatch
* Global, Regional, and National Incidence, Prevalence, and Years Lived With Disability for 301 Acute and Chronic Diseases and Injuries in 188 Countries, 1990–2013: A Systematic Analysis for the Global Burden Of Disease Study 2013, in
Lancet, 2015; 386: 743–800. (Global Burden of Disease Study 2013 Collaborators)
* Hospital Board and Management Practices Are Strongly Related to Hospital Performance on Clinical Quality Metrics, in
Health Affairs, 2015; 34: 1304–11. (T. C. Tsai, ttsai@hsph.harvard.edu)
* Promising Practices for Achieving Patient-Centered Hospital Care: A National Study of High-Performing US Hospitals, in
Medical Care, 2015; 53: 758–67. (H. J. Aboumatar)
* Evolving Models of the Immunopathogenesis of T Cell–Mediated Drug Allergy: The Role of Host, Pathogens, and Drug Response, in
Journal of Allergy and Clinical Immunology, 2015; 136: 219–34. (E. J. Phillips, elizabeth.j.phillips@vanderbilt.edu)
* Magnesium and Dialysis: The Neglected Cation, in
American Journal of Kidney Diseases, 2015; 66: 523–31. (D. J. Leehey, dleehey@lumc.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
Aug. 25, 2015 * Vol. 22, No. 163
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2015; 163).
Low-Dose Aspirin or NSAIDs & Colorectal Cancer Risk: In a population-based, case–control study from northern Denmark, continuous use of low-dose aspirin or long-term use of nonaspirin NSAIDs was associated with reduced risk of colorectal cancer (doi: 10.7326/M15-0039). Analysis of drug-use patterns among those with first-time colorectal cancer in 1994–2011 showed these patterns: “Among 10,280 case patients and 102,800 control participants, the adjusted odds ratios (ORs) for colorectal cancer associated with ever use (≥2 prescriptions) of low-dose aspirin and nonaspirin NSAIDs were 1.03 (95% CI, 0.98 to 1.09) and 0.94 (CI, 0.90 to 0.98), respectively. Continuous long-term use (≥5 years) of low-dose aspirin was associated with a 27% reduction in colorectal cancer risk (OR, 0.73 [CI, 0.54 to 0.99]), whereas the overall OR for cumulative long-term use (continuous or noncontinuous) was close to unity. Nonaspirin NSAID use was associated with a substantial reduction in colorectal cancer risk, particularly for long-term, high-intensity use (average defined daily dose ≥0.3) of agents with high cyclooxygenase-2 selectivity (OR, 0.57 [CI, 0.44 to 0.74]).” (S. Friis, friis@cancer.dk)
Epidural Corticosteroid Injections: In patients with radiculopathy, epidural corticosteroid injections provide immediate reductions in pain but also function, according to a systematic review and meta-analysis of 30 placebo-controlled trials (doi: 10.7326/M15-0934). “However, benefits were small and not sustained, and there was no effect on long-term surgery risk,” the authors conclude. Limited evidence from eight trials of patients with spinal stenosis showed no effectiveness, , the group wrote, adding these details about the review: “For radiculopathy, epidural corticosteroids were associated with greater immediate-term reduction in pain (weighted mean difference on a scale of 0 to 100, −7.55 [95% CI, −11.4 to −3.74]; SOE, moderate), function (standardized mean difference after exclusion of an outlier trial, −0.33 [CI, −0.56 to −0.09]; SOE, low), and short-term surgery risk (relative risk, 0.62 [CI, 0.41 to 0.92]; SOE, low). Effects were below predefined minimum clinically important difference thresholds, and there were no longer-term benefits. Limited evidence showed no clear effects of technical factors, patient characteristics, or comparator interventions on estimates. There were no clear effects of epidural corticosteroid injections for spinal stenosis (SOE, low to moderate). Serious harms were rare, but harms reporting was suboptimal (SOE, low).” (R. Chou, chour@ohsu.edu)

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (2015; 136).
Drug Allergy Workshop: Experts provide insights into drug allergy research and recommendations for the future in a report from a 2013 National Institute of Allergy and Infectious Diseases workshop on drug allergy (pp. 262–271.e2). In addition to numerous specific recommendations, the panel provided analysis of problems of studying drug allergy, beginning with terminology: “Many physicians and some investigators use the term ‘allergy’ only in the context of IgE-mediated disease. However, it is clear that many [drug reactions] discussed at the workshop, such as hepatic necrosis and Stevens–Johnson syndrome (SJS), are immunologically mediated but not dependent on IgE. Several expert panel members suggested that ‘drug hypersensitivity’ could be a better term to use than ‘drug allergy.’ Although this is a valid suggestion, ‘drug hypersensitivity’ has been suggested as the term to use for a reaction that might be immunologically mediated, and ‘drug allergy’ has been recommended as the term to use for any adverse DR that has a proved immunologic mechanism; it is this definition that is used in this document. However, additional discussion will be required among research disciplines to harmonize terminology. For example, reactions to taxanes are termed ‘toxic’ by oncologists and ‘pseudoallergic’ by allergists, whereas they are perhaps best termed simply as ‘immediate’ until such time as they are more completely characterized. The expert panel was tasked with evaluating and developing research agendas for all immunologic reactions in which the drug or drug metabolites drive an immune response, irrespective of whether they are IgE-mediated.” (L. M. Wheatley, lisa.wheatley@nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 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
Aug. 26, 2015 * Vol. 22, No. 164
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 25 issue of JAMA (2015; 314).
Maintaining Cognition in Older Adults: Two studies and an editorial examine interventions for maintaining cognitive function in older adults.
Among patients at risk for late age-related macular degeneration (AMD), oral supplementation with long-chain polyunsaturated fatty acids (LCPUFAs) or lutein/zeaxanthin had no statistically significant effect on cognitive function, Age-Related Eye Disease Study 2 (AREDS2) investigators conclude (
pp. 791–801). At 82 U.S. medical centers, study participants received LCPUFA 2 g and/or lutein 10 mg/zeaxanthin 2 mg or placebo with varying amounts of vitamins C or E, beta-carotene, and zinc. Results on a composite battery of tests (scale range, –22 to 17) showed: “A total of 89% (3,741/4,203) of AREDS2 participants consented to the ancillary cognitive function study and 93.6% (3,501/3,741) underwent cognitive function testing. The mean (SD) age of the participants was 72.7 (7.7) years and 57.5% were women. There were no statistically significant differences in change of scores for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was −0.19 (99% CI, −0.25 to −0.13) for participants randomized to receive LCPUFAs vs −0.18 (99% CI, −0.24 to −0.12) for those randomized to no LCPUFAs (difference in yearly change, −0.03 [99% CI, −0.20 to 0.13]; P = .63). Similarly, the yearly change in the composite cognitive function score was −0.18 (99% CI, −0.24 to −0.11) for participants randomized to receive lutein/zeaxanthin vs −0.19 (99% CI, −0.25 to −0.13) for those randomized to not receive lutein/zeaxanthin (difference in yearly change, 0.03 [99% CI, −0.14 to 0.19]; P = .66). Analyses were also conducted to assess for potential interactions between LCPUFAs and lutein/zeaxanthin and none were found to be significant.” (E. Y. Chew, echew@nei.nih.gov)
A second study—of moderate-intensity physical activity—also had no significant overall effect on cognition compared with a health education program (
pp. 781–90). A total of 1,635 community-dwelling adults aged 70–89 years had these outcomes in subgroups engaged in structured walking, resistance training, and flexibility exercises or educational workshops and upper-extremity stretching: “Participants in the physical activity group who were 80 years or older (n = 307) and those with poorer baseline physical performance (n = 328) had better changes in executive function composite scores compared with the health education group (P = .01 for interaction for both comparisons). Incident [mild cognitive impairment] or dementia occurred in 98 participants (13.2%) in the physical activity group and 91 participants (12.1%) in the health education group (odds ratio, 1.08 [95% CI, 0.80 to 1.46]).” (K. M. Sink, kmsink@wakehealth.edu)
“Unlike studies of exercise, investigations evaluating the relationship between specific dietary supplements and cognitive decline have had more consistently negative findings,” editorialists write (
pp. 774–5). “Although severe nutritional deficiencies are known to contribute to cognitive impairment in older adults (such as vitamin B12 deficiency and niacin deficiency), [randomized controlled trials (RCTs)] have failed to demonstrate benefits from nutritional supplementation to improve cognition or prevent dementia. For example, vitamin E has not been shown to protect against the development of dementia in RCTs of individuals with [mild cognitive impairment]. Even though specific dietary supplements may not be efficacious, results from the the PREDIMED trial demonstrated that consumption of a Mediterranean diet supplemented with olive oil or nuts was associated with improved cognitive function. Epidemiological evidence has also suggested that adherence to a Mediterranean diet may be associated with a reduced risk of dementia, with this effect possibly mediated by beneficial cardiovascular effects. Thus, long-term adherence to a balanced, heart-healthy diet may have greater cognitive benefits than more narrow focus on supplementing specific micronutrients.” (S. S. Gill, sudeep.gill@ices.on.ca)

>>>PNN NewsWatch
* A small black particle created by opening the cap of several ophthalmic products has prompted recalls by Allergan.

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
Aug. 27, 2015 * Vol. 22, No. 165
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 27 issue of the New England Journal of Medicine (2015; 373).
Early Antiretroviral Therapy: Timing of antiretroviral therapy (ART) in early HIV infection is the topic of two studies and an editorial.
Initiation of ART before CD4+ counts have declined to 500 cells/cu mm yields net benefits over waiting until levels reach 350 cells/cu mm, according to a study of asymptomatic adults (
pp. 795–807). When the Strategic Timing of Antiretroviral Therapy (START) study began in 2009, the recommended therapy for early HIV infection was to wait until counts had declined to 350 cells/cu mm. HIV-positive adults with CD4+ counts of 500 cellls/cu mm or more were assigned to either immediate ART or deferred ART (until counts reached 350 cells/cu mm), with this impact on a primary composite end point of any serious AIDS-related event, serious non–AIDS-related event, or death from any cause: “A total of 4,685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person–years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person–years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P <0.001). Hazard ratios for serious AIDS-related and serious non–AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P <0.001) and 0.61 (95% CI, 0.38 to 0.97; P = 0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions.” (J. D. Lundgren, jens.lundgren@regionh.dk)
In the TEMPRANO ANRS 12136 study, immediate ART and 6 months of isoniazid preventive therapy (IPT) reduced rates of severe illness among HIV-infected adults with high CD4+ cell counts, compared with deferred ART and no IPT, researchers report (
pp. 808–22). A composite end point of diseases included in the AIDS case definition, non–AIDS-defining cancer, non–AIDS-defining invasive bacterial disease, or death from any cause at 30 months showed these patterns in four study groups: “A total of 2,056 patients (41% with a baseline CD4+ count of ≥500 cells per cubic millimeter) were followed for 4,757 patient–years. A total of 204 primary end-point events were observed (3.8 events per 100 person–years; 95% confidence interval [CI], 3.3 to 4.4), including 68 in patients with a baseline CD4+ count of at least 500 cells per cubic millimeter (3.2 events per 100 person–years; 95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial diseases accounted for 42% and 27% of primary end-point events, respectively. The risk of death or severe HIV-related illness was lower with early ART than with deferred ART (adjusted hazard ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88; adjusted hazard ratio among patients with a baseline CD4+ count of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to 1.01). The 30-month probability of grade 3 or 4 adverse events did not differ significantly among the strategies.” (X. Anglaret, xavier.anglaret@isped.u-bordeaux2.fr)
“Converting the new evidence from these two trials into treatment programs for all people living with HIV will require substantial additional resources,” an editorialist writes (
pp. 875–6). “Although several countries have made generous contributions for AIDS treatment and prevention programs, the need for additional donations to the hardest-hit poor countries comes at a time when international funding for AIDS is not as readily available.… AIDS services need to continue to increase efficiencies to achieve more from the available resources through innovations such as home HIV testing, simplified treatment protocols, and expanded community care.” (S. S. Abdool Karim)

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
Aug. 28, 2015 * Vol. 22, No. 166
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2015; 63).
Pain in Community-Dwelling Older Adults with Dementia: After demonstrating a high risk for pain in community-living older adults with dementia, authors conclude, “Creative interventions and programs are needed to manage pain adequately in this vulnerable population” (pp. 1503–11). Representative data from the National Health and Aging Trends Study 2011 wave show these patterns: “Of the 7,609 participants with complete data on cognitive function, 802 had dementia (67.2% aged ≥80, 65.0% female, 67.9% white, 49.7% proxy response, 32.0% lived alone, 18.8% lived in residential care); 670 (63.5%) participants with dementia experienced bothersome pain, and 347 (43.3%) had pain that limited activities. These rates were significantly higher than in a propensity score–matched cohort without dementia (54.5% bothersome pain, P <.001, 27.2% pain that limited activity, P <.001). Proxies reported slightly higher rates of pain than self-respondents, but differences were statistically significant only for activity-limiting pain (46.6% proxy vs 40.1% self, P = .03). Correlates of bothersome pain included arthritis, heart and lung disease, less than high school education, activity of daily living disability, depressive and anxiety symptoms, and low energy. Of those reporting pain, 30.3% stated that they rarely or never took any medications for pain.” (L. Hunt, Lauren.Hunt@ucsf.edu)
Weight Loss & Cholinesterase Inhibitors: Consistent with findings from randomized controlled trials, “real world” data from the VA system show an increased risk of weight loss among older patients with dementia who are treated with cholinesterase inhibitors (pp. 1512–8). Based on a primary outcome of 10-pound losses over 12 months, investigators found these results in national data: “Of 6,504 individuals that met study criteria, 1,188 started on cholinesterase inhibitors were matched to 2,189 started on other medications. The propensity-matched cohorts were well balanced on baseline covariates. Participants initiated on cholinesterase inhibitors had a higher risk of weight loss than matched controls at 12 months (hazard ratio = 1.23, 95% confidence interval (CI) = 1.07–1.41). At 12 months, 29.3% of participants taking cholinesterase inhibitors had experienced weight loss, compared with 22.8% of nonusers, corresponding to a number needed to harm of 21.2 (95% CI = 12.5–71.4) over 1 year. There were no significant differences in the risk of weight loss within subgroups.” (M. Sheffrin, meera.sheffrin@ucsf.edu)
Prescription Opioids & Cognition: In a prospective cohort study conducted in Seattle’s Group Health system, patients with heaviest use of prescription opioids had a slightly increased risk of dementia, compared with those with little or no use, but researchers conclude that “little evidence of long-term cognitive harm specific to opioids was found” in the study (pp. 1519–26). The Cognitive Abilities Screening Instrument (CASI) was administered every 2 years to 3,434 community-dwelling individuals aged 65 and older without dementia with at least 10 years of Group Health enrollment at baseline. Regression and estimating equations provided these results for opioid and NSAID users: “Seven hundred ninety-seven participants (23%) developed dementia over a mean follow-up of 7.3 years; 637 (19%) had possible or probable Alzheimer’s disease. For cumulative opioid use, the hazard ratios (HRs) for dementia were 1.06 (95% confidence interval (CI) = 0.88–1.26) for 11 to 30 [total standardized doses (TSDs)], 0.88 (95% CI = 0.70–1.09) for 31 to 90 TSDs, and 1.29 (95% CI = 1.02–1.62) for 91 or more TSDs, versus 0 to 10 TSDs. A similar pattern was seen for NSAID use. Heavier opioid use was not associated with more-rapid cognitive decline.” (S. Dublin, dublin.s@ghc.org)

>>>PNN NewsWatch
* FDA has approved evolocumab (Repatha, Amgen) as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C and as an adjunct to diet and other LDL-lowering therapies for the treatment of patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-C. The monoclonal antibody becomes the second approved proprotein convertase subtilisin/kexin type 9 inhibitor.

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
Aug. 31, 2015 * Vol. 22, No. 167
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 29 issue of Lancet (2015; 386).
Ebola Vaccine Delivered Via Ring Vaccination Strategy: In an interim analysis of an open-label study, an Ebola vaccine candidate appears to be “highly efficacious and safe” and “most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy,” researchers report (pp. 857–66). The trial, conducted in Guinea, used a recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV). For adults who were contacts or contacts of contacts of laboratory-confirmed cases of Ebola virus disease, these results are reported: “Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7,651 people were included in the planned interim analysis. 48 of these clusters (4,123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3,528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74.7–100.0; p = 0.0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75.1% (95% CI −7.1 to 94.2; p = 0.1791), and 76.3% (95% CI −15.5 to 95.1; p = 0.3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing.” (M. P. Kieny, kienym@who.int)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Digoxin Safety & Efficacy: Across a wide variety of observational and randomized controlled trials, use of digoxin “is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital,” according to a systematic review and meta-analysis (h4451): “52 studies were systematically reviewed, comprising 621,845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4,006,210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P = 0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P <0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P <0.001; n = 29,525).” (D. Kotecha, d.kotecha@bham.ac.uk)

>>>PNN JournalWatch
* Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association, in
Diabetes Care, 2015; 38: 1777–803. (C. S. Fox, foxca@nhlbi.nih.gov)
* Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies, in
Diabetes Care, 2015; 38: 1804–12. (C. Knott, craig.knott.10@ucl.ac.uk)
* Antiretroviral Pharmacokinetics in Pregnant Women, in
Pharmacotherapy, 2015; doi: 10.1002/phar.1626. (M. McLaughlin, milgriff@nm.org)
* Statins for Poststroke Seizures: The First Antiepileptogenic Agent [editorial]?, in
Neurology, 2015; 85: 661–2. (J. Guo)
* Toward a New Paradigm of Knee Osteoarthritis [editorial], in
Arthritis & Rheumatology, 2015; 67: 1987–9. (T. E. McAlindon, tmcalindon@tuftsmedicalcenter.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 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
Sept. 1, 2015 * Vol. 22, No. 168
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 1 issue of the Annals of Internal Medicine (2015; 163).
Placebos in Osteoarthritis: In clinical trials of treatments for osteoarthritis, placebo controls vary greatly in their perceived effectiveness, with intra-articular and topical pain-reduction therapies superior to oral placebos, according to a systematic review and network meta-analysis (pp. 365–72). Among 149 randomized trials of adults with knee osteoarthritis, these results were noted for pain outcomes for widely used pharmaceuticals as compared with different types of placebos: “Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.” (R. R. Bannuru, rbannuru@tuftsmedicalcenter.org)
Practice Tool for Monitoring Anticoagulation in AF: “A systematic and proactive clinical monitoring approach, guided by a checklist, will optimize the benefit–risk ratio in this new era of anticoagulant therapy,” conclude authors who present such a practice tool, one endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society (pp. 382–5). The point-of-care checklist “is organized into sections that correspond to key categories of [direct oral anticoagulant] monitoring: A (adherence), B (bleeding), C (creatinine clearance), D (drug interactions), E (examination), and F (follow-up)” and “accompanied by quick-reference tables summarizing dosing, interactions, and periprocedural management,” the authors write. (D. J. Gladstone, david.gladstone@sunnybrook.ca)
Antibiotics in Era of Resistance: Authors argue against dispensing with controlled clinical trials as bills in Congress propose changes in regulatory approval of antibiotics in response to “fears of a postantibiotic future” (pp. 386–8): “Despite anti-infectives having among the shortest development times and highest approval rates among therapeutic classes, some propose that the requirements of adequate and well-controlled trials make the study of new antibiotics infeasible. To address perceived hurdles, these bills propose a regulatory pathway in poorly defined ‘limited populations’ without requiring demonstrated benefits in populations with resistant disease. Studies would be done in patients with effective options rather than those with unmet medical needs, allowing approval even with inferior effectiveness in the population studied. No requirement for diagnostics means that the drugs may be prescribed empirically outside the limited population. The bills would alter the standard of approval from substantial evidence to ‘sufficient evidence’ derived from ‘small clinical data sets’ and would consider preclinical data, animal models, and pharmacologic data to be ‘confirmatory evidence.…’
“The controlled clinical trial was developed relatively recently in the history of medicine. Investigators developed this methodology to protect patients. As [infectious disease leader Maxwell] Finland stated, ‘Clinical investigators and authors of medical and scientific publications have the duty to protect the medical profession and the public against the abuse of preliminary scientific information and against the improper and premature exploitation of conclusions based on inadequate data.’ The past reminds us that present patient safety and rigorous evaluations of drug effectiveness should still be considered along with uncertain depictions of the future.” (S. H. Podolsky)

>>>PNN NewsWatch
* FDA warned on Friday that the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. FDA, recommending that the drugs be considered as causes of severe or persistent joint pain, has added a new warning and precaution about this risk to DPP-4 labels.

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
Sept. 2, 2015 * Vol. 22, No. 169
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 1 issue of JAMA (2015; 314).
Finerenone & Albuminuria in Diabetic Nephropathy: The nonsteroidal mineralocorticoid receptor antagonist finerenone, added to ACE inhibitor or ARB therapy in patients with diabetic nephropathy, improved the urinary albumin–creatinine ratio (UACR), researchers report (pp. 884–94). In the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) study, 821 patients received finerenone or placebo in a dose-ranging study, with these results: “The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68–0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65–0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58–0.77; P <.001]; for 20 mg/d, 0.62 [90% CI, 0.54–0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.” (G. L. Bakris, gbakris@gmail.com)
Integrative Clinical Sequencing in Pediatric Cancer: Among 102 children and young adults with relapsed, rare, or refractory cancer, “incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients,” investigators conclude (pp. 913–25). Seeking to incorporate genomic sequencing into clinical care, the authors report these results for the 91 patients with adequate tumor tissue for analysis: “Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening.” (A. M. Chinnaiyan, arul@umich.edu)
The “most troubling reality” from this study “is the number of children with currently incurable refractory cancer and a potentially actionable finding in which the investigators simply could not find a drug that might have provided some measure of antitumor benefit,” editorialists write (
pp. 881–3). “Reasons cited ranged from lack of pediatric dosing information to no available clinical trial. The pediatric oncology community will need to completely rethink models of drug development in the genomic era as rare diseases become even more rare based on genetically defined subsets.” (J. M. Maris, maris@chop.edu)
Flibanserin at FDA: Authors of a Viewpoint review the science and politics at an advisory committee meeting that led to FDA’s recent approval of flibanserin for hypoactive sexual desire disorder in premenopausal women (pp. 869–70): “The Even the Score advocacy campaign, the shifting efficacy end points and use of a patient-reported outcome measure, the tenuous risk–benefit balance among the studied population and potential for widespread off-label use, and an unmet medical need … are not totally unfamiliar territory for the FDA, but represent a challenge when they occur simultaneously. What makes the approval process for flibanserin even more unique is the politically charged atmosphere in which the FDA will decide how all these trade-offs should best be navigated.” (W. Gellad, walid.gellad@pitt.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 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
Sept. 3, 2015 * Vol. 22, No. 170
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 3 issue of the New England Journal of Medicine (2015; 373).
Imetelstat for Myeloproliferation: Two research articles and an editorial examine clinical utility of the antisense oligonucleotide imetelstat.
Imetelstat, a “13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase,” was effective in a study of patients with high-risk or intermediate-2–risk myelofibrosis “but also had the potential to cause clinically significant myelosuppression,” researchers report (
pp. 908–19). Doses of 9.4 mg/kg every 1–3 weeks were administered as 2-hour intravenous infusions, with these effects on a primary end point of overall response rate and secondary end points of adverse events, spleen response, and independence from red-cell transfusions: “A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior [Janus kinase (JAK)] inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P = 0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P = 0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P = 0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%).” (A. Tefferi, tefferi.ayalew@mayo.edu)
In 18 patients with essential thrombocytopenia, imetelstat administered intravenously once weekly yielded “rapid and durable hematologic and molecular responses,” the second study concludes (
pp. 920–8). Dosed to a platelet count of 250,000–300,000/cu mm, “imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response,” the authors write. “At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15% to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity.” (G. M. Baerlocher, gabriela.baerlocher@insel.ch)
Noting that this drug seems to be working in different ways in the two conditions examined in these articles, editorialists conclude (
pp. 965–6): “Whether the mechanism is on target or off, the results of the clinical studies published here spark new possibilities for the treatment of myeloproliferative neoplasms. Further analysis of both the mechanism and, more importantly, the long-term side-effect profile of imetelstat may provide a new approach to treat these debilitating disorders.” (M. Armanios)

>>>PNN NewsWatch
* FDA yesterday approved a substance P/neurokinin-1 (NK-1) receptor antagonist, rolapitant (Varubi, Tesaro), in combination with other antiemetic agents in adults for prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic chemotherapy. The drug has a half-life of 7 days. It is administered 1–2 hours before chemotherapy administration in combination with a 5-HT3 receptor antagonist and dexamethasone. A CYP2D6 inhibitor, rolapitant is contraindicated for use with the CYP2D6 substrate thioridazine.

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
Sept. 4, 2015 * Vol. 22, No. 171
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Sept. issue of Pediatrics (2015; 136).
Coadministration of HPV, Meningococcal & Tdap Vaccines: In a study 1,241 boys and girls aged 11–15 years, coadministration of 9-valent human papillomavirus vaccine ((9vHPV; Gardasil 9) with meningococcal vaccine (MCV4; Menactra; Neisseria meningitidis serotypes A/C/Y/W-135) and diphtheria/tetanus/acellular pertussis vaccine (Tdap; Adacel) was “generally well tolerated and did not interfere with the antibody response to any of these vaccines,” researchers report (pp. e563–72). Participants receiving 9vHPV vaccine on day 1 and months 2 and 6 received MCV4/Tdap either on day 1 or at month 1. Antibody analysis and monitoring for serious adverse effects (AEs) produced these results: “The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus ≥0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs.” (A. Schilling)
Improving Pneumococcal Vaccination Rates in Rheumatology: In a quality improvement project, pneumococcal vaccination rates were improved among pediatric and adult patients with systemic lupus erythematosus and/or currently on immunosuppressive medications through simple interventions such as a presentation to rheumatology providers, creation of immunization algorithm, previsit planning, placing reminders on clinic forms, and sending reminder e-mails to providers, a study shows (pp. e680–6): “The preintervention immunization rates for 90 patient visits compared with the immunization rates for the 53-week postintervention period with 1,033 patient visits and 299 separate patients were all statistically significant. The 13-valent pneumococcal conjugate vaccine rate increased from 6.7% to 48.4% (chi square = 58.3, P <.001), 23-valent pneumococcal polysaccharide vaccine rate increased from 8.9% to 28.4% (chi square = 16.0, P <.001), and combined rate increased from 0% to 23.2% (chi square = 25.2, P <.001). The improvement was sustained with shifts in the data for each vaccine and combined immunizations for final average rates of 60.9% for 13-valent pneumococcal conjugate vaccine, 39.2% for 23-valent pneumococcal polysaccharide vaccine, and 33.7% for combined.” (J. G. Harris)

>>>Psychiatry Report
Source:
Sept. issue of the American Journal of Psychiatry (2015; 172).
Brexpiprazole in Acute Schizophrenia: In a randomized study of patients with acute exacerbations of schizophrenia, brexpiprazole 2 and 4 mg/d was effective and generally well tolerated in comparison with placebo (pp. 870–80). Participants also received a low dose of the drug, 0.25 mg/d, in the 6-week study, with these outcomes using the Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint measure), Clinical Global Impressions Scale (CGI) severity score (key secondary endpoint measure), and other efficacy and tolerability measures: “The baseline overall mean PANSS total score was 95.2, and the CGI severity score was 4.9. Study completion rates were 62.2%, 68.1%, and 67.2% for patients in the 0.25-, 2-, and 4-mg brexpiprazole groups, respectively, versus 59.2% in the placebo group. At week 6, compared with placebo, brexpiprazole dosages of 2 and 4 mg produced statistically significantly greater reductions in PANSS total score (treatment differences: –8.72 and –7.64, respectively) and CGI severity score (treatment differences: –0.33 and –0.38). The most common treatment-emergent adverse event for brexpiprazole was akathisia (2 mg: 4.4%; 4 mg: 7.2%; placebo: 2.2%). Weight gain with brexpiprazole was moderate (1.45 and 1.28 kg for 2 and 4 mg, respectively, versus 0.42 kg for placebo at week 6). There were no clinically or statistically significant changes from baseline in lipid and glucose levels and extrapyramidal symptom ratings.” (C. U. Correll)

>>>PNN NewsWatch
* PNN will not be published on Mon., Sept. 7, Labor 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
Sept. 8, 2015 * Vol. 22, No. 172
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 5 issue of Lancet (2015; 386).
Methylprednisolone in Multiple Sclerosis: In 199 adults with relapsing–remitting multiple sclerosis who had recent relapses, 3 days of oral methylprednisolone was not inferior to intravenous doses of the drug, a study shows, based on improvement of disability scores 1 month after treatment and safety profiles (pp. 974–81). Block randomization to oral or intravenous methylprednisolone 1,000 mg once daily for 3 days showed these effects on a primary endpoint of proportion of patients who had improved by day 28 without retreatment with corticosteroids: “Between Jan 29, 2008, and June 14, 2013, we screened 200 patients and enrolled 199. We randomly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7.0 days (SD 3.6) and 7.4 days (3.9), respectively. In the per-protocol population, 66 (81%) of 82 patients in the oral group and 72 (80%) of 90 patients in the intravenous group achieved the primary endpoint (absolute treatment difference 0.5%, 90% CI −9.5 to 10.4). Rates of adverse events were similar, but insomnia was more frequently reported in the oral group (77 [77%]) than in the intravenous group (63 [64%]).” (G. Edan, gilles.edan@chu-rennes.fr)
Effects of Obesity Treatment on Diabetes Management: In 60 patients with obesity and type 2 diabetes, surgery was more effective than medical treatment for achieving long-term remission of diabetes, researchers report (pp. 964–73): “Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the [Roux-en-Y] gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p =0.0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6.5% or less (≤47.5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p = 0.0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use.” (G. Mingrone, gmingrone@rm.unicatt.it)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2015; 351).
Psychotropic Drug Prescribing in Intellectual Disability: In 571 U.K. general practices, “the proportion of people with intellectual disability who have been treated with psychotropic drugs far exceeds the proportion with recorded mental illness,” according to a cohort study of 33,016 adults with intellectual disability (h4326). “Antipsychotics are often prescribed to people without recorded severe mental illness but who have a record of challenging behaviour,” the authors conclude. “[These] findings suggest that changes are needed in the prescribing of psychotropics for people with intellectual disability. More evidence is needed of the efficacy and safety of psychotropic drugs in this group, particularly when they are used for challenging behaviour.” (R. Sheehan, r.sheehan@ucl.ac.uk)

>>>PNN NewsWatch
* Uridine triacetate (Xuriden, Wellstat Therapeutics) last week became the first FDA-approved treatment for patients with hereditary orotic aciduria. The rare metabolic disorder has been reported in 20 patients worldwide. Oral uridine triacetate granules are administered in food, milk, or formula to replace the missing RNA component.

>>>PNN JournalWatch
* Effect of Bivalent Human Papillomavirus Vaccination on Pregnancy Outcomes: Long Term Observational Follow-Up in the Costa Rica HPV Vaccine Trial, in
BMJ, 2015; 351: h4358. (O. A. Panagiotou, restis.panagiotou@nih.gov">orestis.panagiotou@nih.gov)
* Translating Atopic Dermatitis Management Guidelines Into Practice for Primary Care Providers, in
Pediatrics, 2015; 136: 554–65. (L. F. Eichenfield)
* A New Perspective on the Pathophysiology of Borderline Personality Disorder: A Model of the Role of Oxytocin, in
American Journal of Psychiatry, 2015; 172: 840–51. (S. C. Herpertz)

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
Sept. 9, 2015 * Vol. 22, No. 173
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 8 issue of JAMA (2015; 314).
Trends in Diabetes Among Americans: Compared with surveys of Americans in 1988–94, the National Health and Nutrition Examination Survey (NHANES) conducted in 2011–12 shows an increased prevalence of diabetes in the overall population, at 12% to 14%, and in all subgroups, researchers report (pp. 1021–9). The estimated prevalence was higher among participants who were non–Hispanic black, non–Hispanic Asian, and Hispanic, the NHANES data show, with these patterns: “In the overall 2011–2012 population, the unadjusted prevalence (using the hemoglobin A1c, [fasting plasma glucose (FPG)], or [2-hour plasma glucose (2-hour PG)] definitions for diabetes and prediabetes) was 14.3% (95% CI, 12.2%–16.8%) for total diabetes, 9.1% (95% CI, 7.8%–10.6%) for diagnosed diabetes, 5.2% (95% CI, 4.0%–6.9%) for undiagnosed diabetes, and 38.0% (95% CI, 34.7%–41.3%) for prediabetes; among those with diabetes, 36.4% (95% CI, 30.5%–42.7%) were undiagnosed. The unadjusted prevalence of total diabetes (using the hemoglobin A1c or FPG definition) was 12.3% (95% CI, 10.8%–14.1%); among those with diabetes, 25.2% (95% CI, 21.1%–29.8%) were undiagnosed. Compared with non–Hispanic white participants (11.3% [95% CI, 9.0%–14.1%]), the age-standardized prevalence of total diabetes (using the hemoglobin A1c, FPG, or 2-hour PG definition) was higher among non–Hispanic black participants (21.8% [95% CI, 17.7%–26.7%]; P < .001), non–Hispanic Asian participants (20.6% [95% CI, 15.0%–27.6%]; P = .007), and Hispanic participants (22.6% [95% CI, 18.4%–27.5%]; P < .001). The age-standardized percentage of cases that were undiagnosed was higher among non–Hispanic Asian participants (50.9% [95% CI, 38.3%–63.4%]; P = .004) and Hispanic participants (49.0% [95% CI, 40.8%–57.2%]; P = .02) than all other racial/ethnic groups.” (A. Menke, amenke@s-3.com)
These data may represent the peak for diabetes in the U.S., based on conclusions reached in a review article (
pp. 1052–62). “Improved glycemic control and better management of other identified risk factors for the complications of diabetes and more effective treatment of cardiovascular disease and microvascular complications have resulted in a more optimistic outlook for people with diabetes,” the author concludes, adding these details: “The epidemic is largely secondary to an increasing sedentary lifestyle and highly prevalent overweight and obesity contributing to the development of type 2 diabetes. Clinical research efforts have developed and demonstrated effective strategies for prevention, and the annual incidence of diabetes in the United States may be decreasing for the first time in 3 decades. The long-term complications of diabetes cause severe morbidity and mortality. Here too the means of reducing the burden of microvascular and cardiovascular disease have been proved.” (D. M. Nathan, dnathan@MGH.Harvard.edu)
“Although obesity and type 2 diabetes remain major clinical and public health problems in the United States, the current data provide a glimmer of hope,” editorialists add (
pp. 1005–7). “The shift in cultural attitudes toward obesity, the American Medical Association’s (AMA’s) recognition of obesity as a disease, and the increasing focus on societal interventions to address food policy and the built environment are beginning to address some of the broad environmental forces that have contributed to the epidemic of obesity. The effort of the AMA to promote screening, testing, and referral of high-risk patients for diabetes prevention through its Prevent Diabetes STAT program and the CDC’s efforts to increase the availability of diabetes prevention programs, ensure their quality, and promote their use appear to be helping to identify at-risk individuals and provide the infrastructure to support individual behavioral change.” (W. H. Herman)

>>>PNN NewsWatch
* FDA yesterday expanded its alert (see PNN, Aug. 20) regarding compounded or repackaged drugs stored in Becton-Dickinson (BD) general use syringes to include certain additional syringe sizes including 1 mL, 10 mL, 20 mL, and 30 mL BD syringes, and BD oral syringes. An interaction with the rubber stopper in certain lots of these syringes can cause some drugs stored in these syringes to lose potency if filled and not used immediately, FDA 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
Sept. 10, 2015 * Vol. 22, No. 174
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 10 issue of the New England Journal of Medicine (2015; 373).
Antithrombotics in PCI: While findings were equivacol in a comparison of bivalirudin and heparin among patients undergoing percutaneous coronary interventions (PCIs) for acute coronary syndrome, the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) trial provides needed insights into the role of antithrombotic agents during and following these procedures (pp. 997–1009). Investigators found no significant difference between bivalirudin and unfractionated heparin and no significant difference in those receiving a post-PCI bivalirudin infusion, as noted in these results for 7,213 patients: “The rate of major adverse cardiovascular events was not significantly lower with bivalirudin than with heparin (10.3% and 10.9%, respectively; relative risk, 0.94; 95% confidence interval [CI], 0.81 to 1.09; P = 0.44), nor was the rate of net adverse clinical events (11.2% and 12.4%, respectively; relative risk, 0.89; 95% CI, 0.78 to 1.03; P = 0.12). Post-PCI bivalirudin infusion, as compared with no infusion, did not significantly decrease the rate of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events (11.0% and 11.9%, respectively; relative risk, 0.91; 95% CI, 0.74 to 1.11; P = 0.34).” (M. Valgimigli, marco.valgimigli@insel.ch)
“The MATRIX trial provides the best evidence to date on the question of whether prolonging the infusion of bivalirudin after the end of the PCI procedure is beneficial,” an editorialist writes (
pp. 1069–70). “It had been hoped that rates of early stent thrombosis among patients receiving bivalirudin would be reduced by prolonging either the full-dose infusion for 4 hours or longer or a reduced dose (0.25 mg per kilogram per hour) for 6 hours or longer, a period that is sufficient for P2Y12 inhibitors to achieve maximal inhibition of platelet aggregation. However, neither the primary end point, nor any component of it, was reduced in the group receiving the prolonged infusion of bivalirudin.” (P. B. Berger)
Cyclosporine Before PCI: Among 970 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI), I.V. cyclosporine neither improved clinical outcomes nor prevented adverse left ventricular modeling at 1 year compared with placebo, researchers report (pp. 1021–31). Administered within 12 hours of symptom onset in patients with complete coronary artery occlusion, cyclosporine 2.5 mg/kg or placebo before PCI provided these outcomes in 970 patients: “The rate of the primary outcome [composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year] was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P = 0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups.” (M. Ovize, michel.ovize@chu-lyon.fr)
Eculizumab During Pregnancy: Administered during 75 pregnancies in 61 women to prevent complications of paroxysmal nocturnal hemoglobinuria (PNH), eculizumab provided benefit and had a high rate of fetal survival and a low rate of maternal complications, according to survey results (pp. 1032–9). “There were no maternal deaths and three fetal deaths (4%),” the authors report. “Six miscarriages (8%) occurred during the first trimester.… A total of 22 births (29%) were premature.… A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples.” (R. J. Kelly, richardkelly@nhs.net)
Sebelipase Alfa in Lysosomal Acid Lipase Deficiency: In a Phase III trial of 66 adults and children with lysosomal acid lipase deficiency, sebelipase alfa reduced multiple disease-related hepatic and lipid abnormalities, compared with placebo, a study shows (pp. 1010–20). Deficiency of this enzyme is “an underappreciated cause of cirrhosis and severe dyslipidemia,” the authors report. (B. K. Burton, bburton@luriechildrens.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
Sept. 11, 2015 * Vol. 22, No. 175
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Sept. issue of Chest (2015; 148).
Outcomes After Asthma Controller Step Down: About one-third of patients with asthma had exacerbations in the 2 years following step-down of controller medications, according to a retrospective analysis of a U.S. claims database (pp. 630–9). Conducted with data from 2000 to 2012, the study used 4-month intervals to identify events indicating asthma exacerbation (inpatient visit, emergency department [ED], or dispensing of systemic corticosteroid linked to an asthma visit). Asthma stability before step-down was defined as not having an asthma exacerbation and having fewer than two rescue inhaler medications in a 4-month period. Results showed: “Thirty-two percent of the 26,292 included individuals had an asthma exacerbation in the 24-month period following step-down of asthma controller medication, though only 7% had an ED visit or hospitalization for asthma. The length of asthma stability prior to stepping down asthma medication was strongly associated with the risk of an asthma exacerbation in the subsequent 24-month period: < 4 months’ stability, 44%; 4 to 7 months, 34%; 8 to 11 months, 30%; and ≥ 12 months, 21% (P < .001).” (M. A. Rank, rank.matthew@mayo.edu)
Genotype-Guided Warfarin Therapy: Benefits of genotype-guided dosing (GD) of warfarin therapy are not evident in the first month of treatment, a meta-analysis of randomized controlled trials (RCTs) shows, with only a shorter time to maintenance dose (TMD) improved in comparison with standard dosing (pp. 701–10). After 1 month, better efficacy and safety measures were significantly improved with genotype-guided therapy, as noted in these results: “Ten RCTs with a total of 2,505 patients were included in the meta-analysis. GD compared with standard dosing resulted in a similar % time in therapeutic range (TTR) at ≤ 1 month follow-up (39.7% vs 40.2%; mean difference [MD], −0.52 [95% CI, −3.15 to 2.10]; P = .70) and higher % TTR (59.4% vs 53%; MD, 6.35 [95% CI, 1.76-10.95]; P = .007) at > 1 month follow-up, a trend toward lower risk of major bleeding (risk ratio, 0.46 [95% CI, 0.19-0.1.11]; P = .08) at ≤ 1 month follow-up and lower risks of major bleeding (0.34 [95% CI, 0.16-0.74], P = .006) at > 1-month follow-up, and shorter … TMD (24.6 days vs 34.1 days; MD, −9.54 days [95% CI, −18.10 to −0.98]; P = .03) at follow-up but had no effects on international normalized ratio [INR] > 4.0, nonmajor bleeding, thrombotic outcomes, or overall mortality.” (K. Dahal, kdahal@lrgh.org)

>>>Cardiology Report
Source:
Sept. 15 issue of the Journal of the American College of Cardiology (2015; 66).
Race & ACE Inhibition in Hypertension Outcomes: Compared with whites with hypertension, blacks with the disease had poorer outcomes when treated with ACE inhibitors, according to a retrospective cohort comparative effectiveness study (pp. 1224–33). In a municipal health care system, 434,646 patients were divided into four groups: Black-ACE, Black-NoACE, White-ACE, White-NoACE. Results showed poor cardiovascular outcomes in blacks but not whites with ACE inhibitor therapy: “Our analysis included 59,316 new users of ACE inhibitors, 47% of whom were black. Baseline characteristics were comparable for all groups after inverse probability weighting adjustment. For the composite outcome, the race treatment interaction was significant (p = 0.04); ACE use in blacks was associated with poorer cardiovascular outcomes (ACE vs. NoACE: 8.69% vs. 7.74%; p = 0.05) but not in whites (6.40% vs. 6.74%; p = 0.37). Similarly, the Black-ACE group had higher rates of [acute myocardial infarction] (0.46% vs. 0.26%; p = 0.04), stroke (2.43% vs. 1.93%; p = 0.05), and congestive heart failure (3.75% vs. 2.25%; p < 0.0001) than the Black-NoACE group. However, the Black-ACE group was no more likely to develop adverse effects than the White-ACE group.” (G. Ogedegbe)

>>>PNN NewsWatch
* FDA yesterday issued three medication safety alerts. The warning about adverse bone effects with canagliflozin (Invokana, Invokamet) has been strengthened, Insulet Corp. has initiated a lot-specific recall of nearly 41,000 boxes of the OmniPod Insulin Management System, and all nonexpired drug products produced for sterile use by Medistat RX of Foley, AL, are being recalled because of possible microbial contamination.

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
Sept. 14, 2015 * Vol. 22, No. 176
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 12 issue of Lancet (2015; 386).
Interleukin Therapy in Asthma: Evidence supporting the use of anti-interleukins monoclonal antibodies in treatment of severe asthma is reviewed (pp. 1086–96): “There is strong evidence supporting the role for interleukins derived from T-helper-2 (Th2) cells and innate lymphoid cells, such as interleukins 4, 5, and 13, as underlying the eosinophilic and allergic inflammatory processes in nearly half of these patients. An anti-IgE antibody, omalizumab, which binds to circulating IgE, a product of B cells from the actions of interleukin 4 and interleukin 13, is used as treatment for severe allergic asthma. Studies examining cytokine blockers such as anti-interleukin-5, anti-interleukin-4R-alpha, and anti-interleukin-13 monoclonal antibodies in patients with severe asthma with recurrent exacerbations and high blood eosinophil counts despite use of inhaled corticosteroids have reported improved outcomes in terms of exacerbations, asthma control, and forced expiratory volume in 1 s. The US Food and Drug Administration’s recommendation to use an anti-interleukin-5 antibody for the treatment of severe eosinophilic asthma suggests that there will be a therapeutic place for these anti-Th2 agents.” (K. F. Chung, f.chung@imperial.ac.uk)

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2015; 35).
Treatment of Gonococcal Infections: Multidrug-resistant strains of Neisseria gonorrhoeae have emerged in the U.S. over the past decade, according to a review article, leading to the need for new approaches to treatment (doi: 10.1002/phar.1627): “The 2015 CDC guidelines recommend dual therapy with intramuscular ceftriaxone and oral azithromycin as first-line treatment, although components of this regimen are met with a high level of resistance. Although ceftriaxone resistance has not yet been reported in the United States, it is only a matter of time before such isolates are detected, thus ushering in a new era of difficult-to-manage uncomplicated gonococcal infection. The potential public health crisis and patient-associated sequelae (e.g., pelvic inflammatory disease, epididymitis, and human immunodeficiency virus infection) linked with untreatable gonorrhea are cause for great concern. To try to stem this tide, a number of new agents targeted against N. gonorrhoeae are being investigated in clinical trials.” (J. W. Lancaster, j.lancaster@neu.edu)
Vancomycin Dosing in Obesity: “Extremely obese patients may require a lower weight-based daily dose than obese patients to reach target vancomycin trough concentrations,” concludes a retrospective cohort study of the VA database (doi: 10.1002/phar.1625). Among 263 patients with obesity and 71 patients with extreme obesity, these patterns were observed in treatment of suspected methicillin-resistant Staphylococcus aureus pneumonia in 2002–12: “The mean total daily vancomycin dose was lower in obese versus extremely obese patients (2005 ± 736 vs 2306 ± 934 mg, p <0.05). The mean weight-based daily dose was higher in obese patients (20 ± 7 vs 17 ± 7 mg/kg/day, p <0.05). In each group, ~ 20% of patients achieved optimal target trough concentrations. In obese patients, the standard dose of ~ 30 mg/kg/day was appropriate for target trough concentration attainment (odds ratio 5.15, 95% confidence interval 1.69–15.64). In extremely obese patients, a lower dosage of 20 to 25 mg/kg/day was appropriate for target trough concentration attainment (odds ratio 6.07, 95% confidence interval 1.01–36.51).” (K. L. LaPlante, KerryLaPlante@uri.edu)

>>>PNN JournalWatch
* Risk Factors for Asthma: Is Prevention Possible?, in
Lancet, 2015; 386: 1075–85. (R. Beasley, Richard.Beasley@mrinz.ac.nz)
* Cannabinoids in the Treatment of Epilepsy, in
New England Journal of Medicine, 2015; 373: 1048–58. (D. Friedman, daniel.friedman@nyumc.org)
* Mortality Associated With Seasonal and Pandemic Influenza Among Pregnant and Nonpregnant Women of Childbearing Age in a High-HIV-Prevalence Setting—South Africa, 1999–2009, in
Clinical Infectious Diseases, 2015; 61: 1063–70. (S. Tempia, stefanot@nicd.ac.za)
* Improvements in US Breast Cancer Survival and Proportion Explained by Tumor Size and Estrogen-Receptor Status, in
Journal of Clinical Oncology, 2015; 33: 2870–6. (M. H. Gail, gailm@mail.nih.gov)
* A Practical Guide for Pharmacists to Establish a Transitions of Care Program in an Outpatient Setting, in
Journal of the Am. Pharm. Assoc., 2015; 55: 527–33. (S. H. Otsuka, s.otsuka@usciences.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
Sept. 15, 2015 * Vol. 22, No. 177
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 15 issue of the Annals of Internal Medicine (2015; 163).
Diet & Physical Activity in Type 2 Diabetes Prevention: Two review articles serve as the basis for clinical guidelines for combining diet and physical activity promotion programs in prevention of type 2 diabetes in patients with elevated risk, and an editorial comments on this approach.
Review of 53 studies leads authors to conclude that “combined diet and physical activity promotion programs are effective at decreasing diabetes incidence and improving cardiometabolic risk factors in persons at increased risk” (
pp. 437–51). Intensive programs, studied in 13 of the trials, were more effective, the writers add. (E. Balk, ethan_balk@brown.edu)
A second review, assessing costs and finding that promotional programs are cost-effective, concludes that “costs are lower when programs are delivered to groups in community or primary care settings” (
pp. 452–60). “From a health system perspective, 16 studies reported a median [incremental cost-effectiveness ratio] of $13,761 per quality-adjusted life–year (QALY) saved,” the authors report. “Group-based programs were more cost-effective (median, $1,819 per QALY) than those that used individual sessions (median, $15,846 per QALY).” (R. Li, eok8@cdc.gov)
In an official statement, the Community Preventive Services Task Force recommends combined diet and physical activity promotion programs to reduce progression to type 2 diabetes in persons at increased risk (
pp. 465–8): “The Task Force recommends the use of combined diet and physical activity promotion programs by health care systems, communities, and other implementers to provide counseling and support to clients identified as being at increased risk for type 2 diabetes. Economic evidence indicates that these programs are cost-effective.” (Community Guide website; www.thecommunityguide.org/diabetes/index.html)
“Health care providers should assume a greater role in performing recommended screening and linking high-risk patients with combined diet and physical activity promotion programs,” an editorialist concludes (
pp. 475–6). “As a society, we should no longer hold for ransom the potential to reduce the burden of diabetes by continuing to await further evidence that interventions will be cost-saving or prevent myocardial infarctions or deaths.” (R. T. Ackermann, r.ackermann@northwestern.edu)
Hospital Readmissions Reductions & Safety-Net Hospitals: In 2014, safety-net programs were “disproportionately likely to be affected” by reductions in payments under Medicare’s value-based purchasing (VBP) and the Hospital Readmissions Reduction Program (HRRP), a study shows, but the financial penalties were small (pp. 427–36). Cross-sectional analysis of 3,022 acute-care hospitals showed these patterns of penalties for those facilities in the top quartile of the Medicare disproportionate share hospital (DSH) patient percentage and Medicare uncompensated care (UCC) payments per bed: “Safety-net hospitals in the top quartile of each measure were more likely to be penalized under VBP than other hospitals (62.9% vs. 51.0% under the DSH definition and 60.3% vs. 51.5% under the UCC per-bed definition). This was also the case under the HRRP (80.8% vs. 69.0% and 81.9% vs. 68.7%, respectively). Safety-net hospitals also had larger payment penalties ($115,900 vs. $66,600 and $150,100 vs. $54,900, respectively). On a per-bed basis, this translated to $436 versus $332 and $491 versus $314, respectively. Sensitivity analysis setting the cutoff at the top decile rather than the top quartile decile led to similar conclusions with somewhat larger differences between safety-net and other hospitals. The quadratic fit of the data indicated that the larger effect of these penalties is in the middle of the distribution of the DSH and UCC measures.” (J. M. Hockenberry, jason.hockenberry@emory.edu)
“Tethering physicians’ rewards to box checking and redundant documentation risks both substituting insurers’ priorities for patients’ goals and demoralizing physicians,” editorialists write in response to the study (
pp. 473–4). “Paying for quality has strong intuitive appeal. However, as with other medical interventions, intuition may mislead, and adopting everywhere policies that have been proven nowhere puts millions at risk for unintended side effects.” (S. Woolhandler, swoolhan@hunter.cuny.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
Sept. 16, 2015 * Vol. 22, No. 178
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Oct. 1 issue of Clinical Infectious Diseases (2015; 61).
Solithromycin for Uncomplicated Gonorrhea: In a Phase II trial, single oral doses of the fluoroketolide solithromycin (CEM-101) “was 100% effective for treatment of culture-proven gonorrhea at genital, oral, and rectal sites,” researchers report (pp. 1043–8). The trial tested two doses, 1200 and 1000 mg, with these clinical results against Neisseria gonorrhoeae: “A total of 59 participants were enrolled and treated in this trial; 28 participants received 1200 mg of solithromycin and 31 received 1000 mg. Forty-six (78%) participants had positive cultures for N. gonorrhoeae at the time of enrollment: 24 of the 28 persons (86%) who received 1200 mg of oral solithromycin, and 22 of 31 (71%) who received 1000 mg. In addition, 8 participants had positive pharyngeal gonococcal cultures, and 4 had positive rectal cultures. All patients with positive cultures for N. gonorrhoeae were cured at all sites of infection. Chlamydia trachomatis and Mycoplasma genitalium coinfections were evaluated using nucleic acid amplification tests and were negative at 1 week of follow-up in 9 of 11 (82%) participants positive for C. trachomatis and 7 of 10 (70%) participants positive for M. genitalium. Mild dose-related gastrointestinal side effects (nausea, loose stools, vomiting) were common but did not limit therapy.” (E. W. Hook III, ehook@uab.edu)
Nephrotoxicity of Low-Dose Gentamicin in Children: Addition of gentamicin in treatment of uncomplicated Enterococcus faecalis bacteremia in children provides minimal benefits yet increases risk of acute kidney injury (AKI), a study shows (pp. 1119–24). Retrospective analysis of children on ampicillin monotherapy versus those receiving ampicillin and low-dose gentamicin yielded these results: “One hundred sixty-three (52%) patients received ampicillin with low-dose gentamicin, and 150 (48%) patients received ampicillin monotherapy. Incorporating propensity-score weighting with additional adjustment for source control measures, patients receiving combination therapy experienced bacterial clearance 10 hours faster than children receiving ampicillin monotherapy (adjusted mean difference 0.42; confidence interval (CI), .02 to .82; P = .04). Bacteremic relapse was similar between the two groups (17% vs 18%); adjusted hazards ratio (aHR) 1.12; 95% CI, .65 to 1.92. Children receiving low-dose gentamicin had approximately twice the risk of developing AKI compared to children not receiving this agent, adjusting for the receipt of additional nephrotoxins (aHR 1.94; 95% CI, 1.48–2.97).” (P. D. Tamma, ptamma1@jhmi.edu)

>>>Oncology Highlights
Source:
Sept. 10 issue of the Journal of Clinical Oncology (2015; 33).
Intraperitoneal Chemotherapy for Ovarian Cancer: Addition of intraperitoneal (IP) chemotherapy to intravenous (IV) doses “may be an important and underused strategy to improve ovarian cancer outcomes,” authors of a prospective cohort study conclude (pp. 2841–7). Among 823 women with stage III ovarian cancer who received IP/IV chemotherapy in 2003–12, these comparisons with 402 matched control patients were made: “Use of IP/IV chemotherapy increased from 0% to 33% between 2003 and 2006, increased to 50% from 2007 to 2008, and plateaued thereafter. Between 2006 and 2012, adoption of IP/IV chemotherapy varied by institution from 4% to 67% (P <.001) and 43% of patients received modified IP/IV regimens at treatment initiation. In the propensity score–matched sample, IP/IV chemotherapy was associated with significantly improved overall survival (3-year overall survival, 81% v 71%; hazard ratio, 0.68; 95% CI, 0.47 to 0.99), compared with IV chemotherapy, but also more frequent alterations in chemotherapy delivery route (adjusted rates discontinuation or change, 20.4% v 10.0%; adjusted odds ratio, 2.83; 95% CI, 1.47 to 5.47).” (A. A. Wright, alexi_wright@dfci.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. The agency also approved a new, shared risk evaluation and mitigation strategy, the Clozapine REMS Program. Requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program.

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
Sept. 17, 2015 * Vol. 22, No. 179
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 17 issue of the New England Journal of Medicine (2015; 373).
Clearing Amyloids in Systemic Amyloidosis: Two-step antibody treatment “triggered clearance of amyloid deposits from the liver and some other tissues,” conclude authors who studied 15 patients with systemic amyloidosis (pp. 1106–14). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) was used first to clear serum amyloid P component (SAP). A fully humanized monoclonal IgG1 anti-SAP antibody was then infused in open-label fashion, with these results: “There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.” (M. B. Pepys, m.pepys@ucl.ac.uk)
Considered with the possible use of a once-monthly anti-amyloidosis monoclonal antibody (NEOD001) now in a Phase III trial, the combination approach proposed in this study creates interesting but uncertain possibilities for future management of systemic amyloidosis, according to an accompanying editorial (
pp. 1167–9): “These drug-development projects are challenged by the heterogeneity of amyloid types, their natural histories and patterns of organ involvement, the adequacy and availability of defined study populations, the robustness of primary end points, the scarcity of expert amyloid physicians, and the manageability of regulatory requirements, accrual timelines, and investor horizons. We do not know whether anti-SAP antibody can reduce cardiac mortality in [immunoglobulin-light-chain (AL) type] amyloidosis or in wild-type transthyretin-related amyloid deposition. We do not know whether NEOD001 can reduce cardiac mortality in AL amyloidosis or reverse AL amyloidosis kidney damage. We do not know whether NEOD001 might be a better partner than anti-SAP antibody for CPHPC. Although overall survival is part of the primary end point of the NEOD001 phase 3 trial, accelerated phase 2 and phase 3 testing of combination therapies will require wise use of [N-terminal prohormone of brain natriuretic peptide] and other biomarkers as correlates of time-to-event end points.” (R. L. Comenzo)
Acute Myeloid Leukemia: “Exciting developments in our understanding of the molecular pathogenesis of [acute myeloid leukemia (AML)] have not yet been translated into clinical practice,” a review article concludes (pp. 1136–52). “New compounds hold promise to improve treatment outcomes; however, it is unlikely that any of these compounds, when used as single agents, will cure the disease. A major challenge will be to identify predictors for a response to specific agents, which will allow for the rational design of combinatorial therapies.” (C. D. Bloomfield, clara.bloomfield@osumc.edu)
Empowering Consumers Through Advertising: FDA’s efforts to improve rules governing direct-to-consumer advertising (DTAC) “probably don’t go far enough to really empower consumers to make smart decisions about the drugs they put into their bodies,” writes the author of a Perspective article (pp. 1085–7). “Unfortunately, the FDA’s guidance will do nothing to help consumers understand whether drugs really have substantial benefits. Research has shown that a more expansive Drug Facts box could comprehensibly convey data on the proportion of patients who actually benefited from the drug in key trials and how many had adverse events. If patients and prescribers used such information to make intelligent choices about one drug versus another—or about forgoing medication altogether—it could drive genuine competition and innovation in the pharmaceutical market. That would reflect the sort of ‘consumer empowerment’ that free-speech advocates have used to justify DTCA in the first place. But such an advance awaits bolder action by the FDA and the pharmaceutical industry.” (C. T. Robertson)

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
Sept. 18, 2015 * Vol. 22, No. 180
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Sept. issue of the Journal of Allergy and Clinical Immunology (2015; 136).
Overlapping Asthma–COPD: Two articles and an editorial explore treatment of patients with asthma–chronic obstructive pulmonary disease (COPD) overlap syndromes.
Several patient types have overlapping symptoms and underlying pathophysiology of asthma and COPD, an author writes (
pp. 531–45): “Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness.” (P. J. Barnes, p.j.barnes@imperial.ac.uk)
This condition, the asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS), requires a precise definition, characterization of its phenotypes, and identification of targeted treatment opportunities, another article concludes (
pp. 546–52). “There is little evidence at present to support specific treatment recommendations for ACOS on the basis of efficacy or effectiveness, yet these patients continue to present for diagnosis and management, mainly in primary care,” the author notes. “This article highlights the need for clinical guidance about ACOS, summarizes recommendations about its diagnosis and treatment from a sample of national asthma and COPD guidelines, and proposes a way forward, as suggested in a collaborative Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease report, to provide health professionals with interim recommendations about syndromic recognition and initial treatment based on both potential effectiveness and potential risk.” (H. K. Reddel, helen.reddel@sydney.edu.au)
An accompanying editorial focuses “on treated patients with chronic asthma who never smoked and had persistent expiratory airflow obstruction and associated loss of lung elastic recoil because of unsuspected emphysema, with in part shared pathophysiologic structural changes seen in patients with COPD” (
pp. 553–5). After exploring “an overlap of genome endotypes in patients with asthma and those with COPD,” the writers conclude, “Further studies are needed to confirm these observations and the underlying mechanisms, and hopefully, this will lead to more successful targeted pharmacologic interventions.” (A. F. Gelb, afgelb@msn.com)

>>>PNN NewsWatch
* FDA yesterday approved the second-generation antipsychotic cariprazine (Vraylar; Forest, Actavis Pharma) for acute treatment of manic or mixed episodes associated with bipolar I disorder and for treatment of schizophrenia in adults. Approval was based on three short-term trials, lasting 3 weeks each, in which patients on the drug had significantly better scores on three rating scales. The most commonly reported adverse reactions with an incidence 5% or more and at least twice the rate of placebo in bipolar mania were extrapyramidal symptoms, akathisia, dyspepsia, vomiting, somnolence, and restlessness and in schizophrenia were extrapyramidal symptoms and akathisia.

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
Sept. 21, 2015 * Vol. 22, No. 181
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2015; 351).
Reanalysis of Primary Study Data for Adolescent Antidepressants: Conducted under the restoring invisible and abandoned trials (RIAT) initiative, reanalysis of data from a published, company-sponsored antidepressant study finds that neither active treatment “showed efficacy major depression in adolescents, and there was an increase in harms with both drugs,” a report concludes (h4320). In SmithKline Beecham’s Study 329, 275 adolescents with major depression for 8 weeks or more were randomized to paroxetine 20–40 mg, imipramine 200–300 mg, or placebo for 8 weeks. Analysis of the full data set using the total Hamilton depression scale (HAM-D) score and other measures showed these results: “The efficacy of paroxetine and imipramine was not statistically or clinically significantly different from placebo for any prespecified primary or secondary efficacy outcome. HAM-D scores decreased by 10.7 (least squares mean) (95% confidence interval 9.1 to 12.3), 9.0 (7.4 to 10.5), and 9.1 (7.5 to 10.7) points, respectively, for the paroxetine, imipramine, and placebo groups (P = 0.20). There were clinically significant increases in harms, including suicidal ideation and behaviour and other serious adverse events in the paroxetine group and cardiovascular problems in the imipramine group.”
Based on these findings, the authors conclude: “Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.” (J. Jureidini,
Jon.Jureidini@adelaide.edu.au)
Discrepancies in Retracted Articles: Scientists who were blinded to retraction status and having no special expertise in the field identified significantly more mathematical or logical discrepancies in 50 articles that had been retracted than in 50 comparator articles published in the same journals, researchers report (h4708). Concluding that “discrepancies could be an early and accessible signal of unreliability in clinical trial reports,” the authors provide these study results: “Of 479 discrepancies found in the 100 trial reports, 348 were in the 50 retracted reports and 131 in the 50 unretracted reports. On average, individual retracted reports had a greater number of discrepancies than unretracted reports (median 4 (interquartile range 2–8.75) v 0 (0–5); P <0.001). Papers with a discrepancy were significantly more likely to be retracted than those without a discrepancy (odds ratio 5.7 (95% confidence interval 2.2 to 14.5); P <0.001). In particular, three types of discrepancy arose significantly more frequently in retracted than unretracted reports: factual discrepancies (P = 0.002), arithmetical errors (P = 0.01), and missed P values (P = 0.02). Results from a retrospective analysis indicated that citations and journal impact factor were unlikely to affect the result.” (G. D. Cole, g.cole@imperial.ac.uk)

>>>PNN NewsWatch
* Sharp increases in the prices of “old neglected drugs” are reported in a New York Times article. The practice is protested in a letter to Turing Pharmaceuticals from the Infectious Diseases Society of America and the HIV Medicine Association. The article cites an increase in the price of Daraprim (pyrimethamine) from $13.50 to $750 per tablet, leading some hospitals to require special reviews of orders for the drug.

>>>PNN JournalWatch
* Innovations in Diabetes Care Around the World: Case Studies of Care Transformation Through Accountable Care Reforms, in
Health Affairs, 2015; 34: 1489–97. (M. McClellan, mmclellan@brookings.edu)
* Increased Use of Prescription Drugs Reduces Medical Costs in Medicaid Populations, in
Health Affairs, 2015; 34: 1586–93. (M. C. Roebuck, mcr@rxeconomics.com)
* Patient-Centered Medical Homes and Access to Services for New Primary Care Patients, in
Medical Care, 2015; 53: 857–62. (J. Aysola)
* Review: A20-Binding Inhibitor of NF-Kappa-B Activation 1 Is a Physiologic Inhibitor of NF-Kappa-B: A Molecular Switch for Inflammation and Autoimmunity, in
Arthritis & Rheumatism, 2015; 67: 2292–302. (D. W. Powell, david.powell@louisville.edu)
* American Heart Association Response to the 2015 Institute of Medicine Report on Strategies to Improve Cardiac Arrest Survival, in
Circulation, 2015; 132: 1049–70. (R. W. Neumar)

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
Sept. 22, 2015 * Vol. 22, No. 182
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2015; 163).
Interventions for Tobacco Cessation: Authors present evidence and recommendations for tobacco cessation in adults, including pregnant women.
Based on a review of 54 reviews conducted for the U.S. Preventive Services Task Force (USPSTF), authors conclude that both “behavioral and pharmacotherapy interventions improve rates of smoking cessation among the general adult population, alone or in combination” (
doi: 10.7326/M15-0171). Evidence regarding the efficacy of electronic nicotine-delivery devices is limited, the group adds, based on this evidence: “Behavioral interventions increased smoking cessation at 6 months or more (physician advice had a pooled risk ratio [RR] of 1.76 [95% CI, 1.58 to 1.96]). Nicotine replacement therapy (RR, 1.60 [CI, 1.53 to 1.68]), bupropion (RR, 1.62 [CI, 1.49 to 1.76]), and varenicline (RR, 2.27 [CI, 2.02 to 2.55]) were also effective for smoking cessation. Combined behavioral and pharmacotherapy interventions increased cessation by 82% compared with minimal intervention or usual care (RR, 1.82 [CI, 1.66 to 2.00]). None of the drugs were associated with major cardiovascular adverse events. Only 2 trials addressed efficacy of electronic cigarettes for smoking cessation and found no benefit. Among pregnant women, behavioral interventions benefited cessation and perinatal health; effects of nicotine replacement therapy were not significant.” (Agency for Healthcare Research and Quality Web site; www.ahrq.gov)
After reviewing the above evidence, the USPSTF makes four recommendations for tobacco cessation in adults (
doi: 10.7326/M15-2023; USPSTF, www.uspreventiveservicestaskforce.org):
* The USPSTF recommends that clinicians ask all adults about tobacco use, advise them to stop using tobacco, and provide behavioral interventions and FDA-approved pharmacotherapy for cessation to adults who use tobacco. (A recommendation)
* The USPSTF recommends that clinicians ask all pregnant women about tobacco use, advise them to stop using tobacco, and provide behavioral interventions for cessation to pregnant women who use tobacco. (A recommendation)
* The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of pharmacotherapy interventions for tobacco cessation in pregnant women. (I statement)
* The USPSTF concludes that the current evidence is insufficient to recommend electronic nicotine delivery systems for tobacco cessation in adults, including pregnant women. The USPSTF recommends that clinicians direct patients who smoke tobacco to other cessation interventions with established effectiveness and safety (previously stated). (I statement)
Leukotriene-Receptor Antagonists in Asthma: Leukotriene-receptor antagonists (LTRAs) as monotherapy in adults and adolescents “improved asthma control compared with placebo, but which patients are most likely to respond to treatment with LTRAs remains unclear,” conclude authors of a systematic review and meta-analysis (doi: 10.7326/M15-1059). “Of the 2,008 abstracts that were screened, 50 trials met eligibility criteria,” the investigators write. “Random-effects meta-analyses of 6 trials of LTRA monotherapy showed that LTRAs reduced the risk for an exacerbation (summary risk ratio [RR], 0.60 [95% CI, 0.44 to 0.81]). In 4 trials of LTRAs as add-on therapy to inhaled corticosteroids, the summary RR for exacerbation was 0.80 (CI, 0.60 to 1.07). Leukotriene-receptor antagonists either as monotherapy or add-on therapy to inhaled corticosteroids increased FEV1, whereas FEV1 percentage of predicted values was only improved in trials of LTRA monotherapy. Adverse event rates were similar in the intervention and comparator groups.” (M. Miligkos, mmiligkos@med.uth.gr)

>>>PNN NewsWatch
* FDA is investigating a “rare but serious risk of slowed or difficult breathing” associated with use of tramadol in children aged 17 years and younger. The risk is higher after surgery for removal of the tonsils and/or adenoids and is thought to be greater in ultrarapid metabolizers of the drug.
*
FDA yesterday announced it has awarded 18 new research grants totaling more than $19 million to boost the development of products for patients with rare diseases.

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
Sept. 23, 2015 * Vol. 22, No. 183
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 22/29 issue of JAMA (2015; 314).
Dextromethorphan–Quinidine for Agitation in Alzheimer Dementia: In 220 patients with probable Alzheimer disease, dextromethorphan–quinidine “demonstrated clinically relevant efficacy for agitation and was generally well tolerated,” researchers report (pp. 1242–54). Participants were randomized in a 3:4 proportion to active drug or placebo in stage 1 of the study, and nonresponders to placebo were rerandomized 1:1 in stage 2. These changes from baseline were noted on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (0–12 scale, with 0 no symptoms and 12 daily severe symptoms): “With the sequential parallel comparison design, 152 patients received dextromethorphan–quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan–quinidine vs placebo (ordinary least squares z statistic, −3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan–quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, −1.5; 95% CI, −2.3 to −0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan–quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, −1.6; 95% CI, −2.9 to −0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan–quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan–quinidine vs 4.7% with placebo. Dextromethorphan–quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation.” (J. L. Cummings, cumminj@ccf.org)
Current treatment of agitation in patients with dementia in the U.S. and European Union generally involves use of off-label second-generation antipsychotics, editorialists write (
pp. 1233–5). “Emerging evidence indicates that several other treatment approaches such as stepped analgesia and citalopram may have equivalent or better efficacy than antipsychotic agents, although adverse events including the prolongation of QTc may be a challenge with citalopram. Within this clinical treatment environment, pending further evidence, there is a reasonably strong case to prioritize dextromethorphan–quinidine as an off-label treatment for agitation, possibly as a safer alternative to atypical antipsychotics. However, while further studies are conducted to verify the efficacy and safety of this approach, it will be important to achieve a robust international expert consensus regarding the prioritization of potential treatments for agitation in patients with dementia to improve the consistency of clinical practice. This approach also must understand and incorporate patient and caregiver views regarding the evaluation of risk and benefits in relation to these treatments.” (A. Corbett, anne.corbett@kcl.ac.uk)

>>>PNN NewsWatch
* FDA yesterday approved the combination of trifluridine and tipiracil (Lonsurf, Taiho Oncology) for treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. Approval was based on results of the RECOURSE trial of 800 patients with previously treated mCRC who received active drugs or placebo with best supportive care until their disease worsened or adverse effects became intolerable. The two-drug combination reduced the risk of death by 32% compared with placebo. Median overall survival (OS) was 7.1 months (95% CI: 6.5, 7.8) and 5.3 months (95% CI: 4.6, 6.0) for Lonsurf and placebo, respectively. The most common adverse drug reactions or laboratory abnormalities were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea.

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
Sept. 24, 2015 * Vol. 22, No. 184
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 24 New England Journal of Medicine (2015; 373).
Daratumumab Monotherapy in Multiple Myeloma: In a Phase I/II trial that included patients with heavily pretreated and refractory multiple melanoma, the CD38-targeting, human IgG1-kappa monoclonal antibody daratumumab “had a favorable safety profile and encouraging efficacy,” researchers report (pp. 1207–19). A dose-escalation phase of the study (part 1) tested doses of daratumumab from 0.005 to 24 mg/kg. This was followed by a dose-expansion phase (part 2) in which 30 patients received daratumumab 8 mg/kg and 42 patients received 16 mg/kg once weekly for 8 doses, twice monthly for 8 doses, and monthly for up to 24 months.
Results showed: “No maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.” (H. M. Lokhorst,
h.lokhorst@vumc.nl)
These “surprising and very encouraging” results, editorialists write, “are probably due to [daratumumab’s] pleiotropic mechanisms of action against myeloma” (
pp. 1264–6). “Even with this enthusiasm, unanswered questions remain. How do tumors escape the effects of daratumumab? Can daratumumab, like rituximab in the treatment of lymphoma, be active in many phases of treatment, such as in induction, consolidation, and maintenance therapies? Can daratumumab resistance be predicted? As we begin to tackle the complexity of these questions, it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma.” (N. Raje)
Treatment of Unexplained Infertility: Investigators compared gonadotropin, clomiphene, and letrozole in treatment of women with unexplained infertility, finding that letrozole did not reduce the frequency of multiple gestations as some have proposed (pp. 1230–40). Ovarian stimulation for up to four cycles in 900 ovulatory women showed the following: “After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P = 0.003) or gonadotropin alone (P <0.001) but not with clomiphene alone (P = 0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P = 0.15) or clomiphene alone (8 of 85, 9%; P = 0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P = 0.006).” (M. P. Diamond, michael.diamond@gru.edu)

>>>PNN NewsWatch
* Three medication errors associated with vial and carton labeling of a two-drug product prompted an FDA warning this week. Avycaz (ceftazidime and avibactam; Actavis) was initially approved with vial and carton labels displaying individual strengths of the two active ingredients (i.e., 2 g/0.5 g); however, the product is dosed based on the sum of the active ingredients (i.e., 2.5 g). FDA has revised the labels to indicate that each vial contains Avycaz 2.5 g, equivalent to ceftazidime 2 g and avibactam 0.5 g.

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
Sept. 25, 2015 * Vol. 22, No. 185
Providing news and information about medications and their proper use

>>>Medical Care Report
Source:
Oct. issue of Medical Care (2015; 53).
RN Workforce & the Baby Boomers: A doubling of nursing school enrollments over the past decade and the ongoing “surge of entry of new RNs into the workforce … may not be sufficient to meet demand” as the baby boomers retire, researchers conclude, but “such projections are uncertain in the face of a rapidly evolving health care delivery system” (pp. 850–6). In projecting the size and age of the nursing workforce in 2030, the authors use data on registered nurses (RNs) from the U.S. Census Current Population Survey (1979–2000, N = 72,222) and American Community Survey (2001–13, N = 342,712): “Annual retirements from the nursing workforce will accelerate from 20,000 a decade ago to near 80,000 in the next decade as baby boomer RNs continue to age. We project that this outflow will be more than offset by continued strong entry of new RNs into the workforce. Overall, we project that the registered nursing workforce will increase from roughly 2.7 million FTE RNs in 2013 to 3.3 million in 2030. We also find that the workforce will reach its peak average age in 2015 at 44.4. This increase in workforce size, which was not expected in forecasts made a decade ago, is contingent on new entry into nursing continuing at its current rate. Even then, supply would still fall short of demand as recently projected by the Health Resources and Services Agency in the year 2025 by 128,000 RNs (4%).” (D. I. Auerbach)

>>>Health Affairs Highlights
Source:
Sept. issue of Health Affairs, a theme issue on Noncommunicable Diseases: The Growing Burden (2015; 34).
Prescription & Medical Costs in Medicaid: Investigators analyze data on 1.5 million Medicaid enrollees to quantify the reduction in medical costs associated with increased use of prescription medications (pp. 1586–93): “For three distinct groups of enrollees, we estimated the effects of aggregate prescription drug use—and, more specifically, the use of medications to treat eight chronic noncommunicable diseases—on total nondrug, inpatient, outpatient, and other Medicaid spending. We found that a 1 percent increase in overall prescription drug use was associated with decreases in total nondrug Medicaid costs by 0.108 percent for blind or disabled adults, 0.167 percent for other adults, and 0.041 percent for children. Reductions in combined inpatient and outpatient spending from increased drug utilization in Medicaid were similar to an estimate for Medicare by the Congressional Budget Office. Moving forward, policy makers evaluating proposed changes that alter medication use among the nearly seventy million Medicaid recipients should consider the net effects on program spending to ensure that scarce federal and state health care dollars are allocated efficiently.” (M. C. Roebuck, mcr@rxeconomics.com)
Global Trends in Noncommunicable Diseases: “Noncommunicable diseases are the leading health concerns of the modern era, accounting for two-thirds of global deaths, half of all disability, and rapidly growing costs,” write authors of an overview on burdens of noncommunicable diseases (pp. 1444–55). Data from 49 countries for 1980 to 2012 show these trends: “Mortality for cardiovascular disease, stomach cancer, and cervical cancer declined, while mortality for diabetes, liver cancer, and female chronic respiratory disease and lung cancer increased. In contrast to the relatively steep cardiovascular and cancer mortality declines observed in high-income countries, mortality for cardiovascular disease and chronic respiratory disease was flat in most low- and middle-income countries, which also experienced increasing breast and colon cancer mortality. These divergent mortality patterns likely reflect differences in timing and magnitude of risk exposures, health care, and policies to counteract the diseases.…” (M. K. Ali, mkali@emory.edu)

>>>PNN NewsWatch
* US Compounding (USC) is voluntarily recalling all lots of sterile products aseptically compounded and packaged by USC and that remain within expiry because of FDA concern over lack of sterility assurance.
* In today’s
Federal Register, the Environmental Protection Agency proposes regulations governing management and disposal of hazardous pharmaceutical waste by hospitals, pharmacies, and other health care facilities.

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
Sept. 28, 2015 * Vol. 22, No. 186
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2015; 351).
Genotyping for Allopurinol: At 15 Taiwanese medical centers, prospective screening for the HLA-B*58:01 allele and provision of alternate drugs to carriers “significantly decreased the incidence of allopurinol induced [severe cutaneous adverse reactions (SCARs)],,” researchers report (h4848). Screening of 2,926 people of Han Chinese descent and without any history of allopurinol hypersensitivity produced these results with and without genotypic screening: “Participants who tested positive for HLA-B*58:01 (19.6%, n = 571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n = 2,339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms.… Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P = 0.0026; two side one sample binomial test).” (C-Y Shen, bmcys@ibms.sinica.edu.tw)
FDA Expedited Drug Approvals: While FDA has approved an increasing number of drugs under expedited programs over the past two decades, these agents are typically “not first in class and thus potentially less innovative,” a study shows (h4633): “The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P <0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P = 0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P = 0.03 for interaction).” (A. S. Kesselheim, akesselheim@partners.org)

>>>Lancet Highlights
Source:
Sept. 26 issue of Lancet (2015; 386).
Methylprednisolone in Cardiopulmonary Bypass: In the placebo-controlled Steroids In caRdiac Surgery (SIRS) study, “methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass” (pp. 1243–53). At 80 hospital or cardiac surgery centers, 7,507 patients undergoing cardiac surgery in 2007–13 were randomized to placebo or methylprednisolone 250 mg at anesthetic induction and at initiation of cardiopulmonary bypass, with these effects on primary outcomes of 30-day mortality and a composite of death and major morbidity (myocardial injury, stroke, renal failure, or respiratory failure) within 30 days: “Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0.87, 95% CI 0.70–1.07, p = 0.19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1.03, 95% CI 0.95–1.11, p = 0.52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%]).” (R. P. Whitlock, richard.whitlock@phri.ca)

>>>PNN NewsWatch
* FDA on Friday approved Tresiba (insulin degludec injection), a long-acting insulin analogue, and Ryzodeg 70/30 (insulin degludec/insulin aspart injection), a new mixture of the long-acting insulin with a rapid-release analogue, to improve blood glucose control in adults with diabetes mellitus. Both products are from Novo Nordisk.

>>>PNN JournalWatch
* The Asthma–COPD Overlap Syndrome, in
New England Journal of Medicine, 2015; 373: 1241–9. (D.S. Postma, d.s.postma@umcg.nl)

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


PNN Pharmacotherapy Line
Sept. 29, 2015 * Vol. 22, No. 187
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Sept. issue of the Journal of the American Geriatrics Society (2015; 63).
Effects of Influenza Vaccination in Nursing Home Residents: In influenza seasons when the circulating strains match well with vaccine antigens—particularly A/H3N2—hospitalizations for pneumonia and influenza (P&I) and mortality are reduced among residents of nursing homes (NHs), a study shows (pp. 1798–804). Investigators analyzed Medicare claims data linked NH minimum data set assessments to reach these conclusions about CDC surveillance data from 122 cities: “Average weekly all-cause mortality varied across seasons from 3.74 to 4.13 per 1,000 NH residents per week, and hospitalization for P&I varied from 2.05 to 2.43. Vaccine match rates were invariably high for H1N1 but variable across seasons for the other two types. The association between vaccine match and reduction in overall mortality and P&I hospitalizations was strongest for A/H3N2, the influenza strain typically responsible for the most-severe influenza cases. Given the approximately 130,000 deaths and 77,000 P&I hospitalizations of long-stay NH residents during the 32 nonsummer weeks, the model estimated that a 50-percentage-point increase in the A/H3N2 match rate (from <25% to >75%) reduced long-stay NH resident deaths by 2.0% and P&I hospitalizations by 4.2%.” (V. Mor, Vincent_Mor@brown.edu)
Usefulness of Brown Bag Medication Review: At six senior centers and three senior high-rises, older adults found comprehensive brown bag medication reviews useful and implemented 63% of recommendations made in addressing drug-related problems (DRPs) (pp. 1900–5). Participants were 60 years or older (mean ± S. D. age, 75.9 ± 8.5 years) and were taking five or more medications. Based on satisfaction surveys immediately after the med review and at 3 months, implementation surveys at 3 months, and investigator categorization of DRP recommendations, the investigators found: “Participants had a mean of 4.3 ± 2.8 DRPs (range 0–10). DRPs were classified as adverse reactions (30%), treatment effectiveness (28%), treatment costs (13%), information need (8%), and other (21%). Causes included drug selection (40%), wrong dosage (23%), participant problems (e.g., adherence, lack of medication knowledge, 16%), drug use process problems (12%), drug formulation (0.5%), treatment duration (0.5%), and other (7%). Interventions required drug changes (44%), prescriber input (37%), individual counseling (18%), or other (1%). DRP severities were significant (59%) or minor (35%). Participants expressed satisfaction with the program because they were able to ask questions, trusted the answers, and knew more about their medications. After 3 months, they had implemented 63% of the DRP recommendations.” (M. B. O’Connell, mboconnell@wayne.edu)
Vitamin D Delivery Via Meals on Wheels: Reductions in falls were among the benefits experienced by community-dwelling homebound adults aged 65 to 102 years who received vitamin D supplements delivered by Meals on Wheels (MOW), researchers report (pp. 1861–7). A total of 88 patients received vitamin D3 100,000 IU/month or placebo (vitamin E 400 IU/month) based on MOW delivery route. Outcomes were as follows: “Mean ± standard deviation 25(OH)D concentrations were 20.9 ± 11.5 ng/mL at baseline, with 57% having 25(OH)D concentrations less than 20 ng/mL. Retention and adherence were high (>90%). After the 5-month intervention, only one of 34 participants randomized to vitamin D3 had 25(OH)D concentrations less than 20 ng/mL, compared with 18 of 25 participants randomized to placebo (P <.001). In unadjusted analyses, the rate of falls over 5 months was not significantly different according to intervention group (risk ratio (RR) = 0.48, 95% confidence interval (CI) = 0.19–1.19), but after adjustment for sex, race, season of year, baseline 25(OH)D status, and history of falls, participants randomized to vitamin D3 had a lower rate of falling than those randomized to placebo (RR = 0.42, 95% CI = 0.21–0.87).” (D. K. Houston, dhouston@wakehealth.edu)

>>>PNN NewsWatch
* A federal judge on Friday entered a consent decree of permanent injunction against Sunset Natural Products Inc. and its two owners for manufacturing and distributing adulterated dietary supplements at its facility in Miami, FL.

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
Sept. 30, 2015 * Vol. 22, No. 188
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2015; 38).
Lactobacillus reuteri & Incretin, Insulin Secretion: In a study of 21 glucose-tolerant people, supplements of Lactobacillus reuteri increased “insulin secretion, possibly due to augmented incretin release, but [did] not directly affect insulin sensitivity or body fat distribution,” researchers report (pp. 1827–34). Participants, 11 of whom were lean and 10 obese, received 1010 L. reuteri SD5865 or placebo twice daily over 4 weeks. Tests of glucose tolerance, incretin effects, and glucagon-like peptides (GLP)-1 and -2 showed these patterns: “In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines.” (M. Roden, michael.roden@ddz.uni-duesseldorf.de)
An editorialist disagrees with the clinical relevance of this study, concluding that “supplements of this microbe may benefit the manufacturer but are unlikely to help either the frustrated obese patients or their hopeful doctors” (
pp. 1817–9): “This trial was impeccable in design, the range of the outcomes covering virtually all aspects of the hypothesis; the use of state-of-the-art methods suggests high expectations by the investigators. Against this intense experimental effort, the harvest was rather meager (and perhaps transient), almost much ado about nothing. As the authors acknowledge, the study presents several limitations: the sample size was small, the trial duration short, and only one dose was tested. However, the lack of any trend or signal in the data, while it may spare other similar studies in humans, casts reasonable doubt on the hypothesis. Perhaps this probiotic only redresses an altered intestinal flora, helps recovery from an acute perturbation, or acts in concert with some other intervention. Or else, L. reuteri is the wrong probiotic for the problem at hand, i.e., simple obesity.” (E. Ferrannini, ferranni@ifc.cnr.it)
Eat Your Breakfast: In a study of 22 patients with type 2 diabetes who skipped breakfast and later consumed isocaloric lunch and dinner, investigators demonstrate “a long-term influence of breakfast on glucose regulation that persists throughout the day” (pp. 1820–6). Participants were randomly assigned to two test days: one with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB), with these effects: “Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, [free fatty acids (FFA)], and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and [intact glucagon-like peptide-1 (iGLP-1)] were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day.” (D. Jakubowicz, daniela.jak@gmail.com)
Metformin & Cardiovascular Disease: Metformin treatment of type 2 diabetes (mt-T2D) produces metabolic changes that “suggest potential beneficial effects of metformin in the prevention of cardiovascular disease,” a study shows (pp. 1858–67). Among 912 participants in the longitudinal KORA cohort, the authors “found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years’ follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol. Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target.” (R. Wang-Sattler, rui.wang-sattler@helmholtz-muenchen.de)

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