Sep 2014

PNN July–September 2014

PNN Pharmacotherapy Line
July 1, 2014 * Vol. 21, No. 126
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 1 issue of the Annals of Internal Medicine (2014; 161).
Efavirenz & Suicidality: Antiretroviral-naive patients started on efavirenz-containing regimens had a 2-fold increase in suicidality, a study shows, compared with efavairenz-free regimens (pp. 1–10). Investigators looked at participant-level data from four AIDS Clinical Trials Group studies (three of them open label), which randomly assigned patients with HIV to efavirenz-containing (n = 3,241) or -free (n = 2,091) regimens. With suicidality defined as suicidal ideation or completed suicide, results showed: “Seventy-three percent of participants were men, the median age was 37 years, and 32% had documented psychiatric history or received psychoactive medication within 30 days before entering the study. Median follow-up was 96 weeks. Suicidality incidence per 1,000 person–years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group (hazard ratio, 2.28 [95% CI, 1.27 to 4.10]; P = 0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively (hazard ratio, 2.58 [CI, 0.94 to 7.06]; P = 0.065). Eight suicides in the efavirenz group and 1 in the efavirenz-free group were reported.” (C. Tierney)
Herpesvirus Protection From HIV Prophylactic Regimens: Patients taking daily oral preexposure prophylaxis (PrEP) have “modest protection” against acquisition of herpes simplex virus type 2 (HSV-2), researchers report (pp. 11–9). In Kenya and Uganda, uninfected heterosexual men and women in HIV-discordant couples received daily oral PrEP alone or in combination with emtricitabine (FTC–TDF). Effects on HSV-2 seroconversion showed these patterns: “A total of 131 participants seroconverted to HSV-2 (79 of 1,041 assigned to tenofovir or FTC–TDF PrEP [HSV-2 incidence, 5.6 per 100 person–years] and 52 of 481 assigned to placebo [HSV-2 incidence, 7.7 per 100 person–years]). The hazard ratio (HR) for HSV-2 acquisition with daily oral PrEP was 0.70 (95% CI, 0.49 to 0.99; P = 0.047) compared with placebo, and the absolute risk reduction was 2.1 per 100 person–years. Among the 1,044 participants with HSV-2–infected partners, the HR for PrEP was 0.67 (CI, 0.46 to 0.98; P = 0.038) compared with placebo, and the absolute risk reduction was 3.1 per 100 person–years.” (C. Celum)
Interinstitutional Variation in Cancer Management: After finding “substantial variation in institutional practice … among cancer centers” with regard to their management of four common types of cancer, authors of a cohort study advise, “For clinicians, awareness of management decisions with high variation should prompt attention to patient preferences. For health systems, high variation can be used to prioritize comparative effectiveness research, patient–provider education, or pathway development.” (pp. 20–30). The study, conducted at 18 cancer centers in the National Comprehensive Cancer Network, included 25,589 patients with incident breast, colorectal, or lung cancer, or non-Hodgkin lymphoma, with these results for 171 binary management decisions: “Interinstitutional variation was high (median absolute deviation >10%) for 35 of 171 (20%) oncology management decisions, including 9 of 22 (41%) decisions for non-Hodgkin lymphoma, 16 of 76 (21%) for breast cancer, 7 of 47 (15%) for lung cancer, and 3 of 26 (12%) for colorectal cancer. Forty-six percent of high-variance decisions involved imaging or diagnostic procedures and 37% involved choice of chemotherapy regimen. The evidence grade underpinning the 35 high-variance decisions was category 1 for 0%, 2A for 49%, and 2B/other for 51%.” (D. Schrag, deb_schrag@dfci.harvard.edu)

>>>PNN NewsWatch
* “Pharmacists are capable providers in an incapable system,” APhA CEO Tom Menighan writes in The Hill, a politically influential DC periodical. Using a basketball analogy in arguing for pharmacist recognition as providers, Menighan concludes, “When pharmacists and their services are recognized under the law, patients will have access to an array of care services beyond dispensing of medications. It’s up to lawmakers to ensure that not only are pharmacists rightfully recognized for their invaluable contributions to a patient’s health care team, but that patients can have access to the critical care they need. America’s 300,000 pharmacists have one message for Congress: Put me in coach, I’m ready to play.”

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

PNN Pharmacotherapy Line
July 2, 2014 * Vol. 21, No. 127
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 2 issue of JAMA (2014; 312).
EPO & Traumatic Brain Injury: Neurologic outcomes were not improved among 200 patients with closed head injuries when erythropoietin was administered or when hemoglobin concentrations were maintained above 10 g/dL, researchers report (pp. 36–47). At two American level I trauma centers, patients with traumatic brain injuries who were unable to follow commands were randomized to I.V. erythropoietin (500 IU/kg per dose) or saline daily for 3 days and weekly for 2 weeks; transfusion thresholds of 7 or 10 g/dL were maintained with packed red blood cells. Dichotomized Glasgow Outcome Scale results showed the following: “There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P <.001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, −0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009).” (C. S. Robertson, claudiar@bcm.edu)
The intention-to-treat (ITT) method used in this study is examined in a JAMA Guide to Statistics and Methods article (
pp. 85–6): “Although the ITT principle is important for estimating the efficacy of treatments, it should not be applied in the same way in assessing the safety (eg, medication adverse effects) of interventions. For example, it would not make sense to attribute an apparent adverse effect to an intended treatment when, in fact, the patient was never exposed to the experimental drug. For this reason, safety analyses are generally conducted according to the treatment actually received, even though this may not accurately estimate—and may well overestimate—the burden of adverse effects likely to be seen in clinical practice.” (R. J. Lewis, roger@emedharbor.edu)
Everolimus in Advanced Hepatocellular Carcinoma: In 546 adult patients with advanced hepatocellular carcinoma who had failed a course of sorafenib, treatment with everolimus did not improve overall survival in a Phase III study (pp. 57–67). In 17 countries, participants were randomized using a 2:1 ratio to everolimus 7.5 mg/d or placebo, with these results: “No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86–1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75–1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.” (A. X. Zhu, azhu@mgh.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday issued several policy documents defining the agency’s expectations for human drug compounders, including compliance with current good manufacturing practice (CGMP) requirements by registered outsourcing facilities. The CGMP draft interim guidance focuses on sterility assurance and general safety of compounded drug products. Also issued were a proposed rule listing drug products that may not be compounded because of market withdrawals; a final guidance for 503A (nonregistered) compounders, and two notices announcing reopening of nomination processes for bulk drug substances that may be used in compounding.

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


PNN Pharmacotherapy Line
July 3, 2014 * Vol. 21, No. 128
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 3 New England Journal of Medicine (2014; 371).
Epidural Glucocorticoids in Spinal Stenosis: In a study of epidural treatments for pain in patients with lumbar spinal stenosis, addition of glucocorticoids to lidocaine failed to significantly improve short-term outcomes (pp. 11–21). A total of 400 patients with moderate-to-severe leg pain and disability were randomized to epidural injections of glucocorticoids plus lidocaine or lidocaine alone. Based on primary outcomes of scores on the Roland–Morris Disability Questionnaire (RMDQ, scores 0–24) and leg pain ratings on a 0–10 scale, results showed: “At 6 weeks, there were no significant between-group differences in the RMDQ score (adjusted difference in the average treatment effect between the glucocorticoid–lidocaine group and the lidocaine-alone group, −1.0 points; 95% confidence interval [CI], −2.1 to 0.1; P = 0.07) or the intensity of leg pain (adjusted difference in the average treatment effect, −0.2 points; 95% CI, −0.8 to 0.4; P = 0.48). A prespecified secondary subgroup analysis with stratification according to type of injection (interlaminar vs. transforaminal) likewise showed no significant differences at 6 weeks.” (J. L. Friedly, friedlyj@uw.edu)
“This study raises serious questions about the benefits of epidural glucocorticoid injections for spinal stenosis,” an editorialist writes (
pp. 75–6). “In patients who nonetheless proceed with an epidural glucocorticoid injection, repeat injections should be avoided if there is no effect. This recommendation is consistent with recommendations of the North American Spine Society. At present, many insurance companies require epidural injections as part of nonsurgical treatment before surgery is approved. The current trial and [a recent] FDA safety announcement [about serious or catastrophic outcomes with epidural glucocorticoid injections] suggest that this requirement should be reconsidered.” (G. B. J. Andersson)

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Pediatric Adverse Drug Events: Medications commonly associated with adverse events (AEs) in children and adolescents are identified through analysis of the FDA’s Adverse Event Reporting System (FAERS) in 2007–12 (doi: 10.1002/phar.1455): “We identified a total of 78,623 reports in the FAERS database (53.8% in children and 46.2% in adolescents). Serious outcomes were noted in 40% of the children and 43% of the adolescents. The proportion of all case reports for central nervous system stimulants (lisdexamfetamine, 69.8%; methylphenidate, 68.0%) and analgesics (ibuprofen, 72.3%; acetaminophen, 68.6%) was higher in children, whereas tumor necrosis factor blockers (infliximab, 78.2%; adalimumab, 77.1%), atypical antipsychotics (aripiprazole 52.7%; risperidone 58.3%; quetiapine 72.1%) and oral contraceptives (levonogrestrel, 99.2%; drospirenone and ethinyl estradiol, 97.9%) were more commonly reported in adolescents. For most drugs, the types of reactions reported were similar but had different rank order across age groups, with the most dissimilar profiles being observed for isotretinoin and aripiprazole.” (G. T. Schumock, schumock@uic.edu)
Pediatric Antipsychotic Polypharmacy: Based on findings that “certain youth may have a higher likelihood of being prescribed antipsychotic polypharmacy,” authors of a retrospective review advise, “Future examinations of the rationale for combining antipsychotics, along with the long-term safety, tolerability, and cost effectiveness of these therapies, in youth are urgently needed” (doi: 10.1002/phar.1453). Data on 1,427 children and adolescents who were consecutively admitted to and discharged from an inpatient psychiatric unit in 2010–11 showed the following: “Positive correlations with antipsychotic polypharmacy were observed for placement or custody outside the biological family; a greater number of previous psychiatric admissions; longer hospitalizations; admission for violence/aggression or psychosis; and intellectual disability, psychotic, disruptive behavior, or developmental disorder diagnoses. Negative correlations with antipsychotic polypharmacy included admission for suicidal ideation/attempt or depression, and mood disorder diagnoses.” (S. N. Saldaña, Shannon.Saldana@imail.org)

>>>PNN NewsWatch
* PNN will not be published on Fri., July 4, Independence Day.

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

PNN Pharmacotherapy Line
July 7, 2014 * Vol. 21, No. 129
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 5 issue of Lancet (2014; 384).
Outcomes After Preconception Low-Dose Aspirin: Based on findings of no change in pregnancy outcomes, authors do not recommend preconception low-dose aspirin in women who have had previous pregnancy losses (pp. 29–36). The U.S. study included 1,078 women ages 18–40 who were attempting to become pregnant following one or more pregnancy losses. Block randomization to aspirin 81 mg plus folic acid or placebo plus folic acid for up to six menstrual cycles yielded these results: “309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p = 0.0984; absolute difference in livebirth rate 5.09% [95% CI −0.84 to 11.02]). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p = 0.7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p = 0.0446; absolute difference in livebirth rate 9.20% [0.51 to 17.89]). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p = 0.7406; absolute difference in livebirth rate 1.71% [–6.37 to 9.79]). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss.” (E. F. Schisterman, schistee@mail.nih.gov)
Phenylalanine Ammonia Lyase/Polyethylene Glycol for Phenylketonuria: In adults with phenylketonuria, subcutaneous recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) was “fairly safe and well tolerated” and at the highest dose tested, “reduced blood phenylalanine concentrations,” researchers report (pp. 37–44). The open-label, Phase I trial of 25 participants showed these results: “The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0.100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89–106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54.2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection.” (N. Longo, nicola.longo@hsc.utah.edu)

>>>PNN NewsWatch
* FDA on Thursday approved belinostat (Beleodaq, Spectrum Pharmaceuticals) for treatment of patients with peripheral T-cell lymphoma (PTCL) who have relapsed or did not respond to previous treatments. The agency considered this product under its accelerated-approval program and noted this is the third drug approved for PTCL since 2009.

>>>PNN JournalWatch
* Implications of Expanding Indications for Drug Treatment To Prevent Fracture in Older Men in United States: Cross Sectional and Longitudinal Analysis of Prospective Cohort Study, in
BMJ, 2014; 349: g4120. (K. E. Ensrud, ensru001@umn.edu)
* Omega-3 Long-Chain Polyunsaturated Fatty Acids for Extremely Preterm Infants: A Systematic Review, in
Pediatrics, 2014; 134: 120–34. (P. Zhang)
* Treatment of Separation, Generalized, and Social Anxiety Disorders in Youths, in
American Journal of Psychiatry, 2014; 171: 741–8. (J. Mohatt, jum9071@med.cornell.edu)
* Whooping Cough in 2014 and Beyond: An Update and Review, in
Chest, 2014; 146: 205–14. (J. M. Blaylock, jason.m.blaylock.mil@mail.mil)
* Roles of the Pharmacist in the Use of Safe and Highly Effective Long-Acting Reversible Contraception: An Opinion of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1457. (S. Rafie, srafie@ucsd.edu)

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

PNN Pharmacotherapy Line
July 8, 2014 * Vol. 21, No. 130
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July issue of JAMA Internal Medicine (2014; 174).
Statins & Gluttony: In a repeated cross-sectional, nationally representative study, investigators find that patients on statins have increased their caloric and fat intake over time (pp. 1038–45). Data for the years 1999 through 2010 from the National Health and Nutrition Examination Survey show these trends in 27,886 U.S. adults aged 20 or older: “In the 1999–2000 period, the caloric intake was significantly less for statin users compared with nonusers (2,000 vs 2,179 kcal/d; P = .007). The difference between the groups became smaller as time went by, and there was no statistical difference after the 2005–2006 period. Among statin users, caloric intake in the 2009–2010 period was 9.6% higher (95% CI, 1.8–18.1; P = .02) than that in the 1999–2000 period. In contrast, no significant change was observed among nonusers during the same study period. Statin users also consumed significantly less fat in the 1999–2000 period (71.7 vs 81.2 g/d; P = .003). Fat intake increased 14.4% among statin users (95% CI, 3.8–26.1; P = .007) while not changing significantly among nonusers. Also, BMI increased more among statin users (+1.3) than among nonusers (+0.4) in the adjusted model (P = .02).” (T. Sugiyama, tsugiyama-tky@umin.ac.jp)
In addition to known adverse effects of statins, these drugs may present a “moral hazard,” according to the author of an Editor’s Note (
p. 1046): “Focusing on cholesterol levels can be distracting from the more beneficial focus on healthy lifestyle to reduce heart disease risk.” (R. F. Redberg)
Live v. Web Interventions in CHD: At five North Carolina family medicine clinics, patients with no known cardiovascular disease but at high risk for coronary heart disease (CHD) responded equally well to live and Web-based lifestyle and medication (L&M) interventions, researchers report, but use of the Web format was substantially less expensive (pp. 1144–57). The study included those aged 35–79 years with Framingham Risk Scores (FRSs) of 10% or more. Counselor-delivered or Web-based interventions delivered in four intensive and three maintenance sessions yielded these results: “Of 2,274 screened patients, 385 were randomized (192 counselor; 193 web): mean age, 62 years; 24% African American; and mean FRS, 16.9%. Follow-up at 4 and 12 months included 91% and 87% of the randomized participants, respectively. There was a sustained reduction in FRS at both 4 months (primary outcome) and 12 months for both counselor-based (−2.3% [95% CI, −3.0% to −1.6%] and −1.9% [95% CI, −2.8% to −1.1%], respectively) and web-based groups (−1.5% [95% CI, −2.2% to −0.9%] and −1.7% [95% CI, −2.6% to −0.8%] respectively). At 4 months, the adjusted difference in FRS between groups was −1.0% (95% CI, −1.8% to −0.1%) (P = .03), and at 12 months, it was −0.6% (95% CI, −1.7% to 0.5%) (P = .30). The 12-month costs from the payer perspective were $207 and $110 per person for the counselor- and web-based interventions, respectively.” (T. C. Keyserling, thomas_keyserling@med.unc.edu)
Focusing on the weight-loss aspects of this program, editorialists call for changes in CMS regulations that require in-person visits for reimbursements (
pp. 1157–9): “Face-to-face interventions that are less convenient for patients and demand greater professional resource and cost investments hindering their long-term sustainability appear to be the interventions typically reimbursed by payers. Electronically delivered interventions have a mounting evidence base, but widespread adoption will not occur without reimbursement. Alongside this change, we need increased public health and education funding to focus on healthy diet and increased physical activity. Payment models that provide reimbursement across a wide array of delivery approaches are critically needed to address the obesity epidemic in this country.” (T. Moin, tmoin@mednet.ucla.edu)

>>>PNN NewsWatch
* FDA’s guidance on Section 503A (traditional) compounding, published in final form last week in the Federal Register, is essentially unchanged from the draft version, APhA says in a pharmacist.com report. The 503A guidance is advisory, and state boards of pharmacy will continue regulating traditional compounders. Compounders who register as 503B outsourcing facilities will be guided by an advisory FDA document yet to be released.

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

PNN Pharmacotherapy Line
July 9, 2014 * Vol. 21, No. 131
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 9 issue of JAMA (2014; 312).
Antibiotics After Cholecystectomy: Among patients who underwent cholecystectomy for grade I or II acute calculous cholecystitis, postoperative administration of antibiotics made no significant difference in infection rates, researchers report (pp. 145–54). At 17 medical centers, patients received no antibiotics or continued their preoperative amoxicillin/clavulanate regimen three times daily for 5 days, with these open-label results: “An imputed intention-to-treat analysis of 414 patients showed that the postoperative infection rates were 17% (35 of 207) in the nontreatment group and 15% (31 of 207) in the antibiotic group (absolute difference, 1.93%; 95% CI, −8.98% to 5.12%). In the per-protocol analysis, which involved 338 patients, the corresponding rates were both 13% (absolute difference, 0.3%; 95% CI, −5.0% to 6.3%). Based on a noninferiority margin of 11%, the lack of postoperative antibiotic treatment was not associated with worse outcomes than antibiotic treatment. Bile cultures showed that 60.9% were pathogen free. Both groups had similar Clavien complication severity outcomes: 195 patients (94.2%) in the nontreatment group had a score of 0 to I and 2 patients (0.97%) had a score of III to V, and 182 patients (87.8%) in the antibiotic group had a score of 0 to I and 4 patients (1.93%) had a score of III to V.” (J. M. Regimbeau, regimbeau.jean-marc@chu-amiens.fr)
Varenicline & NRT in Smoking Cessation: Tobacco abstinence was more common with the combination of varenicline plus nicotine-replacement therapy (NRT) than with varenicline alone, according to a study of 435 smokers (pp. 155–61). The trial, conducted at seven South African centers in 2011–12, included 12 weeks of NRT or placebo patch started 2 weeks before a target quit date (TQD) and varenicline begun 1 week before the TQD. Results at 12 weeks and 6 months showed the following: “The combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR], 1.85; 95% CI, 1.19–2.89; P = .007) and 24 weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25–3.14; P = .004) and point prevalence abstinence rate at 6 months (65.1% vs 46.7%; OR, 2.13; 95% CI, 1.32–3.43; P = .002). In the combination treatment group, there was a numerically greater incidence of nausea, sleep disturbance, skin reactions, constipation, and depression, with only skin reactions reaching statistical significance (14.4% vs 7.8%; P = .03); the varenicline-alone group experienced more abnormal dreams and headaches.” (C. F. N. Koegelenberg, coeniefn@sun.ac.za)
Antiepileptic Drugs in Neuropathic Pain & Fibromyalgia: “In treating diabetic neuropathy and postherpetic neuralgia compared with placebo, gabapentin and pregabalin are associated with a modest increase in the number of patients experiencing meaningful pain reduction,” conclude authors of a JAMA Clinical Evidence Symposia article (pp. 182–3). “In treating fibromyalgia, compared with placebo, pregabalin alone is associated with a small increase in the number of patients experiencing meaningful pain reduction. There is insufficient evidence for other antiepileptics.” Lack of evidence limits determinations of utility for other antiepileptic drugs, the authors write: “There is no trial evidence for benefit (clonazepam and phenytoin), too little evidence to estimate efficacy (valproic acid), low-quality evidence likely to be subject to biases overestimating efficacy (carbamazepine), or evidence indicating little or no effect (lamotrigine, oxcarbazepine, and topiramate). Lacosamide, 400 mg/d, was associated with a statistically significant benefit for painful diabetic neuropathy compared with placebo (risk ratio, 1.4; 95% CI, 1.01–1.9), but residual biases and limited sample sizes made the clinical relevance of this result uncertain.” (P. Wiffen, phil.wiffen@ndcn.ox.ac.uk)

>>>PNN NewsWatch
* APhA President and Iowa pharmacist Matt Osterhaus has penned an op-ed piece on provider status in the Des Moines Register, according to a CEO blog on pharmacist.com. “[Lack of provider status is] not just an oversight of the pharmacy profession,” Osterhaus wrote. “It’s a serious flaw that affects my patients in Maquoketa and every patient in the country. The quality of care provided and health outcomes achieved are better, and overall health care costs are reduced, when pharmacists are included as a member of a patient’s health care team.”

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

PNN Pharmacotherapy Line
July 10, 2014 * Vol. 21, No. 132
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 10 issue of the New England Journal of Medicine (2014; 371).
Exemestane v. Tamoxifen in Premenopausal Breast Cancer: Combined with ovarian suppression in two Phase III trials of 4,690 premenopausal women with hormone-receptor–positive early breast cancer, exemestane reduced recurrence significantly, compared with tamoxifen (pp. 107–18). Adjuvant therapy with the aromatase inhibitor was tested in conjunction with triptorelin, oophorectomy, or irradiation to achieve suppression of ovarian estrogen, with these results over 5 years in the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT): “After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P <0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P <0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women.” (O. Pagani, ibcsgcc@ibcsg.org)
“A careful assessment of risk versus benefit individualized to each patient should be the first step” in deciding whether to apply these results in clinical practice, an editorialist writes (
pp. 175–6): “The duration of follow-up is short, with almost 50% of recurrence events still expected, and there is no significant difference in overall survival as yet. Particularly in the group of women who did not receive chemotherapy, the number of events is small and the additional benefit of ovarian suppression is unknown. This group of patients could reasonably be treated with tamoxifen with or without ovarian suppression as we await the data from SOFT. For premenopausal women with high-risk breast cancer requiring chemotherapy, ovarian suppression with exemestane for 5 years is a new treatment option with the potential to reduce risk of distant recurrence.” (H. S. Rugo)
Letrozole in Polycystic Ovary Syndrome: The aromatase inhibitor letrozole produced significantly more live births and higher ovulation rates than did clomiphene in a study of 750 women with polycystic ovary syndrome, researchers report (pp. 119–29). Used over five treatment cycles in women ages 18–40, letrozole and clomiphene produced these outcomes: “Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P = 0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P = 0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1,352 treatment cycles [61.7%] vs. 688 of 1,425 treatment cycles [48.3%], P <0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.” (R. S. Legro, rsl1@psu.edu)
Dupilumab in Atopic Dermatitis: In four early-phase safety trials of a new inhibitor of interleukin–4 and –13, dupilumab produced “marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity” with no dose-limiting adverse effects (pp. 130–9). Administered subcutaneously over 4 to 12 weeks, dupilumab improved clinical indices, biomarker levels, and the disease’s RNA expression as reflected in the transcriptome. (L. A. Beck)

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

PNN Pharmacotherapy Line
July 11, 2014 * Vol. 21, No. 133
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
July 8 issue of Circulation (2014; 130).
Rivaroxaban in Older Patients: Rivaroxaban is a safe and effective alternative to warfarin among patients aged 75 years or older with atrial fibrillation, according to a prespecified secondary analysis from the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (pp. 138–46). In all, 6,229 patients in this age group had AF and two or more risk factors for stroke. Results showed: “Over 10,866 patient–years, older participants had more primary events (2.57% versus 2.05%/100 patient–years; P = 0.0068) and major bleeding (4.63% versus 2.74%/100 patient–years; P <0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient–years; hazard ratio = 0.80; 95% confidence interval, 0.63–1.02) and younger patients (2.00% versus 2.10%/100 patient–years; hazard ratio = 0.95; 95% confidence interval, 0.76-1.19; interaction P = 0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient–years; hazard ratio = 1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient–years; hazard ratio = 0.96; 95% confidence interval, 0.78-1.19; interaction P = 0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response.” (J. L. Halperin)

>>>Psychiatry Highlights
Source:
July issue of the American Journal of Psychiatry (2014; 171).
Lithium & Pregnancy: Among 183 lithium-exposed pregnant women, a higher rate of cardiovascular anomalies was observed, leading authors to recommend fetal echocardiography and level-2 ultrasound for those exposed to the drug during organogenesis (pp. 785–94). Using data from the Israeli Teratology Information Service, the investigators found these outcomes for exposed women, 72 disease-matched women, and 748 nonteratogenic-exposed pregnancies: “There were significantly more miscarriages (adjusted odds ratio = 1.94, 95% CI = 1.08–3.48) and elective terminations of pregnancy (17/183 [9.3%] compared with 15/748 [2.0%]) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 [6.5%]; bipolar: 2/61 [3.3%]; nonteratogenic: 19/711 [2.7%]). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the nonteratogenic exposure group (5/123 [4.1%] compared with 4/711 [0.6%]) but not after excluding anomalies that spontaneously resolved (3/123 [2.4%] compared with 2/711 [0.3%]). Ebstein’s anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the prenatal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 [13.7%] compared with 41/683 [6.0%]).” (O. Diav-Citri)
ADHD Meds & Pregnancy: “While most women can successfully avoid the use of stimulant medication during pregnancy, there are cases in which the benefits of stimulant treatment outweigh known and putative risks of in utero medication exposure,” conclude authors of a review article on use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy (pp. 723–8): “There are no guidelines to inform the treatment of ADHD across pregnancy and the postpartum period. Concerns about in utero exposure to stimulants are based primarily on the impact these medications might have on fetal growth. While stimulants do not appear to be associated with major congenital malformations, more human data regarding potential behavioral teratogenicity are needed in order to understand both the short- and long-term risks. Severity of illness, presence of comorbid disorders, and degree of impairment have an impact on treatment decisions. Crucial considerations include driving safety and ability to function in occupational roles.” (M. P. Freeman, mfreeman@partners.org)

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

PNN Pharmacotherapy Line
July 14, 2014 * Vol. 21, No. 134
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 12 issue of Lancet (2014; 384).
Incentives for Completing Hepatitis B Vaccination: Among patients receiving opioid substitution therapy for heroin dependence, “modest financial incentives delivered in routine clinical practice significantly improve[d] adherence to, and completion of, HBV vaccination programmes,” a study shows (pp. 153–63). At 12 U.K. drug-treatment centers, a cluster-randomized trial compared treatment as usual with fixed-value incentives (three vouchers for 10 pounds each) and escalating-value incentives for the three vaccination visits (vouchers for 5, 10, and 15 pounds). Results showed: “Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12.1, 95% CI 3.7–39.9; p <0.0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14.0, 4.2–46.2; p <0.0001). These differences remained significant with sensitivity analyses.” (J. Strang, john.strang@kcl.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 349).
Pertussis Vaccination of Pregnant Women: Pertussis vaccine has been given safely in the third trimester of pregnancy, according to an observational cohort study of 20,074 women and matched historical controls (g4219). Based on analysis of the U.K. Clinical Practice Research Datalink, investigators conclude: “In women given pertussis vaccination in the third trimester, there is no evidence of an increased risk of any of an extensive predefined list of adverse events related to pregnancy. In particular, there was no evidence of an increased risk of stillbirth. Given the recent increases in the rate of pertussis infection and morbidity and mortality in neonates, these early data provide initial evidence for evaluating the safety of the vaccine in pregnancy for health professionals and the public and can help to inform vaccination policy making.” (K. Donegan, katherine.donegan@mhra.gsi.gov.uk)
Alcohol & Cardiovascular Disease: Even among patients who consume light to moderate amounts of alcohol, reduction in intake improves cardiovascular health, report researchers who conducted a meta-analysis of 56 epidemiologic studies of individuals with a low-consumption genetic variant (g4164). The source studies assessed 261,991 individuals of European descent. Researchers looked at odds ratios for coronary heart disease and stroke associated with the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) along with categories of alcohol consumption: “Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (−0.88 (−1.19 to −0.56) mm Hg), interleukin-6 levels (−5.2% (−7.8 to −2.4%)), waist circumference (−0.3 (−0.6 to −0.1) cm), and body mass index (−0.17 (−0.24 to −0.10) kg/m2). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P = 0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).” (J. P. Casas, Juan-P.Casas@lshtm.ac.uk)

>>>PNN JournalWatch
* Review of Clinical Practice Guidelines for the Management of LDL-Related Risk, in
Journal of the American College of Cardiology, 2014; 64: 196–206. (P. B. Morris)
* Sodium/Glucose Cotransporter 2 Inhibitors and Prevention of Diabetic Nephropathy: Targeting the Renal Tubule in Diabetes, in
American Journal of Kidney Diseases, 2014; 64: 16–24. (L. De Nicola, luca.denicola@unina2.it)
* Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America, in
Clinical Infectious Diseases, 2014; 59: e10–e52. (D. L. Stevens, dlsteven@mindspring.com)

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

PNN Pharmacotherapy Line
July 15, 2014 * Vol. 21, No. 135
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 15 issue of the Annals of Internal Medicine (2014; 161).
Changes in Generic Medication Appearance: Among patients with cardiovascular disease following myocardial infarction, changes in appearance of generic medications were associated with decreased persistence with therapy, researchers report based on analysis of a U.S. commercial insurance database (pp. 96–103). Cohort and nested case–control studies found these relationships between nonpersistence and rates of change in cardiovascular medication color and shape in the year following MI: “A total of 29% of patients (3,286 of 11,513) had a change in pill shape or color during the study. Statins had the most changes in appearance, whereas beta-blockers had the fewest. A total of 4,573 episodes of nonpersistence was matched to 19,881 control episodes. The odds of nonpersistence in case patients increased by 34% after a change in pill color (adjusted odds ratio, 1.34 [95% CI, 1.12 to 1.59]) and 66% after a change in pill shape (adjusted odds ratio, 1.66 [CI, 1.43 to 1.94]).” (A. S. Kesselheim, akesselheim@partners.org)
Nurse Management of Chronic Conditions: Using protocols in a team environment, nurses provide effective outpatient care of patients with chronic conditions such as diabetes, hypertension,a nd hyperlipidemia, according to results of a systematic review and meta-analysis of 18 trials (pp. 113–21): “All studies used a registered nurse or equivalent who titrated medications by following a protocol. In a meta-analysis, hemoglobin A1c level decreased by 0.4% (95% CI, 0.1% to 0.7%) (n = 8); systolic and diastolic blood pressure decreased by 3.68 mm Hg (CI, 1.05 to 6.31 mm Hg) and 1.56 mm Hg (CI, 0.36 to 2.76 mm Hg), respectively (n = 12); total cholesterol level decreased by 0.24 mmol/L (9.37 mg/dL) (CI, 0.54-mmol/L decrease to 0.05-mmol/L increase [20.77-mg/dL decrease to 2.02-mg/dL increase]) (n = 9); and low-density-lipoprotein cholesterol level decreased by 0.31 mmol/L (12.07 mg/dL) (CI, 0.73-mmol/L decrease to 0.11-mmol/L increase [28.27-mg/dL decrease to 4.13-mg/dL increase]) (n = 6).” (R. J. Shaw, ryan.shaw@duke.edu)

>>>Infectious Disease Report
Source:
Aug. 1 issue of Clinical Infectious Diseases (2014; 59).
School-Located Influenza Vaccination: School-located influenza vaccination (SLV) programs that achieve immunization of at least one quarter of school populations decrease influenza rates and improve school attendance, according to a results of a study conducted in Los Angeles (pp. 325–32). During the 2010–11 season, rates of influenza-like illness (ILI) at four SLV intervention and four control elementary schools showed these patterns for 4,455 children: “In SLV schools, 26.9%–46.6% of enrolled students received at least 1 dose of either inactivated or live attenuated influenza vaccine compared with 0.8%–4.3% in control schools. Polymerase chain reaction for respiratory viruses (PCR) was performed on 1,021 specimens obtained from 898 children. Specimens were positive for influenza in 217 (21.3%), including 2009 H1N1 (30.9%), H3 (9.2%), and B (59.9%). Children attending SLV schools, regardless of vaccination status, were 30.8% (95% confidence interval, 10.1%–46.8%) less likely to acquire influenza compared with children at control schools. Unvaccinated children were indirectly protected in the school with nearly 50% vaccination coverage compared with control schools (influenza rate, 27.1 vs 60.0 per 1000 children; P = .023). Unvaccinated children missed more school days than vaccinated children (4.3 vs 2.8 days per 100 school days; P <.001).” (P. S. Pannaraj, ppannaraj@chla.usc.edu)
C. difficile Treatments: In trials of therapies for Clostridium difficile infection (CDI), the toxin-binding polymer tolevamer was inferior to antibiotics, and metronidazole was inferior to vancomycin (pp. 345–54). A primary endpoint was clinical success (resolution of diarrhea and absence of severe abdominal discomfort for more than two consecutive days), results for 1,118 patients showed: “Clinical success of tolevamer was inferior to both metronidazole and vancomycin (P < .001), and metronidazole was inferior to vancomycin (P = .02; 44.2% [n = 534], 72.7% [n = 278], and 81.1% [n = 259], respectively). Clinical success in patients with severe CDI who received metronidazole was 66.3% compared with vancomycin, which was 78.5%. (P = .059).” (S. Johnson, stuart.johnson2@va.gov)

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

PNN Pharmacotherapy Line
July 16, 2014 * Vol. 21, No. 136
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 16 issue of JAMA (2014; 312).
Telecare for Chronic Pain: Chronic musculoskeletal pain in primary care patients was effectively managed via collaborative telecare in the Stepped Care to Optimize Pain Care Effectiveness (SCOPE) study, researchers report (pp. 240–8). “This was accomplished by optimizing nonopioid analgesic medications using a stepped care algorithm and monitoring,” the authors conclude, adding these details about their efforts over 12 months for 250 patients: “Overall, mean (SD) baseline [Brief Pain Inventory (BPI)] scores in the intervention and control groups were 5.31 (1.81) and 5.12 (1.80), respectively. Compared with usual care, the intervention group had a 1.02-point lower (95% CI, −1.58 to −0.47) BPI score at 12 months (3.57 vs 4.59). Patients in the intervention group were nearly twice as likely to report at least a 30% improvement in their pain score by 12 months (51.7% vs 27.1%; relative risk, 1.9 [95% CI, 1.4 to 2.7]), with a number needed to treat of 4.1 (95% CI, 3.0 to 6.4) for a 30% improvement. Secondary pain outcomes also improved. Few patients in either group required opioid initiation or dose escalation.” (K. Kroenke, kkroenke@regenstrief.org)
Two features of this study make its telecare intervention particularly attractive, an editorialist writes (
pp. 235–6): “First, the authors relied primarily on a nurse care manager to oversee symptom monitoring and stepped medication adjustment. Thus, the intervention could be implemented for most patients without requiring significant additional time or effort from primary care clinicians. This feature enhances the potential for the intervention to be scaled up to meet the high demand for pain treatment in overburdened primary care practices. Second, telephone delivery may improve access to pain care, in particular for patients in rural areas or those with transportation barriers. As more accountable care organizations enter risk-sharing contracts, providing care that does not involve a face-to-face visit may become more attractive to insurers.” (G. E. Rosenthal, gary-rosenthal@uiowa.edu)
Hydroxychloroquine in Sjögren Syndrome: Over a 24-week period, hydroxychloroquine performed no better than placebo for improving symptoms of primary Sjögren syndrome, a study shows (pp. 249–58). Participants were randomized to hydroxychloroquine 400 mg/d or placebo for 24 weeks, and all participants received active drug for an additional 24 weeks. Results showed: “At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37–2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group.” (J-E Gottenberg, jacques-eric.gottenberg@chru-strasbourg.fr)
Early HIV Detection: A meta-analysis of studies of signs and symptoms of early HIV infection in adults demonstrates the need for routine testing for the virus, investigators conclude (pp. 278–85). The presence of lymphadenopathy was the most useful sign; other symptoms that increased the likelihood of early HIV infection were genital ulcers, weight loss, vomiting, and swollen lymph nodes. “Using data from studies that considered combinations of findings (range of possible findings, 4–17), the summary [likelihood ratio] for individuals with 0 findings was 0.47 (95% CI, 0.38–0.58),” the authors report. (E. Wood, uhri-ew@cfenet.ubc.ca)

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

PNN Pharmacotherapy Line
July 17, 2014 * Vol. 21, No. 137
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 17 issue of the New England Journal of Medicine (2014; 371).
Niacin + Laropiprant for Hypercholesterolemia: Added to statins in high-risk patients with elevated LDL-cholesterol levels, the combination of extended-release niacin 2 g and laropiprant 40 mg daily “did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events” in the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), investigators report (pp. 203–12). Compared with placebo, the drug combination produced these results based on a primary outcome of first vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization): “During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin–laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin–laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P = 0.29). Niacin–laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P <0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P <0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P <0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P <0.001), skin (absolute excess, 0.3 percentage points; P = 0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P <0.001) and bleeding (absolute excess, 0.7 percentage points; P <0.001).” (J. Armitage, jane.armitage@ctsu.ox.ac.uk)
“The consistent findings of a lack of benefit of raising the HDL cholesterol level with the use of niacin when added to effective LDL cholesterol–lowering therapy with statins seriously undermine the hypothesis that HDL cholesterol is a causal risk factor,” an editorialist writes (
pp. 271–3). Adding that it’s “time to face facts” with regard to niacin, the author continues: “The failure (to date) of cholesteryl ester transfer protein inhibitors, such as torcetrapib and dalcetrapib, to show any reduction in cardiovascular risk despite the marked increases in the HDL cholesterol level associated with these drugs lends further credence to the notion that HDL cholesterol is unlikely to be causal. Finally, compelling data from a large mendelian randomization study also argue that the HDL cholesterol level has a role solely as a risk marker and not a risk factor that merits intervention to reduce cardiovascular events. Although higher HDL cholesterol levels are associated with better outcomes, it is time to face the fact that increasing the HDL cholesterol level in isolation seems unlikely to offer the same benefit.” (D. M. Lloyd-Jones)
Single-Pill Combination Antiretroviral Regimens: Adherence and drug-resistance considerations are important in assessing the utility of single-pill combinations in patients with HIV-1 infection, write authors of a Clinical Therapeutics article (pp. 248–59). Reacting to the case of 52-year-old man with a history of homelessness, depression, and polysubstance abuse, the authors make this recommendation under the assumption that genotype testing rules out drug resistance from prior inconsistent antiretroviral use: “Each of the anchor drugs in currently available single-pill combinations would be suitable because of his normal renal function and relatively low HIV-1 RNA level and because he is not taking other medications. The selection of a regimen should be based on potential side effects, food requirements, dosing schedule, and, possibly, anticipated adherence; cost may also be a consideration. Regardless of which regimen is chosen, careful clinical, virologic, and immunologic monitoring, along with regular adherence assessment and counseling, will be key contributors to treatment success.” (M. Gandhi, monica.gandhi@ucsf.edu)

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

PNN Pharmacotherapy Line
July 18, 2014 * Vol. 21, No. 138
Providing news and information about medications and their proper use

>>>Oncology Highlights
Source:
July 10 issue of the Journal of Clinical Oncology (2014; 32).
Treatment Options in Node-Negative Breast Cancer: Women with certain subtypes of small, node-negative breast cancer can be managed without chemotherapy, researchers report, adding that less toxic adjuvant regimens could be studied in these patients (pp. 2142–50). In a prospective cohort study of 4,113 women with T1a,bN0M0 breast cancer who were treated in 2000–09, these outcomes resulted based on tumor size (T1a, T1b), hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab: “Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241).” (N. U. Lin, nlin@partners.org)

>>>Allergy/Immunology Report
Source:
July issue of the Journal of Allergy and Clinical Immunology (2014; 134).
HIV-1 Vaccine Development: Authors of a review article summarize advances, challenges, and promising approaches for HIV-1 vaccine development (pp. 3–10): “The past 2 years have seen a number of basic and translational science advances in the quest for development of an effective HIV-1 vaccine. These advances include discovery of new envelope targets of potentially protective antibodies, demonstration that CD8+ T cells can control HIV-1 infection, development of immunogens to overcome HIV-1 T-cell epitope diversity, identification of correlates of transmission risk in an HIV-1 efficacy trial, and mapping of the coevolution of HIV-1 founder envelope mutants in infected subjects with broad neutralizing antibodies, thereby defining broad neutralizing antibody developmental pathways. Despite these advances, a promising HIV-1 vaccine efficacy trial published in 2013 did not prevent infection, and the HIV-1 vaccine field is still years away from deployment of an effective vaccine.” (B. F. Haynes, hayne002@mc.duke.edu)
Aspirin-Exacerbated Respiratory Disease After NSAID/COX Inhibitor Exposure: A meta-analysis of clinical trials demonstrates that patients with mild-to-moderate asthma with aspirin-exacerbated respiratory disease (AERD) can safely take COX-2 inhibitors and that ingestion of selective NSAIDs carries a small risk (pp. 40–45.e10): “No significant difference in respiratory symptoms (risk difference, −0.01; 95% CI, −0.03 to 0.01; P = .57), decrease in FEV1 of 20% or greater (RD, 0.00; 95% CI, −0.02 to 0.02; P = .77), or nasal symptoms (RD, −0.01; 95% CI, −0.04 to 0.02; P = .42) occurred with COX-2 inhibitors (eg, celecoxib). Selective NSAID exposure caused respiratory symptoms in approximately 1 in 13 patients with AERD (RD, 0.08; 95% CI, 0.02 to 0.14; P = .01). No significant differences were found according to leukotriene antagonist exposure or whether NSAIDs were randomly allocated.” (D. R. Morales, d.r.z.morales@dundee.ac.uk)

>>PNN NewsWatch
* FDA has approved Ruconest (Pharming Group; Santarus), the first recombinant C1-esterase inhibitor product for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE). Ruconest is purified from the milk of transgenic rabbits, FDA said. The orphan product works by restoring the level of functional C1-esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling. Its safety and efficacy were established in a trial of 44 adult and adolescent patients with HAE. The most common adverse reactions reported in the trial were headache, nausea, 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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 21, 2014 * Vol. 21, No. 139
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 19 issue of Lancet (2014; 384).
Prioritizing HIV Prevention: Focused efforts to prevent HIV infections worked better than a uniform approach applied across an entire country, researchers report (pp. 249–56). Looking at various intervention strategies (male circumcision, behavior change communication, early antiretoviral therapy, and pre-exposure prophylaxis), the authors conclude, “The focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention.” A mathematical model yielded these results based on hypothetical uniform versus focused efforts in Kenya: “A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years—almost 100,000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150,000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention.” (S-J Anderson, sarah-jane.anderson@imperial.ac.uk)
Causes of Death in Patients With HIV Infection: Improved CD4 cell counts are linked to reductions in AIDS-related deaths, a study shows (pp. 241–8). Non–AIDS cancer is now the leading non–AIDS cause of death in these patients, and data from 1999 to 2011 show no signs that outcomes with these conditions are improving. Among 49,731 participants in the the Data collection on Adverse events of anti-HIV Drugs (D:ALaugh) study, the mortality rate was 12.7 per 100,000 person–years during this period, with these causes among 3,909 patients who died: AIDS-related (1,123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). (C. J. Smith, c.smith@ucl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 349).
Cardiovascular Risks & HDL Cholesterol: Agents that raise HDL cholesterol have no effects on all-cause mortality and other hard clinical outcomes, according to results of a meta-analysis of 39 trials of 117,411 participants (g4379). “Neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins,” the investigators write. “Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.” (D. Keene, drkeene@doctors.org.uk)

>>>PNN NewsWatch
* Products containing powdered pure caffeine have been associated with at least one death, FDA warns. Explaining that the products are “essentially 100% pure caffeine,” the agency cautioned, “All consumers seeking caffeinated products should be aware of the potentially high potency of these powdered pure caffeine products. Parents should recognize that teenagers and young adults may be drawn to these products for their perceived benefits.”

>>>PNN JournalWatch
* New Workforce Development in Dementia Care: Screening for “Caring”: Preliminary Data, in
Journal of the American Geriatrics Society, 2014; 62: 1364–8. (A. H. Cottingham, ancottin@iu.edu)
* Defining the Clinical Course of Multiple Sclerosis: The 2013 Revisions, in
Neurology, 2014; 83: 278–86. (F. D. Lublin, fred.lublin@mssm.edu)
* Functional Connectivity in the Basal Ganglia Network Differentiates PD Patients From Controls, in
Neurology, 2014; 83: 208–14. (C. E. Mackay, clare.mackay@psych.ox.ac.uk)
* Statin Use Is Associated With a Decreased Risk of Barrett’s Esophagus, in
Gastroenterology, 2014; 147: 314–23. (H. B. El-Serag, hasheme@bcm.edu)
* Strategies To Inhibit Entry of HBV and HDV Into Hepatocytes, in
Gastroenterology, 2014; 147: 48–64. (S. Urban, stephan.urban@med.uni-heidelberg.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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 22, 2014 * Vol. 21, No. 140
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2014; 161).
Antiretroviral-Free HIV-1 Remission/Viral Rebound: Periods of remission of HIV-1 after patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) are not permanent, according to the cases of two men who were treated for hematologic tumors (10.7326/M14-1027). After HSCT with susceptible donor cells, the investigators report these results: “No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients.” These findings show that “long-lived tissue reservoirs may … [contribute] to viral persistence,” the authors conclude. (T. J. Henrich, thenrich@partners.org)

>>>Geriatrics Highlights
Source:
July issue of the Journal of the American Geriatrics Society (2014; 62).
Beers v. STOPP in Detecting Inappropriate Medications: In 407 older adults in Spain, investigators found that the 2012 Beers criteria detected more potentially inappropriate medications (PIMs) than did the Screening Tool of Older Person’s Potentially Inappropriate Prescriptions (STOPP) (pp. 1217–23). However, since there is “scant overlap” between the tools, the authors conclude that their use is complementary in detecting PIMs: “Potentially inappropriate medications were present in 24.3%, 35.4%, and 44% of participants, according to the 2003 Beers criteria, STOPP, and 2012 Beers criteria, respectively. The profile of PIMs was also different (the most frequent being benzodiazepines in both Beers criteria lists and aspirin in the STOPP). The number of drugs was associated with risk of prescribing PIMs in all three models, as was the presence of a psychological disorder in the 2003 Beers criteria (odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.26–3.40) and the 2012 Beers criteria (OR = 2.91, 95% CI = 1.83–4.66). The kappa for degree of agreement between STOPP and the 2012 Beers criteria was 0.35 (95% CI = 0.25–0.44).” (E. Blanco Reina, eblanco@uma.es)
Cost Utility of Pharmacotherapy Follow-up in Nursing Homes: Pharmacotherapy follow-up by pharmacists for older residents of 15 nursing homes in Andalusia was cost-effective, researchers report (pp. 1272–80). Incremental cost-effectiveness ratios (ICERs) were estimated for unadjusted cost per quality-adjusted life–year (QALY) (first scenario), costs adjusted for baseline prescribed medication and QALYs adjusted for baseline utility score (second scenario), and costs and QALYs adjusted for a fuller set of baseline characteristics (third scenario). Results showed: “The general practitioner accepted 88.7% (274/309) of pharmacist recommendations. Pharmacist interventions reduced the average number of prescribed medication by 0.47 drugs (P <.001), whereas the average prescribed medication increased by 0.94 drugs in the control group (P <.001). Both groups reported a lower average EuroQol-5D utility score after 12 months (intervention, −0.0576, P = .002; control, −0.0999, P = .003). For the first scenario, usual care dominated pharmacotherapy follow-up (was less effective and more expensive). Adjusted ICERs were 3,899 euros/QALY ($5,002/QALY) for the second scenario and 6,574 euros/QALY ($8,433/QALY) for the third scenario. For a willingness to pay of 30,000 euros/QALY ($38,487/QALY), the probabilities of the pharmacotherapy follow-up being cost-effective were 35% for the first scenario, 78% for the second, and 76% for the third.” (J. J. Martín, jmartin@ugr.es)

>>>PNN NewsWatch
* FDA reports that American Health Packaging has recalled two unit dose products because of product mix-ups and mislabeling: Ibuprofen Tablets, USP, 600 mg (lot 142588, expiration 01/2016) and Oxcarbazepine Tablets 300 mg (lot 142544, expiration 02/2016).

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

PNN Pharmacotherapy Line
July 23, 2014 * Vol. 21, No. 141
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 23/30 issue of JAMA (2014; 312).
Sofosbuvir Efficacy in HIV/HBV Coinfection: Patients coinfected with HIV and hepatitis C virus (HCV) responded well to the combination of sofosbuvir and ribavirin in a 24-week, open-label, nonrandomized, uncontrolled Phase III trial, achieving high rates of sustained virologic response (SVR) at 12 weeks, researchers report (pp. 353–61). Study participants were 223 patients with HCV genotypes 1, 2, or 3 and whose HIV was well controlled on antiretroviral therapies. Results showed: “Among treatment-naive participants, 87 patients (76%) of 114 (95% CI, 67%–84%) with genotype 1, 23 patients (88%) of 26 with genotype 2 (95% CI, 70%–985), and 28 patients (67%) of 42 with genotype 3 (95% CI, 51%–80%) achieved SVR12. Among treatment-experienced participants, 22 patients (92%) of 24 with genotype 2 (95% CI, 73%–99%) and 16 patients (94%) of 17 (95% CI, 71%–100%) achieved SVR12. The most common adverse events were fatigue, insomnia, headache, and nausea. Seven patients (3%) discontinued HCV treatment due to adverse events. No adverse effect on HIV disease or its treatment was observed.” (M. S. Sulkowski, msulkowski@jhmi.edu)
Using analogies from quantum mechanics, editorialists write, “Based on the pipeline of new drugs anticipated for release over the next 18 months, it is likely that many more quantum leaps and emissions of several more photons are yet to come” (
pp. 347–8). “However, despite the progress, the question remains, can the health care system and society afford them?” The writers point to costs of $94,500 and $189,000 for sofosbuvir/ribavirin for 12- and 24-week courses, adding, “Industry analysts indicate that the pricing of the drug is not based on the cost of ingredients or the duration of therapy, but rather the ‘cost per cure.’ With more than 185 million HCV seropositive people worldwide with HCV infection (~150 million with chronic HCV infection) and with 4.4 million HCV seropositive persons in the United States (~3.7 million with chronic HCV), the world simply cannot afford to pay on a ‘cost per cure’ basis, especially when the majority of persons with chronic infection, an estimated 75%, do not progress to cirrhosis or end-stage liver disease over 20 to 30 years. The difficulty is that it is not possible to accurately identify those patients who will have progressive liver disease, so treatment needs to be available and affordable for everyone with chronic HCV. Hopefully, competition among the new products coming to market in the next 18 months will result in substantially lower pricing for the drugs. Indeed, the release of the new products will be, perhaps for the first time, a genuine test of whether there is a free market, microeconomic system in the pharmaceutical industry.” (M. S. Saag, msaag@uab.edu)
Pregnancy Outcomes & HIV Preexposure Prophylaxis: Negative outcomes were not significantly different in women who became pregnant while receiving antiretroviral preexposure prophylaxis (PrEP), according to findings from the Partners PrEP Study (pp. 362–71). Among 1, 785 HIV-discordant heterosexual couples, use PrEP use by women who had 431 pregnancies showed these outcomes (PrEP was stopped when pregnancy was detected): “Pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, −5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, −4.6%; 95% CI, −18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, −16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo.” (J. M. Baeten, jbaeten@uw.edu)

>>>PNN NewsWatch
* With 2015 shaping up to be the year of the big push on Capitol Hill for pharmacist provider status, having a pharmacist in Congress would be nice. It appears that will be the case, based on Buddy Carter’s 53%–46% victory yesterday over surgeon Bob Johnson in a Republican runoff in Georgia’s First Congressional District. Carter has Democratic opposition in the November elections, but the district leans heavily GOP, having favored Romney in the last presidential race by 56%–43%.

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

PNN Pharmacotherapy Line
July 24, 2014 * Vol. 21, No. 142
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 24 issue of the New England Journal of Medicine (2014; 371).
Sirolimus & mTORC Pathway in Antiphospholipid Syndrome: “A specific molecular pathway, the [mammalian target of rapamycin complex (mTORC)] pathway, leads to intimal hyperplasia, which accompanies the most severe variants of the antiphospholipid syndrome,” conclude researchers who studied 10 patients with this autoimmune disease (pp. 303–12). Using multiple tests, interventions, and examination of postmortem samples, the investigators found these causes of antiphospholipid syndrome and effects of sirolimus: “The vascular endothelium of proliferating intrarenal vessels from patients with antiphospholipid syndrome nephropathy showed indications of activation of the mTORC pathway. In cultured vascular endothelial cells, IgG antibodies from patients with the antiphospholipid syndrome stimulated mTORC through the phosphatidylinositol 3-kinase (PI3K)–AKT pathway. Patients with antiphospholipid syndrome nephropathy who required transplantation and were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy as compared with patients with antiphospholipid antibodies who were not receiving sirolimus. Among 10 patients treated with sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation versus 3 of 27 untreated patients (11%). Activation of mTORC was also found in the vessels of autopsy specimens from patients with catastrophic antiphospholipid syndrome.” (F. Terzi, fabiola.terzi@inserm.fr)
“The limited success of antithrombotic therapy in patients with vasculopathy associated with the antiphospholipid syndrome and the unproven benefit of current immunomodulatory treatments for catastrophic antiphospholipid syndrome highlight the need for improvements,” editorialists write in reaction to this study (
pp. 369–71). “By targeting pathways such as the mTORC pathway, which appears to be causative, sirolimus or other mTORC inhibitors may become the preferred treatment. However, independent confirmation is needed before such an approach is adopted. The clinical outcome data provided [in the above study] are observational and may be subject to bias, and since antiphospholipid antibodies are heterogeneous, it is possible that only a subset of these antibodies targets the mTORC pathway. Nonetheless, if the authors’ findings are confirmed, patients with mTORC-pathway–directed antiphospholipid antibodies may benefit from sirolimus, not only to improve renal allograft survival but also to prevent the development of vasculopathy—goals that require exploration in clinical trials.” (J. W. Eikelboom)
Bionic Pancreas in Type 1 Diabetes: A study of a bionic pancreas in 20 adults and 32 adolescents with type 1 diabetes could be a harbinger of things to come in diabetes therapy (pp. 313–25). The device— a wearable, bihormonal, fully automated Apple iPhone–controlled machine that administers insulin and glucagon in response to serum glucose levels continuously measured by a G4 Platinum monitor (DexCom)—was significantly better than an insulin pump at maintaining target glucose levels (mean of 133 ± 13 vs. 159 ± 30 mg/dL) and reducing the percentage of time with low glucose readings (4.1% vs. 7.3%). Among adolescents, fewer interventions for hypoglycemia were needed (1 per 1.6 d vs. 1 per 0.8 d). (E. R. Damiano, edamiano@bu.edu)

>>>PNN NewsWatch
* FDA yesterday approved idelalisib (Zydelig, Gilead) for treatment of relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma. The drug was approved with a boxed warning about fatal and serious toxicities including liver toxicity, diarrhea and colitis, pneumonitis, and intestinal perforation, and with a Risk Evaluation and Mitigation Strategy.
* Also approved yesterday was
Targiniq ER (oxycodone HCl–naloxone HCl extended-release tablets, Purdue Pharma), an extended-release, long-acting opioid analgesic for treatment of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
* Citing sterility assurance problems,
Unique Pharmaceuticals is recalling all nonexpired drug products for sterile use, 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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 25, 2014 * Vol. 21, No. 143
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2014; 37).
Diabetes & Depression: Presentations and discussions at an international meeting convened by the National Institute of Diabetes and Digestive and Kidney Diseases provide these insights into diabetes and depression (pp. 2067–77): “While the psychological burden of diabetes may contribute to depression in some cases, this explanation does not sufficiently explain the relationship between these two conditions. Shared biological and behavioral mechanisms, such as hypothalamic–pituitary–adrenal axis activation, inflammation, autonomic dysfunction, sleep disturbance, inactive lifestyle, poor dietary habits, and environmental and cultural risk factors, are important to consider in understanding the link between depression and diabetes. Both individual psychological and pharmacological depression treatments are effective in people with diabetes, but the current range of treatment options is limited and has shown mixed effects on glycemic outcomes. More research is needed to understand what factors contribute to individual differences in vulnerability, treatment response, and resilience to depression and metabolic disorders across the life course and how best to provide care for people with comorbid diabetes and depression in different health care settings. Training programs are needed to create a cross-disciplinary workforce that can work in different models of care for comorbid conditions.” (R. I. G. Holt, r.i.g.holt@soton.ac.uk)
Testosterone Treatment & Glucose Metabolism: In a study of 88 men with obesity and type 2 diabetes, treatment with testosterone therapy did not improve glucose metabolism or visceral adiposity, researchers report (pp. 2098–107). Forty weeks of intramuscular testosterone undecanoate (or matching placebo showed the following: “Testosterone therapy did not improve insulin resistance (mean adjusted difference [MAD] for [insulin resistance by homeostatic model assessment] compared with placebo −0.08 [95% CI −0.31 to 0.47; P = 0.23]) or glycemic control (MAD HbA1c 0.36% [0.0–0.7]; P = 0.05), despite a decrease in fat mass (MAD −2.38 kg [−3.10 to −1.66]; P < 0.001) and an increase in lean mass (MAD 2.08 kg [1.52–2.64]; P < 0.001). Testosterone therapy reduced subcutaneous (MAD −320 cm3 [−477 to −163]; P < 0.001) but not visceral abdominal adipose tissue (MAD 140 cm3 [−89 to 369]; P = 0.90).” (M. Grossmann, mathisg@unimelb.edu.au)
Insulin & Weight Gain: In the noninterventional CREDIT (Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy) study, insulin regimen was not independently associated with weight gain; instead, the investigators write, “By the time insulin was started, a high baseline A1C and insulin dose requirements were independently associated with greater weight gain, as was lower baseline BMI” (pp. 2108–13). At 314 centers in 12 countries, 2,179 people starting any insulin had these outcomes at 1 year: “The mean weight gain was 1.78 kg, and 24% gained ≥5.0 kg. Baseline factors associated with weight gain were BMI, A1C, insulin regimen, insulin dose, other glucose-lowering therapies, and hypertension; at 1 year, additional factors were A1C, insulin regimen, insulin dose, and use of other glucose-lowering therapies. In multivariable analysis, weight gain at 1 year was associated with a higher A1C at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline BMI.” (B. Balkau, beverley.balkau@inserm.fr)
Vitamin D & Cardiovascular Risk in Prediabetes: In a 1-year study of 511 people with impaired fasting glucose and/or glucose tolerance, high-dose vitamin D had no beneficial effects on glycemic indices, blood pressure, or lipid status (pp. 2123–31). Weekly doses of vitamin D3 20,000 IU produced these results: “Mean baseline serum 25(OH)D was 59.9 nmol/L and 61.1 nmol/L in the vitamin D and placebo groups, respectively, and increased by 45.8 nmol/L and 3.4 nmol/L, respectively. With adjustment for baseline concentrations, no differences in measures of glucose metabolism, insulin secretion or sensitivity, blood pressure, or hs-CRP were found after 1 year. There was a slight, but significant decrease in total and LDL cholesterol in the vitamin D group compared with the placebo group, but as there was also a decrease in HDL cholesterol, the change in the total/HDL cholesterol ratio did not differ significantly. Only analyzing subjects with 25(OH)D <50 nmol/L did not change the results.” (S. T. Sollid, stina.therese.sollid@unn.no)

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

PNN Pharmacotherapy Line
July 28, 2014 * Vol. 21, No. 144
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Unreported Company Data Support Dabigatran Monitoring: “Boehringer Ingelheim, the maker of dabigatran, has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible,” writes a BMJ reporter in an investigative news article (g4670). “The company also withheld analyses that calculated how many major bleeds dose adjustment could prevent.” A company-conducted subgroup analysis of the RE-LY trial, in which drug plasma concentrations were collected but not used for dosing, conflicted with the trial’s published results, which read, “The large majority of patients achieve a favourable balance of benefit and risk with a fixed dose of DE [dabigatran] 110 or DE [dabigatran] 150, guided by a consideration of patient characteristics.” The BMJ reporter used e-mail messages and documents released in U.S. litigation to find the subgroup analysis and conflict in the company about what to do with it: “In an internal email in 2011, Andreas Clemens, a medical team leader for the drug, stated that he was ‘phobic’ and ‘not happy with the conclusion’—that an optimal balance between benefit and risk occurs in the range of concentrations between 40 ng/mL and 215 ng/mL.” (D. Cohen, dcohen@bmj.com)
Human Albumin in Adults With Sepsis: In adult patients with sepsis of any severity, use of human albumin “seems to be safe,” report authors who conducted a systematic review and meta-analysis, but the evidence “does not support a recommendation for use” (g4561): “Human albumin solutions as part of fluid volume expansion and resuscitation for critically unwell adults with sepsis of any severity (with or without baseline hypoalbuminaemia) were not robustly effective at reducing all-cause mortality.” (A. Patel, amit.patel@imperial.ac.uk)

>>>Lancet Highlights
Source:
July 26 issue of Lancet (2014; 383).
Etrolizumab for Induction in Ulcerative Colitis: In a Phase II trial of induction therapy in patients with ulcerative colitis, etroliziumab “was more likely to lead to clinical remission at week 10 than was placebo,” researchers report (pp. 309–18). Study participants at 40 centers in 11 countries had moderately to severely active ulcerative colitis. Subcutaneous etrolizumab in low or high doses and with or without a loading dose (LD) had these outcomes in comparison with placebo: “Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the [modified intention-to-treat] population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7–36]) patients in the etrolizumab 100 mg group (p = 0.0040) and four (10% [0·2–24]) patients in the 300 mg plus LD group (p = 0.048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious).” (S. Vermeire, severine.vermeire@uzleuven.be)

>>>PNN JournalWatch
* Physical Activity at Altitude: Challenges for People With Diabetes: A Review, in
Diabetes Care, 2014; 37: 2404–13. (P. de Mol, pieter.demol@radboudumc.nl)
* Down the Rabbit Hole: A Chronic Pain Sufferer Navigates the Maze of Opioid Use, in
Health Affairs, 2014; 33: 1294–7. (J. L. Schuster, janice.lynchschuster@altarum.org)
* Genomic Sequencing: Assessing the Health Care System, Policy, and Big-Data Implications, in
Health Affairs, 2014; 33: 1246–53. (K. A. Phillips, PhillipsK@pharmacy.ucsf.edu)
* Variability in Compounding of Oral Liquids for Pediatric Patients: A Patient Safety Concern, in
Journal of the American Pharmacists Association, 2014; 54: 383–9. (S, L. Ciarkowski, ciarkos@umich.edu)
* How Gaps in Regulation of Compounding Pharmacy Set the Stage for a Multistate Fungal Meningitis Outbreak, in
Journal of the American Pharmacists Association, 2014; 54: 441–5. (C. R. Frei, freic@uthscsa.edu)
* Understanding Regional Variation in Medicare Expenditures for Initial Episodes of Prostate Cancer Care, in
Medical Care, 2014; 52: 680–7. (S-Y Wang)

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

PNN Pharmacotherapy Line
July 29, 2014 * Vol. 21, No. 145
Providing news and information about medications and their proper use

>>>Medical Care Report
Source:
Aug. issue of Medical Care (2014; 52).
Racial Gaps in Lipid-Lowering Medication Use: Removal of drug caps under Medicare Part D increased use of lipid-lowering therapies among black and white dual enrollees, a study shows, but blacks continued using the drugs at lower rates than whites (pp. 695–703). Using an interrupted time series with comparison series design cohort study of nationally representative data on fee-for-service dual enrollees, the investigators found these differences between states with and without drug caps in 2004–07 (Part D was implemented in 2006): “At baseline, lipid-lowering drug use was higher in no drug cap states (drug cap: 54.0% vs. nondrug cap: 66.8%) and among whites versus blacks (drug cap: 58.5% vs. 44.9%, no drug cap: 68.4% vs. 61.9%). In strict drug cap states only, Part D was associated with an increase in the proportion with any use [nonelderly: +0.07 absolute percentage points (95% confidence interval, 0.06–0.09), P <0.001; elderly: +0.08 (0.06–0.10), P <0.001] regardless of race. However, we found no evidence of a change in the white–black gap in the proportion of users despite the removal of a significant financial barrier.” (A. Adams)
BMD Self-referral & Osteoporosis Treatment: While treatment levels remained very low, women who self-referred after receiving a mailed invitation for bone mineral density screening were more likely to be screened and to start new antiosteoporosis medications (pp. 743–50). In two Kaiser Permanente regions, women 65 years or older without a dual-energy x-ray absorptiometry (DXA) screening within the prior 5 years had these outcomes after receiving a self-referral invitation: “From >12,000 eligible women, those randomized to self-referral were significantly more likely to receive a DXA than [usual care (UC)] (13.0%–24.1% self-referral vs. 4.9%–5.9% UC, P <0.05). DXA rates did not significantly increase with patient educational materials. Osteoporosis was detected in a greater proportion of self-referral women compared with UC (P <0.001). The number needed to receive an invitation to result in a DXA in [Kaiser Permanente Northwest] and [Kaiser Permanente Georgia] regions was approximately 5 and 12, respectively. New osteoporosis prescription rates were low (0.8%–3.4%) but significantly greater among self-referral versus UC in KPNW.” (A. H. Warriner)

>>>JAPhA Highlights
Source:
Jul/Aug issue of the Journal of the American Pharmacists Association (2014; 54).
Pharmacist-Delivered Medicare Annual Wellness Visits: Two articles and an editorial report positive experiences with pharmacist-delivered Medicare annual wellness visits (AWVs) in physician offices.
Time constraints were limiting the provision of AWVs in a private family office when a pharmacist extended previous services to include these new benefits of the Affordable Care Act (
pp. 427–34). “Pharmacist-delivered MWVs are financially viable and allow for greater pharmacist participation on the primary care team,” the authors conclude. “From September 2012 to February 2013, 174 patients participated in the pharmacist-delivered [AWV]. Pharmacist visits were billed using codes G0438 and G0439, and the practice realized a positive net income for the [AWVs].” (J-V. R. Goode, jrgoode@vcu.edu)
In a similar situation in the Asheville, NC, area, authors found that the cost of employing a pharmacist could be offset by AWV reimbursements in physician offices (
pp. 435–40): “A small practice requires all eligible Medicare patients to complete an AWV to generate enough revenue to support a new pharmacist position. A medium-sized practice requires a 54% utilization rate, and a large practice requires an 18% utilization rate.” (C. G. Wilson, Courtenay.Wilson@mahec.net)
“Pharmacists are uniquely qualified for providing medication management and other health and wellness services, a reimbursement mechanism is available, and we have an ample—and growing—supply of pharmacists,” a
Journal editor notes in an accompanying editorial (pp. 336–8; P. C. Heaton, heatonp@ucmail.uc.edu)

>>>PNN NewsWatch
* With a breakthrough therapy designation, FDA yesterday expanded the approved use of ibrutinib (Imbruvica, Pharmacyclics and Janssen) to include treatment of patients with chronic lymphocytic leukemia with chromosome 17 deletions.

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

PNN Pharmacotherapy Line
July 30, 2014 * Vol. 21, No. 146
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
July and August issues of Arthritis & Rheumatology (2014; 66).
Treating Rheumatoid Arthritis During Pregnancy: In a study of 180 children born to mothers with rheumatoid arthritis (RA), medications during pregnancy had no effects on postnatal growth and “could be beneficial for the future health of the unborn child” because of better control of RA disease activity, investigators conclude (pp. 1705–11). Active RA “and the presence of rheumatoid factor (RF) or anti–citrullinated protein antibodies (ACPAs) are associated with lower birth weight of the child,” the authors explain, and that leads to rapid catch-up in weight for length during the first year of life. Rapid growth is associated with worse cardiovascular and metabolic profiles in young adulthood.
The study looked at the extent of RA disease activity (Disease Activity Score in 28 joints [DAS28]), medication use, and presence of RF or ACPAs during pregnancy, with these results: “Of 167 children with available data, 52 (31%) showed catch-up in weight in the first year of life, of whom 90% (47 of 52) showed rapid catch-up. An elevated DAS28 score in the mother was associated with rapid catch-up in weight of the offspring, independent of maternal medication use or the presence of RF or ACPAs during pregnancy (odds ratio 1.44 [95% confidence interval 1.07–1.95] per 1-point increase in the DAS28). Use of medications during pregnancy had no influence on postnatal growth.” (F. D. O. de Steenwinkel,
f.desteenwinkel@erasmusmc.nl)
Subcutaneous Abatacept Safety in Rheumatoid Arthritis: Safety data from five clinical trials show that long-term subcutaneous (SC) abatacept is similar to intravenous regimens, researchers report (pp. 1987–97). Overall and 6-month incidence rates of events were calculated per 100 patient–years of exposure in 1,879 patients who had an average of 27 months of exposure: “The reported incidence rate of serious infections was 1.79 (95% confidence interval [95% CI] 1.42–2.24); the most frequent infections were pneumonia (incidence rate 0.36 [95% CI 0.22–0.59]), urinary tract infection (incidence rate 0.14 [95% CI 0.06–0.32]), and gastroenteritis (incidence rate 0.10 [95% CI 0.04–0.25]). Tuberculosis occurred rarely (incidence rate 0.09 [95% CI 0.04–0.25]). The reported incidence rate of malignancies was 1.32 (95% CI 1.01–1.72), and the most common was solid organ malignancy (incidence rate 0.69 [95% CI 0.48–0.99]). The incidence rate of autoimmune events was 1.37 (95% CI 1.06–1.78), and the most frequent events were psoriasis (incidence rate 0.33 [95% CI 0.20–0.56]) and Sjögren’s syndrome (incidence rate 0.24 [95% CI 0.13–0.44]). The reported incidence rate of local injection site reactions was 1.72 (95% CI 1.36–2.17); these events occurred primarily during the first 6 months of treatment, and almost all were of mild or moderate intensity.” (R. Alten, Rieke.Alten@Schlosspark-Klinik.de)
TNF-Alpha Blockers in Early Axial Spondyloarthritis: Tumor necrosis factor–alpha (TNF-alpha) blockers are frequently used for inflammatory back pain suggestive of early axial spondyloarthritis (SpA), Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR) cohort investigators report (pp. 1734–44). Among 708 patients with less than 3 years’ duration of suggestive symptoms, a primary outcome of 40% improvement in the Assessment of SpondyloArthritis international Society criteria (ASAS40) showed these results in patients treated with these drugs or any other therapy (usual care): “A total of 30.2% (95% confidence interval [95% CI] 26.7–33.7) patients received at least 1 TNF-alpha blocker during the 24 months of followup. The percentage of ASAS40 responders was 31.5% (62 of 197 patients) in the group receiving TNF-alpha blockers versus 13.2% (26 of 197) in the control group (OR 2.99 [95% CI 1.80–4.99], P = 0.0002). This effectiveness was more pronounced in the subgroup of patients with sacroiliitis identified on magnetic resonance imaging, with 46% of ASAS40 responders receiving TNF-alpha blockers versus 15% of ASAS40 responders receiving usual care (OR 4.99 [95% CI 2.17–11.51]).” (A. Moltó, anna.molto@cch.aphp.fr)

>>>PNN NewsWatch
* FDA Commissioner Margaret A. Hamburg yesterday endorsed the Surgeon General’s call to action to prevent skin cancer. “Consumers should use a broad-spectrum sunscreen with an SPF value of 15 or higher in combination with other protective measures.” Hamburg 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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 31, 2014 * Vol. 21, No. 147
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 31 New England Journal of Medicine (2014; 371).
KAE609 for Falciparum and Vivax Malaria: In an open-label, Phase II study in Thailand, the new synthetic antimalarial spiroindolone analogue KAE609 rapidly cleared parasitemia in adults with uncomplicated Plasmodium falciparum and Plasmodium vivax malaria, researchers report (pp. 403–10). KAE609 was administered in doses of 30 mg/d for three days with these effects on parasite clearance time: “The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5,076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen.” (N. J. White, nickw@tropmedres.ac)
Artemisinin Resistance in Falciparum Malaria: Prolonged courses of artemisinin-based combination therapies in patients with Plasmodium falciparum malaria are working in areas where resistance is causing the standard 3-day treatments to fail, according to authors who mapped artemisinin resistance in Africa and Asia (pp. 411–23). In an open-label trial of 1,241 adults and children in seven Asian and three African countries, artesunate 2 or 4 mg/kg/d for three days followed by a standard three-day course of artemisinin-based combination therapy produced these results: “The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand–Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the ‘propeller’ region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days.” (N. J. White, nickw@tropmedres.ac)
Writing of progress but also missteps in a 20-year effort to address this formerly neglected disease, an editorialist concludes, “The emergence of artemisinin-resistant parasites is a major threat to further advances in malaria control. Every effort needs to be made to contain their spread while at the same time pushing forward with the development of effective alternative treatments that are almost certainly going to be needed in the future.” (
pp. 474–5). He adds, “Chloroquine was such an effective drug that little was done to prepare for its failure. Fortunately, scientists in academia and pharmaceutical companies have learned from this lack of preparation, and despite the current success of artemisinin-based combination therapies, an active program of development of antimalarial drugs has been sustained during the past two decades. This program has been led by the Medicines for Malaria Venture with strong support from academia and the pharmaceutical industry. Consequently, several promising new antimalarial drugs are in the pipeline.” (B. Greenwood)

>>>PNN NewsWatch
* “It truly is time for pharmacists to declare themselves ready and willing to take a major lead in creating and implementing interprofessional chronic disease management programs and to act as equal partners in health care with physicians in this arena,” writes Hershey S. Bell, MD, LECOM pharmacy dean, in a pharmacist.com blog. “What is the business plan? Imagine a practice with 1,000 patients who have two or more chronic diseases. At $41.92 per patient per month … well, the math speaks for itself.”

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

PNN Pharmacotherapy Line
Aug. 1, 2014 * Vol. 21, No. 148
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (2014; 134).
Liquid Medication Dosing Errors: Parents who use milliliters for measuring liquid medication doses for their children make fewer errors, according to a study of 287 parents at two emergency departments (pp. e354–61). Based on a 20% variance in medication doses as defining error, the authors found these associations in a regression analysis of data for English- and Spanish-speaking parents: “Medication errors were common: 39.4% of parents made an error in measurement of the intended dose, 41.1% made an error in the prescribed dose. Furthermore, 16.7% used a nonstandard instrument. Compared with parents who used milliliter-only, parents who used teaspoon or tablespoon units had twice the odds of making an error with the intended (42.5% vs 27.6%, P = .02; adjusted odds ratio=2.3; 95% confidence interval, 1.2–4.4) and prescribed (45.1% vs 31.4%, P = .04; adjusted odds ratio=1.9; 95% confidence interval, 1.03–3.5) dose; associations [were] greater for parents with low health literacy and non–English speakers. Nonstandard instrument use partially mediated teaspoon and tablespoon–associated measurement errors.” (H. S. Yin)
Invasive Pneumococcal Disease After 13-Valent Conjugate Vaccine: The 13-valent pneumococcal conjugate vaccine (PCV13) may not be sufficient for preventing invasive pneumococcal disease (IPD) in children with underlying conditions, a study shows, as nonvaccine serotypes are common in these patients (pp. 210–7). State public health data from Massachusetts show these patterns in the pre-PCV13 (2007–09) and post-PCV13 (2010–12) periods: “There were 168 pre-PCV13 cases of IPD and 85 post-PCV13 cases of IPD in Massachusetts children ≤5 years of age. PCV13 serotypes declined by 18% in the first 2 years after PCV13 use (P = .011). In the post-PCV13 phase, a higher proportion of children were hospitalized (57.6% vs 50.6%), and a higher proportion of children had comorbidity (23.5% vs 19.6%). Neither difference was statistically significant, nor were comparisons of IPD caused by vaccine and nonvaccine types. Children with comorbidities had higher rates of IPD caused by a nonvaccine type (27.6% vs 17.2%; P = .085), were more likely to be hospitalized (80.4% vs 50%; P < .0001), and were more likely to have a longer hospital stay (median of 3 days vs 0.5 days; P = .0001).” (P-Y Iroh Tam)

>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2014; 171).
Prefrontal Cortical Dopamine & Alcoholism: A study demonstrates “unambiguously” that dopamine transmission in the prefrontal cortex is decreased in patients with alcohol dependence (pp. 881–8). “Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism,” the investigators conclude, based on these PET results in 42 patients: “Amphetamine-induced displacement of [11C]FLB 457 binding potential … was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe.” (R. Narendran, narendranr@upmc.edu)

>>>PNN NewsWatch
* Olodaterol (Striverdi Respimat, Boehringer Ingelheim)was approved yesterday by FDA for treatment of patients with chronic obstructive pulmonary disease. The long-acting beta-agonist carries a boxed warning about increased risks of asthma-related deaths with use of the drug. Clinical trials in 3,104 patients with COPD showed improved lung function with olodaterol, compared with placebo. Adverse effects included nasopharyngitis, upper respiratory tract infection, bronchitis, cough, urinary tract infection, dizziness, rash, diarrhea, back pain, and arthralgia.
*
FDA also said yesterday it is issuing a final guidance on the development, review, and approval or clearance of companion diagnostics—tests commonly used in oncology to identify appropriate drug therapy for gene-based cancers. The guidance enables pharmaceutical companies to identify and test such assays during drug development.

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

PNN Pharmacotherapy Line
Aug. 4, 2014 * Vol. 21, No. 149
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 2 issue of Lancet (2014; 384).
Simeprevir for HCV: Results of the QUEST trials of simeprevir, pegylated interferon alfa 2a, and ribavirin in patients with hepatitis C virus (HCV) genotype 1 infections are presented in two articles.
In this Phase III trial of patients with treatment-naive HCV infection, the three-drug combination reduced the time needed for treatment without increasing adverse events seen with peginterferon alfa 2a plus ribavirin, QUEST-1 researchers report (
pp. 403–12). In 13 countries, once-daily simeprevir for 24 or 48 weeks plus the other two drugs had this impact on a primary efficacy endpoint of sustained virological response 12 weeks after the planned end of treatment (SVR12): “Treatment with simeprevir, peginterferon alfa 2a, and ribavirin was superior to placebo, peginterferon alfa 2a, and ribavirin (SVR12 in 210 [80%] patients of 264 vs 65 [50%] of 130, respectively, adjusted difference 29.3% [95% CI 20.1–38.6; p <0.0001). Adverse events in the first 12 weeks of treatment led to discontinuation of simeprevir in two (<1%) patients and discontinuation of placebo in one patient (<1%); fatigue (106 [40%] vs 49 [38%] patients, respectively) and headache (81 [31%] vs 48 [37%], respectively) were the most common adverse events. The prevalences of anaemia (42 [16%] vs 14 [11%], respectively) and rash (72 [27%] vs 33 [25%]) were similar in the simeprevir and placebo groups. Addition of simeprevir did not increase severity of patient-reported fatigue and functioning limitations, but shortened their duration.” (I. M. Jacobson, imj2001@med.cornell.edu)
In the QUEST-2 trial, conducted in 14 countries, patients with HCV genotype 1 infection were randomly assigned to simeprevir or placebo, peginterferon alfa 2a or 2b, plus ribavirin, followed by peginterferon alfa 2a or 2b plus ribavirin (
pp. 414–26). Response-guided therapy yielded these results based on SVR12: “209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32.2%, 95% CI 23.3–41.2; p <0.0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment).” (M. Manns, manns.michael@mh-hannover.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 349).
Bleeding Risk With Anticoagulants: An algorithm (QBleed) based on experiences of 4.4 million patients on anticoagulants yields insights into risks of upper gastrointestinal and intracranial bleeds (g4606): “The final QBleed algorithms incorporated 21 variables. When applied to the validation cohort, the algorithms in women explained 40% of the variation for upper gastrointestinal bleed and 58% for intracranial bleed. The corresponding D statistics were 1.67 and 2.42. The receiver operating curve statistic values were 0.77 and 0.86. The sensitivity values for the top 10th of men and women at highest risk were 38% and 51%, respectively. There were similar results for men.” (J. Hippisley-Cox, Julia.hippisley-cox@nottingham.ac.uk)

>>>PNN NewsWatch
* Empagliflozin (Jardiance, Boehringer Ingelheim) has been approved by FDA for treatment of type 2 diabetes.

>>>PNN JournalWatch
* Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review, in
Pediatrics, 2014; 134: 325–37. (M. A. Maglione)
* Interventions To Reduce Pediatric Medication Errors: A Systematic Review, in
Pediatrics, 2014; 134: 338–60. (M. L. Rinke)

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

PNN Pharmacotherapy Line
Aug. 5, 2014 * Vol. 21, No. 150
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 5 issue of the Annals of Internal Medicine (2014; 161).
Steroids v. Physical Therapy in Shoulder Impingement Syndrome: Patients with unilateral shoulder impingement syndrome (SIS) benefited from both corticosteroid injections (CSIs) and physical therapy in a single-blind trial, but those receiving 6 sessions of manual physical therapy used fewer SIS-related health care resources over a 1-year period (pp. 161–9). Compared with subacromial triamcinolone acetonide 40 mg, manual physical therapy showed these outcomes: “Both groups demonstrated approximately 50% improvement in Shoulder Pain and Disability Index scores maintained through 1 year; however, the mean difference between groups was not significant (1.5% [95% CI, −6.3% to 9.4%]). Both groups showed improvements in Global Rating of Change scale and pain rating scores, but between-group differences in scores for the Global Rating of Change scale (0 [CI, −2 to 1]) and pain rating (0.4 [CI, −0.5 to 1.2]) were not significant. During the 1-year follow-up, patients receiving CSI had more SIS-related visits to their primary care provider (60% vs. 37%) and required additional steroid injections (38% vs. 20%), and 19% needed physical therapy. Transient pain from the CSI was the only adverse event reported.” (D. I. Rhon, daniel.i.rhon.mil@mail.mil)
Hepatitis C Virus Infection Burden in U.S.: New drug therapies and implementation of widespread screening and treatment will make chronic hepatitis C virus (HCV) infection a rare disease by 2036, according to results produced by an individual-level state-transition model (pp. 170–80). The model shows that implementation of birth-cohort screening and availability of highly effective new therapies could make HCV infection a rare disease in 22 years—or a decade earlier with more aggressive screening of all U.S. citizens: “The number of cases of chronic HCV infection decreased from 3.2 million in 2001 to 2.3 million in 2013. One-time birth-cohort screening beginning in 2013 is expected to identify 487,000 cases of HCV infection in the next 10 years. In contrast, 1-time universal screening could identify 933,700 cases. With the availability of highly effective therapies, HCV infection could become a rare disease in the next 22 years. Recently approved therapies for HCV infection and 1-time birth-cohort screening could prevent approximately 124,200 cases of decompensated cirrhosis, 78,800 cases of hepatocellular carcinoma, 126,500 liver-related deaths, and 9,900 liver transplantations by 2050. Increasing the treatment capacity would further reduce the burden of HCV disease.” (J. Chhatwal, JChhatwal@mdanderson.org)
Diagnosing Adult Obstructive Sleep Apnea: Physicians should assess the risk factors for and symptoms of obstructive sleep apnea (OSA) in patients with unexplained daytime sleepiness, according to a new evidence-based clinical practice guideline from the American College of Physicians (pp. 210–20). “The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, nonfatal cardiovascular disease, stroke, hypertension, type 2 diabetes, postsurgical outcomes, and quality of life,” the guideline notes. “Sensitivities, specificities, and likelihood ratios were also assessed as outcomes of diagnostic tests.” Two recommendations are made (A. Qaseem, aqaseem@acponline.org):
* A sleep study for patients with unexplained daytime sleepiness (grade: weak recommendation, low-quality evidence)
* Polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea and portable sleep monitors in patients without serious comorbidities as an alternative to polysomnography when polysomnography is not available for diagnostic testing (grade: weak recommendation, moderate-quality evidence)

>>>PNN NewsWatch
* Charles A. Walton, PhD, FCCP, prominent leader in the early clinical pharmacy practice and education movement, died July 31 at 88. Walton “was a true visionary and evangelical leader who early in his career predicted a time when pharmacists would be providing direct patient care to patients and would be responsible for assuring that patients achieved positive health outcomes,” according to an article distributed to alumni and friends of the University of Texas at Austin College of Pharmacy, which Walton served most of his career.

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

PNN Pharmacotherapy Line
Aug. 6, 2014 * Vol. 21, No. 151
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 6 issue of JAMA (2014; 312).
Primary-Care Interventions for Problem Drug Use: Two investigations and an editorial examine screening and brief interventions in primary care patients with problematic drug use.
A single brief intervention (motivational interviewing, handout, and list of substance abuse resources) with attempted follow-up telephone call had no effect on drug use by patients seen in a safety-net primary care setting, researchers report (
pp. 492–501). Conducted in Washington State, the intervention was compared with enhanced usual care and produced these outcomes: “Mean days used of the most common problem drug at baseline were 14.40 (SD, 11.29) (brief intervention) and 13.25 (SD, 10.69) (enhanced care as usual); at 3 months postintervention, means were 11.87 (SD, 12.13) (brief intervention) and 9.84 (SD, 10.64) (enhanced care as usual) and not significantly different (difference in differences, beta = 0.89 [95% CI, −0.49 to 2.26]). Mean [Addiction Severity Index–Lite] Drug Use composite score at baseline was 0.11 (SD, 0.10) (brief intervention) and 0.11 (SD, 0.10) (enhanced care as usual) and at 3 months was 0.10 (SD, 0.09) (brief intervention) and 0.09 (SD, 0.09) (enhanced care as usual) and not significantly different (difference in differences, beta = 0.008 [95% CI, −0.006 to 0.021]). During the 12 months following intervention, no significant treatment differences were found for either variable. No significant differences were found for secondary outcomes.” (P. Roy-Byrne, roybyrne@uw.edu)
Two brief counseling sessions for illicit drug use or prescription drug misuse “did not have efficacy for decreasing unhealthy drug use in primary care patients identified by screening,” a second study concludes (
pp. 502–13). The interventions were a brief negotiated interview (BNI) and an adaptation of motivational interviewing (MOTIV). Results in 528 adult patients at an urban hospital-based primary care clinic showed: “At baseline, 63% of participants reported their main drug was marijuana, 19% cocaine, and 17% opioids. At 6 months, 98% completed follow-up. Mean adjusted number of days using the main drug at 6 months was 12 for no brief intervention vs 11 for the BNI group (incidence rate ratio [IRR], 0.97; 95% CI, 0.77–1.22) and 12 for the MOTIV group (IRR, 1.05; 95% CI, 0.84–1.32; P = .81 for both comparisons vs no brief intervention). There were also no significant effects of BNI or MOTIV on any other outcome or in analyses stratified by main drug or drug use severity.” (R. Saitz, rsaitz@bu.edu)
“Back to the drawing board” is how editorialists describe the conundrum of how to reduce problematic drug use in primary care (
pp. 488–9): “Although these studies offer no direct evidence of effectiveness for universal drug screening, brief intervention, and referral to treatment in primary care settings, exploring drug use with patients should remain a priority in primary care. The goal for clinical research is to develop and test new interventions with potential for benefiting patients. Drug screening and brief intervention research that focuses on adolescents and young adults is especially needed because rates of marijuana use among young people and the potency of marijuana have increased at the same time that recognition among youth of the health risks of marijuana use have declined. Prospective research also indicates that more people begin combined use of alcohol, tobacco, and drug use early in adolescence than begin use of any single substance. Multiple substance initiators experience a greater likelihood they will develop dependence to multiple substances. Drugs, alcohol, and tobacco use by youth each stimulate brain reward for the other substances, supporting the idea that each is a gateway for the use of the other substances. Research should focus on reducing simultaneous use of alcohol and drugs and combinations of drug use.” (R. Hingson, rhingson@mail.nih.gov)
Genetics & Phenytoin Adverse Reactions: Reduced drug clearance in patients with CYP2C9*3 is associated with phenytoin-related severe cutaneous adverse reactions, a study from Taiwan shows (pp. 525–34). A genome-wide association study of 105 cases and 3,655 controls “showed an overall odds ratio of 11 (95% CI, 6.2–18; z = 8.58; P < .00001) for CYP2C9*3 association” with such cutaneous reactions to the anticonvulsant. (W-H Chung, sihung@ym.edu.tw)

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

PNN Pharmacotherapy Line
Aug. 7, 2014 * Vol. 21, No. 152
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 7 issue of the New England Journal of Medicine (2014; 371).
Genetics of Vascular and Pulmonary Syndrome: In patients with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation, researchers identify a gain-of-function mutations in TMEM173, which encodes the stimulator of interferon genes (STING) protein (pp. 507–18). In tests of an index patient and five unrelated children with similar clinical phenotypes, STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) stimulation, interferon-beta gene IFNB1 assays, and tests of Janus kinase (JAK) inhibition yielded these findings: “We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors.” (R. Goldbach-Mansky, goldbacr@mail.nih.gov)
While JAK inhibitors might prove useful in patients with STING-associated vasculopathy with onset in infancy (SAVI), editorialists write that direct STING inhibition should be tested for use in patients with these and other interferon-mediated disorders (
pp. 568–71): “Considering the severity of the disease and its refractory status to conventional immunosuppressive agents, [these study authors] found that, in these patients, incubation of lymphocytes with JAK inhibitors resulted in reduced levels of STAT1 phosphorylation and a reduction of interferon-beta production in fibroblasts activated by cGAMP. Although these results suggest a possible avenue for treatment in patients with SAVI, it is likely that direct inhibition of STING would be more efficacious. Of note, in a mouse model of another genetic form of the Aicardi–Goutières syndrome due to mutations in the DNA exonuclease Trex1, the development of disease features is STING-dependent. Indeed, considering the emerging role of STING as an essential step in cytosolic DNA signaling, blocking STING may turn out to be an effective therapeutic strategy not only in SAVI and the Aicardi–Goutières syndrome but also in a wider spectrum of DNA-induced type 1 interferon–mediated diseases, including systemic lupus erythematosus.” (Y. J. Crow)
Detecting Creutzfeldt–Jakob Disease: Responding to studies that demonstrate detection of Creutzfeldt–Jakob disease through assays of nasal brushings (pp. 519–29; B. Caughey, bcaughey@nih.gov) or urine (pp. 530–9; C. Soto, claudio.soto@uth.tmc.edu), an editorialist explains that these approaches could also prove useful in other disorders (pp. 571–2): “These assays that use shaking or sonication inputs with amyloid or protease-resistance outputs may prove to be extremely useful in the diagnosis of other protein-aggregation diseases. Most important will be the detection of the abnormal conformers of the amyloid beta (A-beta) peptide, which lies at the center of Alzheimer’s disease. Preliminary data from Salvadores et al. (i.e., Soto’s laboratory) show a sensitivity of 90% and a specificity of 92% for a test that amplifies A-beta oligomers from cerebrospinal fluid. Surprisingly, in this scenario, shaking performed better than sonication, perhaps reflecting the more fragile nature of A-beta oligomers as compared with abnormal PrP seeds. Perhaps these structural properties also relate in some way to the lack of transmissibility of Alzheimer’s disease, as compared with Creutzfeldt–Jakob disease.” (C. L. Masters)

>>>PNN NewsWatch
* FDA yesterday approved oritavancin (Orbactiv, The Medicines Company), the third drug for approved in the past 3 months for treatment of patients with acute bacterial skin and skin structure infections caused by certain susceptible bacteria, including methicillin-susceptible and-resistant Staphylococcus aureus, various Streptococcus species, and Enterococcus faecalis.

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

PNN Pharmacotherapy Line
Aug. 8, 2014 * Vol. 21, No. 153
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 12 issue of the Journal of the American College of Cardiology (2014; 64).
Best Blood Pressure in Patients With Hypertension: Low blood pressure (BP) can be as detrimental as elevated values in patients with hypertension, according to a retrospective cohort study conducted in the Kaiser Permanente Southern California system (pp. 588–97). The results of this “study [add] to the growing uncertainty about BP treatment targets,” the authors conclude. In 2006–10, patients being treated for hypertension had these mortality and end-stage renal diseases (ESRD) outcomes based on BP categories: “Among 398,419 treated hypertensive subjects (30% with diabetes mellitus), mortality occurred in 25,182 (6.3%) and ESRD in 4,957 (1.2%). Adjusted hazard ratios (95% confidence intervals [CI]) for composite mortality/ESRD in systolic BP <110, 110 to 119, 120 to 129, 140 to 149, 150 to 159, 160 to 169, and ≥170 compared with 130 to 139 mm Hg were 4.1 (95% CI: 3.8 to 1.3), 1.8 (95% CI: 1.7 to 1.9), 1.1 (95% CI: 1.1 to 1.1), 1.4 (95% CI: 1.4 to 1.5), 2.3 (95% CI: 2.2 to 2.5), 3.3 (95% CI: 3.0 to 3.6), and 4.9 (95% CI: 4.4 to 5.5) respectively. Diastolic BP 60 to 79 mm Hg were associated with the lowest risk. The nadir systolic and diastolic BP for the lowest risk was 137 and 71 mm Hg, respectively. Stratified analyses revealed that the diabetes mellitus population had a similar hazard ratio curve but a lower nadir at 131 and 69 mm Hg but age ≥70 had a higher nadir (140 and 70 mm Hg).” (J. J. Sim)

>>>Circulation Highlights
Source:
Aug. 5 issue of Circulation (2014; 130).
ESRD Risks After CV Events in Chronic Kidney Disease: Risks of progression to end-stage-renal disease (ESRD) and all-cause mortality (ACM) are increased following cardiovascular (CV) events in patients with chronic kidney disease stages 3–5, researchers report (pp. 458–65). In a retrospective cohort study of 2,964 patients with chronic kidney disease referred to a Toronto clinic, interim CV events (heart failure, myocardial infarction, and stroke) were analyzed, with these results: “Over a median follow-up time of 2.76 years (interquartile range, 1.45–4.62), 447 (15%) subjects had a CV event. In the same time period, 318 (11%) developed ESRD, and 446 (15%) experienced ACM before ESRD (156 [5%] from a CV and 290 [10%] from a non–CV-related cause). When analyzed as a time-dependent variable, an interim CV event was associated with a higher risk of subsequent ESRD (hazard ratio, 5.33; 95% confidence interval, 3.74–7.58) and ACM before ESRD (hazard ratio, 4.15, hazard ratio, 3.30–5.23). The hazard ratio for CV-related death versus non–CV-related death before ESRD was 12.38 (95% confidence interval, 8.30–18.45) versus 2.13 (95% confidence interval, 1.57–2.87).” (D. Naimark, david.naimark@sunnybrook.ca)

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Bleeding in Patients With Liver Disease During Anticoagulation: Risks of minor but not major bleeding are increased during pharmacologic venous thromboembolism (VTE) in hospitalized patients with chronic liver disease (CLD) and concurrent coagulopathy, according to a retrospective chart review conducted in a five-hospital network (doi: 10.1002/phar.1464). The analysis included 256 patients, 80 of whom received pharmacologic VTE prophylaxis and 176 who did not. Results showed: “Differences were observed in the primary outcome of overall hemorrhage (composite of major and minor hemorrhage) for patients receiving VTE prophylaxis versus no VTE prophylaxis (17.5% vs 7.4%, p = 0.02). Logistic regression revealed covariates independently associated with increased hemorrhage risk were pharmacologic VTE prophylaxis use (adjusted odds ratio [AOR] 3.64, p = 0.004), increasing international normalized ratio (AOR 1.31, p = 0.007), and decreasing platelet count (AOR 0.99, p = 0.03).” (J. A. Reichert, jacob.reichert@gmail.com)
Medication-Related Problems in Patients on Medicaid: Analysis of two Medicaid claims databases who participated in telephonic medication therapy management programs concludes that number of medications being taken is a predictor of medication-related problems, but other factors were “clearly important,” calling into question criteria used in determining MTM eligibility (doi: 10.1002/phar.1462; M. E. Snyder, snyderme@purdue.edu).

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

PNN Pharmacotherapy Line
Aug. 11, 2014 * Vol. 21, No. 154
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 9 issue of Lancet (2014; 384).
Nicotinamide in Friedreich’s Ataxia: Nicotinamide, administered over an 8-week period to patients with Friedrich’s ataxia, improved serum frataxin concentrations, researchers report (pp. 504–13). This progressive degenerative disorder is caused by frataxin deficiency that is results from heterochromatinization and transcriptional silencing in intron 1 of frataxin (FXN) gene, the authors explain. Trials of nicotinamide (vitamin B3), a histone deacetylase inhibitor, were conducted using single doses (phase 1), repeated daily doses for 5 days (phase 2), and maximum tolerated doses for 8 weeks (phase 3) in adults with Friedreich’s ataxia, with these results: “Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p = 0.0004). Bayesian analysis predicted that 3.8 g would result in a 1.5-times increase and 7.5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3.5–6 g resulted in a sustained and significant (p <0.0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures [of ataxia] showed no significant changes.” (R. Festenstein, r.festenstein@imperial.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 349).
BCG vaccination: In children, BCG vaccination protects against Myobacterium tuberculosis infection and progression from infection to illness, according to a systematic review and meta-analysis of studies in community congregate settings and households (g4643): “The primary analysis included 14 studies and 3,855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon-gamma release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n = 1,745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77).” (I. Abubakar, i.abubakar@ucl.ac.uk)
Centralizing Stroke Services in Urban Areas: In two English metropolitan areas, centralization of acute stroke services reduced mortality and length of hospital stay, according to analysis of hospital data from 2008 to 2012 (g4757). A “hub-and-spoke” model of acute stroke care combined with hyperacute services provided in centers in London and Greater Manchester yielded these results: “In London there was a significant decline in risk adjusted mortality at 3, 30, and 90 days after admission. At 90 days the absolute reduction was −1.1% (95% confidence interval −2.1 to −0.1; relative reduction 5%), indicating 168 fewer deaths (95% confidence interval 19 to 316) during the 21 month period after reconfiguration in London. In both areas there was a significant decline in risk adjusted length of hospital stay: −2.0 days in Greater Manchester (95% confidence interval −2.8 to −1.2; 9%) and −1.4 days in London (−2.3 to −0.5; 7%). Reductions in mortality and length of hospital stay were largely seen among patients with ischaemic stroke.” (S. Morris, steve.morris@ucl.ac.uk)

>>>PNN JournalWatch
* 2013 ACC/AHA Guideline Recommends Fixed-Dose Strategies Instead of Targeted Goals to Lower Blood Cholesterol, in
Journal of the Am. College of Cardiology, 2014; 64: 601–12. (S. C. Smith)
* A Polypill Strategy to Improve Global Secondary Cardiovascular Prevention: From Concept to Reality, in
Journal of the American College of Cardiology, 2014; 64: 613–21. (J. M. Castellano)
* Contemporary Reviews in Cardiovascular Medicine: Update on Chronic Thromboembolic Pulmonary Hypertension, in
Circulation, 2014; 130: 508–18. (I. M. Lang, irene.lang@meduniwien.ac.at)
* Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report, in
Chest, 2014; 146: 449–75. (J. Ornelas, jornelas@chestnet.org)

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

PNN Pharmacotherapy Line
Aug. 12, 2014 * Vol. 21, No. 155
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. issue of JAMA Internal Medicine (2014; 174).
Anticoagulation After Traumatic Brain Injury: Anticoagulation restarted after traumatic brain injury yields more benefits than risks, according to retrospective analysis of Medicare claims for patients 65 years or older in 2006–09 (pp. 1244–51). The analysis included beneficiaries hospitalized for traumatic brain injury within the prior month and showed these outcomes with warfarin use in the 30 days following discharge: “Medicare beneficiaries with traumatic brain injury were predominantly female (64%) and white (92%), with a mean (SD) age of 81.3 (7.3) years, and 82% had atrial fibrillation. Over the 12 months following hospital discharge, 55% received warfarin during 1 or more 30-day periods. We examined the lagged effect of warfarin use on outcomes in the following period. Warfarin use in the prior period was associated with decreased risk of thrombotic events (relative risk [RR], 0.77 [95% CI, 0.67–0.88]) and increased risk of hemorrhagic events (RR, 1.51 [95% CI, 1.29–1.78]). Warfarin use in the prior period was associated with decreased risk of hemorrhagic or ischemic stroke (RR, 0.83 [95% CI, 0.72–0.96]).” (I. H. Zuckerman, izuckerman@impaqint.com)
Statins & Physical Activity: Supporting the results of the “statins & gluttony” article published last month (see PNN, July 8), an analysis of 5,994 men in the Osteoporotic Fractures in Men Study finds modestly reduced levels of physical activity in those on statins (pp. 1263–70). Results over a decade showed the following: “[Physical Activity Scale for the Elderly (PASE)] score declined by a mean (95% CI) of 2.5 (2.0 to 3.0) points per year for nonusers and 2.8 (2.1 to 3.5) points per year for prevalent users, a nonstatistical difference (0.3 [−0.5 to 1.0] points). For new users, annual PASE score declined at a faster rate than nonusers (difference of 0.9 [95% CI, 0.1 to 1.7] points).… Statin users expended less [metabolic equivalents (METs)] (0.03 [95% CI, 0.02–0.04] METs less) and engaged in less moderate physical activity (5.4 [95% CI, 1.9–8.8] fewer minutes per day), less vigorous activity (0.6 [95% CI, 0.1–1.1] fewer minutes per day), and more sedentary behavior (7.6 [95% CI, 2.6–12.4] greater minutes per day).” (D. S. H. Lee, leedavid@ohsu.edu)
Consistency in Generic Drug Labels: Reacting to a Nov. 2013 FDA proposal for a website that would serve as a centralized repository for drug safety information, authors of a Viewpoint write (pp. 1213–4): “Until a centralized online drug information and safety resource becomes available, the FDA’s proposal to give generic drug manufacturers control over updating their own drug labels would address an important gap in public health oversight. Currently, manufacturers of generic drugs have no responsibility to monitor the evolving knowledge about adverse effects and safe use of their products, though they must inform the FDA of all adverse event reports about their products that they receive. Brand-name manufacturers generally scale back their drug safety efforts once a drug is produced by generic manufacturers and may stop marketing the drug entirely. Without the changes in the proposed rule, the FDA would have to take the initiative in most cases to help push forward label updates for generic drugs with multiple manufacturers, as occurred with metoclopramide.” (J. D. Duke, jonduke@regenstrief.org)

>>>PNN NewsWatch
* Shift workers are taking drugs to help them stay awake or get to sleep despite weak evidence for their benefit, according to a new Cochrane review. Small numbers of trials tested drugs used by shift workers, and the results suggest that for some people they might do more harm than good. The review included 15 trials involving a total of 718 people. In nine trials, the melatonin helped shift workers sleep for around 24 minutes longer during the night or day, compared with placebos. However, it did not help them get to sleep any quicker. One trial of zoplicone showed the drug was no more effective than placebos for helping shift workers sleep during the day. Remaining trials focused on caffeine and two drugs, modafinil and armodafinil. In one trial, caffeine reduced sleepiness during night shifts, when workers also napped before shifts. Modafinil and armodafinil increased alertness and reduced sleepiness. However, they also caused headaches, nausea, and a rise in blood pressure in a substantial number of people.

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

PNN Pharmacotherapy Line
Aug. 13, 2014 * Vol. 21, No. 156
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 13 issue of JAMA (2014; 312).
Analytic Strategy & Treatment Outcomes in Meta-analyses: Differences in strategies used in clinical trials can affect results of meta-analyses, a study shows, and this “underlines the need for systematic sensitivity analyses” (pp. 623–30). Based on calculation of the ratio of odds ratios (ROR), evaluation of 163 meta-analyses showed these results for inclusion of all trials versus alternative strategies (single most precise trial, meta-analysis restricted to the 25% largest trials, limit meta-analysis [adjusted for small-study effect], and meta-analysis restricted to trials at low overall risk of bias): “Treatment outcomes were larger in the meta-analysis of all trials than in the single most precise trial (combined ROR, 1.13 [95% CI, 1.07–1.19]) for subjective outcomes and 1.03 (95% CI, 1.01–1.05) for objective outcomes). The difference in treatment outcomes between these strategies was substantial in 47 of 92 (51%) meta-analyses of subjective outcomes (meta-analysis of all trials showing larger outcomes in 40/47) and in 28 of 71 (39%) meta-analyses of objective outcomes (meta-analysis of all trials showing larger outcomes in 21/28). The combined ROR for subjective and objective outcomes was, respectively, 1.08 (95% CI, 1.04–1.13) and 1.03 (95% CI, 1.00–1.06) when comparing meta-analysis of all trials and meta-analysis of the 25% largest trials, 1.17 (95% CI, 1.11–1.22) and 1.13 (95% CI, 0.82–1.55) when comparing meta-analysis of all trials and limit meta-analysis, and 0.94 (95% CI, 0.86–1.04) and 1.03 (95% CI, 1.00–1.06) when comparing meta-analysis of all trials and meta-analysis restricted to trials at low risk of bias.” (A. Dechartres, agnes.dechartres@htd.aphp.fr)
These findings “reinforce the need for circumspection in study interpretation,” editorialists write (
pp. 603–5). “Meta-analysis has the potential to be the best source of evidence to inform decision making. The underlying methods have become much more sophisticated in the last few decades, but achieving this potential will require continued advances in the underlying science, parallel to the advances that have occurred with other biomedical research design and statistics. Until that occurs, an informed reader must approach these studies, as with all other literature, as imperfect information that requires critical appraisal and assessment of applicability of the findings to individual patients. This is not easy, and it requires skill and intelligence. Whatever clinical evidence looks like, and wherever it is placed on a pyramid, there are no shortcuts to truth.” (R. M. Golub, robert.golub@jamanetwork.org)
Treatment of HCV Infection: Availability of new, short-duration, simpler therapies for hepatitis C virus (HCV) infections could lead to “treatment of many more” of the 185 million infected people worldwide, a review article concludes (pp. 631–40): “Patients infected with HCV genotype 1 represent 60% to 75% of HCV infections in the United States. Hepatitis C virus genotype 1 is more difficult to cure than genotype 2 or genotype 3. Patients with HCV genotype 1 should receive treatment with sofosbuvir + pegylated interferon + ribavirin because of the shorter duration of therapy and high rates of [sustained virologic response (SVR)] (89%–90%). Simeprevir + pegylated interferon + ribavirin is an alternative for patients with HCV genotype 1 (SVR, 79%–86%). Patients with HCV genotypes 2 and 3, representing 20% to 29% of US HCV infections, should receive therapy with sofosbuvir + ribavirin alone (SVR for genotype 2, 12 weeks’ duration: 82%–93%; SVR for genotype 3, 24 weeks’ duration, 80%–95%). Patients with HIV–HCV coinfection and patients with compensated cirrhosis (ie, cirrhosis but preserved synthetic liver function) should receive the same treatment as HCV-monoinfected patients.” (S. Kottilil, skottilil@niaid.nih.gov)
E-cigarettes & Vaping: Increasing popularity of vaping (use of e-cigarettes) “has been associated with a surge in nicotine use among adolescents,” authors of a Viewpoint article warn, and evidence of dangers of the practice is emerging (pp. 595–6; L. O. Gostin, gostin@law.georgetown.edu).

>>>PNN NewsWatch
* The Pharmacy Society of Wisconsin is receiving a “Power of A” Summit Award from the American Society of Association Executives for its Wisconsin Pharmacy Quality Collaborative program, pharmacist.com reports.

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

PNN Pharmacotherapy Line
Aug. 14, 2014 * Vol. 21, No. 157
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 14 issue of the New England Journal of Medicine (2014; 371).
Sodium, Potassium & BP: Two research studies and an editorial examine the relationships among urinary sodium and potassium, blood pressure, and outcomes.
In an analysis of data from 102,216 adults from 18 counties, 24-hour sodium and potassium excretion estimates (as a proxy for intake) show a nonlinear relationship between sodium and blood pressure and also that higher potassium intake is associated with lower systolic blood pressure (
pp. 601–11). “Blood pressure was nonlinear and was most pronounced in persons consuming high-sodium diets, persons with hypertension, and older persons,” the authors conclude based on these results: “Regression analyses showed increments of 2.11 mm Hg in systolic blood pressure and 0.78 mm Hg in diastolic blood pressure for each 1-g increment in estimated sodium excretion. The slope of this association was steeper with higher sodium intake (an increment of 2.58 mm Hg in systolic blood pressure per gram for sodium excretion >5 g per day, 1.74 mm Hg per gram for 3 to 5 g per day, and 0.74 mm Hg per gram for <3 g per day; P <0.001 for interaction). The slope of association was steeper for persons with hypertension (2.49 mm Hg per gram) than for those without hypertension (1.30 mm Hg per gram, P <0.001 for interaction) and was steeper with increased age (2.97 mm Hg per gram at >55 years of age, 2.43 mm Hg per gram at 45 to 55 years of age, and 1.96 mm Hg per gram at <45 years of age; P <0.001 for interaction). Potassium excretion was inversely associated with systolic blood pressure, with a steeper slope of association for persons with hypertension than for those without it (P <0.001) and a steeper slope with increased age (P <0.001).” (A. Mente, andrew.mente@phri.ca)
An optimal amount of sodium intake and higher amounts of potassium were associated with the best outcomes in a second study (
pp. 612–23). Estimated urinary sodium and potassium excretion values showed these relationships with death and major cardiovascular events: “The mean estimated sodium and potassium excretion was 4.93 g per day and 2.12 g per day, respectively. With a mean follow-up of 3.7 years, the composite outcome occurred in 3,317 participants (3.3%). As compared with an estimated sodium excretion of 4.00 to 5.99 g per day (reference range), a higher estimated sodium excretion (≥7.00 g per day) was associated with an increased risk of the composite outcome (odds ratio, 1.15; 95% confidence interval [CI], 1.02 to 1.30), as well as increased risks of death and major cardiovascular events considered separately. The association between a high estimated sodium excretion and the composite outcome was strongest among participants with hypertension (P = 0.02 for interaction), with an increased risk at an estimated sodium excretion of 6.00 g or more per day. As compared with the reference range, an estimated sodium excretion that was below 3.00 g per day was also associated with an increased risk of the composite outcome (odds ratio, 1.27; 95% CI, 1.12 to 1.44). As compared with an estimated potassium excretion that was less than 1.50 g per day, higher potassium excretion was associated with a reduced risk of the composite outcome.” (M. O’Donnell, donnm@mcmaster.ca">odonnm@mcmaster.ca)
Reacting to these and a third related article (
pp. 624–34; D. Mozaffarian, dariush.mozaffarian@tufts.edu), an editorialist writes that the studies “highlight the need to collect high-quality evidence on both the risks and benefits of low-sodium diets” (pp. 677–9). “Reducing dietary sodium and, to a lesser extent, increasing dietary potassium have been included in many guidelines for the treatment of hypertension and prevention of cardiovascular disease. However, recent studies have raised questions about potential adverse effects associated with low sodium intake on important health outcomes, including cardiovascular disease and death.” (S. Oparil)

>>>PNN NewsWatch
* FDA yesterday approved the first orexin receptor antagonist, suvorexant (Belsomra, Merck, Sharp & Dohme) for use as needed to treat difficulty in falling and staying asleep. Suvorexant should be taken no more than once per night, within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of waking. The total dose should not exceed 20 mg once daily, and 20-mg doses have been shown to affect next-day driving.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 844/270-0717 (fax). Copyright © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.
PNN Pharmacotherapy Line
Aug. 15, 2014 * Vol. 21, No. 158
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Sept. 1 issue of Clinical Infectious Diseases (2014; 59).
Pneumococcal Vaccine in Children With Chronic Conditions: In the current era of universal vaccination of children with pneumococcal conjugate vaccine, rates of pneumococcal disease remain high among those with high-risk and at-risk conditions, researchers report (pp. 615–23). A retrospective cohort analysis of claims 2007–10 data reveals these patterns among children with such conditions and comparable peers without elevated risks: “Among at-risk children, rate ratios for invasive pneumococcal disease (vs children without at-risk/high-risk conditions) were 1.8 (95% confidence interval [CI], 1.4–2.3) in children <5 years of age and 3.3 (95% CI, 2.4–4.4) in children 5–17 years of age. Corresponding rate ratios for high-risk children were 11.2 (95% CI, 7.0–17.9) and 40.1 (95% CI, 28.8–56.0). Rate ratios increased in asthmatic children with increasing disease severity and in all at-risk children by the number of concurrent at-risk conditions. Rate ratios for pneumococcal pneumonia and all-cause pneumonia demonstrated similar patterns.” (S. I. Pelton, spelton@bu.edu)
Pseudomonal Eradication Failure in Cystic Fibrosis: Two easily assayed phenotypes of Pseudomonas aeruginosa are associated with eradication failure in children with cystic fibrosis, a study shows, opening the possibility of testing-guided therapy (pp. 624–31). In the 18-month EPIC trial, 194 children with cystic fibrosis had these results of 22 in vitro phenotypes and antibiotic-eradication outcomes: “Baseline P. aeruginosa isolates frequently exhibited phenotypes thought to represent chronic adaptation, including mucoidy. Wrinkly colony surface and irregular colony edges were both associated with increased risk of eradication failure (hazard ratios [95% confidence intervals], 1.99 [1.03–3.83] and 2.14 [1.32–3.47], respectively). Phenotypes reflecting defective quorum sensing were significantly associated with subsequent mucoidy, but no phenotype was significantly associated with subsequent exacerbations during the trial.” (N. Mayer-Hamblett, nicole.hamblett@seattlechildrens.org)

>>>Oncology Highlights
Source:
Aug. 10 issue of the Journal of Clinical Oncology (2014; 32).
Treating Metastatic Pancreatic Cancer: Responding to a research article published last fall in the New England Journal of Medicine (see PNN, Oct. 31), an editorialist assesses the current state of research into treatment of metastatic pancreatic cancer (pp. 2405–7): “The trial reported by Von Hoff et al clearly adds to the treatment options available to patients with metastatic pancreatic cancer, and its toxicity profile should allow this regimen to be effectively integrated into the multimodality management of patients with potentially resectable, borderline resectable, and locally advanced pancreatic cancer. However, it is also clear that the limited advances achieved with this cytotoxic chemotherapy regimen should not impede our long-term efforts to develop more specific and effective systemic therapies for patients affected by this difficult disease.” (J. L. Abbruzzese, james.abbruzzese@duke.edu)
Vitamin D & Colorectal Cancer Survival: Higher 25-hydroxyvitamin D (25-OHD) levels are associated with increased survival among patients with stage I to III colorectal cancer (COC), according to a study of 1,598 patients (pp. 2430–9). Kaplan–Meier analysis of prospective data showed “strong associations between plasma 25-OHD concentration and CRC-specific (P = .008) and all-cause mortality (P = .003). Adjusted HRs were 0.68 (95% CI, 0.50 to 0.90) and 0.70 (95% CI, 0.55 to 0.89), respectively (highest v lowest 25-OHD tertile), particularly in stage II disease (HR, 0.44; P = .004 for CRC-specific mortality).” (M. G. Dunlop, malcolm.dunlop@igmm.ed.ac.uk)

>>>PNN NewsWatch
* FDA has approved a new indication for bevacizumab (Avastin, Genentech)—treatment of patients with persistent, recurrent or late-stage (metastatic) cervical cancer.
* Consumers should be aware of fraudulent products being promoted on the Internet for preventing or treating infections of the
Ebola virus, FDA said. Experimental vaccines and treatment are in early stages of development, the agency added, and no products are currently approved by FDA for these indications. Dietary supplements by law cannot be promoted for prevention or cure of 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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 18, 2014 * Vol. 21, No. 159
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 16 issue of Lancet (2014; 384).
Risk-Based Treatment of Hypertension: As with lipid-lowering strategies, equations for estimating baseline cardiovascular risk are useful in making decisions about blood-pressure lowering in individual patients, according to findings of a meta-analysis (pp. 591–8). Using individual patient data from studies comparing hypotensive agents and placebo, the investigators found that “lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases”: “11 trials and 26 randomised groups met the inclusion criteria, and included 67,475 individuals, of whom 51,917 had available data for the calculation of the risk equations. 4,167 (8%) had a cardiovascular event during a median of 4.0 years (IQR 3.4–4.4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6.0% (SD 2.0), 12.1% (1.5), 17.7% (1.7), and 26.8% (5.4). In each consecutive higher risk group, blood pressure–lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7–27), 15% (4–25), 13% (2–22), and 15% (5–24), respectively (p = 0.30 for trend). However, in absolute terms, treating 1,000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8–21), 20 (8–31), 24 (8–40), and 38 (16–61) cardiovascular events, respectively (p = 0.04 for trend).” (Blood Pressure Lowering Treatment Trialists’ Collaboration)
Bivalirudin v. Heparin in PCI: In patients undergoing percutaneoous coronary interventions (PCIs), those receiving bivalirudin in clinical trials had higher rates of myocardial infarction and stent thrombosis but lower rates of bleeding, compared with heparin (pp. 599–606). A meta-analysis provides these insights into a primary efficacy endpoint of incidence of major adverse cardiac events (MACE) up to 30 days after PCI: “We included data from 16 trials involving 33,958 patients, of whom 2,422 experienced MACE and 1,406 had a major bleed. There was an increase in the risk of MACE with bivalirudin-based regimens compared with heparin-based regimens (risk ratio 1.09, 95% CI 1.01–1.17; p = 0.0204), which was largely driven by increases in myocardial infarction (1.12, 1.03–1.23) and seemingly also by ischaemia-driven revascularisation (1.16, 0.997–1.34) with bivalirudin compared with heparin, with no effect on mortality (0.99, 0.82–1.18). Bivalirudin increased the risk of stent thrombosis (risk ratio 1.38, 95% CI 1.09–1.74; p = 0.0074), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4.27, 2.28–8.00; p <0.0001). Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio 0.62, 95% CI 0.49–0.78; p <0.0001), but the magnitude of this effect varied greatly (p <0.0001) depending on whether glycoprotein IIb/IIIa inhibitors were used predominantly in the heparin arm only (0.53, 0.47–0.61; p <0.0001), provisionally in both arms (0.78, 0.51–1.19; p = 0.25), or planned in both arms (1.07, 0.87–1.31; p = 0.53).” (M. S. Sabatine, msabatine@partners.org)

>>>PNN JournalWatch
* Tranexamic Acid Use and Postoperative Outcomes in Patients Undergoing Total Hip or Knee Arthroplasty in the United States: Retrospective Analysis of Effectiveness and Safety, in
BMJ, 2014; 349: g4829. (S. G. Memtsoudis, memtsoudiss@hss.edu)
* Peritoneal Dialysis–Related Peritonitis: Towards Improving Evidence, Practices, and Outcomes, in
American Journal of Kidney Diseases, 2014; 64: 278–89. (D. W. Johnson, david.johnson2@health.qld.gov.au)
* Bone Disease in CKD: A Focus on Osteoporosis Diagnosis and Management, in
American Journal of Kidney Diseases, 2014; 64: 290–304. (P. D. Miller, millerccbr@aol.com)
* Risks for Infection in Patients With Asthma (or Other Atopic Conditions): Is Asthma More Than a Chronic Airway Disease?, in
Journal of Allergy and Clinical Immunology, 2014; 134: 247–57.e3. (Y. J. Juhn, juhn.young@mayo.edu)
* Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report, in
Chest, 2014; 146: 449–75. (J. Ornelas, jornelas@chestnet.org)
* Standards of Practice for Clinical Pharmacists, in
Pharmacotherapy, 2014; doi: 10.1002/phar.1438. (American College of Clinical Pharmacy, accp@accp.com)
* Clinical Pharmacy Should Adopt a Consistent Process of Direct Patient Care, in
Pharmacotherapy, 2014; doi: 10.1002/phar.1459. (American College of Clinical Pharmacy, accp@accp.com)

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

PNN Pharmacotherapy Line
Aug. 19, 2014 * Vol. 21, No. 160
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 19 issue of the Annals of Internal Medicine (2014; 161).
Second-Generation Antipsychotics & Acute Kidney Injury: Results of a population-based cohort study in Ontario support safety concerns about second-generation antipsychotic agents, investigators conclude (pp. 242–8). Data from 2003 to 2012 show increased risk of acute kidney injury (AKI) and related adverse outcomes among 97,777 patients receiving a new ambulatory prescription for oral dosage forms of the drugs: “Atypical antipsychotic drug use versus nonuse was associated with a higher risk for hospitalization with AKI (relative risk [RR], 1.73 [95% CI, 1.55 to 1.92]). This association was consistent when AKI was assessed in a subpopulation for which information on serum creatinine levels was available (5.46% vs. 3.34%; RR, 1.70 [CI, 1.22 to 2.38]; absolute risk increase, 2.12% [CI, 0.80% to 3.43%]). Drug use was also associated with hypotension (RR, 1.91 [CI, 1.60 to 2.28]), acute urinary retention (RR, 1.98 [CI, 1.63 to 2.40]), and all-cause mortality (RR, 2.39 [CI, 2.28 to 2.50]).” (A. X. Garg, amit.garg@lhsc.on.ca)
Evidence-Based Risk Communication: For communicating risk to patients, visuals and absolute risks are better understood than numbers needed to treat, according to a systematic review of 84 articles reporting 91 unique studies (pp. 270–80): “Studies showed that visual aids (icon arrays and bar graphs) improved patients’ understanding and satisfaction. Presentations including absolute risk reductions were better than those including relative risk reductions for maximizing accuracy and seemed less likely than presentations with relative risk reductions to influence decisions to accept therapy. The presentation of numbers needed to treat reduced understanding. Comparative effects of presentations of frequencies (such as 1 in 5) versus event rates (percentages, such as 20%) were inconclusive.” The authors caution that most studies were “small and highly variable in terms of setting, context, and methods of administering interventions.” (D. A. Zipkin, daniella.zipkin@duke.edu)
Longevity in Patients With Cystic Fibrosis: Patients with cystic fibrosis (CF) are living longer, researchers conclude, and the health care system should prepare to care for more affected adults (pp. 233–41). Trends in CF survival in 2000–10 show these patterns and provide the following estimates of longevity for those born with the condition in 2010: “Between 2000 and 2010, the number of patients in the [Cystic Fibrosis Foundation Patient Registry] increased from 21,000 to 26,000, median age increased from 14.3 to 16.7 years, and adjusted mortality decreased by 1.8% per year (95% CI, 0.5% to 2.7%). Males had a 19% (CI, 13% to 24%) lower adjusted risk for death than females. Median survival of children born and diagnosed with CF in 2010 is projected to be 37 years (CI, 35 to 39 years) for females and 40 years (CI, 39 to 42 years) for males if mortality remains at 2010 levels and more than 50 years if mortality continues to decrease at the rate observed between 2000 and 2010.” (K. A. Sabadosa, Kathryn.A.Sabadosa@Dartmouth.edu)
Hepatocellular Carcinoma Screening: In response to a study showing uncertain benefits from screening of patients with chronic liver disease for hepatocellular carcinoma (HCC) (pp. 261–9; D. Kansagara, kansagar@ohsu.edu), editorialists conclude (pp. 300–1): “We should pair any screening with efforts to collect better data, including baseline characteristics and long-term outcomes in screened and unscreened patients, which may help reduce our uncertainty. In the [Veterans Health Administration (VHA)] and integrated systems with electronic records and cancer registries, most of these data can be collected as part of routine clinical care. Given the high mortality from HCC and the high costs of delivering a truly effective program of early detection and treatment, better evidence is imperative. We hope that the VHA and other health systems can collaborate to develop such evidence so patients and their clinicians can be confident they are getting (and delivering) the best care available.” (D. Atkins)

>>>PNN NewsWatch
* Janet L. Teeters, MS, Director of the Accreditation Services Division at ASHP, died on August 15 following an equestrian accident. She was to have spoken at the National Pharmacy Preceptors Conf., which opens tomorrow in Washington, DC.

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

PNN Pharmacotherapy Line
Aug. 20, 2014 * Vol. 21, No. 161
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 20 issue of JAMA (2014; 312).
Smoking Cessation Intervention After Hospitalization: Automated telephone calls and free medication enabled higher rates of smoking cessation than did a standard recommendation in a group of 397 daily smokers following hospital discharge, researchers report (pp. 719–28). Participants were mostly white with a mean age of 53 years when they were discharged in 2010–12. Compared with recommendations to use pharmacotherapy and counseling to stop smoking, those receiving the intervention had these results at 6 months: “Smokers randomly assigned to sustained care (n = 198) used more counseling and more pharmacotherapy at each follow-up assessment than those assigned to standard care (n = 199). Biochemically validated 7-day tobacco abstinence at 6 months was higher with sustained care (26%) than with standard care (15%) (relative risk [RR], 1.71 [95% CI, 1.14–2.56], P = .009; number needed to treat, 9.4 [95% CI, 5.4–35.5]). Using multiple imputation for missing outcomes, the RR for 7-day tobacco abstinence was 1.55 (95% CI, 1.03–2.21; P = .04). Sustained care also resulted in higher self-reported continuous abstinence rates for 6 months after discharge (27% vs 16% for standard care; RR, 1.70 [95% CI, 1.15–2.51]; P = .007).” (N. A. Rigotti, nrigotti@partners.org)
Mental Health Comorbidities in Diabetes: A Viewpoint article discusses common comorbidities in patients with diabetes, including depression, anxiety, and eating disorders (pp. 691–2): “From economic, public health, and humanitarian perspectives, identifying and treating the mental health comorbidities among patients with diabetes should be a priority. Young adults with diabetes are especially vulnerable to mental health comorbidities as they experience multiple transitions—geographically, socially, and between pediatric and adult care—that may place them at risk for loss to medical follow-up and poor health outcomes. The high prevalence and costs of depression in the context of diabetes, combined with evidence that behavioral factors are important for effective diabetes self-management, create an important opportunity to integrate mental health screening and treatment into multidisciplinary team diabetes care, to improve patient and public health outcomes, and to help decrease health care expenditures.” (B. J. Anderson, bja@bcm.edu)

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2014; 62).
Antidepressants & Bone Health: The relationship among depression, antidepressants, and bone health in older adults is a complicated one, and the evidence is insufficient to conclude that serotonin reuptake inhibitors affect bone health, according to a systematic review (pp. 1434–41). “Depression and depressive symptoms are associated with low bone mass and accelerated bone loss in older adults; putative mechanisms underlying this relationship are discussed,” the authors conclude based on analysis of 19 observational studies. “A change in current recommendations for the use of antidepressants in older adults is not justified at the present time. Given the high public health significance of this question, more studies are required to determine whether (and in whom) antidepressants may be deleterious for bone health.” (M. A. Gebara, gebaram@psychiatry.wustl.edu)
Hypotensive Drugs & Falls: In a prospective population-based cohort study, higher doses of antihypertensive medications were “independently associated with falls in older people” (pp. 1527–33). Among 409 participants ages 60–86 years, “those who fell were on a higher [daily defined dose (DDD)] of antihypertensives (1.51 ± 2.16 than those who did not (1.03 ± 1.42) (P = .007).” Risk was particularly higher among patients with a history of stroke. (M. Callisaya, michele.callisaya@monash.edu)

>>>PNN NewsWatch
* FDA yesterday approved eliglustat (Cerdelga, Genzyme) for long-term treatment of adult patients with the type 1 form of the rare genetic condition Gaucher disease. The orally active glucosylceramide analog treats this deficiency of glucocerebrosidase by inhibiting glucosylceramide synthase, which reduces production of glucosylceramide, the substance that builds up in the cells and tissues of people with Gaucher disease.

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

PNN Pharmacotherapy Line
Aug. 21, 2014 * Vol. 21, No. 162
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 21 issue of the New England Journal of Medicine (2014; 371).
GS-5806 Activity Against Respiratory Syncytial Virus: In a viral-challenge study conducted in healthy adults, the orally active inhibitor of respiratory syncytial virus (RSV) entry GS-5806 reduced viral load and clinical disease, researchers report (pp. 711–22). Participants received a challenge RSV strain intranasally. At the first positive RSV infection test or 5 days, participants were randomized to GS-5806 or placebo in one of seven dosing cohorts. Results showed the following: “Among the 54 participants … who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P <0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P = 0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, −20.2 vs. 204.9 × hours; P = 0.005).… Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.” (J. P. DeVincenzo, jdevincenzo@uthsc.edu)
This study “lends further weight to the concept that fusion of the host cell membranes with viral surface proteins is a potential target for additional antiviral compounds for enveloped viruses,” an editorialist writes (
pp. 776–7). “Because the evaluation of GS-5806 is at an early stage, there are unanswered questions to consider that will influence the further development, usefulness, and uptake of the drug. A partial list would be the design and end point of an efficacy trial, the choice of dose and duration of therapy, safety and pharmacokinetics in young children, the implications of the development of resistance, ease of manufacture, and cost. Most important is whether GS-5806 or related compounds will have clinical effects with limited or manageable side effects in the most likely candidates for its use: very sick infants or young children, immunosuppressed persons in whom RSV can cause a persistent and severe infection, and elderly persons with underlying cardiopulmonary disease.” (P. F. Wright)
Culture Conversion With Bedaquiline: In patients with multidrug-resistant tuberculosis, addition of bedaquiline to a preferred antitubercular drug regimen reduces the time to culture conversion significantly, a study shows (pp. 723–32). A Phase IIb trial of this diarylquinoline and mycobacterial ATP synthase inhibitor included 160 patients who received combination therapy with placebo or bedaquiline 400 mg daily for 2 weeks and then 200 mg three times daily for 22 weeks, with these results: “Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P <0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.” (B. Dannemann, bdannema@its.jnj.com)
Medicare Part D Impact: After reviewing the “impact and evolution of Medicare Part D,” a Perspective author concludes that components of the Affordable Care Act and emergence of accountable care organizations have implications for Part D (pp. 693–5): “The long-term success of payment and delivery-system reforms will depend in part on integrating Part D policy with broader reforms—either by requiring data sharing for monitoring quality or by aligning financial incentives between provider organizations and Part D plans.” (J. M. Donohue)

>>>PNN NewsWatch
* FDA yesterday allowed marketing of the first zinc transporter 8 autoantibody (ZnT8Ab) test (KRONUS Zinc Transporter 8 Autoantibody ELISA Assay, KRONUS Market Development Associates). Because many people with type 1 diabetes produce ZnT8Ab, the test helps in diagnosing type 1 versus other types of the disease.

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

PNN Pharmacotherapy Line
Aug. 22, 2014 * Vol. 21, No. 163
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Aug. issue of Health Affairs (2014; 33).
Pharmacist Intervention in Pennsylvania Project: “Pharmacist-provided intervention is a cost-effective tool that may be applied in community pharmacies and health care sites across the country,” concludes a study of medication adherence and related reduction of health care costs (pp. 1444–52). The large-scale, Rite-Aid–based study “evaluated the impact of a pharmacy-based intervention on adherence to five chronic medication classes,” yielding these findings: “To implement the study, 283 pharmacists from a national community pharmacy chain were assigned to the intervention group. Collectively, they screened 29,042 patients for poor adherence risk and provided brief interventions to people with an elevated risk. Compared to a control group of 295 pharmacists who screened 30,454 patients, the intervention significantly improved adherence for all medication classes, from 4.8 percent for oral diabetes medications to 3.1 percent for beta-blockers. Additionally, there was a significant reduction in per patient annual health care spending for patients taking statins ($241) and oral diabetes medications ($341).” (J. L. Pringle, jlp127@pitt.edu)
Part D Affordability in Patients With Chronic Conditions: Cost-related nonadherence rose in 2009–11 among Medicare Part D beneficiaries with multiple chronic conditions, researchers report (pp. 1435–43). Based on analysis of medication affordability in the first 6 years of Part D coverage, these results emerged: “We found continued incremental improvements in medication affordability in the period 2007–09 that eroded during the period 2009–11. Among elderly beneficiaries with four or more chronic conditions, we observed an increase in the prevalence of cost-related nonadherence from 14.4 percent in 2009 to 17.0 percent in 2011, reversing previous downward trends. Similarly, the prevalence among the sickest elderly of forgoing basic needs to purchase medicines decreased from 8.7 percent in 2007 to 6.8 percent in 2009 but rose to 10.2 percent in 2011. Our findings highlight the need for targeted policy efforts to alleviate the persistent burden of drug treatment costs on this vulnerable population.” (J. M. Madden, jeanne_madden@hphc.org)

>>>Medical Care Report
Source:
Sept. issue of Medical Care (2014; 52).
Opioid Use Among Disabled Medicare Beneficiaries: The proportion of disabled Medicare beneficiaries using opioids increased in 2007–11, peaking in 2010, according to a study of fee-for-service patients under 65 years of age (pp. 852–9). In some geographic areas, the mean daily morphine equivalent dose (MED) approached overdose amounts, the authors report, adding these details: “The adjusted proportion with any opioid use was 43.9% in 2007, 44.7% in 2010, and 43.7% in 2011. The proportion with chronic use rose from 21.4% in 2007 to 23.1% in 2011. Among chronic users: mean MED peaked at 81.3 mg in 2010, declining to 77.4 mg in 2011; in 2011, 19.8% received ≥100 mg MED; 10.4% received ≥200 mg. In 2011, Hospital Referral Region–level measures varied broadly (5th–95th percentile): any use: 33.0%–58.6%, chronic use: 13.9%–36.6%; among chronic users, mean MED: 45 mg–125 mg; mean annual opioid prescribers: 2.4–3.7.” (N. E. Morden, Nancy.e.morden@dartmouth.edu)
Comprehension of FDA Medication Guides: Investigators successfully applied patient-centered strategies to presentation of information from FDA in an effort to increase comprehension (pp. 781–9). “Although some age and literacy disparities were reduced with the Health Literacy format in particular, both older age and low literacy remained independently associated with poorer comprehension,” the group concludes. “More aggressive strategies will likely be needed to gain assurances that all patients are informed about their prescribed medications.” (M. S. Wolf)

>>>PNN NewsWatch
* In 45 days, hydrocodone combination products will move from Schedule III to Schedule II, DEA announced yesterday. Pressure for the shift began with a physician’s petition in 1999, DEA said, and the decision is supported by an HHS evaluation and FDA advisory committee. Most pharmacy groups opposed the change, citing patient-access concerns, burdens on the health care system, and new requirements on pharmacies.

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

PNN Pharmacotherapy Line
Aug. 25, 2014 * Vol. 21, No. 164
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 23 issue of Lancet (2014; 384).
Needle-Free Jet Influenza Vaccination Injection: Compared with needle-and-syringe injection of influenza vaccine, a needle-free jet injection device was noninferior in immune responses generated, a study shows (pp. 674–81). Administration of Afluria trivalent influenza vaccine with the Stratis needle-free system produced a higher frequency of local injection site reactions, the authors report, but was otherwise comparable in 1,250 adults: “In the intention-to-treat immunogenicity population, all participants with two serum samples were included (575 in the jet injector group and 574 in the needle and syringe group). The immune response to Afluria when given by needle-free jet injector met the criteria for non-inferiority for all six coprimary endpoints. The jet injector group met the geometric mean titre criterion for non-inferiority for the A/H1N1, A/H3N2, and B strains (upper bound of the 95% CI for the geometric mean titre ratios were 1.10 for A/H1N1, 1.17 for A/H3N2, and 1.04 for B strains). The jet injector group met the seroconversion rate criterion for non-inferiority for the A/H1N1, A/H3N2, and B strains (upper bound of the 95% CI of the seroconversion rate differences were 6.0% for A/H1N1, 7.0% for A/H3N2, and 5.7% for B strains). We recorded serious adverse events in three participants, none of which were study related.” (L. McAllister, linda.mcallister@pharmajet.com)
Isoniazid + Antiretroviral Therapy for TB Prevention: In geographic areas with moderate to high incidence of tuberculosis, isoniazid prophylaxis should be added to antiretroviral therapy in patients with HIV infection, according to data from a randomized controlled trial conducted in South Africa (pp. 682–90). A pragmatic trial of 1,329 people with HIV-1 infection showed the following for isoniazid versus placebo supplementation: “We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2.3 per 100 person–years, 95% CI 1.6–3.1), and 58 in the placebo group (3.6 per 100 person–years, 2.8–4.7; hazard ratio [HR] 0.63, 95% CI 0.41–0.94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1.9, 95% CI 0.90–4.09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0.43 [0.21–0.86] and 0.43 [0.20–0.96]; for positive tests 0.86 [0.37–2.00] and 0.55 [0.26–1.24], respectively).” (M. X. Rangaka, mxrangaka@yahoo.co.uk)
Second-Line Treatment of Stage IV NSCLC: Used after platinum-based therapy of stage IV non-small-cell-lung cancer (NSCLC), ramucirumab plus docetaxel improved survival among 1,253 participants (pp. 665–73). In the Phase III REVEL trial, ramucirumab plus docetaxel produced these results: “Median overall survival was 10.5 months (IQR 5.1–21.2) for 628 patients allocated ramucirumab plus docetaxel and 9.1 months (4.2–18.0) for 625 patients who received placebo plus docetaxel (hazard ratio 0.86, 95% CI 0.75–0.98; p = 0.023). Median progression-free survival was 4.5 months (IQR 2.3–8.3) for the ramucirumab group compared with 3.0 months (1.4–6.9) for the control group (0.76, 0.68–0.86; p <0.0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population.” (E. B. Garon, egaron@mednet.ucla.edu)

>>>PNN JournalWatch
* Use of Antiepileptic Drugs During Pregnancy and Risk of Spontaneous Abortion and Stillbirth: Population Based Cohort Study, in
BMJ, 2014; 349: g5159. (B. H. Bech, bhb@ph.au.dk)
* Review: Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis: How Similar and Distinct?, in
Arthritis & Rheumatology, 2014; 66: 1967–78. (J. Varga, j-varga@northwestern.edu)
* Treatment Patterns for Prostate Cancer: Comparison of Medicare Claims Data to Medical Record Review, in
Medical Care, 2014; 52: 10.1097/MLR.0b013e318277eba5 (X. Li)
* Registered Nurses Are Delaying Retirement, A Shift That Has Contributed to Recent Growth in the Nurse Workforce, in
Health Affairs, 2014; 33: 1474–80. (D. I. Auerbach, auerbach@rand.org)

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

PNN Pharmacotherapy Line
Aug. 26, 2014 * Vol. 21, No. 165
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2014; 174).
Cannabis Laws & Opioid Overdoses: Overdoses with opioid analgesics are lower in states with medical cannabis laws, report investigators who also found a time effect as such laws went into effect (doi: 10.1001/jamainternmed.2014.4005). “Further investigation is required to determine how medical cannabis laws may interact with policies aimed at preventing opioid analgesic overdose,” the authors conclude, adding these details about their time-series analysis of state laws and causes of death in 1999–2010: “Three states (California, Oregon, and Washington) had medical cannabis laws effective prior to 1999. Ten states (Alaska, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Mexico, Rhode Island, and Vermont) enacted medical cannabis laws between 1999 and 2010. States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% CI, −37.5% to −9.5%; P = .003) compared with states without medical cannabis laws. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over time: year 1 (−19.9%; 95% CI, −30.6% to −7.7%; P = .002), year 2 (−25.2%; 95% CI, −40.6% to −5.9%; P = .01), year 3 (−23.6%; 95% CI, −41.1% to −1.0%; P = .04), year 4 (−20.2%; 95% CI, −33.6% to −4.0%; P = .02), year 5 (−33.7%; 95% CI, −50.9% to −10.4%; P = .008), and year 6 (−33.3%; 95% CI, −44.7% to −19.6%; P < .001). In secondary analyses, the findings remained similar.” (M. A. Bachhuber, marcus.bachhuber@gmail.com)
While the authors attribute these findings to use of medical marijuana as an adjuvant to prescription opioids in patients with pain, the author of an accompanying commentary expresses a different view (
doi: 10.1001/jamainternmed.2014.2716): “Opioid overdose–associated mortality in [people] without a valid prescription is likely related to opiate and polydrug/alcohol addiction developed through recreational abuse, most often presaged by longstanding psychiatric illness.… Increased access to medical-grade marijuana, procured legally or illegally, may offer an alternative intoxicant that may compete with opiate misuse and, thereby, be similarly protective. Preclinical and imaging studies have established that the psychogenic ‘pain’ of psychiatric illness, which often leads to drug and alcohol abuse and addiction, operates through the same neural circuits as pain generated by other medical conditions. Both opioids and cannabinoids independently reduce stress reactivity and increase dopamine-mediated reward. Hence, medical marijuana use may similarly lessen the drive to use opiates at lethal levels in individuals with nonpain, psychiatric conditions who have psychotropic medications as a frequent concomitant of exposure at the time of death. It is also possible that for some, medical marijuana is a substitute for opioids, rather than an adjuvant.” (M. J. Hayes, mhayes@maine.edu)

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (2014; 134).
Roflumilast & Corticosteroid Resistance in COPD: In the test tube, the active metabolite of roflumilast reversed corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease (COPD), a study shows (pp. 314–22.e9). Neutrophils from smokers and healthy nonsmokers were also tested, showing these effects when incubated with roflumilast N-oxide (RNO) and/or dexamethasone: “Peripheral neutrophils from patients with COPD showed a primed phenotype with an increased basal release of IL-8 and MMP-9 and expressed a corticosteroid resistance molecular profile characterized by an increase in phosphoinositide 3-kinase delta, macrophage migration inhibitory factor, and glucocorticoid receptor beta expression and a decrease in HDAC activity and mitogen-activated protein kinase phosphatase 1 expression. RNO demonstrated robust anti-inflammatory effects on neutrophils from patients with COPD, reversing their resistance to corticosteroids. The combination of RNO and dexamethasone showed additive/synergistic effects, which were consistent with the reversal of corticosteroid-resistant molecular markers by RNO.” (J. Milara, xmilara@hotmail.com)

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

PNN Pharmacotherapy Line
Aug. 27, 2014 * Vol. 21, No. 166
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 27 issue of JAMA (2014; 312).
Self-titration of Hypertension: Lower systolic blood pressures resulted when patients self-monitored hypertension and self-titrated medications rather than receiving usual, clinician-directed care, report investigators with the Telemonitoring and Self-Management in Hypertension 2 (TASMINH 2) trial (pp. 799–808). The unblinded study, conducted at 59 U.K. primary care practices, included 552 adults at least 35 years of age with histories of stroke, coronary heart disease, diabetes, or chronic kidney disease and baseline blood pressures of 130/80 mm Hg or more. Results showed the following over 12-month periods in 2011–13: “Primary outcome data were available from 450 patients (81%). The mean baseline blood pressure was 143.1/80.5 mm Hg in the intervention group and 143.6/79.5 mm Hg in the control group. After 12 months, the mean blood pressure had decreased to 128.2/73.8 mm Hg in the intervention group and to 137.8/76.3 mm Hg in the control group, a difference of 9.2 mm Hg (95% CI, 5.7–12.7) in systolic and 3.4 mm Hg (95% CI, 1.8–5.0) in diastolic blood pressure following correction for baseline blood pressure. Multiple imputation for missing values gave similar results: the mean baseline was 143.5/80.2 mm Hg in the intervention group vs 144.2/79.9 mm Hg in the control group, and at 12 months, the mean was 128.6/73.6 mm Hg in the intervention group vs 138.2/76.4 mm Hg in the control group, with a difference of 8.8 mm Hg (95% CI, 4.9–12.7) for systolic and 3.1 mm Hg (95% CI, 0.7–5.5) for diastolic blood pressure between groups. These results were comparable in all subgroups, without excessive adverse events.” (R. McManus, richard.mcmanus@phc.ox.ac.uk)
This trial “is an important step toward adaptation of treatment for patients who want to actively take part in their own risk-factor control,” write editorialists (
pp. 795–6). “Future trials studying the effects of self-titration on cardiovascular events are needed. With the gain in knowledge from the TASMIN-SR trial, it may be possible to make the recruitment of patients less restricted, to incorporate education about self-measurement as a standard procedure and focus on which scheme for titration to use, or to study the timing of the home blood pressure recordings. In many countries antihypertensive drugs are now available as inexpensive generic drugs. The time has come to fully use these noncostly medications and to design optimal individualized care of patients. The TASMIN-SR trial involving patients at high risk of cardiovascular disease demonstrates that self-titration safely achieves a clinically important blood pressure reduction based on almost one extra (0.91) higher intake of defined daily dose in the intervention group compared with the control patients. Based on these findings, a ‘bring it home’ blood pressure–lowering strategy appears suitable for patients with hypertension and comorbidities.” (P. M. Nilsson, Peter.Nilsson@med.lu.se)
High-Dose Erythropoietin in Preterm Infants: Preterm infants who received high doses of erythropoietin within 42 hours of birth had significantly reduced risk of brain injury on MRI at term-equivalent age, researchers report based on secondary analysis of data from a randomized clinical trial (pp. 817–24). In the randomized trial, 495 patients are being evaluated for neurodevelopment at 24 months (primary outcome; results not yet available). The secondary outcome of MRI results for 165 nonrandomized infants showed the following: “At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35–0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05–0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30–0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13–0.89).” (P. S. Hüppi, petra.huppi@hcuge.ch)
Investing in Disease Prevention: “Increasing federal funding for prevention science and fostering stronger public–private partnerships are important steps toward providing policy makers with evidence-based tools to use limited resources [for preventing noncommunicable diseases] effectively and efficiently,” Viewpoint authors write (pp. 791–2; D. Yach, dyach@thevitalitygroup.com)

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

PNN Pharmacotherapy Line
Aug. 28, 2014 * Vol. 21, No. 167
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 28 issue of the New England Journal of Medicine (2014; 371).
Contraceptive Coverage Under ACA: Delving into the pharmacology of contraceptive medications and the controversy over whether they can prevent implantation of fertilized eggs, authors review the recent U.S. Supreme Court decision in the Hobby Lobby case and its impact on the Affordable Care Act (ACA) (pp. 862–6): “The majority decision, written by Justice Samuel Alito, is a setback for both the ACA’s foundational goal of access to universal health care and for women’s health care specifically. It is also especially worrisome that abortion is again at the center of the continuing debate over the implementation of the ACA and that the challenge of abortion has been expanded to include birth control. This has happened even though, in the opinion of medical experts, the four methods of contraception under scrutiny do not induce abortion; rather, they prevent abortion by preventing pregnancy. This controversy could occur only because in assessing the competing claims about abortion and birth control, the Court’s majority focused on the religious claims of the corporations without discussing scientific or medical opinions. As Judge Mary Beck Briscoe observed in her dissent in the 10th Circuit, the belief of Hobby Lobby’s owners ‘is not one of religious belief but rather of purported scientific fact.’” (G. J. Annas)
Curious Case of the $50,000 Threshold: Authors examine the continued logic of using the $50,000 per quality-adjusted life–year (QALY) as the threshold for acceptable gain from health care interventions (pp. 796–7): “Given the evidence suggesting that $50,000 per QALY is too low in the United States, it might best be thought of as an implied lower boundary. Instead, we would recommend that analysts use $50,000, $100,000, and $200,000 per QALY. If one had to select a single threshold outside the context of an explicit resource constraint or opportunity cost, we suggest using either $100,000 or $150,000.” (P. J. Neumann)

>>>Nephrology Report
Source:
Sept. issue of the American Journal of Kidney Diseases (2014; 64).
Extracorporeal Treatment for Barbiturate Poisoning: The EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup provides recommendations for management of barbiturate overdoses using extracorporeal treatment (ECTR) (pp. 347–58): “Long-acting barbiturates are dialyzable and short-acting barbiturates are moderately dialyzable. Four key recommendations were made. (1) The use of ECTR should be restricted to cases of severe long-acting barbiturate poisoning. (2) The indications for ECTR in this setting are the presence of prolonged coma, respiratory depression necessitating mechanical ventilation, shock, persistent toxicity, or increasing or persistently elevated serum barbiturate concentrations despite treatment with multiple-dose activated charcoal. (3) Intermittent hemodialysis is the preferred mode of ECTR, and multiple-dose activated charcoal treatment should be continued during ECTR. (4) Cessation of ECTR is indicated when clinical improvement is apparent. This report provides detailed descriptions of the rationale for all recommendations. In summary, patients with long-acting barbiturate poisoning should be treated with ECTR provided at least one of the specific criteria in the first recommendation is present.” (T. D. Nolin, nolin@pitt.edu)
Cefazolin Kinetics in Nocturnal Home Hemodialysis: In a research letter, investigators describe the pharmacokinetics of cefazolin when used intravenously in patients on nocturnal home dialysis using a target peak level of 48 mg/L (pp. 479–80): “Patients were predominantly men (9/15) and had a mean age of 46 ± 7.8 years, median body weight of 71 (IQR, 63–81) kg, and median dialysis vintage of 4 (IQR, 2–14) years. No adverse effects were reported with cefazolin. During dialysis, median clearance was 1.65 (IQR, 1.36–2.19) L/h and half-life was 3.44 (IQR, 2.93–4.36) h. The calculated volume of distribution was 0.13 (IQR, 0.079–0.16) L/kg.… The median percentage of cefazolin removed from blood in a 6-hour dialysis session was 74.3%, corresponding to 906.4 (IQR, 727.2–1,203.8) mg. About 67% of this amount was recovered in dialysate fluid, which suggests 33% is cleared from blood nonrenally.” (M. Battistella, marisa.battistella@uhn.ca)

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

PNN Pharmacotherapy Line
Aug. 29, 2014 * Vol. 21, No. 168
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (2014; 37).
Second-Line Therapy of Type 2 Diabetes: In moving “beyond metformin” in treatment of patients with type 2 diabetes, clinicians must develop personalized regimens using agents from six major antidiabetic medication classes— insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors, according to members of an expert panel (pp. 2647–59): “All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most—metformin, SUs, insulin, and perhaps now also TZDs—are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients’ clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs.” (W. T. Cefalu, william.cefalu@pbrc.edu)
Lifetime Cost of Diabetes: The “substantially higher lifetime medical expenditures” associated with diabetes despite reduced life expectancy has implications for devotion of resources to preventing the disease, researchers conclude (pp. 2557–64). Combining data from the 2006–09 Medical Expenditure Panel Surveys and the 2005–08 National Health Interview Surveys showed the following: “The discounted excess lifetime medical spending for people with diabetes was $124,600 ($211,400 if not discounted), $91,200 ($135,600), $53,800 ($70,200), and $35,900 ($43,900) when diagnosed with diabetes at ages 40, 50, 60, and 65 years, respectively. Younger age at diagnosis and female sex were associated with higher levels of lifetime excess medical spending attributed to diabetes.” The group concludes, “If prevention costs can be kept sufficiently low, diabetes prevention may lead to a reduction in long-term medical costs.” (X. Zhuo, xzhuo@cdc.gov)
Intensive Lifestyle Intervention in Overweight & Obesity: In the the Look AHEAD trial, participants receiving intensive lifestyle interventions (ILI) aimed at weight loss had significantly fewer hospitalizations and lower health care costs and used fewer medications over a 10-year period (pp. 2548–56). The study included 5,121 adults with type 2 diabetes and overweight or obesity who were randomized to ILI or diabetes support and education (DSE), with these results: “ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P <0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P < 0.001). ILI produced a mean relative per-person 10-year cost savings of $5,280 (95% CI 3,385–7,175); however, these were not evident among individuals with a history of cardiovascular disease.” (M. A. Espeland, mespelan@wakehealth.edu)

>>>Pharmacotherapy Report
Source:
Early-release article from Pharmacotherapy (2014; 34).
Physician–Pharmacist Asthma Care: Physician–pharmacist collaborative management of patients with asthma “reduced asthma-related [emergency department] visits and hospitalizations and improved asthma control and quality of life,” a study concludes (doi: 10.1002/phar.1468). However, statistical significance was reached for a resource-based primary outcome only in those with uncontrolled asthma at baseline. (T. H. Gums, tyler-gums@uiowa.edu)

>>>PNN NewsWatch
* The CDC Advisory Committee on Immunization Practices has recommended that adults 65 years or older receive the pneumococcal conjugate vaccine (Prevnar 13—Pfizer) in addition to pneumococcal polysaccharide vaccine (Pneumovax—Merck), pharmacist.com reports.
*
PNN will not be published on Mon., Sept. 1, 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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 2, 2014 * Vol. 21, No. 169
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 2 issue of the Annals of Internal Medicine (2014; 161).
Drug-Free HIV-1 Remission After Stem Cell Transplantation: As reported in an early-online article (see PNN, July 22), periods of remission of HIV-1 after patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) are not permanent, according to the cases of two men who were treated for hematologic tumors (pp. 319–27). After HSCT with susceptible donor cells, the investigators report these results: “No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients.” These findings show that “long-lived tissue reservoirs may … [contribute] to viral persistence,” the authors conclude. (T. J. Henrich, thenrich@partners.org)
Low-Carb v. Low-Fat Diets: Focusing on carbohydrates rather than fats for weight loss and cardiovascular-risk reduction may be a preferable strategy based on results of a 148-participant trial (pp. 309–18). The study randomized patients–all of whom were free of cardiovascular disease and diabetes at baseline–to low-carbohydrate (<40 g/d) or low-fat (<30% of daily energy intake from total fat [<7% saturated fat]) diets for 1 year, with these results: “Sixty participants (82%) in the low-fat group and 59 (79%) in the low-carbohydrate group completed the intervention. At 12 months, participants on the low-carbohydrate diet had greater decreases in weight (mean difference in change, −3.5 kg [95% CI, −5.6 to −1.4 kg]; P = 0.002), fat mass (mean difference in change, −1.5% [CI, −2.6% to −0.4%]; P = 0.011), ratio of total–high-density lipoprotein (HDL) cholesterol (mean difference in change, −0.44 [CI, −0.71 to −0.16]; P = 0.002), and triglyceride level (mean difference in change, −0.16 mmol/L [−14.1 mg/dL] [CI, −0.31 to −0.01 mmol/L {−27.4 to −0.8 mg/dL}]; P = 0.038) and greater increases in HDL cholesterol level (mean difference in change, 0.18 mmol/L [7.0 mg/dL] [CI, 0.08 to 0.28 mmol/L {3.0 to 11.0 mg/dL}]; P < 0.001) than those on the low-fat diet.” (L. Bazzano, lbazzano@tulane.edu)

>>>Lancet Highlights
Source:
Aug. 30 issue of Lancet (2014; 384).
BMI & Cancer: Increased body mass index is associated with higher risks of 22 types of cancers, researchers report, but substantial population-level effects suggest different mechanisms are in play (pp. 755–65). Data on 5.24 million individuals from the Clinical Practice Research Datalink show these associations: “Each 5 kg/m2 increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1.62, 99% CI 1.56–1.69; p <0.0001), gallbladder (1.31, 1.12–1.52; p <0.0001), kidney (1.25, 1.17–1.33; p <0.0001), cervix (1.10, 1.03–1.17; p = 0.00035), thyroid (1.09, 1.00–1.19; p = 0.0088), and leukaemia (1.09, 1.05–1.13; p ≤0.0001). BMI was positively associated with liver (1.19, 1.12–1.27), colon (1.10, 1.07–1.13), ovarian (1.09, 1.04–1.14), and postmenopausal breast cancers (1.05, 1.03–1.07) overall (all p <0.0001), but these effects varied by underlying BMI or individual-level characteristics.… Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m2 population-wide increase in BMI would result in 3,790 additional annual UK patients developing one of the ten cancers positively associated with BMI.” (K. Bhaskaran, krishnan.bhaskaran@lshtm.ac.uk)

>>>PNN JournalWatch
* Fluid Resuscitation in Sepsis: A Systematic Review and Network Meta-analysis, in
Annals of Internal Medicine, 2014; 161: 347–55. (D. J. Cook, debcook@mcmaster.ca)
* Effectiveness of Quality Improvement in Hospitalization for Bronchiolitis: A Systematic Review, in
Pediatrics, 2014; 134: 571–81. (S. Ralston)
* Disruptive Mood Dysregulation Disorder: A New Diagnostic Approach to Chronic Irritability in Youth, in
American Journal of Psychiatry, 2014; 171: 918–24. (R. G. Klein, rachel.klein@nyumc.org)

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

PNN Pharmacotherapy Line
Sept. 3, 2014 * Vol. 21, No. 170
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 3 issue of JAMA (2014; 312).
Weight Loss With Diet Programs: Many of the available weight-loss diets can help people with overweight or obesity, according to a meta-analysis of 48 randomized controlled trials of 7,286 individuals (pp. 923–33). The analysis included named dietary programs (e.g., Atkins, Jenny Craig, Weight Watchers) and dietary approaches similar to these reduced-calorie, low-carbohydrate, and low-fat diets: “Compared with no diet, the largest weight loss was associated with low-carbohydrate diets (8.73 kg [95% credible interval {CI}, 7.27 to 10.20 kg] at 6-month follow-up and 7.25 kg [95% CI, 5.33 to 9.25 kg] at 12-month follow-up) and low-fat diets (7.99 kg [95% CI, 6.01 to 9.92 kg] at 6-month follow-up and 7.27 kg [95% CI, 5.26 to 9.34 kg] at 12-month follow-up). Weight loss differences between individual diets were minimal. For example, the Atkins diet resulted in a 1.71 kg greater weight loss than the Zone diet at 6-month follow-up. Between 6- and 12-month follow-up, the influence of behavioral support (3.23 kg [95% CI, 2.23 to 4.23 kg] at 6-month follow-up vs 1.08 kg [95% CI, −1.82 to 3.96 kg] at 12-month follow-up) and exercise (0.64 kg [95% CI, −0.35 to 1.66 kg] vs 2.13 kg [95% CI, 0.43 to 3.85 kg], respectively) on weight loss differed.” (E. J. Mills, Pmillsej@stanford.edu)
Regardless of the name, dieting is “still about energy,” writes an editorialist (
pp. 900–1): “Along with other recent data, [these findings] underscore the importance of effective diet and lifestyle interventions that promote behavioral changes to support adherence to a calorie-restricted, nutrient-dense diet that ultimately accomplishes weight loss. Choosing the best diet suited to an individual’s food preferences may help foster adherence, but beyond weight loss, diet quality including micronutrient composition may further benefit longevity.” (L. Van Horn, lvanhorn@northwestern.edu)
Evidence Regarding Bariatric Surgery: Responding to two articles in this issue of JAMA on surgical interventions for obesity (vagal-nerve blockade study, pp. 915–22, C. J. Billington, billi005@umn.edu; review of long-term outcomes with bariatric surgery, pp. 934–42, N. Puzziferri, nancy.puzziferri@utsouthwestern.edu), editorialists reach these conclusions (pp. 898–9): “Perhaps the most concerning finding of [the review article] is that only half of 29 studies reported information on complications at least 2 years after surgery. Without sound information on the long-term risks of bariatric procedures, including the rate of revisions, failed weight loss, and weight regain, severely obese patients and their physicians cannot engage in meaningful shared decision-making conversations.
“The 2 obesity treatment studies … were thoughtfully conducted and contribute important information to the evidence base of bariatric surgery. Additional high-quality studies of bariatric procedural innovations are needed, with more long-term (>5 years) studies of established bariatric procedures with high rates of follow-up and standardized reporting of outcomes. To facilitate this, professional societies and members of the obesity research community should develop guidelines for the design and conduct of bariatric surgery trials and for standardized reporting of all major efficacy and safety outcomes.” (D. E. Arterburn,
arterburn.d@ghc.org)

>>>Pediatrics Highlights
Source:
Sept. issue of Pediatrics (2014; 134).
Vaccine Message Framing: Parents expressed greater intentions to have their infants vaccinated when direct benefits to the child were emphasized rather than only societal benefits, a study shows (pp. e675–83). Online delivery of one of four messages regarding measles–mumps–rubella (MMR) vaccination showed these outcomes using a vaccine-intent scale of 0 (extremely unlikely) to 100 (extremely likely): “Compared with the [CDC Vaccine Information Statement]–only group (mean intention = 86.3), parents reported increased vaccine intentions for their infants when receiving additional information emphasizing the MMR vaccine’s benefits either directly to the child (mean intention = 91.6, P = .01) or to both the child and society (mean intention = 90.8, P = .03). Emphasizing the MMR vaccine’s benefits only to society did not increase intentions (mean intention = 86.4, P = .97).” (K. S. Hendrix)

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

PNN Pharmacotherapy Line
Sept. 4, 2014 * Vol. 21, No. 171
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 4 issue of the New England Journal of Medicine (2014; 371).
Management of Myeloma: Lenalidomide use in treatment of patients with myeloma is the topic of two research studies and an editorial.
In an open-label trial of patients with multiple myeloma, consolidation therapy with high-dose melphalan plus stem-cell transplantation yielded the highest rates of progression-free survival, followed by lenalidomide maintenance therapy, FIRST trial researchers report (
pp. 895–905). In the study, 273 patients aged 65 years or younger received high-dose melphalan plus stem-cell transplantation or melphalan–prednisone–lenalidomide (MPR) consolidation therapy after induction, while 251 patients were assigned to lenalidomide maintenance therapy or no maintenance therapy, with these results: “The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P <0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P = 0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P <0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P = 0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively).” (A. Palumbo, appalumbo@yahoo.com)
Among 1,623 transplant-ineligible patients with myeloma in the FIRST trial, continuous lenalidomide–dexamethasone given until disease progression significantly improved progression-free survival, compared with MPT (
pp. 906–17): “The median progression-free survival was 25.5 months with continuous lenalidomide–dexamethasone, 20.7 months with 18 cycles of lenalidomide–dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide–dexamethasone vs. MPT and 0.70 for continuous lenalidomide–dexamethasone vs. 18 cycles of lenalidomide–dexamethasone; P <0.001 for both comparisons). Continuous lenalidomide–dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide–dexamethasone, 56% with 18 cycles of lenalidomide–dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide–dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide–dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers.” (T. Facon, thierry.facon@chru-lille.fr)
“These two articles considerably further our understanding of therapy for myeloma and how to best integrate new agents to treat this disease,” editorialists write (
pp. 961–2). “In patients who are 65 years of age or younger, high-dose chemotherapy with stem-cell transplantation remains a standard of care associated with prolongation of progression-free and overall survival. Maintenance therapy after transplantation or standard-dose therapy has a clear effect on the duration of remission, but there is conflicting evidence regarding its impact on long-term outcomes. Finally, in transplant-ineligible patients, new agents with acceptable toxicity provide the opportunity for continuous therapy that may offer some advantage over a defined course of treatment.” (D. Avigan)
Influenza Vaccination During Pregnancy: Influenza vaccine administered during pregnancy to 2,310 women provided partial protection in both HIV-infected and -uninfected mothers and their non-HIV-exposed infants (pp. 918–31; S. A. Madhi, shabirm@nicd.ac.za).

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

PNN Pharmacotherapy Line
Sept. 5, 2014 * Vol. 21, No. 172
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Sept. 9 issue of the Journal of the American College of Cardiology (2014; 64).
Examining the Cardiovascular Risk Assessment Tool: Age is “a major driver of risk” for atherosclerotic cardiovascular disease (ASCVD) in both men and women, conclude authors who examined the Pooled Cohort Equations used in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines (pp. 959–68). Assessing primary prevention with a “clinically relevant” 10-year ASCVD risk threshold of ≥7.5%, the investigators found: “We demonstrated that a hypothetical man or woman can reach clinically relevant risk thresholds throughout the eligible age spectrum of 40 to 79 years of age, depending on the associated risk factor burden in all race-sex groups. Age continues to be a major determinant of 10-year ASCVD risk for both men and women. Compared with the previous risk assessment tool used in cholesterol guidelines, the inclusion of a stroke endpoint and use of race-specific coefficients permit identification of at-risk African Americans and non–Hispanic white women at much younger ages and lower risk factor levels.” (K. N. Karmali)
Body Mass, Fat Distribution & Incident Hypertension: Data from the longitudinal Dallas Heart Study show that increased visceral but not subcutaneous adiposity is associated with incident hypertension (pp. 997–1002). Followed for a median of 7 years, participants had these outcomes based on body mass index (BMI) and type of adiposity: “Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m2), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when [visceral adipose tissue [VAT], [subcutaneous adipose tissue], and [lower body fat] were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase).” (A. Chandra)

>>>Circulation Report
Source:
Sept. 2 issue of Circulation (2014; 130).
Reassessing Asymptomatic WPW Syndrome: Electrophysiologic properties are more important than symptoms in patients with Wolff–Parkinson–White syndrome, according to data from a registry developed during an 8-year prospective study (pp. 811–9): “In the no-[radiofrequency catheter ablation (RFA)] group, [ventricular fibrillation (VF)] occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (P <0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation (P <0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank P <0.001).” (C. Pappone, cpappone@gvmnet.it)

>>>PNN NewsWatch
* Pembrolizumab (Keytruda, Merck) was approved yesterday by FDA for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Pembrolizumab, the first approved drug that blocks PD-1 (programmed death receptor–1), received an accelerated approval and was designated as a “breakthrough” agent by FDA.
* A pharmacist who practiced at the
New England Compounding Center at the time contaminated products were made was arrested in Boston yesterday just before boarding a flight to Hong Kong, USA Today reports. Glenn Adam Chin was a supervisor with responsibility for sterility and quality assurance in the company’s cleanroom in 2012. Now facing one count of mail fraud, Chin is the first person to be charged criminally in the case.
* The dietary supplements company at the center of the trial—and conviction—of former Virginia Governor Robert McDonnell now operates as
Rock Creek Pharmaceuticals, reports the Washington Post. Its predecessor, Star Scientific, was headed by Jonnie R. Williams Sr. Testimony at the trial indicated he befriended Gov. McDonnell and his wife and received favorable state deals and publicity.

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

PNN Pharmacotherapy Line
Sept. 8, 2014 * Vol. 21, No. 173
Providing news and information about medications and their proper use

>>>ICAAC Highlights
Source:
Research presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) of the American Society for Microbiology.
* While producing a more rapid decline in bacterial count, a 4-month moxifloxacin regimen did not demonstrate noninferiority in patients with pulmonary tuberculosis, a Phase III trial shows (
N Engl J Med. doi: 10.1056/NEJMoa1407426). Three groups were studied: isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group); ethambutol replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group); isoniazid replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). Results showed: “Of the 1,931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group.… There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.” (S. H. Gillespie, shg3@st-andrews.ac.uk)
* Prevention of exacerbations may not be the best parameter for determining success of continued glucocorticoid therapy in patients with severe chronic obstructive pulmonary disease, according to findings of a 12-month study of 2,485 patients (
10.1056/NEJMoa1407154; H. Magnussen, magnussen@pulmoresearch.de) and an accompanying editorial (10.1056/NEJMe1409219; J. J. Reilly) released by the New England Journal of Medicine in conjunction with ICAAC presentations. Following a 6-week lead-in period of triple therapy (tiotropium, salmeterol, fluticasone), patients continued triple therapy or withdrew the fluticasone in three steps over 12 weeks, with these results: “As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P <0.001); a similar between-group difference (43 ml) was seen at week 52 (P = 0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group.” The editorialist added: “The findings may prompt clinicians to consider other preventive interventions, such as daily azithromycin, in patients who continue to have frequent exacerbations while receiving long-acting bronchodilators.”
* An anti-interleukin-5 agent, mepolizumab, had a “significant glucocorticoid-sparing effects” in 135 patients with severe eosinophilic asthma, researchers report in a
New England Journal of Medicine article (10.1056/NEJMoa1403291). The patients, already on daily oral glucocorticoid therapy for control of asthma, had reduced exacerbations and improved asthma symptom control when on the agent, with a 2.39 times greater reduction in glucocorticoid dose with mepolizumab as compared with placebo. (E. H. Bel, e.h.bel@amc.uva.nl)

>>>PNN JournalWatch
* New Approaches to TB Vaccination, in
Chest, 2014; 146: 804–12. (Z. Xing, xingz@mcmaster.ca)
* Myocardial Catastrophe: A Case of Sudden, Severe Myocardial Dysfunction, in
Circulation, 2014; 130: 854–62. (J. M. Kirshenbaum, jkirshenbaum@partners.org)
* 20 Years of Cardiac Resynchronization Therapy, in
Journal of the American College of Cardiology, 2014; 64: 1047–58. (F. Leyva)
* Colistin: Understanding and Applying Recent Pharmacokinetic Advances, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1484. (J. M. Pogue, jpogue@dmc.org)
* Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Safety, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1477. (P. P. Dobesh, pdobesh@unmc.edu)

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

PNN Pharmacotherapy Line
Sept. 9, 2014 * Vol. 21, No. 174
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
Early-release articles from the Annals of Internal Medicine (2014; 161).
Low-Dose Aspirin in Preeclampsia: In an updated recommendation statement, the U.S. Preventive Services Task Force recommends that women at high risk of preeclampsia receive low-dose aspirin (81 mg/d) after the 12th week of gestation (10.7326/M14-1884). The statement updates a 1996 recommendation on use of aspirin in pregnancy. It applies to “asymptomatic pregnant women who are at increased risk for preeclampsia and who have no prior adverse effects with or contraindications to low-dose aspirin,” the task force writes, rating the evidence supporting the recommendation at the B level. The statement differs from the previous 1996 one “in that new evidence on the effectiveness and harms of low-dose aspirin on maternal and perinatal health outcomes now allows the USPSTF to recommend its use in women at high risk for preeclampsia. This recommendation also differs from the 1996 recommendation in that it discusses defining ‘high preeclampsia risk’ in pregnant women in more detail.” (USPSTF website, www.uspreventiveservicestaskforce.org)
Comparative Effectiveness of Drugs for Preventing Fractures: While “good-quality evidence” supports the use of several medications for improving bone density in patients with osteoporotic-range densities or prior hip/vertebral fractures, adverse effects of the drugs vary and comparative effectiveness of the agents is unclear, according to authors of a systematic review (10.7326/M14-0317): “From more than 52,000 titles screened, 294 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use, atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.” (C. J. Crandall, ccrandall@mednet.ucla.edu)
Clear reporting on adverse effects in this review will help physicians make informed decisions about treatments, authors of an accompanying editorial write (
10.7326/M14-2006) However, they caution that the reviewers’ conclusions may not apply to persons aged 75 years or older with nonskeletal risk factors for fracture because this population is insufficiently represented in current clinical trials. (H. A. Bischoff–Ferrari, Heike.Bischoff@usz.ch)

>>>Internal Medicine Report II
Source:
Sept. issue of JAMA Internal Medicine (2014; 174).
Ezetimibe Use After ENHANCE: Ezetimibe use for lowering lipids peaked in 2008 in conjunction with announcement of the results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial in Jan. of that year (pp. 1486–93). ENHANCE results showed a decline in lipid levels but no effects on atherosclerotic progression. Claims from a U.S. pharmacy benefits manager show declining drug initiations and increasing discontinuations thereafter: “From 2007 to 2010, 29.1% of the 10,597,296 continuously eligible adults obtained at least 1 lipid-lowering agent prescription. Among these adults, 17.8% were prescribed ezetimibe and 95.3% another lipid-lowering agent, predominantly statins. Ezetimibe use peaked in January 2008, when 2.5% of all adults were ezetimibe users, but declined to 1.8% by December 2010. The ENHANCE trial announcement was associated with a nonsignificant 0.16% fewer monthly ezetimibe users (P = .11) but a significant 0.14% more monthly monotherapy users and 0.30% fewer users of ezetimibe concomitant with other lipid-lowering agents (both P = .01). The ENHANCE trial was also associated with 0.44% fewer monthly ezetimibe initiations (P = .002) and 10.4% more monthly ezetimibe discontinuations (P < .001), particularly of ezetimibe monotherapy for both. More than half of adults who initiated ezetimibe use did so without first being prescribed another lipid-lowering agent, both before (50%–60%) and after (60%–70%) the trial. Those aged 50 to 64 years and those living in the East South Central US Census division were both more likely to initiate and less likely to discontinue ezetimibe after the ENHANCE trial.” (J. S. Ross, joseph.ross@yale.edu)

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

PNN Pharmacotherapy Line
Sept. 10, 2014 * Vol. 21, No. 175
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 10 issue of JAMA (2014; 312).
Darapladib in Acute Coronary Syndrome: Direct inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) had no effect on 30-day rehospitalization rates in 13,026 participants after an acute coronary syndrome (ACS)event in the SOLID-TIMI 52 trial (pp. 1006–15). The orally active selective Lp-PLA2 inhibitor darapladib or placebo was administered once daily to randomized patients at 868 sites in 36 countries with these results: “During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91–1.09]; P = .93). The composite of cardiovascular death, [myocardial infarction], or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90–1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82–1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).” (M. L. O’Donoghue, modonoghue@partners.org)
Colchicine After Cardiac Surgery: In the Colchicine for Prevention of the Postpericardiotomy Syndrome and Postoperative Atrial Fibrillation (COPPS) trial, perioperative use of this drug “reduced the incidence of postpericardiotomy syndrome but not of postoperative [atrial fibrillation (AF)] or postoperative pericardial/pleural effusion,” researchers conclude (pp. 1016–23). “The increased risk of gastrointestinal adverse effects reduced the potential benefits of colchicine,” the group adds, noting these details about placebo or colchicine for 1 month after cardiac surgery: “The primary end point of postpericardiotomy syndrome occurred in 35 patients (19.4%) assigned to colchicine and in 53 (29.4%) assigned to placebo (absolute difference, 10.0%; 95% CI, 1.1%–18.7%; number needed to treat = 10). There were no significant differences between the colchicine and placebo groups for the secondary end points of postoperative AF (colchicine, 61 patients [33.9%]; placebo, 75 patients [41.7%]; absolute difference, 7.8%; 95% CI, −2.2% to 17.6%) or postoperative pericardial/pleural effusion (colchicine, 103 patients [57.2%]; placebo, 106 patients [58.9%]; absolute difference, 1.7%; 95% CI, −8.5% to 11.7%), although there was a reduction in postoperative AF in the prespecified on-treatment analysis (placebo, 61/148 patients [41.2%]; colchicine, 38/141 patients [27.0%]; absolute difference, 14.2%; 95% CI, 3.3%–24.7%). Adverse events occurred in 21 patients (11.7%) in the placebo group vs 36 (20.0%) in the colchicine group (absolute difference, 8.3%; 95% CI; 0.76%–15.9%; number needed to harm = 12), but discontinuation rates were similar. No serious adverse events were observed.” (M. Imazio, massimo_imazio@yahoo.it)
Statin Therapy in Children: Among 214 children heterozygous for familial hypercholesterolemia (FH), a cohort study shows that long-term therapy with statins normalized carotid intimal (IMT) progression (pp. 1055–7): “After 10 years, mean carotid IMT was still significantly greater in patients with FH compared with siblings (0.480 mm [95% CI, 0.472–0.489 mm] vs 0.469 mm [95% CI, 0.459–0.480 mm], respectively; P = .02). In contrast, progression of carotid IMT from baseline was similar in both groups (patients with FH, 0.039 mm [95% CI, 0.032–0.046 mm] vs siblings, 0.037 mm [95% CI, 0.032–0.042 mm]; P = .52). In patients with FH, age at statin initiation was significantly associated with carotid IMT at follow-up (regression coefficient, 0.003 mm [SE, 0.001 mm]; P = .009).” (B. A. Hutten, b.a.hutten@amc.uva.nl)

>>>PNN NewsWatch
* A final DEA rule released this week allowing pharmacies to conduct drug-take-back programs presents “cost and liability issues,” APhA reports on pharmacist.com. “Potential unknown liabilities could result from stolen or tampered-with receptacles and the placement of inappropriate substances in a receptacle.”

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

PNN Pharmacotherapy Line
Sept. 11, 2014 * Vol. 21, No. 176
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 11 issue of the New England Journal of Medicine (2014; 371).
Angiotensin–Neprilysin Inhibition in Heart Failure: In patients with class II, III, or IV heart failure and an ejection fraction of 40% or less, the angiotensin receptor–neprilysin inhibitor LCZ696 was superior to enalapril in reductions in mortality and hospitalization, according to results of the PARADIGM-HF trial (pp. 993–1004). Based on a composite outcome of cardiovascular deaths and HF hospitalizations, investigators found these patterns in 8,442 participants assigned to LCZ696 200 mg or enalapril 10 mg twice daily: “The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P <0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P <0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P <0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P <0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.” (M. Packer, milton.packer@utsouthwestern.edu)
“PARADIGM-HF may well represent a new threshold of hope for patients with heart failure,” writes an editorialist (
pp. 1062–4). “Efforts to design novel pharmacotherapies that exploit our growing knowledge of pathophysiological pathways are increasingly coming to the clinical arena. The dual (or more) action of such drugs may translate into even greater long-term survival for patients. The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy.” (M. Jessup)
In a related Perspective article, authors provide a 28-year timeline for a “paradigm shift heart-failure therapy” (
pp. 989–91): “At the timeline’s beginning, two drugs with no mortality benefit—digoxin and diuretics—represented first-line treatment for heart failure. By the timeline’s last entry, ACE inhibitors, beta-blockers, aldosterone antagonists, cardiac devices, and now angiotensin-receptor–neprilysin inhibitors have strong evidence bases demonstrating a reduction in mortality. Still, in the intervention arm of PARADIGM-HF, the mortality rate among patients with heart failure remains about 20% over 2 years, highlighting the reality that this newest entry hardly concludes the compelling story of heart-failure treatment. We anticipate that progress will continue, and we hope that a timeline crafted three decades from now will reveal novel therapies and new paradigms that push our understanding of heart failure to a level unimaginable today.” (C. A. Sacks)
Legal Challenges & Medical Marijuana: Visits by DEA agents physicians’ homes and offices in advance of implementation of Massachusetts’ new medical-marijuana laws are described in a Perspective article as “meant to intimidate the physicians and to discourage them from taking an active role in medical-marijuana dispensaries” (pp. 983–5). The writer, while acknowledging that “federal drug laws are unlikely to change any time soon,” maintains that liberalization of state laws represent a “tipping point” and says an effort in Congress to restrain DEA and the rest of the Dept. of Justice from interfering with state medical-marijuana laws “seems likely to pass.” (G. J. Annas)

>>>PNN NewsWatch
* FDA yesterday approved a combination product containing naltrexone hydrochloride and bupropion hydrochloride in extended-release tablets (Contrave, Takeda and Orexigen Therapeutics) indicated for chronic weight management in addition to a reduced-calorie diet and physical activity.
*
FDA also this week expressed continued concerns about safety of products from Downing Labs/NuVision Pharmacy of Texas.

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

PNN Pharmacotherapy Line
Sept. 12, 2014 * Vol. 21, No. 177
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Sept. issue of Chest (2014; 146).
Mycobacterial Infections in Rheumatoid Arthritis: Among patients in Ontario with rheumatoid arthritis (RA), myobacterial infections occur commonly, with nontuberculous mycobacteria (NTM) disease more common than tuberculosis (TB), a study shows (pp. 563–72). A cohort analysis of data on all Ontarians aged 15 years or older showed these patterns when linked to public health files: “We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50–2.47]) and NTM disease (2.07, [1.84–2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person–years, NTM disease (HR, 41.6; 95% CI, 37.1–46.5) was more common than TB (HR, 8.5; 95% CI, 6.5–10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA.” (T. K. Marras, ted.marras@uhn.ca)
High-Dose N-Acetylcysteine in COPD: In a study of Chinese patients with chronic obstructive pulmonary disorder (COPD), those at high risk for exacerbations benefited from prophylactic high-dose N-acetylcysteine (NAC) therapy over a 1-year period, researchers report (pp. 611–23). Study participants had spirometry-confirmed stable COPD when they were randomized to NAC 600 mg twice daily or placebo in addition to usual therapy, with these results: “Of the 120 patients with COPD randomized (men, 93.2%; mean age, 70.8 ± 0.74 years; prebronchodilator FEV1, 53.9 ± 2.0%; baseline characteristics comparable between treatment groups), 108 (NAC, 52; placebo, 56) completed the 1-year study. For high-risk patients (n = 89), high-dose NAC compared with placebo significantly reduced exacerbation frequency (0.85 vs 1.59 [P = .019] and 1.08 vs 2.22 [P = .04] at 8 and 12 months, respectively), prolonged time to first exacerbation (P = .02), and increased the probability of being exacerbation free at 1 year (51.3% vs 24.4%, P = .013). This beneficial effect of high-dose NAC vs placebo was not significant in low-risk patients.” (H. N. Tse, drhoinam@gmail.com)

>>>Allergy/Immunology Report
Source:
Sept. issue of the Journal of Allergy and Clinical Immunology (2014; 134).
Airway Epithelium & Allergies: “Epithelial cells are crucial in determining the outcome of allergen inhalation,” authors write in a review of allergic sensitization (pp. 499–507). “Although lung epithelial cells were initially merely regarded as a passive barrier impeding allergen penetrance, we now realize that they recognize allergens through expression of pattern recognition receptors and mount an innate immune response driven by activation of nuclear factor kappa-B.” (B. N. Lambrecht, bart.lambrecht@ugent.be)
Lipids & Allergies: Authors of a review article examine the complicated relationships among allergens, lipid mediators, and allergen sensitization in people, concluding that “these findings will have a major influence on how allergic sensitization will be viewed and studied in the future” (pp. 521–9): “Allergic sensitization is a multifactorial process that is not only influenced by the allergen and its biological function per se but also by other small molecular compounds, such as lipids, that are directly bound as ligands by the allergen or are present in the allergen source. Several members of major allergen families bind lipid ligands through hydrophobic cavities or electrostatic or hydrophobic interactions. These allergens include certain seed storage proteins, Bet v 1–like and nonspecific lipid transfer proteins from pollens and fruits, certain inhalant allergens from house dust mites and cockroaches, and lipocalins. Lipids from the pollen coat and furry animals and the so-called pollen-associated lipid mediators are codelivered with the allergens and can modulate the immune responses of predisposed subjects by interacting with the innate immune system and invariant natural killer T cells. In addition, lipids originating from bacterial members of the pollen microbiome contribute to the outcome of the sensitization process. Dietary lipids act as adjuvants and might skew the immune response toward a Th2-dominated phenotype. In addition, the association with lipids protects food allergens from gastrointestinal degradation and facilitates their uptake by intestinal cells.” (H. Breiteneder, heimo.breiteneder@meduniwien.ac.at)

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

PNN Pharmacotherapy Line
Sept. 15, 2014 * Vol. 21, No. 178
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Benzodiazepine Use & Alzheimer’s Disease: In a study of 1,796 cases and 7,184 controls, benzodiazepine use was linked to risk of first diagnosis of Alzheimer’s disease, with stronger associations with long-term use (g5205). Investigators compared benzodiazepine use in patients with new-onset Alzheimer’s disease and control patients: “Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91–180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).” (S. Billioti de Gage, sophie.billioti-de-gage@u-bordeaux.fr)
Integrated COPD Management in Primary Care: In a pragmatic study from the Netherlands, integrated disease management in primary care of patients with chronic obstructive pulmonary disorder showed little benefit beyond usual care, researchers report (g5392). Reasons for the equivocal results in comparison with earlier positive trials could be “differences between interventions (provider versus patient targeted), selective reporting of positive trials, or little room for improvement in the already well developed Dutch healthcare system,” the investigators conclude. The intervention included a 2-day training program for participating physicians, practice nurses, and physiotherapists “on incorporating integrated disease management in practice, including early recognition of exacerbations and self management, smoking cessation, physiotherapeutic reactivation, optimal diagnosis, and drug adherence.” Results showed: “Of a total of 1,086 patients from 40 clusters, 20 practices (554 patients) were randomly assigned to the intervention group and 20 clusters (532 patients) to the usual care group. No difference was seen between groups in the [Clinical COPD Questionnaire] at 12 months (mean difference –0.01, 95% confidence interval –0.10 to 0.08; P = 0.8). After 12 months, no differences were seen in secondary outcomes between groups, except for the [Patient Assessment Chronic Illness Care (PACIC)] domain ‘follow-up/coordination’ (indicating improved integration of care) and proportion of physically active patients. Exacerbation rates as well as number of days in hospital did not differ between groups. After 24 months, no differences were seen in outcomes, except for the PACIC follow-up/coordination domain.” (A. .L Kruis, a.l.kruis@lumc.nl)

>>>Lancet Highlights
Source:
Sept. 13 issue of Lancet (2014; 383).
Global Burden of HIV, TB & Malaria: A Global Burden of Disease Study 2013 assesses incidence and mortality of HIV, tuberculosis, and malaria (pp. 1005–70): “Globally in 2013, there were 1.8 million new HIV infections (95% uncertainty interval 1.7 million to 2.1 million), 29.2 million prevalent HIV cases (28.1 to 31.7), and 1.3 million HIV deaths (1.3 to 1.5). At the peak of the epidemic in 2005, HIV caused 1.7 million deaths (1.6 million to 1.9 million).… Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64.0% of cases (63.6 to 64.3) and 64.7% of deaths (60.8 to 70.3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1.2 million deaths (1.1 million to 1.4 million) in 2004.…” (C. J. L. Murray)

>>>PNN JournalWatch
* Hospital-wide Rollout of Antimicrobial Stewardship: A Stepped-Wedge Randomized Trial, in
Clinical Infectious Diseases, 2014; 59: 867–74. (N. Daneman, nick.daneman@sunnybrook.ca)
* Review: Unraveling Lyme Disease, in
Arthritis & Rheumatology, 2014; 66: 2313–23. (L. K. Bockenstedt, linda.bockenstedt@yale.edu)
* Interaction of Radiation Therapy With Molecular Targeted Agents (part of a Special Series on Radiation Oncology), in
Journal of Clinical Oncology, 2014; 32: 2866–93. (P. M. Harari, harari@humonc.wisc.edu)
* Instruments for Evaluating Medication Use and Prescribing in Older Adults, in
Journal of the American Pharmacists Association, 2014; 54: 530–7. (J. L. Olin)

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

PNN Pharmacotherapy Line
Sept. 16, 2014 * Vol. 21, No. 179
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 16 issue of the Annals of Internal Medicine (2014; 161).
Generic v. Brand-Name Statins: In an analysis of medical and pharmacy claims data, Medicare beneficiaries started on generic statins were more adherent and had better clinical outcomes than did those on brand-name products, researchers report (pp. 400–7). The study included beneficiaries aged 65 years or older in 2006–08. Statin adherence based on proportion of days covered (PDC) up to 1 year after a first prescription for a statin yielded these results based on a composite outcome of hospitalization for an acute coronary syndrome or stroke and all-cause mortality: “A total of 90,111 patients who initiated a statin during the study was identified; 83,731 (93%) initiated a generic drug, and 6,380 (7%) initiated a brand-name drug. The mean age of patients was 75.6 years, and most (61%) were female. The average PDC was 77% for patients in the generic group and 71% for those in the brand-name group (P <0.001). An 8% reduction in the rate of the clinical outcome was observed among patients in the generic group versus those in the brand-name group (HR, 0.92 [95% CI, 0.86 to 0.99]). The absolute difference was −1.53 events per 100 person–years (CI, −2.69 to −0.19 events per 100 person–years).” (J. J. Gagne, jgagne1@partners.org)
“Inability to pay can cause unintentional nonadherence by limiting a patient’s ability to act on their intention to adhere,” editorialists write in response to this study (
pp. 447–8). Describing differences between intentional and nonintentional adherence, the authors note: “When affordability problems exist, patients may delay having medications dispensed, delay obtaining a prescription, or reduce the dose of a drug to extend its course. Gagne and colleagues make the distinction between generic and brand-name drugs, but the operating factor for patients is affordability. Although these findings require confirmation in other populations, they add to our understanding of the comparative effectiveness of generic medications and the importance of economic factors in medication adherence.” (W. Cullen, waltern.cullen@ucd.ie)
Urinary Incontinence in Women: In a new clinical practice guideline, the American College of Physicians makes recommendations for nonsurgical management of urinary incontinence (UI) in women (pp. 429–40). The group’s advice focuses on these six evidence-based points (A. Qaseem, aqaseem@acponline.org):
* First-line treatment with pelvic floor muscle training in women with stress UI (Grade: strong recommendation, high-quality evidence)
* Bladder training in women with urgency UI (Grade: strong recommendation, moderate-quality evidence)
* Pelvic floor muscle training with bladder training in women with mixed UI (Grade: strong recommendation, moderate-quality evidence)
* No systemic pharmacologic therapy for stress UI (Grade: strong recommendation, low-quality evidence)
* Pharmacologic treatment in women with urgency UI if bladder training was unsuccessful. Clinicians should base the choice of pharmacologic agents on tolerability, adverse effect profile, ease of use, and cost of medication. (Grade: strong recommendation, high-quality evidence)
* Weight loss and exercise for obese women with UI (Grade: strong recommendation, moderate-quality evidence)

>>>PNN NewsWatch
* Results of the APhA Foundation’s Project IMPACT: Diabetes demonstrate how pharmacists and other health care providers can work together to successfully empower patients disproportionately affected by diabetes to achieve improved clinical outcomes, the organization says in a news release. Published in the Journal of the American Pharmacists Association, two peer-reviewed articles collectively highlight the clinical and process outcomes as well as the unique characteristics of the patients and care delivery in 25 diverse Project IMPACT communities in 17 states. The communities were given flexibility to customize additional care strategies in order to best meet the needs of their patients. Approaches included group education classes, joint provider visits, grocery store tours, cooking classes, and transportation incentives. One year following the end of the patient care study period, 96% of communities report sustaining team-based care that includes pharmacists’ patient care services.

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

PNN Pharmacotherapy Line
Sept. 17, 2014 * Vol. 21, No. 180
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 17 issue of JAMA (2014; 312).
COPD Treatments in Older Adults: Deaths and hospitalizations for chronic obstructive pulmonary disease (COPD) were fewer when long-acting beta-agonists (LABAs) plus inhaled corticosteroids were added to therapy in older adults, compared with LABAs alone (pp. 1114–21). Effects were greater in patients who also had asthma and those not on a long-acting anticholinergic medication, the investigators write, based on a longitudinal analysis of patients in Ontario from 2003 to 2011. In all, 8,712 new users of LABAs plus inhaled corticosteroids and 3,160 new users of LABAs alone were identified and these results recorded: “The main outcome [of composite outcome of death and COPD hospitalization] was observed among 5,594 new users of LABAs and inhaled corticosteroids (3,174 deaths [36.4%]; 2,420 COPD hospitalizations [27.8%]) and 2,129 new users of LABAs alone (1,179 deaths [37.3%]; 950 COPD hospitalizations [30.1%]). New use of LABAs and inhaled corticosteroids was associated with a modestly reduced risk of death or COPD hospitalization compared with new use of LABAs alone (difference in composite outcome at 5 years, −3.7%; 95% CI, −5.7% to −1.7%; hazard ratio [HR], 0.92; 95% CI, 0.88-0.96). The greatest difference was among COPD patients with a codiagnosis of asthma (difference in composite at 5 years, −6.5%; 95% CI, −10.3% to −2.7%; HR, 0.84; 95% CI, 0.77-0.91) and those who were not receiving inhaled long-acting anticholinergic medication (difference in composite at 5 years, −8.4%; 95% CI, −11.9% to −4.9%; HR, 0.79; 95% CI, 0.73–0.86).” (A. S. Gershon, andrea.gershon@ices.on.ca)
The results of this “real-world” study stand in contrast to findings from randomized controlled trials (RCTs), writes an editorialist (
pp. 1101–2): “The outcomes of treatment in these ‘real-world’ patients were somewhat better than might have been expected from RCTs, but the patients were also much more diverse and often sicker. The study by Gershon et al shows that findings from appropriately conducted database analyses complement data from RCTs and should be considered when determining treatment algorithms.” (P. M. A. Calverley, pmacal@liverpool.ac.uk)
Treatment of Acute Venous Thromboembolism: In an efficacy and safety meta-analysis of treatments for acute venous thromboembolism, no statistically significant differences were found among most treatments when compared with the combination of low-molecular-weight heparin (LMWH) and vitamin K antagonists, researchers report (pp. 1122–35). In 45 trials of 44,989 patients, “findings suggest that the [unfractionated heparin (UFH)]–vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.” The authors added: “Compared with the LMWH–vitamin K antagonist combination, a treatment strategy using the UFH–vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15–1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%–2.51%) for the UFH–vitamin K antagonist combination and 1.30% (95% CrI, 1.02%–1.62%) for the LMWH–vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35–0.89) and apixaban (HR, 0.31; 95% CrI, 0.15–0.62) were associated with a lower risk of bleeding than was the LMWH–vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%–0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%–0.50%) for apixaban, and 0.89% (95% CrI, 0.66%–1.16%) for the LMWH–vitamin K antagonist combination.” (M. Carrier, mcarrier@ottawahospital.on.ca)
Ebola Epidemic: Civil unrest, weak development, and fragile health systems complicate the international response to the Ebola virus epidemic in West Africa, authors of a Perspective article explain (pp. 1095–6). “A sustainable solution to [Ebola virus disease], and other emerging threats, requires binding commitments for funding and technical assistance to build national preparedness capabilities, including surveillance, laboratories, health systems, and rapid response.” (L. O. Gostin, gostin@law.georgetown.edu)

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

PNN Pharmacotherapy Line
Sept. 18, 2014 * Vol. 21, No. 181
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 18 New England Journal of Medicine (2014; 371).
Ivabradine in Stable Coronary Artery Disease: Addition of the negative chronotropic agent ivabradine to standard therapy for stable coronary artery disease without clinical heart failure did not improve a composite outcome of death from cardiovascular causes or nonfatal myocardial infarction, researchers report (pp. 1091–9). Among 19,102 patients with this condition plus heart rates of 70 beats per minute or more—including 12,049 with activity-limiting angina—these results were noted with standard therapy plus ivabradine at doses titrated to achieve heart rates of 55–60 beats per minute: “At 3 months, the mean (± SD) heart rate of the patients was 60.7 ± 9.0 beats per minute in the ivabradine group versus 70.6 ± 10.1 beats per minute in the placebo group. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P = 0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P = 0.02 for interaction). The incidence of bradycardia was higher with ivabradine than with placebo (18.0% vs. 2.3%, P <0.001).” (K. Fox, kim.fox@imperial.ac.uk)
Commenting on this Study Assessing the Morbidity–Mortality Benefits of the
If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) trial, editorialists assess the “surprising finding” of worsened clinical outcomes in patients with chronic angina (pp. 1152–3): “What action should physicians who have ivabradine available to them take on the basis of this subgroup finding? Our recommendation is to exercise caution among patients with more severe forms of angina and to consider adjusting beta-blocker doses to effective levels before initiating ivabradine. The experience from the trial of ivabradine in heart failure suggests that nearly 60% of patients were receiving inadequate doses of beta-blockers and that the majority of benefit with ivabradine was among patients who could not take beta-blockers or who were taking a lower dose. Whether this holds true for patients with angina is unknown, but this cautious approach may be reasonable until we understand this finding better.” (E. M. Ohman)
Prednisolone/Immunotherapy in Tuberculous Pericarditis: In a study of 1,400 adults with tuberculous pericarditis, “neither prednisolone nor [the immunotherapy agent Mycobacterium indicus pranii] had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis,” a study shows (pp. 1121–30). Treatment with prednisolone or placebo for 6 weeks plus M. indicus pranii or placebo in five injections over 3 months produced these results in study participants, two-thirds of whom had concomitant HIV infection: “There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P = 0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P = 0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P = 0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P = 0.03, respectively), owing mainly to an increase in HIV-associated cancer.” (B. M. Mayosi, bongani.mayosi@uct.ac.za)

>>>PNN NewsWatch
* FDA has approved naloxegol (Movantik—AstraZeneca), an orally administered, peripherally acting opioid receptor antagonist indicated for opioid-induced constipation in adults with chronic noncancer pain.

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

PNN Pharmacotherapy Line
Sept. 19, 2014 * Vol. 21, No. 182
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Sept. issue of Health Affairs, a theme issue on advancing global health policy (2014; 33).
Chronic-Care Models: Authors analyze quality improvements from use of the Chronic Care Model (CCM), developed in the late 1990s, in two large surveys of experiences of patients with diabetes in the U.S. and Germany (pp. 1540–8): “The study populations were enrolled in either Geisinger Health System in Pennsylvania or Barmer, a German sickness fund that provides medical insurance nationwide. Our findings suggest that patients with type 2 diabetes who were enrolled in the care models that exhibited key features of the CCM were more likely to receive care that was patient-centered, high quality, and collaborative, compared to patients who received routine care. This study demonstrates that quality improvement can be realized through the application of the Chronic Care Model, regardless of the setting or distinct characteristics of the program.” (S. Stock, Stephanie.Stock@uk-koeln.de)
Global Threat of Antimicrobial Resistance: Antimicrobial agents’ “transformational benefits are threatened because of the rapidly advancing phenomenon of antimicrobial resistance,” authors write in looking at the worldwide situation (pp. 1620–6): “As a result of complex factors across many sectors and international actors, the global impact of antimicrobial resistance is an escalating economic and health crisis. This article draws on the collective expertise and summit report of the Antimicrobial Resistance Working Group from the 2013 World Innovation Summit for Health, in Doha, Qatar. It defines a framework of principles and tasks for key policy makers to raise international awareness of antimicrobial resistance and lead transformative action through policy-driven improvements in sanitation, antimicrobial conservation, agricultural practices, and research and development.” (O. P. Keown, .keown@imperial.ac.uk">o.keown@imperial.ac.uk)

>>>Medical Care Report
Source:
Oct. issue of Medical Care (2014; 52).
Hospitalizations & Nursing-Home-Resident Medication Use: Both before and after hospitalizations of nursing home residents, researchers report evidence of “moderate levels” of high-risk medication use in a Medicare dataset (pp. 884–90). Claims for 52,559 dual-eligible nursing home residents who were 65 years of age or older showed these patterns of use of Beers-criteria medications in the 30 days before and after hospitalizations during 2008: “Around 1 in 5 (21%) hospitalized nursing home residents used at least 1 high-risk medication the day before hospitalization. Among individuals with high-risk medication use at hospitalization, the proportion using these medications dropped to 45% after nursing home readmission but increased thereafter, to 59% by the end of the 30-day period.” (D. G. Stevenson)
“Ratchet Effect” Following Hospitalization for Chronic Disease: A study from western Australia describes a “ratchet effect” in health care utilization following an initial event related to chronic disease that leads to hospitalization (pp. 901–8). A cohort study of individuals hospitalized in 2002–10 showed these patterns for changes in “rates of cardinal events associated with diagnoses of heart failure, type 2 diabetes, chronic obstructive pulmonary disease, cataract with diabetes, asthma, and dialysis”: “Cardinal events make up 40%–60% of all chronic disease admissions. A previously undescribed ratchet effect following cardinal events specifically associated with type 2 diabetes, heart failure, and chronic obstructive pulmonary disease is observed. This involves a 2- to 3-fold increase in inpatient days and emergency department presentations that are sustained for at least 4 years.” (D. Whyatt, david.whyatt@uwa.edu.au)

>>>PNN NewsWatch
* FDA yesterday approved subcutaneous dulaglutide (Trulicity, Lilly) for once-weekly management of type 2 diabetes in adults as an adjunct to diet and exercise. To be marketed as single-dose 0.75- and 1.5-mg pens, dulaglutide was studied in five large Phase III trials in which improvements in glycosylated hemoglobin were demonstrated with use of the drug. Dulaglutide product labeling carries a boxed warning that thyroid C-cell tumors have been observed in rodent studies but that it is unknown whether the drug causes thyroid C-cell tumors, including medullary thyroid carcinoma, in humans.

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

PNN Pharmacotherapy Line
Sept. 22, 2014 * Vol. 21, No. 183
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 20 issue of Lancet (2014; 383).
Collaborative Care for Depression in Patients With Cancer: An integrated collaborative care program for depression in patients with cancer is effective and provides a model for care of other patients with depression and comorbid conditions, SMaRT (Symptom Management Research Trials) Oncology-2 Team members conclude (pp. 1099–108). Within a randomized controlled effectiveness trial, outpatients with major depression in Scotland were assigned to depression care for people with cancer or usual care. Under the depression care model, a team of cancer nurses and psychiatrists worked with primary care physicians to deliver multicomponent collaborative care for 48 weeks.
Based on treatment responses of 50% or more change in Symptom Checklist Depression Scale (SCL-20) score, range 0–4) at 24 weeks, the investigators found: “500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37–53), adjusted odds ratio 8.5 (95% CI 5.5–13.4), p <0.0001. Compared with patients in the usual care group, participants allocated to the depression care for people with cancer programme also had less depression, anxiety, pain, and fatigue; and better functioning, health, quality of life, and perceived quality of depression care at all timepoints (all p <0.05). During the study, 34 cancer-related deaths occurred (19 in the depression care for people with cancer group, 15 in the usual care group), one patient in the depression care for people with cancer group was admitted to a psychiatric ward, and one patient in this group attempted suicide. None of these events were judged to be related to the trial treatments or procedures.” (M. Sharpe,
michael.sharpe@psych.ox.ac.uk)
Pembrolizumab in Ipilimumab-Refractory Advanced Melanoma: In an open-label Phase I trial, the anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab showed promise as an effective treatment of adult with ipilimumab-refractory advanced melanoma, a condition with “few effective treatment options,” researchers report (pp. 1109–17). Patients received computer-assigned doses of 2 or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal occurred. An overall response rate (ORR) based on the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) provided these results: “173 patients received pembrolizumab 2 mg/kg (n = 89) or 10 mg/kg (n = 84). Median follow-up duration was 8 months. ORR was 26% at both doses—21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI −14 to 13; p = 0.96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient.” (C. Robert, caroline.robert@gustaveroussy.fr)

>>>PNN JournalWatch
* Genetics of Epilepsy: The Testimony of Twins in the Molecular Era, in
Neurology, 2014; 83: 1042–8. (S. F. Berkovic, s.berkovic@unimelb.edu.au)
* Molecular Targets on Mast Cells and Basophils for Novel Therapies, in
Journal of Allergy and Clinical Immunology, 2014; 134: 530–4. (I. T. Harvima, ilkka.harvima@kuh.fi)
* Tryptophan Supplementation and Postoperative Delirium—A Randomized Controlled Trial, in
Journal of the American Geriatrics Society, 2014; 62: 1764–71. (T. Robinson, thomas.robinson@ucdenver.edu)
* Rural Geriatric Glue: A Nurse Practitioner–Led Model of Care for Enhancing Primary Care for Frail Older Adults Within an Ecosystem Approach, in
Journal of the American Geriatrics Society, 2014; 62: 1772–80. (S. Prasad, sprasad@smgh.ca)
* Communicating Genomic Risk in Primary Health Care: Challenges and Opportunities for Providers, in
Medical Care, 2014; 52: 933–4. (S. Kowal, skowal@ualberta.ca)
* Drug Shortages [blog], in
Health Affairs, 2014 Sept 11. (K. Stencel)

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

PNN Pharmacotherapy Line
Sept. 23, 2014 * Vol. 21, No. 184
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2014; 174).
Treatment of Overt Hepatic Encephalopathy: For treatment of hepatic encephalopathy (HE) in patients with cirrhosis, polyethylene glycol 3350–electrolyte solution (PEG) more rapidly resolved symptoms than did lactulose, researchers report (doi: 10.1001/jamainternmed.2014.4746). In the Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution study, 50 patients had these outcomes during hospitalization after block randomization to PEG or standard-of-care lactulose: “A total of 25 patients were randomized to each treatment arm. Baseline clinical features at admission were similar in the groups. Thirteen of 25 patients in the standard therapy arm (52%) had an improvement of 1 or more in [hepatic encephalopathy scoring algorithm (HESA)] score, thus meeting the primary outcome measure, compared with 21 of 23 evaluated patients receiving PEG (91%) (P <.01); 1 patient was discharged before final analysis and 1 refused participation. The mean (SD) HESA score at 24 hours for patients receiving standard therapy changed from 2.3 (0.9) to 1.6 (0.9) compared with a change from 2.3 (0.9) to 0.9 (1.0) for the PEG-treated groups (P = .002). The median time for HE resolution was 2 days for standard therapy and 1 day for PEG (P = .01). Adverse events were uncommon, and none was definitely study related.” (D. C. Rockey, rockey@musc.edu)
This study demonstrates “that rapid bowel purge may be a cost-effective and successful treatment in the acute setting,” editorialists write (
doi: 10.1001/jamainternmed.2014.3501). “Questions remain, particularly comparisons with combined rifaximin–lactulose and use in the chronic setting, but the exploration of PEG treatment opens the opportunity for further studies. Future therapies interfering with ammoniagenesis also show promise and warrant further investigation. While hepatic encephalopathy is a common complication of cirrhosis and can be quite difficult to manage, the evolving therapeutic options hold great promise.” (N. L. Shah, ns3zt@virginia.edu)
Generic Use Among Vulnerable Populations: Uptake on the $4 generic discount drug program (GDDP) at Walmart took time to mature among patients in vulnerable populations, according to authors of a Research Letter (doi: 10.1001/jamainternmed.2014.4497). Other studies showed low use of the GDDP among vulnerable patients when it was introduced in 2006. Analysis of 2010 claims showed these patterns: “Of the 13,486 adults who had at least 1 prescription drug event in 2010, 3,208 were GDDP users; the weighted rate of GDDP use was 23.1%. Use of the GDDP was more likely among the elderly, sicker, and uninsured groups. Use of the GDDP was also more likely among people living in rural areas and central regions of the United States. However, the rate of GDDP use was not significantly different across different educational level, income, and racial/ethnic groups.” (S. H. Hong, shhong@uthsc.edu)

>>>Nephrology Report
Source:
Oct. issue of the American Journal of Kidney Diseases (2014; 64).
Vitamin D in Chronic Kidney Disease: Recommendations of the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative are presented with regard to 25-hydroxyvitamin D testing and supplementation in patients with chronic kidney disease (CKD) (pp. 499–509): “The benefits of and thresholds for 25-hydroxyvitamin D administration in individuals with … CKD remain uncertain. In this report, NKF-KDOQI endeavors to provide health care providers with the latest information on a controversial area in the management of CKD, the role for nutritional vitamin D. Although knowledge of the biological mechanisms of vitamin D for bone maintenance in individuals with all stages of CKD has expanded, no consensus currently exists within the medical community regarding methods for 25-hydroxyvitamin D supplementation or optimal 25-hydroxyvitamin D levels in individuals with CKD. Within this report, existing CKD guidelines are summarized and scrutinized and ongoing clinical trials are cited as sources for future guidance on the optimal management of vitamin D in CKD.” (H. Kramer, hkramer@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 © 2014, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 24, 2014 * Vol. 21, No. 185
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 24 issue of JAMA (2014; 312).
Electronic Medication Packaging & Adherence: In published studies, electronic medication packaging (EMP) devices have been associated with improved adherence primarily when “integrated into the care delivery system and designed to record dosing events,” authors of a systematic review conclude (pp. 1237–47): “Thirty-seven studies (32 randomized and 5 nonrandomized) including 4,326 patients met inclusion criteria (10 patient interface-only ‘simple’ interventions and 29 ‘complex’ interventions integrated into the health care system [2 qualified for both categories]). Overall, the effect estimates for differences in mean adherence ranged from a decrease of 2.9% to an increase of 34.0%, and the those for differences in the proportion of patients defined as adherent ranged from a decrease of 8.0% to an increase of 49.5%. We identified 5 common EMP characteristics: recorded dosing events and stored records of adherence, audiovisual reminders to cue dosing, digital displays, real-time monitoring, and feedback on adherence performance.” (A. S. Kesselheim, akesselheim@partners.org)
Prevalence & Incidence of Diagnosed Diabetes: In the United States, nationally representative data from 1980 to 2012 “suggest a doubling of the incidence and prevalence of diabetes during 1990–2008, and a plateauing between 2008 and 2012,” researchers report (pp. 1218–26). Certain subgroups—non–Hispanic blacks, Hispanics, and those with less than a high-school education—continued to experience increases in prevalence and incidence after 2008, the group notes based on these details from the National Health Interview Study and its reported annual percentage change (APC): “The APC for age-adjusted prevalence and incidence of diagnosed diabetes did not change significantly during the 1980s (for prevalence, 0.2% [95% CI, −0.9% to 1.4%], P = .69; for incidence, −0.1% [95% CI, −2.5% to 2.4%], P = .93), but each increased sharply during 1990–2008 (for prevalence, 4.5% [95% CI, 4.1% to 4.9%], P <.001; for incidence, 4.7% [95% CI, 3.8% to 5.6%], P <.001) before leveling off with no significant change during 2008-2012 (for prevalence, 0.6% [95% CI, −1.9% to 3.0%], P = .64; for incidence, −5.4% [95% CI, −11.3% to 0.9%], P = .09). The prevalence per 100 persons was 3.5 (95% CI, 3.2 to 3.9) in 1990, 7.9 (95% CI, 7.4 to 8.3) in 2008, and 8.3 (95% CI, 7.9 to 8.7) in 2012. The incidence per 1,000 persons was 3.2 (95% CI, 2.2 to 4.1) in 1990, 8.8 (95% CI, 7.4 to 10.3) in 2008, and 7.1 (95% CI, 6.1 to 8.2) in 2012.” (L. S. Geiss, lgeiss@cdc.gov)
Financial Barriers & Prenatal Genetic Testing: Removal of financial barriers combined with computerized decision support resulted in fewer patients electing to have prenatal genetic screening but better choices overall, a study shows (pp. 1210–7). At prenatal clinics in the San Francisco area, 710 pregnant women at 11 weeks’ gestation were randomized to a computerized, interactive decision-support guide and access to prenatal testing with no out-of-pocket expense or usual care based on current guidelines, with these results: “Women randomized to the intervention group, compared with those randomized to the control group, were less likely to have invasive diagnostic testing (5.9% vs 12.3%; odds ratio [OR], 0.45 [95% CI, 0.25–0.80]) and more likely to forgo testing altogether (25.6% vs 20.4%; OR, 3.30 [95% CI, 1.43–7.64], reference group screening followed by invasive testing). Women randomized to the intervention group also had higher knowledge scores (9.4 vs 8.6 on a 15-point scale; mean group difference, 0.82 [95% CI, 0.34–1.31]) and were more likely to correctly estimate the amniocentesis-related miscarriage risk (73.8% vs 59.0%; OR, 1.95 [95% CI, 1.39–2.75]) and their estimated age-adjusted chance of carrying a fetus with trisomy 21 (58.7% vs 46.1%; OR, 1.66 [95% CI, 1.22–2.28]). Significant differences did not emerge in decisional conflict or regret.” (M. Kuppermann, kuppermannm@obgyn.ucsf.edu)
“Pre- and posttest genetic counseling, as well as access to genetics professionals, are optimal methods for conveying the risks and benefits of various testing strategies,” an editorialist writes (
pp. 1203–5). “Learning more about women’s values and preferences and providing educational tools for women to use in their clinicians’ offices, are essential for widespread implementation.” (S. M. Dolan, siobhanmdolan@yahoo.com)

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

PNN Pharmacotherapy Line
Sept. 25, 2014 * Vol. 21, No. 186
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 25 issue of the New England Journal of Medicine (2014; 371).
Mepolizumab in Eosinophilic Asthma: In the first of two trials of this drug presented in this issue, the interleukin-5-modulating monoclonal antibody mepolizumab reduced the dose of systemic glucocorticoids needed to control symptoms in patients with severe eosinophilic asthma (pp. 1189–97). Among 135 patients, mepolizumab 100 mg every 4 weeks subcutaneously was compared with placebo during a 20-week period, with these effects on a primary outcome of percentage reduction in the glucocorticoid dose: “The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P = 0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P = 0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P = 0.04) and a reduction of 0.52 points with respect to asthma symptoms (P = 0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo.” (E. H. Bel, e.h.bel@amc.uva.nl)
In a second trial, intravenous or subcutaneous mepolizumab reduced the frequency of exacerbations and improved markers of asthma control in patients with severe asthma (
pp. 1198–207). A total of 576 patients with recurrent asthma exacerbations and eosinophilic inflammation despite high inhaled glucocorticoid doses had these responses to mepolizumab every 4 weeks for 32 weeks: “The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P <0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P = 0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P = 0.03). The improvement from baseline in the [St. George’s Respiratory Questionnaire] score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the [5-item Asthma Control Questionnaire] score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P <0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo.” (H. G. Ortega, hector.g.ortega@gsk.com)
Since these studies did not monitor airway eosinophils, “it is not possible to know whether better outcomes could have been achieved by adjusting the mepolizumab dose to suppress these levels,” an editorialist writes (
pp. 1249–51). “In addition, further evaluation is required to determine the most effective dose and the most effective route and frequency of administration of the drug in these patients, particularly in those who require daily oral glucocorticoids. Given that multiple cytokines and pathways contribute to eosinophil recruitment to the airway, the simultaneous administration of more than one monoclonal antibody might have additive clinical efficacy. In the meantime, it is reasonable to consider anti–interleukin-5 therapy for patients with severe asthma who are receiving high doses of systemic glucocorticoids and who continue to have an elevated eosinophil count in sputum or blood regardless of their atopic status.” (P. Nair)

>>>PNN NewsWatch
* The Nova Biomedical StatStrip Glucose Hospital Meter System has been cleared for use in critically ill patients, FDA said yesterday.

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

PNN Pharmacotherapy Line
Sept. 26, 2014 * Vol. 21, No. 187
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2014; 37).
Insulin Requirements & Obstetric Outcomes: In pregnant women with preexisting diabetes, falling insulin requirements are associated with increased risk of placental dysfunction and other adverse obstetric outcomes, researchers report (pp. 2685–92). Retrospective review of 139 pregnancies showed these patterns during late pregnancy: “A total of 25.2% of women had >15% fall in insulin requirements with nulliparity as the only predictor at baseline (odds ratio [OR] 2.5 [95% CI 1.1–5.7], P = 0.03). Falling insulin requirements were associated with an increased risk of preeclampsia (OR 3.5 [1.1–10.7], P < 0.05) and the composite of clinical markers of placental dysfunction (4.4 [1.73–11.26], P = 0.002). Although falling insulin requirements were associated with higher rates of [small for gestational age] (3.4 [1.0–11.3], P = 0.048), they were not associated with other adverse neonatal outcomes. However, there was a higher incidence of neonatal intensive care unit admission (15.5 [3.1–77.6], P = 0.001) and earlier delivery in this group (median 37.7 weeks [IQR 34.3–38.4] vs. 38.3 weeks [37.4–38.9], P = 0.014).” (S. Padmanabhan, suja_padman@yahoo.com.au)
Changing the Natural History of Type 2 Diabetes: Arguing that current medical practice “waste[s] the first ~10 years of the natural history” of type 2 diabetes, authors of a Commentary advocate for detection and treatment of prediabetes and early diabetes as a means of preventing or delaying hypoglycemia and complications of the disease (pp. 2668–76): “Evidence for [earlier interventions] comes from trials where lifestyle change and/or glucose-lowering medications decreased progression from prediabetes to diabetes. After withdrawal of these interventions, there was no ‘catch-up’—cumulative development of diabetes in the previously treated groups remained less than in control subjects. Moreover, achieving normal glucose levels even transiently during the trials was associated with a substantial reduction in subsequent development of diabetes. These findings indicate that we can change the natural history through routine screening to find prediabetes and early diabetes, combined with management aimed to keep glucose levels as close to normal as possible, without hypoglycemia. We should also test the hypothesis with a randomized controlled trial.” (L. S. Phillips, lawrence.phillips@emory.edu)
New Pediatric Medications for Type 2 Diabetes: With prevalence of type 2 diabetes (T2D) increasing in the pediatric population, editorialists call for collaboration in the study of new antidiabetic agents for children and adolescents (pp. 2663–7): “A collaborative effort will facilitate the collection of adequate and well-controlled pediatric efficacy and safety clinical trial data to inform pediatric use of new drugs to treat T2D. An approach relying on a multiarm trial is one particularly attractive approach that leverages efficiencies gained from use of a shared control group, with efficiencies gained from a shared research infrastructure. Success in pediatric drug development has often involved collaboration. Indeed, reliance on consortia-based approaches to evaluate novel therapies was successful for other relatively uncommon pediatric diseases (e.g., juvenile idiopathic arthritis and schizophrenia) and should be met with similar success in T2D.” (J. Karres, janina.karres@ema.europa.eu)

>>>PNN NewsWatch
* Published today on the AJHP and JAPhA websites is a Council on Credentialing in Pharmacy resource paper on credentialing and privileging of pharmacists. It “supplement[s] the Council on Credentialing in Pharmacy Guiding Principles for Post-licensure Credentialing of Pharmacists and … assist[s] those who are introducing or enhancing a credentialing and privileging system for pharmacists within their health care settings,” the Council writes. “[The school accreditation/individual licensure] process provides an established framework to assure stakeholders of the ability of pharmacists to provide care and services that reflect sound, entry-level practice. However, evolving patient care and health system needs and demands have heightened the requisite skills needed by pharmacists to deliver more complex services. Ongoing professional development and competency assessment are integral parts of health professionals’ expectations to maintain a contemporary practice.”

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

PNN Pharmacotherapy Line
Sept. 29, 2014 * Vol. 21, No. 188
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 27 issue of Lancet (2014; 383).
Losmapimod in NSTEMI: The oral p38 MAPK inhibitor losmapimod may improve outcomes following acute coronary syndromes, SOLSTICE investigators concluded based on a randomized controlled trial of patients with non-ST-segment elevation myocardial infarction (NSTEMI) (pp. 1187–95). Oral losmapimod 7.5 or 15.0 mg loading dose followed by 7.5 mg twice daily or matching placebo produced these changes in serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks; cardiac events (death, myocardial infarction, recurrent ischemia, stroke, and heart failure) at 90 days; high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 hours and 12 weeks; and troponin I area under the curve (AUC) over 72 hours: “Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n = 388 and placebo n = 138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64.1 nmol/L, 95% CI 53.0–77.6 vs 110.8 nmol/L, 83.1–147.7; p = 0.0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37.2 ng/L, 95% CI 32.3–42.9 vs 49.4 ng/L, 38.7–63.0; p = 0.04). Mean troponin I AUC values did not differ.” (L. K. Newby, kristin.newby@duke.edu)
Long-Term Medication Effectiveness in Parkinson Disease: As initial therapy of Parkinson disease, levodopa regimens have “very small but persistent benefits” compared with levodopa-sparing approaches, researchers report (pp. 1196–205). In a pragmatic, open-label trial, patients newly diagnosed with Parkinson disease had these outcomes based on assignment to levodopa alone or levodopa-sparing therapy with dopamine agonists or monoamine oxidase type B inhibitors (MAOBI): “Between Nov 9, 2000, and Dec 22, 2009, 1,620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1.8 points (95% CI 0.5–3.0, p = 0.005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years’ observation. PDQ-39 mobility scores were 1.4 points (95% CI 0.0–2.9, p = 0.05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0.03 (95% CI 0.01–0.05; p = 0.0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0.81, 95% CI 0.61–1.08, p = 0.14), admissions to institutions (0.86, 0.63–1.18; p = 0.4), and death (0.85, 0.69–1.06, p = 0.17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p <0.0001).” (PD MED Collaborative Group, PD-trials@bham.ac.uk)

>PNN NewsWatch
* Patients taking omalizumab (Xolair, Genentech/Novartis) have a slightly higher risk of cardiovascular and cerebrovascular events than do patients with asthma who do not receive the drug, FDA reports.

>PNN JournalWatch
* Antipsychotics, Mood Stabilisers, and Risk of Violent Crime, in
Lancet, 2014; 384: 1206–14. (S. Fazel, seena.fazel@psych.ox.ac.uk)
* Antibiotic Treatment Failure in Four Common Infections in UK Primary Care 1991–2012: Longitudinal Analysis, in
BMJ, 2014; 349: g5493. (C. J. Currie, currie@cardiff.ac.uk)
* The Effects of Dipeptidyl Peptidase-4 Inhibition on Microvascular Diabetes Complications, in
Diabetes Care, 2014; 37: 2884–94. (A. Avogaro, angelo.avogaro@unipd.it)
* Diabetic Kidney Disease: A Report From an ADA Consensus Conference, in
American Journal of Kidney Diseases (also published in the Oct. Diabetes Care), 2014; 64: 510–33. (J. L. Chiang, jchiang@diabetes.org)
* CKD and Nonalcoholic Fatty Liver Disease, in
American Journal of Kidney Diseases, 2014; 64: 638–52. (G. Targher, giovanni.targher@univr.it)
* Sublingual Administration of Tacrolimus: Current Trends and Available Evidence, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1492. (C. T. Doligalski, cdoligalski@tgh.org)

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

PNN Pharmacotherapy Line
Sept. 30, 2014 * Vol. 21, No. 189
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Reproducibility of Published Naranjo ADR Probabilities: In a review of published case reports that used the Naranjo Adverse Drug Reaction Probability Scale (APS) to determine the strength of the association between drug exposure and outcomes, “exact agreement between raters’ scores and the published APS score was infrequent.” researchers report (10.1002/phar.1496). “Authors of case reports [should] include all pertinent details of the case and … journals [should] ensure the robustness of the causality assessment during peer review,” the researchers conclude based on this analysis of 24 case reports: “Exact agreement between all raters’ scores and the published APS scores was found in five (21%) of the 24 reports. Agreement between individual rater’s scores and the published categorical score ranged from 42% to 79%. Weighted kappa ranged from 0.12 to 0.61, corresponding to strengths of agreement between poor and good. Difference in scoring by raters resulted in 18% and 27% of case reports being reclassified into higher and lower than reported APS categories, respectively.” (A. Wyllie, awyllie@mtsinai.on.ca)
N-Acetylcysteine in Pediatric Rotavirus-Associated Diarrhea: Results of the cases of four pediatric patients with rotavirus-associated diarrhea suggest that N-acetylcysteine (NAC) “treatment after the first diarrheal episode could be an efficient strategy for treating rotavirus-affected children and preventing the associated severe life-threatening accompanying dehydration,” authors conclude (10.1002/phar.1489): “We describe the cases of four rotavirus-unvaccinated 12–13-month-old girls and a 5-year-old boy who developed rotavirus-associated diarrhea confirmed by enzyme-linked immunosorbent assay, Western blotting, and immunochemistry analyses. After the first day of diarrheal episodes, three of the five patients were immediately administered oral [NAC] 60 mg/kg daily, divided into three equal doses every 8 hours. The other two patients did not receive NAC and served as controls. Administration of NAC resulted in a decreased number of diarrheal episodes, excretion of fecal rotavirus antigen, and resolution of symptoms after 2 days of treatment.” (C. A. Guerrero, caguerrerof@unal.edu.co)
Pharmacists’ Emerging Pharmacogenomic Roles: “Education, training, and practice-based resources are needed to support [pharmacists’ emerging pharmacogenomic] roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models,” conclude writers who describe development and operation of the University of Florida Health Personalized Medicine Program (10.1002/phar.1481): “[The program] began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel-CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1,000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25–30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care.” (J. A. Johnson, johnson@cop.ufl.edu)
Glucose With Short-Term Atenolol or Hydrochlorothiazide: In Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) participants, atenolol or hydrochlorothiazide use was a significant predictor of glucose change, explaining 13% of variability in a regression analysis (10.1002/phar.1483; J. A. Johnson, johnson@cop.ufl.edu).

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