Mar 2014

PNN January–March 2014

PNN Pharmacotherapy Line
Jan. 2, 2014 * Vol. 21, No. 1
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 1 issue of JAMA (2014; 311).
Vitamin E & Memantine in AD: In 613 patients with mild to moderate Alzheimer disease (AD), daily doses of alpha-tocopherol 2,000 IU but not memantine 20 mg slowed functional decline and may have alleviated caregiver burden, according to results of the TEAM-AD VA Cooperative Randomized Trial (pp. 33–44). Participants were given one or both drugs or placebo. Results based on the 78-point Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score showed the following: “Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of ‘infections or infestations,’ with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).” (M. Dysken, maurice.dysken@va.gov)
“Many features of the trial by Dysken et al reflect the best in trials of AD therapy, especially its size, duration, and separation from commercial motivation,” editorialists write (
pp. 29–30). Trials using functional ability are becoming more common in AD research, they note, but “use of functional ability measures for this purpose overtly or tacitly uses impairment in functional ability as though it were solely a consequence of AD progression.” Specific to this trial, the editorialists add, “The significant difference in the primary outcome, ADCS-ADL score, was not confirmed by significant differences in the secondary outcomes that might reflect functional ability, such as scores on the Caregiver Activity Scale (CAS) and the Dependence Scale, although there was nonsignificant change in the same direction for CAS score.” (D. A. Evans, denis_evans@rush.edu)

>>>NEJM Highlights
Source:
Jan. 2 issue of the New England Journal of Medicine (2014; 370).
Management of Atherosclerotic Renal-Artery Stenosis: For prevention of clinical events in patients with atherosclerotic renal-artery stenosis, stenting is no better than comprehensive medical management, researchers report (pp. 13–22). In the CORAL trial, 947 participants had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease. Medical therapy with or without renal-artery stenting showed the following changes in a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or need for renal-replacement therapy: “Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P = 0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P = 0.03).” (C. J. Cooper, christopher.cooper@utoledo.edu)
“Until new treatments are found to be safe and effective, patients in everyday practice who have moderately severe atherosclerotic renovascular disease and either hypertension or stage 3 chronic kidney disease should receive medical therapy to control blood pressure and prevent the progression of atherosclerosis but should not be corralled into getting a renal-artery stent,” an editorialist advises (
pp. 78–9; J. A. Bittl).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 3, 2014 * Vol. 21, No. 2
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Jan. issue of Pediatrics (2014; 133).
Pertussis Exposure in Health Care Workers: In pediatric health care settings, occupational exposure to pertussis occurs frequently despite effective implementation of infection prevention and control (IPC) guidelines, researchers report (pp. 15–21). From 2002 through 2011 in a large quaternary pediatric care network, analysis of occupational exposures among health care workers (HCWs) and associated characteristics showed these “missed opportunities”: “A total of 1,193 confirmed HCW pertussis exposures were associated with 219 index cases during the study period. Of these, 38.8% were infants <6 months old and 7 were HCWs. Most (77.5%) of exposures occurred in the emergency department or an ambulatory site; 27.0% of exposures occurred after documented initiation of IPC precautions. We identified 450 laboratory-confirmed pertussis cases through [electronic health record] review, of which 49.8% (N = 224) had no [occupational health] or IPC investigation. The majority of uninvestigated cases (77.2%) were from ambulatory sites.” (D. E. Kuncio)
Vitamin D Intoxication From Dietary Supplement: Authors from Turkey report a case of vitamin D intoxication in 7 children who used a fish oil supplement with 4000 times the labeled concentration of vitamin D3 (pp. e240–4; C. Kara).

>>>Psychiatry Highlights
Source:
Jan. issue of American Journal of Psychiatry (2014; 171).
SSRIs & Upper GI Bleeds: Men on short-term courses of SSRIs are at increased risk of upper gastrointestinal bleeding, according to a study of psychiatric inpatients in Taiwan (pp. 54–61). Case–control analysis of records in the country’s national health insurance database shows these patterns after 7, 14, and 28 days of SSRI therapy: “A total of 5,377 patients with upper gastrointestinal bleeding were enrolled. The adjusted odds ratio for the risk of upper gastrointestinal bleeding after SSRI exposure was 1.67 (95% CI = 1.23–2.26) for the 7-day window, 1.84 (95% CI = 1.42–2.40) for the 14-day window, and 1.67 (95% CI = 1.34–2.08) for the 28-day window. SSRIs with high and intermediate, but not low, affinity for serotonin transporter were associated with upper gastrointestinal bleeding. An elevated risk of upper gastrointestinal bleeding after SSRI exposure was seen in male but not female patients.” (C-L Lu, cllu@vghtpe.gov.tw)
High-Dose Citalopram: Cardiovascular risks make the safety of high-dose citalopram unclear, according to authors of a Commentary article (pp. 20–2). They conclude: “Ultimately, it is up to clinicians and their patients to weigh … potential risks with … potential benefits. Clearly, there is a perceived clinical benefit to citalopram dosages above 40 mg/day; 12% of prescriptions in our study exceeded this threshold. Even if a randomized controlled trial did not find greater efficacy for 60 mg compared with 40 mg of citalopram, randomized controlled trials are limited in their generalizability to real-world patients and practices. No study methodology is perfect. Patients, providers, and health systems deserve to have all available information on which to base their health care decisions. We believe that FDA warnings should incorporate studies across scientific disciplines assessing medication risks, along with the potential risks and benefits of complying with the warnings themselves.” (K. Zivin, kzivin@umich.edu)

>>>Pharmacotherapy Report
Source:
Early-release article from Pharmacotherapy (2014; 34).
Pediatric Antibiotic Costs in U.S. v. U.K.: Use and cost of antibiotics prescribed for young children are substantially higher in the U.S. than in the U.K., according to an analysis conducted by the Boston Collaborative Drug Surveillance Program (10.1002/phar.1387). U.S. data for 160,000 young children covered by private insurers were compared with U.K. data from general practices in 2009, with these results: “In the United States, ~75% of privately insured children were prescribed one or more antibiotics compared with an estimated 50% in the United Kingdom. The annual cost was more than five times higher in the United States compared with the United Kingdom The usage and cost of antibiotics in young privately insured children is far higher in the United States than in the United Kingdom, where the government pays the cost of prescription drugs.” (H. Jick, hjick@bu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 6, 2014 * Vol. 21, No. 3
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 4 issue of Lancet (2014; 383).
RNA Interference Drug & LDL Cholesterol: In healthy volunteers with elevated lipids, an RNA interference (RNAi) drug lowered LDL cholesterol levels, researchers report (pp. 60–8). “These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins,” the authors wrote of their Phase I trial. “This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings.” Intravenous ALN-PCS in doses ranging from 0.015 to 0.4 mg/kg produced these effects in comparison with placebo: “Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0.015 mg/kg [n = 3], 0.045 mg/kg [n = 3], 0.090 mg/kg [n = 3], 0.150 mg/kg [n = 3], 0.250 mg/kg [n = 6], or 0.400 mg/kg [n = 6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0.400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p < 0.0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p < 0.0001).” (K. Fitzgerald, kfitzgerald@alnylam.com)
Ramucirumab for Advanced Gastric Adenocarcinoma: Vascular endothelial growth factor receptor-2 (VEGFR-2)-mediated signaling is “an important therapeutic target in advanced gastric cancer,” conclude authors of a Phase III trial of ramucirumab monotherapy in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma (pp. 31–9). At 119 centers in 29 countries on all inhabited continents, participants had these responses to ramucirumab 8 mg/kg or placebo once every 2 weeks: “355 patients were assigned to receive ramucirumab (n = 238) or placebo (n = 117). Median overall survival was 5.2 months (IQR 2.3–9.9) in patients in the ramucirumab group and 3.8 months (1.7–7.1) in those in the placebo group (hazard ratio [HR] 0.776, 95% CI 0.603–0.998; p = 0.047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0.774, 0.605–0.991; p = 0.042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.” (C. S. Fuchs, cfuchs@partners.org)

>>>PNN JournalWatch
* Diagnosis, Management, and Prevention of Rotavirus Gastroenteritis in Children, in
BMJ, 2013; 347: f7204. (U. D. Parashar, uap2@cdc.gov)
* Management of Antiplatelet Therapy in Patients With Coronary Artery Disease Requiring Cardiac and Noncardiac Surgery, in
Circulation, 2013; 128: 2785–98. (D. J. Angiolillo, dominick.angiolillo@jax.ufl.edu)
* Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update: A Scientific Statement From the American Heart Association, in
Circulation, 2014; 128: 2813–51. (S. K. Ganesh)
* Antithrombotic Treatment in Transcatheter Aortic Valve Implantation: Insights for Cerebrovascular and Bleeding Events, in
Journal of the American College of Cardiology, 2013; 62: 2349–59. (J. Rodés-Cabau)
* High-Dose Atorvastatin Reduces Periodontal Inflammation: A Novel Pleiotropic Effect of Statins, in
Journal of the American College of Cardiology, 2013; 62: 2382–91. (S. Subramanian)
* Isotonic Versus Hypotonic Maintenance IV Fluids in Hospitalized Children: A Meta-Analysis, in
Pediatrics, 2014; 133: 105–13. (J. Wang)
* Schizophrenia Complicated by Chronic Hepatitis C Virus and Hepatic Encephalopathy, in
American Journal of Psychiatry, 2014; 171: 25–31. (M. Viron, mark.viron@state.ma.us)
* Recent Changes in Pregnancy and Lactation Labeling: Retirement of Risk Categories, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1385. (N. M. Patel-Shori, nmpatel@temple.edu)
* Use of Compounded Bioidentical Hormone Therapy in Menopausal Women: An Opinion Statement of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1394. (S. E. McBane, smcbane@mail.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 706/613-0200 (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
Jan. 7, 2014 * Vol. 21, No. 4
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 7 issue of the Annals of Internal Medicine (2014; 160).
Opioid Prescribing: A review article shows that “recent guidelines on chronic pain agree on several opioid risk mitigation strategies, including upper dosing thresholds; cautions with certain medications; attention to drug–drug and drug–disease interactions; and use of risk assessment tools, treatment agreements, and urine drug testing” (pp. 38–47). Thirteen guidelines published in 2007–13 were assessed with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument and A Measurement Tool to Assess Systematic Reviews (AMSTAR): “Overall AGREE II scores were 3.00 to 6.20 (on a scale of 1 to 7). The AMSTAR ratings were poor to fair for 10 guidelines. Two received high AGREE II and AMSTAR scores. Most guidelines recommend that clinicians avoid doses greater than 90 to 200 mg of morphine equivalents per day, have additional knowledge to prescribe methadone, recognize risks of fentanyl patches, titrate cautiously, and reduce doses by at least 25% to 50% when switching opioids. Guidelines also agree that opioid risk assessment tools, written treatment agreements, and urine drug testing can mitigate risks. Most recommendations are supported by observational data or expert consensus.” (T. K. Nuckols, tnuckols@mednet.ucla.edu)
Meaningful Use of Health IT: “Strong evidence supports the use of clinical decision support and computerized provider order entry,” conclude authors of a systematic review of health information technology (IT) with an emphasis on meaningful use functionality as defined by the federal government (pp. 48–54). “However, insufficient reporting of implementation and context of use makes it impossible to determine why some health IT implementations are successful and others are not,” the authors add. “The most important improvement that can be made in health IT evaluations is increased reporting of the effects of implementation and context.” Review of the published English-language literature in 2010–13 showed the following: “Fifty-seven percent of the 236 studies evaluated clinical decision support and computerized provider order entry, whereas other meaningful use functionalities were rarely evaluated. Fifty-six percent of studies reported uniformly positive results, and an additional 21% reported mixed-positive effects. Reporting of context and implementation details was poor, and 61% of studies did not report any contextual details beyond basic information.” (S. S. Jones, spencer.jones@vanguardhealth.com)
Treatment of Diabetic Macular Edema: Intraocular injection of a vascular endothelial growth factor (VEGF) inhibitor with or without laser surgery is the most cost-effective treatment of diabetic macular edema, according to a cost-effectiveness analysis (pp. 18–29; S. Pershing, pershing@stanford.edu)
Dietary Prevention of Diabetes: A Mediterranean diet supplemented with extra-virgin olive oil (EVOO) without energy restrictions lowered the risk of diabetes among 3,541 men and women in Spain who were at high cardiovascular risk, researchers report (pp. 1–10). A subgroup analysis of the Prevención con Dieta Mediterránea trial showed these patterns in 2003–10 for the EVOO-supplemented Mediterranean diet, the same diet supplemented with nuts, or a control diet consisting of advice on avoiding fats (all with no interventions for increasing activity or decreasing caloric intake): “During follow-up, 80, 92, and 101 new-onset cases of diabetes occurred in the Mediterranean diet supplemented with EVOO, Mediterranean diet supplemented with mixed nuts, and control diet groups, respectively, corresponding to rates of 16.0, 18.7, and 23.6 cases per 1,000 person–years. Multivariate-adjusted hazard ratios were 0.60 (95% CI, 0.43 to 0.85) for the Mediterranean diet supplemented with EVOO and 0.82 (CI, 0.61 to 1.10) for the Mediterranean diet supplemented with nuts compared with the control diet.” (J. Salas-Salvadó, jordi.salas@urv.cat)

>>>PNN NewsWatch
* Two lots of Clinimix (Amino Acid in Dextrose) Injection and one lot of Clinimix E Injection (Amino Acid with Electrolytes in Dextrose with Calcium) are being recalled because of complaints of particulate matter, Baxter and FDA said yesterday. Affected lots were distributed in May 2012 through Oct. 2013 and carry the product codes 2B7729 (lot P287045, exp 06/14), 2B7717 (lot P275883, exp 10/13) and 2B7709 (lot P28512, exp 05/14).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 8, 2014 * Vol. 21, No. 5
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 8 issue of JAMA, a theme issue marking the 50th anniversary of issuance of the Surgeon General’s report on Smoking and Health (2013; 311).
Pharmacotherapy for Smoking Cessation: Research and review articles explore use of pharmacologic agents in achieving tobacco cessation.
In patients with schizophrenia or bipolar disorder who achieved smoking cessation with standard treatment, maintenance varenicline therapy and cognitive behavioral therapy improved 1-year tobacco abstinence rates, compared with cognitive behavioral therapy alone, and the effect persisted for 6 months after varenicline discontinuation, a study shows (
pp. 145–54). Participants had 2 or more weeks of continuous abstinence at week 12 of open treatment upon study entry. Based on a 7-day rate of continuous abstinence at study week 52, researchers found these effects of cognitive behavioral therapy with or without varenicline 1 mg twice daily: “Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2–19.2; P < .001). From weeks 12 through 64, 45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5–15.7; P = .004), and from weeks 12 through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events.” (A. E. Evins, a_eden_evins@hms.harvard.edu)
Prolonged abstinence was improved among cigarette smokers through use of combination pharmacotherapy for 12 weeks, according to a study of 315 adults (
pp. 155–63). Varenicline plus bupropion produced these changes in abstinence rates at week 12 and 7-day point prevalence abstinence in comparison with varenicline alone: “At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05–2.12; P = .03 and OR, 1.36; 95% CI, 0.95–1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04–2.22; P = .03 and OR, 1.32; 95% CI, 0.91–1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93–2.07; P = .11 and OR, 1.40; 95% CI, 0.96–2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03).” (J. O. Ebbert, ebbert.jon@mayo.edu)
In a Clinical Evidence Synopsis, authors examine quit rates in studies of pharmacotherapy support of tobacco cessation (
pp. 193–4): “Higher rates of smoking cessation were associated with [nicotine-replacement therapy (NRT)] (17.6%) and bupropion (19.1%) compared with placebo (10.6%). Varenicline (27.6%) and combination NRT (31.5%) (eg, patch plus inhaler) were most effective for achieving smoking cessation. None of the therapies was associated with an increased rate of serious adverse events.” (K. Cahill, kate.cahill@phc.ox.ac.uk)
e-Cigarettes as Disruptive Technology: Should tobacco control advocates support use of e-cigarettes as a means of harm reduction? That question is explored in a Viewpoint article that explains that the other major philosophy in tobacco control—abstinence—appears stalled (pp. 135–6): “The more appealing e-cigarette innovations become, the more likely they will be a disruptive technology. Although the science is insufficient to reach firm conclusions on some issues, e-cigarettes, with prudent tobacco control regulations, do have the potential to make the combusting of tobacco obsolete.” (D. B. Abrams, dabrams@legacyforhealth.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 706/613-0200 (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
Jan. 9, 2014 * Vol. 21, No. 6
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 9 issue of the New England Journal of Medicine (2013; 370).
Glycemic Control in Pediatric Critical Care: In a trial comparing tight versus conventional glucose control in pediatric intensive-care units (ICUs), no major clinical differences were found, researchers report (pp. 107–18). Hypoglycemic episodes were more common with tight control, but its 12-month costs were lower. Study participants in the Control of Hyperglycaemia in Paediatric Intensive Care (CHiP) study were patients younger than 17 admitted to pediatric ICUs with an expected requirement for mechanical ventilation and vasoactive drugs for 12 hours or more. Tight (target blood glucose range of 72–126 mg/dL) and conventional (target blood glucose less than 216 mg/dL) control showed these results based on a primary outcome of number of days alive and free from mechanical ventilation at 30 days after randomization: “A total of 1,369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], −0.42 to 1.14); the effects did not differ according to subgroup. Severe hypoglycemia (blood glucose, <36 mg per deciliter [2.0 mmol per liter]) occurred in a higher proportion of children in the tight-glycemic-control group than in the conventional-glycemic-control group (7.3% vs. 1.5%, P < 0.001). Overall, the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group. The mean 12-month costs were similar in the two groups in the cardiac-surgery subgroup, but in the subgroup that had not undergone cardiac surgery, the mean cost was significantly lower in the tight-glycemic-control group than in the conventional-glycemic-control group: −$13,120 (95% CI, −$24,682 to −$1,559).” (D. Macrae, d.macrae@rbht.nhs.uk)
Definitive clinical advice regarding glycemic control in pediatric critical care cannot be offered until more data are available, an editorialist writes (
pp. 168–9): “In the CHiP trial, the non–cardiac-surgery patients appeared to differ importantly from cardiac-surgery patients, with a higher predicted mortality, and in prior data, these patients also had a higher rate and severity of hyperglycemia. Although the improved 1-year health care outcomes in the non–cardiac-surgery patients is compelling, it remains impossible to determine best practice for the child who requires critical care for reasons other than cardiac surgery or burns until either a meta-analysis of several trials is performed on an individual-data level or until data from an ongoing large, multicenter trial (ClinicalTrials.gov number, NCT01565941) are accrued. Future clinical trials should use the most advanced technology to reduce the incidence, severity, and duration of adverse events, most saliently, hypoglycemia.” (M. S. D. Agus)
Pharmacogenetics & Lithium Therapy: In patients of Han Chinese descent, variations in the gene encoding glutamate decarboxylase–like protein 1 (GADL1) affect responses to lithium when used for maintenance treatment of bipolar I disorder, a study conducted by the Taiwan Bipolar Consortium shows (pp. 119–28). After testing for single-nucleotide polymorphisms (SNPs) in a larger group, sequencing of the genomes of 94 patients showed the following: “Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P = 5.50×10−37 and P = 2.52×10−37, respectively) and in the replication sample of 100 patients (P = 9.19×10−15 for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort.” (A. T-A Cheng, bmandrew@gate.sinica.edu.tw)

>>>PNN NewsWatch
* FDA yesterday approved dapaglifozin (Farxiga, Bristol-Myers Squibb) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The sodium-glucose co-transporter 2 (SGLT2) inhibitor blocks reabsorption of glucose by the kidney, increases glucose excretion, and lowers blood glucose levels.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 10, 2014 * Vol. 21, No. 7
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Jan. 7 issue of the Journal of the American College of Cardiology (2013; 63).
Rosuvastatin for Preventing Contrast-Induced Acute Kidney Injury: A pair of research studies examine use of short-term rosuvastatin for preventing contrast-induced acute kidney injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD).
In 2,998 such patients who were undergoing coronary/peripheral arterial angiography with or without percutaneous intervention, rosuvastatin 10 mg/d given for 3 days before and 2 days after imaging significantly reduced the risk of CI-AKI, researchers report (
pp. 62–70). Based on increases in serum creatinine concentration ≥0.5 mg/dL (44.2 µmol/L) or 25% above baseline at 72 h after exposure to contrast medium, the authors found these patterns in risk of CI-AKI: “Patients randomized to the rosuvastatin group had a significantly lower incidence of CI-AKI than controls [receiving standard care] (2.3% vs. 3.9%, respectively; p = 0.01). During 30 days’ follow-up, the rate of worsening heart failure was significantly lower in the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p = 0.02).” (Y. Han)
In 504 patients with acute coronary syndrome (ACS), high-dose rosuvastatin given on admission for early invasive procedures prevented CI-AKI and improved short-term clinical outcomes in the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy On Contrast-Induced Acute Kidney Injury and Myocardial Damage in Patients With Acute Coronary Syndrome) study (
pp. 71–9). Rosuvastatin 40 mg on admission and 20 mg/d or no statin treatment was provided to participants, all of whom were statin-naive on admission. Using the same definition for CI-AKI as in the above study, the investigators found: “The incidence of CI-AKI was significantly lower in the statin group than in controls (6.7% vs. 15.1%; adjusted odds ratio: 0.38; 95% confidence interval [CI]: 0.20 to 0.71; p = 0.003). The benefits against CI-AKI were consistent, even applying different CI-AKI definition criteria and in all the pre-specified risk categories. The 30-day incidence of adverse cardiovascular and renal events (death, dialysis, myocardial infarction, stroke, or persistent renal damage) was significantly lower in the statin group (3.6% vs. 7.9%, respectively; p = 0.036). Moreover, statin treatment given on admission was associated with a lower rate of death or nonfatal myocardial infarction at 6 month follow-up (3.6% vs. 7.2%, respectively; p = 0.07).” (M. Leoncini)

>>>Circulation Report
Source:
Jan. 7 issue of Circulation (2013; 129).
Cardiovascular Events & Smoking-Cessation Drugs: Pharmacotherapies used in smoking cessation “do not appear to raise the risk of serious cardiovascular disease events,” according to a network meta-analysis of trials in 10 electronic databases (pp. 28–41). Based on 63 randomized controlled trials (RCTs) that included any of the three licensed smoking-cessation therapies, the investigators found “no increase in the risk of all cardiovascular disease events with bupropion (relative risk [RR], 0.98; 95% confidence interval [CI], 0.54–1.73) or varenicline (RR, 1.30; 95% CI, 0.79–2.23). There was an elevated risk associated with nicotine replacement therapy that was driven predominantly by less serious events (RR, 2.29; 95% CI, 1.39–3.82). When we examined major adverse cardiovascular events, we found a protective effect with bupropion (RR, 0.45; 95% CI, 0.21–0.85) and no clear evidence of harm with varenicline (RR, 1.34; 95% CI, 0.66–2.66) or nicotine replacement therapy (RR, 1.95; 95% CI, 0.26–4.30).” (E. J. Mills, millsej@stanford.edu)
After noting the difficulties inherent in pooling trial data and noting that only six direct comparisons of the cessation drugs were made in the 63 trials, editorialists conclude that the “evidence is not of sufficient strength to warrant reconsideration of guidelines” (
pp. 8–10): “Given the number of smokers who will quit with pharmacotherapy, we need better information on any risks that they may face from the drugs used to increase the success of cessation. Additionally, if nicotine delivery products other than combustible tobacco products, eg, electronic cigarettes, come into widespread usage, the long-term consequences of nicotine alone will assume increasing significance.” (J. M. Samet, jsamet@med.usc.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 706/613-0200 (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
Jan. 13, 2014 * Vol. 21, No. 8
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 11 issue of Lancet (2014; 383).
Vitamin D Supplements & Bone Mineral Density: Continued use of vitamin D supplements by community-dwelling adults without specific risk factors “seems to be inappropriate,” investigators conclude based on a systematic review and meta-analysis of studies of effects on bone mineral density (pp. 146–55). Nearly half of adults older than 50 are using vitamin D supplements, the group writes, but the literature shows the following: “Of 3,930 citations identified by the search strategy, 23 studies (mean duration 23.5 months, comprising 4,082 participants, 92% women, average age 59 years) met the inclusion criteria. 19 studies had mainly white populations. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies (n = 1,791). In ten studies (n = 2,294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in each study, so 70 tests of statistical significance were done across the studies. There were six findings of significant benefit, two of significant detriment, and the rest were non-significant. Only one study showed benefit at more than one site. Results of our meta-analysis showed a small benefit at the femoral neck (weighted mean difference 0.8%, 95% CI 0.2–1.4) with heterogeneity among trials (I2 = 67%, p < 0.00027). No effect at any other site was reported, including the total hip. We recorded a bias toward positive results at the femoral neck and total hip.” (I. R. Reid, i.reid@auckland.ac.nz)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Harm Reporting in Systematic Reviews: Poor reporting of adverse events in primary studies are compounded in systematic reviews, researchers report (f7668). A systematic review of systematic reviews with an adverse event (an adverse reaction, harm, or complication associated with any health care intervention) as the main outcome showed the following: “Of 4,644 reviews identified, 309 were systematic reviews or meta-analyses primarily assessing harms (13 from [Cochrane Database of Systematic Reviews]; 296 from [Database of Abstracts of Reviews of Effects]). Despite a short time interval, the comparison between the years of 2008 and 2010–11 showed no difference on the quality of reporting over time (P = 0.079). Titles in fewer than half the reviews (proportion of reviews 0.46 (95% confidence interval 0.40 to 0.52)) did not mention any harm related terms. Almost one third of DARE reviews (0.26 (0.22 to 0.31)) did not clearly define the adverse events reviewed, nor did they specify the study designs selected for inclusion in their methods section. Almost half of reviews (n = 170) did not consider patient risk factors or length of follow-up when reviewing harms of an intervention. Of 67 reviews of complications related to surgery or other procedures, only four (0.05 (0.01 to 0.14)) reported professional qualifications of the individuals involved. The overall, unweighted, proportion of reviews with good reporting was 0.56 (0.55 to 0.57); corresponding proportions were 0.55 (0.53 to 0.57) in 2008, 0.55 (0.54 to 0.57) in 2009, and 0.57 (0.55 to 0.58) in 2010–11.” (S. Vohra, svohra@ualberta.ca)

>>>PNN NewsWatch
* FDA has approved GlaxoSmithKline’s trametinib (Mekinist) for use with the company’s dabrafenib (Tafinlar) for treatment of patients with advanced unresectable or metastatic melanoma. The accelerated approval was based on studies showing cancer shrinkage or disappearance with combination therapy in 76% of patients for an average of 10.5 months, compared with 54% with dabrafenib monotherapy for an average of 5.6 months.

>>>PNN JournalWatch
* Adverse Event Reporting in Cancer Clinical Trial Publications, in
Journal of Clinical Oncology, 2014; 32: 83–9. (M. D. Galsky, matthew.galsky@mssm.edu)
* Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology, in
Journal of Clinical Oncology, 2014; 32: 129–60. (L. Krilov, lada.krilov@asco.org)
* How Will Physicians Respond to the Next Influenza Pandemic?, in
Clinical Infectious Diseases, 2014; 58: 233–7. (D. S. Fedson, dfedson@wanadoo.fr)
* Searching for an Optimal Hand Hygiene Bundle: A Meta-analysis, in
Clinical Infectious Diseases, 2014; 58: 248–59. (M. Schweizer, marin-schweizer@uiowa.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 706/613-0200 (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
Jan. 14, 2014 * Vol. 21, No. 9
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. issue of the JAMA Internal Medicine (2014; 174).
Cardiovascular Events With Estradiol v. Conjugated Equine Estrogens: In an observational study of postmenopausal women who were using oral hormone therapy, cardiovascular risks were higher with oral conjugated equine estrogens (CEEs) than with oral estradiol (pp. 25–31). Risks of incident venous thrombosis were significantly higher with CEEs, and myocardial infarctions showed a statistical trend in the population-based, case–control study of patients in a large health-maintenance organization in 2003–09: “We studied 68 venous thrombosis, 67 myocardial infarction, and 48 ischemic stroke cases, with 201 matched controls; all participants were current users of oral CEEs or estradiol. In adjusted analyses, current oral CEEs use compared with current oral estradiol use was associated with an increased venous thrombosis risk (odds ratio, 2.08; 95% CI, 1.02–4.27; P = .045) and an increased myocardial infarction risk that did not reach statistical significance (odds ratio, 1.87; 95% CI, 0.91–3.84; P = .09) and was not associated with ischemic stroke risk (odds ratio, 1.13; 95% CI, 0.55–2.31; P = .74). Among 140 controls, CEEs users compared with estradiol users had higher endogenous thrombin potential–based normalized activated protein C sensitivity ratios (P < .001), indicating a stronger clotting propensity.” (N. L. Smith, nlsmith@u.washington.edu)
Gabapentin for Alcohol Dependence: In a placebo-controlled trial conducted in 150 men and women with alcohol dependence, gabapentin was effective for treatment of alcohol dependence and improving relapse-related insomnia, dysphoria, and craving, researchers report (pp. 70–7). Participants in the 12-week trial conducted in 2004–10 received placebo or gabapentin 900 or 1800 mg/d and manual-guided counseling, with these results: “Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%–13.7%) in the placebo group, 11.1% (95% CI, 5.2%–22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%–30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%–37.2%) in the placebo group, 29.6% (95% CI, 19.1%–42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%–58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.” (B. J. Mason, mason@scripps.edu)
AF & MI Risk: Patients with atrial fibrillation (AF), in addition to being at increased risk of stroke, are at increased risk of myocardial infarction (MI), a prospective cohort study of 23,928 U.S. residents shows (pp. 107–14). Analysis of expert-adjudicated total MI events in 2003–07 with follow-up through 2009 showed these patterns: “Over 6.9 years of follow-up (median 4.5 years), 648 incident MI events occurred. In a sociodemographic-adjusted model, AF was associated with about 2-fold increased risk of MI (hazard ratio [HR], 1.96 [95% CI, 1.52–2.52]). This association remained significant (HR, 1.70 [95% CI, 1.26–2.30]) after further adjustment for total cholesterol, high-density lipoprotein cholesterol, smoking status, systolic blood pressure, blood pressure–lowering drugs, body mass index, diabetes, warfarin use, aspirin use, statin use, history of stroke and vascular disease, estimated glomerular filtration rate, albumin to creatinine ratio, and C-reactive protein level. In subgroup analysis, the risk of MI associated with AF was significantly higher in women (HR, 2.16 [95% CI, 1.41–3.31]) than in men (HR, 1.39 [95% CI, 0.91–2.10]) and in blacks (HR, 2.53 [95% CI, 1.67–3.86]) than in whites (HR, 1.26 [95% CI, 0.83–1.93]); for interactions, P = .03 and P = .02, respectively. On the other hand, there were no significant differences in the risk of MI associated with AF in older (≥75 years) vs younger (<75 years) participants (HR, 2.00 [95% CI, 1.16–3.35] and HR, 1.60 [95% CI, 1.11–2.30], respectively); for interaction, P = .44.” (E. Z. Soliman, esoliman@wakehealth.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 706/613-0200 (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
Jan. 15, 2014 * Vol. 21, No. 10
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 15 issue of JAMA (2014; 311).
Varespladib & Cardiovascular Events in Acute Coronary Syndrome: More harm than good resulted from use of the secretory phospholipase A2 (sPLA2) inhibitor varespladib in patients with acute coronary syndrome (ACS), report investigators with the Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) study (pp. 252–62). The risk of recurrent cardiovascular events was not lowered and the risk of myocardial infarction (MI) was higher in patients receiving active therapy, study results show. At 362 academic and community hospitals on four continents, 5,145 patients were randomized within 96 hours of presentation with ACS to varespladib 500 mg or placebo for 16 weeks, with these results: “At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97–1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16–2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02–1.82; P = .04).” (S. J. Nicholls, stephen.nicholls@sahmri.com)
Coronary Artery Calcium Density & Cardiovascular Risks: The density of coronary artery calcium (CAC) should be considered in CAC scoring systems, Multi-Ethnic Study of Atherosclerosis (MESA) investigators conclude (pp. 271–8). Measurement of CAC volume and density in 3,398 older adults of various races and ethnicities led to this conclusion: “CAC volume was positively and independently associated with [coronary heart disease (CHD)] and [cardiovascular disease (CVD)] risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk.” (M. H. Criqui, mcriqui@ucsd.edu)
Wider testing of CAC in asymptomatic individuals is not justified, an editorialist writes (
pp. 247–8): “In recent clinical guidelines of the American Heart Association/American College of Cardiology, measurement of CAC was considered to be reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10%–20% 10-year risk). However, even with the added discrimination provided by the density score, use of CAC testing that is wider than this cannot presently be justified. The very modest change in area under the curve beyond CAC score alone … suggests that very few such patients would be reclassified to clinically meaningful risk scores with this added measure of risk for CHD events. Among patients at intermediate risk, those in whom CAC has its greatest utility, 13.9% of patients were correctly reclassified. Thus, although CAC density scoring can be useful for increasing the discrimination of CAC testing at little or no cost, the evidence on CAC testing in general is not sufficient to justify wider testing based on these relatively modest findings.” (P. Greenland, p-greenland@northwestern.edu)

>>>PNN NewsWatch
* Tamiflu Oral Suspension is in short supply, FDA said yesterday. Capsules remain available, and FDA reminds health professionals that approved instructions for preparing a suspension from the 75-mg capsules are in product labeling and on the FDA drug-shortages website.
* Health professionals should stop prescribing and dispensing combination drug products containing more than
325 mg of acetaminophen, FDA said yesterday. “There are no available data to show that taking more than 325 mg of acetaminophen per dosage unit provides additional benefit that outweighs the added risks for liver injury,” FDA said, but limiting the acetaminophen dose “will reduce the risk of severe liver injury from inadvertent acetaminophen overdose, which can lead to liver failure, liver transplant, and death.” When pharmacists receive prescriptions for combination products with more than 325 mg of acetaminophen per dosage unit, FDA recommended that they contact prescribers to discuss a product with a lower dose of acetaminophen. A two-tablet or two-capsule dose may still be prescribed, if appropriate, FDA added.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 16, 2014 * Vol. 21, No. 11
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 16 issue of the New England Journal of Medicine (2014; 370).
Pritelivir for HSV-2 Infection: In 156 patients with genital herpes simplex virus 2 (HSV-2) infection, the viral helicase–primase complex inhibitor pritelivir reduced rates of genital HSV shedding and days with lesions in a dose-dependent manner, researchers report (pp. 201–10). The dose-ranging study compared oral pritelivir 5, 25, or 75 mg daily or 400 mg weekly with placebo during 28 days of treatment: “HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups.” (A. Wald, annawald@u.washington.edu)
Pritelivir has “a significant advantage” over currently approved DNA polymerase inhibitors, editorialists write (
pp. 273–4): “The polymerase (UL30), together with its accessory subunit (UL42), function in concert with three subunits of the helicase–primase complex (UL5, UL8, and UL52) and ICP8 to direct the synthesis of viral DNA. Pritelivir interferes with this process by inhibiting the helicase–primase complex. This mechanism gives pritelivir a significant advantage because resistance to it maps to UL5; pritelivir thus remains active against viruses that are resistant to acyclovirs, typically because they harbor mutations in the thymidine kinase and DNA polymerase. Because of its unique mechanism of action, pritelivir provides an alternative to the nucleoside therapeutic agents and exhibits a distinct profile of antiviral resistance. Resistance to the nucleoside analogues is encountered regularly in the immunocompromised host, particularly in recipients of stem-cell transplants and patients in whom antiretroviral therapy for the acquired immunodeficiency syndrome has failed.” (R. J. Whitley)
Daclatasvir/Sofosbuvir for Chronic HCV Infection: In a multiphase, open-label trial, untreated and previously treated patients with chronic hepatitis C virus (HCV) infection responded to once-daily oral daclatasvir plus sofosbuvir, with high rates of sustained virologic response in patients with all three types of HCV and in some for whom prior therapy with telaprevir or boceprevir had not worked (pp. 211–21). With a primary end point of sustained virologic response (HCV RNA level of <25 IU/mL) at week 12 after the end of therapy, investigators found: “Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.” (M. S. Sulkowski, msulkowski@jhmi.edu)
Interferon-free HCV Therapy: Sustained virologic response rate of 88% at 8 weeks and 95% at 12 weeks was observed in a Phase IIb study of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin for treatment of 571 patients with HCV (pp. 222–32; K. V. Kowdley, kris.kowdley@vmmc.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 706/613-0200 (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
Jan. 17, 2014 * Vol. 21, No. 12
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Jan. issue of the Journal of Allergy and Clinical Immunology (2014; 133).
Race, Ethnicity & Pharmacogenetics: “Large consortium-based sequencing studies are using next-generation whole-genome sequencing to provide a diverse genome map of different admixed populations, which can be used for future pharmacogenetic studies,” authors of a review article write (pp. 16–26). “These studies will include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches that account for ancestral genetic structure, complex haplotypes, gene–gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci,” the authors conclude based on these findings: “To date, pharmacogenetic studies have been primarily performed in trial cohorts consisting of non-Hispanic white subjects of European descent. A ‘bottleneck’ or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries, has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry might introduce genetic variation, which has the potential to alter the therapeutic efficacy of commonly used asthma therapies, such as beta-2-adrenergic receptor agonists (beta-agonists). Pharmacogenetic studies of admixed ethnic groups have been limited to small candidate gene association studies, of which the best example is the gene coding for the receptor target of beta-agonist therapy, the beta-2-adrenergic receptor (ADRB2).” (D. A. Meyers, dmeyers@wakehealth.edu)

>>>Infectious Diseases Report
Source:
Feb. 1 issue of Clinical Infectious Diseases (2014; 58).
Influenza Vaccine Effectiveness: Prior-year influenza immunizations reduced effectiveness of the 2011–12 vaccine, especially against the A(H3N2) strain that circulated that season, researchers report (pp. 319–27). Data from the U.S. Influenza Vaccine Effectiveness Network showed these patterns for patients with acute respiratory illnesses of 7 or fewer days’ duration: “The 2011–2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval [CI], 36–56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44–79) against type A (H1N1) pdm09 but only 39% (95% CI, 23–52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35–73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes.” (S. E. Ohmit, sohmit@umich.edu)

>>>Neurology Highlights
Source:
Jan. issue of Neurology (2014; 82).
Psychiatric Disorders & Multiple Sclerosis: An evidence-based guideline provides advice on assessing and managing psychiatric disorders in patients with multiple sclerosis (MS) (pp. 174–81). “Clinicians may consider a telephone-administered cognitive behavioral therapy program for treating depressive symptoms (Level C),” the report states. “Although pharmacologic and nonpharmacologic therapies are widely used to treat depressive and anxiety disorders in individuals with MS, evidence is insufficient to support/refute the use of the antidepressants and individual and group therapies reviewed herein (Level U). For pseudobulbar affect, a combination of dextromethorphan and quinidine may be considered (Level C). Evidence is insufficient to determine the psychiatric effects in individuals with MS of disease-modifying and symptomatic therapies and corticosteroids; risk factors for suicide; and treatment of psychotic disorders (Level U). Research is needed on the effectiveness in individuals with MS of pharmacologic and nonpharmacologic treatments frequently used in the non-MS population.” (American Academy of Neurology, guidelines@aan.com)

>>>PNN NewsWatch
* The number of Medicare beneficiaries eligible for medication therapy management services under Part D would “expand greatly” if a proposed CMS rule is finalized, APhA reports on pharmacist.com.
*
PNN will not be published on Mon. Jan. 20, King Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 21, 2014 * Vol. 21, No. 13
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 21 issue of the Annals of Internal Medicine (2014; 160).
Canine Vaccination for Prevention of Human Rabies in Tanzania: In rural Tanzania, “annual canine rabies vaccination campaigns conferred extraordinary value and dramatically reduced the health burden of rabies” in people, researchers report (pp. 91–100). A cost-effectiveness analysis conducted from the perspective of the health policymaker and over a 10-year time horizon showed these results in the base-case and sensitivity analyses: “Annual canine vaccination campaigns were very cost-effective in [two] districts compared with no canine vaccination. In Serengeti, annual campaigns with as much as 70% coverage were cost-saving.…
“Across a wide range of variable assumptions and levels of societal willingness to pay for life–years, the optimal vaccination coverage for Serengeti was 70%. In Ngorongoro, although optimal coverage depended on willingness to pay, vaccination campaigns were always cost-effective and life-saving and therefore preferred.” (M. C. Fitzpatrick,
meagan.fitzpatrick@yale.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Prenatal Antidepressant Exposure & Newborn Pulmonary Hypertension: Babies born to women taking SSRI antidepressants during late pregnancy have a significant but low risk of developing persistent pulmonary hypertension as newborns, according to a systematic review and meta-analysis (f6932). Seven studies met selection criteria, and evidence regarding SSRIs was sufficient for analysis: “Although exposure to SSRIs in early pregnancy was not associated with persistent pulmonary hypertension of the newborn (odds ratio 1.23, 95% confidence interval 0.58 to 2.60; P = 0.58), exposure in late pregnancy was (2.50, 1.32 to 4.73; P = 0.005). Effects were not significant for any of the moderator variables examined, including study design, congenital malformations, and meconium aspiration. It was not possible to assess for the effect of caesarean section, body mass index, or preterm delivery. The absolute risk difference for development of persistent pulmonary hypertension of the newborn after exposure to SSRIs in late pregnancy was 2.9 to 3.5 per 1,000 infants; therefore an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn.” (S. Grigoriadis, sophie.grigoriadis@sunnybrook.ca)
Smoking Cessation Support by Health Professionals: Health professionals should support patients’ smoking cessation efforts by incorporating new medicines that have emerged in the past decade, according to authors of a clinical review (f7535). The authors make these key points (N. Zwar, n.zwar@unsw.edu.au):
* Throughout the world tobacco smoking is the leading cause of preventable death and illness.
* As smoking rates in the general population fall in developed countries, a greater proportion of smokers have coexisting problems such as mental illness.
* Cessation support from doctors and other health professionals increases quit rates.
* Tobacco dependence is most effectively treated with a comprehensive approach involving behavioral support and pharmacotherapy.
* Effective medicines include nicotine replacement therapy, varenicline, bupropion, nortriptyline, and cytisine.

>>>PNN JournalWatch
* Prevention of Preterm Parturition, in
New England Journal of Medicine, 2014; 370: 254–61. (J. D. Iams, stefanie.palmer@osumc.edu)
* Combination Corticosteroid/Beta-Agonist Inhaler as Reliever Therapy: A Solution for Intermittent and Mild Asthma?, in
Journal of Allergy and Clinical Immunology, 2014; 133: 39–41. (R. Beasley, Richard.Beasley@mrinz.ac.nz)
* Albuterol Administration Is Commonly Associated With Increases in Serum Lactate in Patients With Asthma Treated for Acute Exacerbation of Asthma, in
Chest, 2014; 145: 53–9. (L. M. Lewis, lewisl@wusm.wustl.edu)
* Evidence of Comparative Effectiveness Without Evidence of Effectiveness: The Case of Phosphate Binders in CKD, in
American Journal of Kidney Diseases, 2014; 63: 13–5. (K. Uhlig)
* The Plasma Cell Signature in Autoimmune Disease, in
Arthritis & Rheumatology, 2014; 66: 173–84. (K. Streicher, streicherk@medimmune.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 706/613-0200 (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
Jan. 22, 2014 * Vol. 21, No. 14
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 22/29 issue of JAMA (2014; 311).
Variation in Pivotal-Trial Evidence for Approved Drugs: For novel therapeutic agents approved by FDA in 2005–12, the quality of evidence from pivotal efficacy trials varied greatly across approved indications, researchers report (pp. 368–77). Using the quality indicators of randomization, blinding, comparator, and trial end points, investigators found these results after examining publicly available FDA documents for 188 novel therapeutic agents approved for 206 indications on the basis of 448 pivotal efficacy trials: “The median number of pivotal trials per indication was 2 (interquartile range, 1–2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%–92.2%]), double-blinded (79.5% [95% CI, 75.7%–83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%–90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270–1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%–40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%–52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%–39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%–23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval.” (J. S. Ross, joseph.ross@yale.edu)
Reasons for FDA Delay & Denial of Approval of New Drugs: Among new drug applications submitted to FDA in 2000–12 for new molecular entities (NMEs), failure to select optimal drug doses and suitable study end points “accounted for significant delays in [their] approval,” a study concludes (pp. 378–84). Retrospective review of FDA documents and data extraction showed these patterns for submitted NMEs: “Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Seventy-one applications required 1 or more resubmissions before approval, with a median delay to approval of 435 days following the first unsuccessful submission. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. The frequency of safety deficiencies was similar among never-approved drugs compared with those with delayed approval (43 of 80 never approved [53.8%] vs 37 of 71 eventually approved [52.1%]; difference, 1.7% [95% CI, −14.86% to 18.05%]; P = .87). However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals (61 of 80 never approved [76.3%] vs 28 of 71 eventually approved [39.4%]; difference, 36.9% [95% CI, 20.25% to 50.86%]; P < .001).” (L. V. Sacks, leonard.sacks@fda.hhs.gov)
Commenting on the above two studies and a third analysis about medical-device approvals at FDA (
pp. 385–91; A. S. Kesselheim, akesselheim@partners.org), editorialists make these points about “opening the FDA black box” during a time of increased openness (pp. 361–3): “Drugs@FDA is becoming more usable and complete, FDA staff might not have published data about unapproved drugs in an earlier era, and the FDA is currently exploring ways to share individual-patient data from clinical trials and has cosponsored a recent Institute of Medicine committee to issue guidelines for such sharing. Although these reports represent important steps in improving understanding of FDA decision making, further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public’s health.” (S. N. Goodman, steve.goodman@stanford.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 23, 2014 * Vol. 21, No. 15
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 23 issue of the New England Journal of Medicine (2014; 370).
Monoclonal Antiamyloid Therapy in Alzheimer Disease: Two research articles and an editorial explore use of monoclonal antibodies that bind amyloid in patients with Alzheimer disease.
In the Phase III EXPEDITION 1 and 2 trials of 1,012 and 1,040 patients, respectively, solanezumab did not improve cognition or functional ability, study investigators report (
pp. 311–21). Patients with mild-to-moderate Alzheimer disease received placebo or intravenous solanezumab 400 mg every 4 weeks for 18 months. Results showed the following on the Alzheimer’s Disease Assessment Scale (ADAS-cog11; higher scores worse) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; lower scores worse): “Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was −0.8 points for the ADAS-cog11 score (95% confidence interval [CI], −2.1 to 0.5; P = 0.24) and −0.4 points for the ADCS-ADL score (95% CI, −2.3 to 1.4; P=0.64) in EXPEDITION 1 and −1.3 points (95% CI, −2.5 to 0.3; P = 0.06) and 1.6 points (95% CI, −0.2 to 3.3; P = 0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were −1.7 points in patients with mild Alzheimer’s disease (95% CI, −3.5 to 0.1; P = 0.06) and −1.5 in patients with moderate Alzheimer’s disease (95% CI, −4.1 to 1.1; P = 0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P = 0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P = 0.49).” (R. S. Doody, rdoody@bcm.edu)
Similar outcomes were found in two Phase III trials of bapineuzumab despite grouping of patients based on presence of the apolipoprotein E (
APOE) epsilon-4 allele (pp. 322–33). All patients had mild-to-moderate Alzheimer disease. One study included 1,121 carriers; the other had 1,331 noncarriers. Using the ADAD-cog11 and the Disability Assessment for Dementia (DAD; lower scores worse), investigators found these responses to various doses of the monoclonal antibody: “There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were −0.2 (P = 0.80) and −1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE epsilon-4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to [positron-emission tomographic amyloid imaging with Pittsburgh compound B] and cerebrospinal fluid phospho-tau concentrations in APOE epsilon-4 allele carriers but not in noncarriers.” (S. Salloway, ssalloway@butler.org)
“Both the bapineuzumab trials and the solanezumab trials have provided valuable information,” editorialists write (
pp. 377–8): “They have brought into question the interpretation placed on some biomarkers—especially the CSF level of phospho-tau, but also brain volume. We advocate continuing to investigate ways to modulate Aß levels in the brain while accepting that we lack clarity on the roles that different forms of Aß play in the disease.” (E. Karran)
E-Cigarettes in Tobacco ‘Endgame’: Noting that “e-cigarettes seek to mimic the personal experience and public performance of smoking,” Perspective authors call for FDA to “move swiftly to regulate them so that their potential harms are better understood—and so that they can contribute to the goal of harm reduction” (pp. 293–5). The stakes in the public-health debate “are heightened by the current discussion of the tobacco endgame, which aims to eliminate smoking or reduce it to very low levels,” the authors explain. (A. L. Fairchild)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 24, 2014 * Vol. 21, No. 16
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (2014; 37).
Gradual Intensification of Lispro Therapy: Compared with insulin therapy intensification using basal ± mealtime insulin in patients with type 2 diabetes who eat light breakfasts, a strategy of initiation and gradual intensification with premixed insulin lispro enabled more patients to achieve glycosylated hemoglobin levels less than 7%, researchers report (pp. 372–80). The strategy produced more nocturnal hypoglycemia than the basal–bolus regimen, and the overall A1C reductions seen were not as great as in previous treat-to-target trials. In the open-label study, these results were reported with up to three injections of insulin lispro mix 25 and/or 50 or with basal insulin glargine plus up to three injections of insulin lispro: “Patients (n = 344; 176 [51%] females; mean [SD] age 54.3 [8.8] years; BMI 29.4 [4.6] kg/m2; baseline HbA1c 9.02 [0.97]%) were randomized to premix (n = 171) or basal+ (n = 173). In the per-protocol analysis (n = 230), least squares means (95% CI) end point HbA1c were 7.40% (7.15–7.65) and 7.55% (7.27–7.82) in respective arms. Between-treatment difference was −0.14% (−0.42 to 0.13), with noninferiority met. Significantly more patients in premix achieved HbA1c targets of <7.0% compared with basal+ (48.2 vs. 36.2%; P = 0.024). Self-monitored blood glucose profiles, body weight changes, total insulin doses, and overall hypoglycemia (65 vs. 60%) were similar in premix and basal+ (P = 0.494), except nocturnal episodes (34.3 vs. 23.7%; P = 0.018) were more common in premix.” (D. Giugliano, dario.giugliano@unina2.it)
Caffeine & Type 2 Diabetes: Coffee consumption is associated with lower risks for type 2 diabetes, according to a systematic review and dose–response meta-analysis of 28 studies of 1.1 million participants (pp. 569–86): “Compared with no or rare coffee consumption, the relative risk (RR; 95% CI) for diabetes was 0.92 (0.90–0.94), 0.85 (0.82–0.88), 0.79 (0.75–0.83), 0.75 (0.71–0.80), 0.71 (0.65–0.76), and 0.67 (0.61–0.74) for 1–6 cups/day, respectively. The RR of diabetes for a 1 cup/day increase was 0.91 (0.89–0.94) for caffeinated coffee consumption and 0.94 (0.91–0.98) for decaffeinated coffee consumption (P for difference = 0.17).” (F. B. Hu, nhbfh@channing.harvard.edu)

>>>Geriatrics Report
Source:
Jan. issue of the Journal of the American Geriatrics Association (2014; 62).
Cranberry Capsules & UTIs: In 928 residents of long-term care facilities (LTCFs) at high risk of UTIs, cranberry capsules twice daily for 12 months reduced the incidence of clinically defined but not strictly defined UTIs (pp. 103–10). In these patients, 76% of whom were women, those with low risk of UTIs had no significant change in UTI incidence, as shown in these results: “In participants with high UTI risk at baseline (n = 516), the incidence of clinically defined UTI was lower with cranberry capsules than with placebo (62.8 vs 84.8 per 100 person–years at risk, P = .04); the treatment effect was 0.74 (95% confidence interval (CI) = 0.57–0.97). For the strict definition, the treatment effect was 1.02 (95% CI = 0.68–1.55). No difference in UTI incidence between cranberry and placebo was found in participants with low UTI risk (n = 412).” (M. A. A. Caljouw, m.a.a.caljouw@lumc.nl)
An economic evaluation of cranberry capsules in these patients shows these results (
pp. 111–6): “In the weeks after a clinical UTI, participants showed a significant but moderate deterioration in quality of life, survival, care dependency, and costs. In high-UTI-risk participants, cranberry costs were estimated at 439 euros per year (1.00 euro = 1.37 U.S. dollar), which is 3,800 euros per prevented clinically defined UTI (95% confidence interval = 1,300 euros to infinity). Using the strict UTI definition, the use of cranberry increased costs without preventing UTIs. Taking cranberry capsules had a 22% probability of being cost-effective compared with placebo (at a willingness to pay of 40,000 euros per [quality-adjusted life–year]). In low-UTI-risk participants, use of cranberry capsules was only 3% likely to be cost-effective.” (W. B. van den Hout, w.b.van_den_hout@lumc.nl)

>>>PNN NewsWatch
* FDA yesterday notified Ranbaxy Laboratories that it is prohibited from manufacturing and distributing active pharmaceutical ingredients from its facility in Toansa, India, for FDA-regulated drug products.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 27, 2014 * Vol. 21, No. 17
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 25 issue of Lancet (2014; 383).
Treating to Stable Low Disease Activity in Rheumatoid Arthritis: At 161 sites worldwide, OPTIMA trial investigators found that treatment of patients with early rheumatoid arthritis to a stable low disease activity target had beneficial effects on clinical, functional, and structural outcomes (pp. 321–32). More patients in an adalimumab-continuation group (40 mg every other week) achieved the low disease target than did those in a methotrexate-monotherapy group (initiated at 7.5 mg/week, increased by 2.5 mg every 1–2 weeks to a maximum weekly dose of 20 mg by week 8), the authors report, adding these details: “The study was done between Dec 28, 2006, and Aug 3, 2010. 1,636 patients were assessed and 1,032 were randomised in [the 26 weeks of] period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2–28%], p = 0.0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in [the 52 weeks of] period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups.” (J. S. Smolen, josef.smolen@meduniwien.ac.at)

>>>Health Affairs Report
Source:
Jan. issue of Health Affairs, a theme issue on Exploring Alternatives to Malpractice Litigation (2014; 33).
Disclosing Medical Errors to Patients, Families: Increasing the involvement of patients and families in analysis of medical error events can be “desirable,” participants at a national conference conclude, but the discussion needs “to be structured in a patient-centered way to be successful” (pp. 46–52). A two-phase study of 28 interviews with patients, family members, clinicians, and administrators followed by a 1-day conference of patients and health care experts “describes when and how information from patients might be incorporated into the event analysis process and by offering recommendations on how this might be accomplished.” (J. M. Etchegaray)
Patient-Safety Impact of Liability Safe Harbor: Liability protection for physicians who follow designated guidelines could improve patient safety, an article concludes, while having little impact on outcomes of litigation (pp. 59–66): “With the support of an Agency for Healthcare Research and Quality planning grant, we conducted an empirical analysis of closed liability claims in Oregon to determine the potential effects of hypothetical safe harbor legislation. We found that such legislation would have changed the liability outcome in favor of the physician defendant in only 1 percent of 266 claims from the period 2002–09 that we reviewed. Nevertheless, if safe harbors can induce greater physician adherence to care guidelines, they have the potential to improve patient safety. Implementing safe harbor legislation, however, requires overcoming a number of hurdles, including selecting and updating approved guidelines, obtaining broad stakeholder support, and withstanding challenges to the legal validity of the legislation. More experimentation with safe harbors is needed to determine their effects on the performance of the liability system and on health care quality and costs.” (A. Kachalia)

>>>PNN JournalWatch
* Novel Use and Utility of Integrated Electronic Health Records to Assess Rates of Prediabetes Recognition and Treatment: Brief Report From an Integrated Electronic Health Records Pilot Study, in
Diabetes Care, 2014; 37: 565–8. (J. A. Schmittdiel, julie.a.schmittdiel@kp.org)
* Mechanisms of Obesity-Induced Gastrointestinal Neoplasia, in
Gastroenterology, 2014; 146: 357–73. (P. R. Holt, holtp@rockefeller.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 706/613-0200 (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
Jan. 28, 2014 * Vol. 21, No. 18
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Annals of Internal Medicine (2014; 160).
Bringing Clarity to Cholesterol Guidelines: Four articles seek to help health professionals make sense of the ACA/AHA guidelines released amidst controversy last Nov.
In a synopsis of the recommendations, guideline panel members summarize key features of the guidelines and how the recommendations will work in practice to reduce the risk for atherosclerotic cardiovascular disease (ASCVD), a leading cause of death, lost quality of life, and increased health care costs (
doi: 10.7326/M14-0126). They conclude: “Until heart-healthy lifestyles are adopted throughout the lifespan, the need for preventive measures using evidence-based drug therapy will remain high. As with all clinical guidelines, the 2013 ACC/AHA cholesterol guidelines must be implemented in conjunction with sound clinical judgment. These evidence-based recommendations focus statin treatment on patients likely to obtain the greatest benefit, thereby reducing the ASCVD burden in adults.” (J. S. Schwartz, schwartz@wharton.upenn.edu)
“The decision to discontinue the treat-to-target approach to lipid management makes sense for many reasons,” Commentary authors write in praise of the doctor–patient collaboration recommended in the guidelines (
doi: 10.7326/M13-2850). But the writers advise health providers to seek a middle ground when making treatment decisions: “The guidelines offer support for shared decision making in treatment decisions, primary prevention, and patients whose age or other clinical features fall outside of the recommendations. However, treatment recommendations for primary prevention in a patient with a 10-year risk greater than 7.5% are definitive, and shared decision making seems to have been considered almost as an afterthought. Because data on primary prevention are less robust than those on secondary prevention, we believe that shared decision making should dictate whether lower-risk patients (perhaps with a 10-year risk >10% or >15%) are treated with a statin. Information about the number needed to treat to prevent a clinically relevant cardiac event, balanced by the number needed to harm for serious adverse events (such as rhabdomyolysis and new-onset diabetes) and bother symptoms (such as muscle pain and weakness), would be inherent to this decision.” (J. Downs, john.downs@va.gov)
A second commentary applauds the panel for basing statin treatment on risk factors rather than LDL-C targets because this approach greatly simplifies treatment for clinicians and patients (
doi: 10.7326/M13-2805). In risk discussions, physicians should focus on the patient’s 5 P’s: preference based on values and priorities, precision of the risk estimate, participation in ongoing care and improvement of lifestyle, potency of treatment and dose, and price. (R. S. Blumenthal, rblument@jhmi.edu)
An editorial explores why guidelines seem to generate controversy and urges physicians to listen to the evidence, not the noise created by the disagreement over the new recommendations (
doi: 10.7326/M14-0112): “The surge in media attention accompanying the release of a guideline gives those who were left out the opportunity to attract some of the limelight. In addition, the 24/7 news cycle and blogosphere provide limitless occasions to magnify disagreements and provoke adversarial debate with little attention to the nuances supporting each position. The mudslinging outcry that increasingly seems to accompany guidelines is damaging, creates the impression that health care professionals are clueless, and risks compromising evidence-based medicine.” (E. Guallar, eguallar@jhsph.edu)

>>>PNN NewsWatch
* Vitamin D supplementation with or without calcium has little effect on skeletal, vascular, or cancer outcomes, according to a trial sequential meta-analysis published in The Lancet Diabetes & Endocrinology (doi:10.1016/S2213-8587(13)70212-2; M. J. Bolland, m.bolland@auckland.ac.nz). “The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48,647 patients), stroke or cerebrovascular disease (eight trials 46,431 patients), cancer (seven trials, 48,167 patients), and total fracture (22 trials, 76,497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more,” the authors report.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 29, 2014 * Vol. 21, No. 19
Providing news and information about medications and their proper use

>>>Kidney Diseases Report
Source:
Feb. American Journal of Kidney Diseases (2014; 63).
Mortality & Oral Intradialytic Nutritional Supplement: Among patients with low albumin levels, use of an oral nutritional supplement between hemodialysis sessions was associated with reduced mortality in a retrospective propensity-matched cohort study (pp. 276–85). Compared with patients at facilities where the supplement protocol was not used, patients receiving prescriptions for a nutritional supplement had these outcomes during 2 months in 2010: “Of 6,453 eligible patients in 101 eligible hemodialysis facilities, the protocol was prescribed to 2,700, and 1,278 of these were propensity matched to controls. Mean age was 61 ± 15 (SD) years and median dialysis vintage was 34 months. There were 258 deaths among protocol assignees versus 310 among matched controls during a mean follow-up of 14 months. In matched analyses, protocol prescription was associated with a 29% reduction in the hazard of all-cause mortality (HR, 0.71; 95% CI, 0.58–0.86); adjustment had minimal impact on models. In time-dependent models incorporating change in albumin level, protocol status remained significant but was attenuated in models incorporating a 30-day lag. Similar results were seen in sensitivity analyses of 439 patients receiving supplements who were propensity-matched to controls, with 116 deaths among supplement users versus 140 among controls (HR, 0.79; 95% CI, 0.60–1.05), achieving statistical significance in adjusted models.” (D. E. Weiner, dweiner@tuftsmedicalcenter.org)
Estrogens & Phosphorus Levels: Estrogen therapy may account for differences in serum phosphorus levels observed in postmenopausal women, according to cross-sectional analysis of data on 7,005 participants in the National Health and Nutrition Examination Survey for 2003–06 (pp. 198–205): “In both males and premenopausal females, serum phosphorus levels decline progressively with age. In males, the decline continues over the entire age range of 21–85 years. In contrast, in females, serum phosphorus levels increase between ages 46–60 years (sex × age interaction; P < 0.001). The increase in serum phosphorus levels in older women is independent of changes in serum parathyroid hormone levels, daily dietary phosphorus intake, and estimated glomerular filtration rate. In analysis of covariance, we show that postmenopausal women receiving estrogen therapy have significantly lower serum phosphorus levels than non–estrogen users after adjusting for age, race, body mass index, daily dietary phosphorus intake, and serum albumin, serum parathyroid hormone, and 25-hydroxyvitamin D levels (3.83 vs 3.98 mg/dL; P < 0.001).” (K. Sakhaee, khashayar.sakhaee@utsouthwestern.edu)

>>>Medical Care Highlights
Source:
Feb. issue of Medical Care (2014; 52).
Primary Care Workforce Innovations: Team care, creating workforce connections, and role change are three of five workforce innovation concepts identified in a study of published articles that describe deviations in primary care practices “from what would be expected in the typical practice in the year 2000” (pp. 101–11). “Many workforce innovations added personnel to existing practices, whereas others sought to retrain existing personnel or even develop roles outside the traditional practice,” the authors report. “Most of these sought to minimize the impact on the existing practice roles and functions, particularly that of physicians. The group concludes: “Most conceptualizations of the primary care workforce described in the literature do not reflect the level of innovation needed to meet the needs of the burgeoning numbers of patients with complex health issues, the necessity for roles and identities of physicians to change, and the call for fundamentally redesigned practices. However, we identified 5 key workforce innovation concepts that emerged from the literature: team care, population focus, additional resource support, creating workforce connections, and role change.” (A. Friedman)
Accompanying point–counterpoint articles (
pp. 95–6) “highlight the limitations of existing primary care shortage predictions and discuss strategies to deliver primary care services without necessarily increasing the number of primary care physicians for a given population. Innovative solutions can be used to reduce or even eliminate projected primary care shortages while changing the prevailing paradigm of primary care.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 30, 2014 * Vol. 21, No. 20
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 30 issue of the New England Journal of Medicine (2014; 370).
Romosozumab & Osteoporosis: A monoclonal antibody that increases bone formation by inhibiting the osteocyte-derived glycoprotein sclerostin increased bone mineral density and bone formation and decreased bone resorption among 419 postmenopausal women, researchers report (pp. 412–20). In the Phase II trial, women ages 55–85 years received one of several monthly or every-3-month doses of romosozumab, placebo, or an active comparator, with these effects on a primary end point of percentage change from baseline in bone mineral density at the lumbar spine at 12 months: “All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.” (M. R. McClung, mmcclung@orost.com)
Sclerostin inhibition is “a potential breakthrough in osteoporosis therapeutics,” an editorialist writes (
pp. 476–7): “Many questions about romosozumab remain. Will changes in [bone mineral density (BMD)] translate into potent antifracture efficacy? Will it be safe over time? In the current study, there were no clinically significant adverse events other than injection-site irritation. Will longer administration (>1 year) cause bony complications such as cranial-nerve palsies or spinal stenosis? What duration of treatment is associated with the highest rate of response? Why did BMD not improve at the wrist? A phase 3 clinical trial of romosozumab is under way in a cohort of postmenopausal women with osteoporosis (ClinicalTrials.gov number, NCT01631214) and may answer some of these questions. For now, more than a decade after the introduction of teriparatide, we may at last have a sequel to the anabolic story.” (C. B. Becker)
Childhood Obesity: The epidemic of obesity in the U.S. among children ages 5–14 years is occurring primarily among those who entered kindergarten overweight or obese, a study shows (pp. 403–11). Based on data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998–1999, investigators found: “When the children entered kindergarten (mean age, 5.6 years), 12.4% were obese and another 14.9% were overweight; in eighth grade (mean age, 14.1 years), 20.8% were obese and 17.0% were overweight. The annual incidence of obesity decreased from 5.4% during kindergarten to 1.7% between fifth and eighth grade. Overweight 5-year-olds were four times as likely as normal-weight children to become obese (9-year cumulative incidence, 31.8% vs. 7.9%), with rates of 91.5 versus 17.2 per 1,000 person–years. Among children who became obese between the ages of 5 and 14 years, nearly half had been overweight and 75% had been above the 70th percentile for body-mass index at baseline.” (S. A. Cunningham, sargese@emory.edu)
Assessing Lipid-Lowering Drugs With Uncertain Benefits: Favorable effects of investigational lipid-lowering drugs on lowering LDL cholesterol or triglyceride levels or raising HDL cholesterol levels is no longer a guarantee of FDA approval, write authors of a Perspectives article that reviews the history of Vascepa (pp. 396–9). The new drug application of the purified n–3 fatty acid formulation of ethyl eicosapentaenoic acid (EPA) was based on FDA-sanctioned trial data and the launch of a cardiovascular-safety study, but an advisory committee voted 9–2 against approval. “The deliberations over Vascepa highlight several challenging issues in the development of new treatments for lipid disorders,” the authors write. “Vascepa represents an important example of a drug whose clinical outcome benefits have not yet been established, and we do not yet fully understand its safety profile. The FDA’s decision about Vascepa may not set a firm precedent, however, since the estimated likelihood and magnitude of both benefits and risks are unique to each new candidate drug.” (W. R. Hiatt)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Jan. 31, 2014 * Vol. 21, No. 21
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2014; 34).
Linezolid v. Vancomycin in MRSA Pneumonia: Among adults with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia admitted to Veterans Affairs hospitals in 2002–10, vancomycin and linezolid produced similar individual clinical outcomes, researchers report, but linezolid produced a higher rate of a composite clinical outcome (10.1002/phar.1390). The analysis of VA national databases showed these outcomes for 4,943 patients who received at least 3 days of continuous intravenous vancomycin therapy and 328 similar patients on linezolid: “A composite outcome of clinical success was defined as discharge from the hospital or intensive care unit by day 14 after treatment initiation, in the absence of death, therapy change, or intubation by day 14.… A significantly lower rate of therapy change was observed in the linezolid group (adjusted hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.48–0.96). The clinical success rate was significantly higher among patients treated with linezolid (adjusted HR 1.25, 95% CI 1.07–1.47). Comparable findings were observed in the subgroup analyses.” (K. L. LaPlante, kerrylaplante@uri.edu)
Rifampin, Efavirenz & Pharmacogenetics: In a crossover study of 12 healthy volunteers, polymorphisms in a gene for a solute carrier organic anion transporter increased the risk of lower plasma rifampin exposure, but pharmacokinetic correlations between plasma rifampin levels and induction of efavirenz clearance were inconsistent (10.1002/phar.1388). Participants received either efavirenz 600 mg/d or efavirenz 600 mg with rifampin 600 mg/d for 8 days. Results showed: “Of 11 evaluable subjects, the median interquartile range, rifampin peak concentration (Cmax), area under the concentration-time curve (AUC0–24 hour), and weight-normalized clearance were 8.9 (7.3–13.8) µg/ml, 48.8 (29.6–67.4) µg·h/ml, and 0.19 (0.11–0.29) L/h/kg, respectively. Solute carrier organic anion transporter family member 1B1 (SLCO1B1) c.388AG and SLCO1B1 c.463CA polymorphisms jointly had significant effect on rifampin Cmax (R2 = 0.75). Male sex and SLCO1B1 c.463CA polymorphism together influenced rifampin AUC0–24 hour (R2 = 0.52) and weight-normalized clearance (R2 = 0.65). All four volunteers with rifampin Cmax less than 8 µg/ml (lower end of the normal range) had c.463CA genotype. Rifampin Cmax and AUC0–24 hour had no significant relationship with the efavirenz AUC0–24 hour ratio or weight-normalized clearance ratio in the presence versus absence of rifampin (p > 0.05).” (A. Kwara, akwara@lifespan.org)

>>>Chest Highlights
Source:
Jan. issue of Chest (2014; 145).
Vitamin D & COPD: In 356 patients with chronic obstructive pulmonary disorder who were followed for 2 years, vitamin D status had no impact on exacerbations or mortality (pp. 37–43). The longitudinal study was part of a prospective cohort study conducted in Dutch and Swiss primary care settings. All patients had been free of COPD exacerbations for 4 weeks or more at study entry, after which results showed: “Baseline mean ± SD serum 25-hydroxyvitamin D concentration was 15.5 ± 8.9 ng/dL, and 274 patients (77.0%) had 25-hydroxyvitamin D deficiency (< 20 ng/dL). Compared with patients with severe 25-hydroxyvitamin D deficiency (< 10 ng/dL, n = 106 [29.8%]), patients with moderately deficient (10–19.99 ng/dL, n = 168 [47.2%]) and insufficient (20–29.99 ng/dL, n = 58 [16.3%]) concentrations had the same risk for exacerbations (incidence rate ratio, 1.01 [95% CI, 0.77–1.57] vs 1.00 [95% CI, 0.62–1.61], respectively). In patients with desirable concentrations (> 30 ng/dL, n = 24 [6.7%]), the risk was lower, although not significantly (incidence rate ratio, 0.72 [95% CI, 0.37–1.42]). In patients taking vitamin D supplements, using different cutoffs for 25-hydroxyvitamin D or competing risk models did not materially change the results. We did not find a statistically significant association of 25-hydroxyvitamin D concentration with mortality.” (M. A. Puhan, milo.puhan@ifspm.uzh.ch)
Vitamin D’s “moment in the sun” may be behind us, an editorialist writes (
pp. 5–6): “Supplementation of vitamin D in patients with COPD beyond [600–800 IU/d] and in the absence of data cannot be supported at this time.” (D. M. Mannino, dmannino@uky.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 706/613-0200 (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
Feb. 3, 2014 * Vol. 21, No. 22
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Benzodiazepines, Opioids in COPD: Analysis of patients in Sweden with chronic obstructive pulmonary disease (COPD) requiring long-term oxygen therapy shows that lower-dose opioids were not associated with increased hospital admissions or mortality and therefore may be appropriate for symptom reduction (g445). The population-based longitudinal consecutive cohort study included 2,249 patients in the national Swedevox Register as beginning oxygen therapy in 2005–09. Looking for relationships between the effects of benzodiazepines and opioids on clinical and other variables, the investigators found: “1,681 (76%) patients were admitted to hospital, and 1,129 (50%) died under observation. No patient was lost to follow-up. Benzodiazepines and opioids were not associated with increased admission: hazard ratio 0.98 (95% confidence interval, 0.87 to 1.10) and 0.98 (0.86 to 1.10), respectively. Benzodiazepines were associated with increased mortality (1.21, 1.05 to 1.39) with a dose response trend. Opioids also had a dose response relation with mortality: lower dose opioids (≤30 mg oral morphine equivalents a day) were not associated with increased mortality (1.03, 0.84 to 1.26) in contrast with higher dose opioids (1.21, 1.02 to 1.44). Concurrent benzodiazepines and opioids in lower doses were not associated with increased admissions (0.86, 0.53 to 1.42) or mortality (1.25, 0.78 to 1.99). Associations were not modified by being naive to the drugs or by hypercapnia.” (M. Ekström, pmekstrom@gmail.com)

>>>Lancet Highlights
Source:
Feb. 1 issue of Lancet (2014; 383).
Third-Generation Drug-Eluting Stents in PCI: In the DUTCH PEERS study, two third-generation, permanent-polymer-based drug-eluting stents with novel, flexible designs were similarly efficacious and safe, researchers report (pp. 413–23). Concerns that such stents might not be longitudinally stable were not borne out, as a negative safety- and efficacy-based end point was reached in only about 5% of those receiving the cobalt–chromium-based zotarolimus-eluting stent (Resolute Integrity, Medtronic) or the platinum–chromium-based everolimus-eluting stent (Promus Element, Boston Scientific). “Definite stent thrombosis occurred in three (0.3%) patients in the zotarolimus-eluting stent group and six (0.7%) patients in the everolimus-eluting stent group (p = 0.34),” the authors wrote. “Longitudinal stent deformation was seen only in the everolimus-eluting stent group (nine [1.0%] of 905 vs 0 of 906, p = 0.002; nine of 1,591 [0.6%] everolimus-eluting stents implanted became deformed), but was not associated with any adverse events.” (C. von Birgelen, c.vonbirgelen@mst.nl)

>>>PNN NewsWatch
* After a priority review, FDA on Friday approved the melatonin agonist tasimelteon (Hetlioz, Vanda Pharmaceuticals) for treatment of non–24-hour sleep-wake disorder (“non-24&rdquoWinking in totally blind individuals, an indication for which no product was previously approved. While most people who are totally blind can perceive light well enough to prevent non-24, FDA said as many as 100,000 Americans are thought to have this disorder, which can occur at any age. In two clinical trials of 104 patients with non-24, tasimelteon significantly improved nighttime sleep and daytime sleep duration, compared with placebo. Adverse effects of the drug are headache, elevated serum liver enzymes, nightmares or unusual dreams, disturbed night’s sleep, upper respiratory or urinary tract infections, and drowsiness.

>>>PNN JournalWatch
* Interventions To Improve Cortisol Regulation in Children: A Systematic Review, in
Pediatrics, 2014; 133: 312–26. (N. Slopen)
* Improving Outcomes for Underserved Adolescents With Asthma, in
Pediatrics, 2014; 133: e418–27. (M. T. Britto)
* Anticoagulation Management in Individuals With Hip Fracture, in
Journal of the American Geriatrics Society, 2014; 62: 159–64. (L. J. Gleason, lgleason@bidmc.harvard.edu)
* Alcohol Consumption and Cognitive Decline in Early Old Age, in
Neurology, 2014; 82: 332–9. (S. Sabia, s.sabia@ucl.ac.uk)
* Management of Extravasation Injuries: A Focused Evaluation of Noncytotoxic Medications, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1396. (T. H. Kiser, ty.kiser@ucdenver.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 706/613-0200 (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
Feb. 4, 2014 * Vol. 21, No. 23
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 4 issue of the Annals of Internal Medicine (2014; 160).
2014 Adult Immunization Schedule: The CDC’s Advisory Committee on Immunization Practices has released its recommended 2014 adult immunization schedule (pp. 190–7). Key changes and updates include the following (C. B. Bridges, cbridges@cdc.gov):
*
Influenza: Information on the use of the recombinant influenza (RIV) and inactivated influenza (IIV) vaccines among egg-allergic patients was added to the footnote and indicates that RIV or IIV can be used among persons with hives-only allergy to eggs, as it contains no egg protein.
*
Td/Tdap: The tetanus, diphtheria, acellular pertussis (Tdap) and tetanus, diphtheria (Td) vaccines footnote was edited to harmonize with the language used in the pediatric immunization schedule. A single dose of Tdap vaccine is recommended for previously unvaccinated persons aged 11 years or older, and Td booster should be administered every 10 years thereafter.
*
HPV: Information was added to the human papillomavirus (HPV) vaccine footnote to clarify the timing between the second and third doses and to harmonize language between the pediatric and adult immunization schedules. No changes in recommendations were made.
*
Zoster: Being a health care worker is no longer an indication for vaccination. This change was also made to the HPV vaccine footnote.
*
PCV13: Because PCV13 is recommended to be administered before PPSV23 among persons for whom both vaccines are recommended, the PCV13 footnote now precedes the PPSV23 footnote and includes wording to remind providers of the appropriate order of these vaccines when both are indicated.
*
Meningococcal vaccine: The meningococcal vaccine footnote was edited to clarify which persons need either one or two doses of vaccine and to provide greater clarity regarding which patients should receive meningococcal conjugate (MeanACWY-D) versus the meningococcal polysaccharide (MenACWY-CRM).
*
Hib: The Haemophilus influenzae type b (Hib) vaccine recommendations were updated. The vaccine is recommended for certain adults at increased risk for Hib who have not received the vaccine before, except for those with HIV because their risk for Hib infection is low. Adults who have had successful hematopoietic stem cell transplant are recommended to receive a three-dose series of Hib vaccine 6 to 12 months after the transplant regardless of prior Hib vaccination status.
Physicians & Adult Vaccine Delivery: In a national survey, 607 American general internists and family physicians identify financial and other barriers to provision of adult vaccinations in their practices (pp. 161–70): “Characteristics significantly associated with reporting greater financial barriers included private practice setting, fewer than 5 providers in the practice, and, for general internists only, having more patients with Medicare Part D. The most commonly reported reasons for referring patients elsewhere included lack of insurance coverage for the vaccine (55% for general internists and 62% for family physicians) or inadequate reimbursement (36% and 41%, respectively). Patients were most often referred to pharmacies/retail stores and public health departments.” (M. Brtnikova, michael.brtnikova@ucdenver.edu)
Prescription Drug Abuse: A position paper developed by the American College of Physicians provides guidance to prescribers and policymakers regarding measures to effectively address the problem of prescription drug abuse (pp. 198–200). The 10 recommendations address detection, deterrence, and treatment of prescription drug abuse and “touch on the importance of maintaining patient involvement, dignity, and privacy and the importance of limiting third-party administrative and regulatory mandates on physicians attempting to provide care and address this issue.” (N. Kirschner, nkirschner@acponline.org)

>>>PNN NewsWatch
* FDA yesterday approved the expanded use of the Dexcom G4 Platinum Continuous Monitoring System for patients with diabetes ages 2 to 17 years. The G4 Platinum System, which monitors blood glucose levels in people with diabetes, had been approved for patients ages 18 and older.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 5, 2014 * Vol. 21, No. 24
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 5 issue of JAMA (2014; 311).
Immediate Blood Pressure Reduction in Ischemic Stroke: In the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS), immediate provision of antihypertensive agents did not change mortality or disability outcomes at 14 days or at hospital discharge, researchers report (pp. 479–89). The study, conducted at 26 Chinese hospitals, included 4,071 patients with nonthrombolyzed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Compared with discontinuance of medications that lower blood pressure, antihypertensive therapy aimed at lowering systolic blood pressure by 10–25% within 24 hours produced these results: “Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (−12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (−7.2%) in the control group within 24 hours after randomization (difference, −5.5% [95% CI, −4.9 to −6.1%]; absolute difference, −9.1 mm Hg [95% CI, −10.2 to −8.1]; P < .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, −9.3 mm Hg [95% CI, −10.1 to −8.4]; P < .001). The primary outcome [of death and major disability at 14 days or hospital discharge] did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93).” (J. He, jhe@tulane.edu)
Studies on the question of blood-pressure reduction after acute ischemic stroke vary, an editorialist notes, but CATIS results show that intervention “does not matter much” in the subacute period of 12 hours to 2 weeks (
pp. 469–70): “Physiologic reasoning suggests that an optimal strategy for management of blood pressure might be to avoid blood pressure–lowering agents during the first 12 hours after stroke onset, when collateral circulation compromise is still a substantial concern in most patients, and then to implement blood pressure lowering beginning in the 12- to 36-hour period if there has not been any early neurologic worsening, to help avert secondary injury and ensure that the patient will be transitioned to long-term antihypertensive therapy for secondary prevention. This time-indexed approach would be based on knowing when the actual stroke began, not when the patient presented for medical care. The CATIS time-to-randomization subgroup analysis provides a tantalizing hint that this approach might be advantageous, with a suggestion of better 6-month outcomes if blood pressure lowering was withheld in the first 12 hours and if it was started beyond 24 hours.” (J. L. Saver, jsaver@mednet.ucla.edu)
Treating Hypertension: In conjunction with print publication of the high blood pressure guideline produced by former members of the Eighth Joint National Committee (JNC8; pp. 507–20; P. A. James, paul-james@uiowa.edu), authors of three viewpoint articles and three editorials discuss the controversies of that and other guidelines released in Nov. and Dec. 2013. Editorialists make these points about the JNC8 guideline and those for lipids management (pp. 474–6): “It also must be recognized that the philosophy used to create both past and present hypertension recommendations differs from that used in the recent revisions of the cholesterol guidelines. The authors of the new cholesterol treatment guidelines emphasized assessing an individual’s aggregate cardiovascular risk and then treating those at greatest overall risk with more aggressive therapy. Because older individuals have higher cardiovascular risk profiles, they more frequently receive a recommendation for intervention. Rather than considering a patient’s total risk profile, the current panel’s hypertension recommendations focus on a single risk factor (ie, [blood pressure (BP)]) and recommend less (as opposed to more) aggressive treatment of BP in older individuals. These differences may be rationally based on the adverse effect profiles of the 2 interventions, yet such divergent philosophies may cause confusion among clinicians and patients alike.” (E. D. Peterson)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 6, 2014 * Vol. 21, No. 25
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 6 issue of the New England Journal of Medicine (2014; 370).
Intussusception & Rotavirus Vaccine: Two studies and an editorial examine intussusception in infants receiving rotavirus vaccinations.
Infants cared for in three U.S. health plans had significantly increased of intussusception after the first doses of the pentavalent RotaTeq (RV5), and a suggestion of excess cases was noted with the monovalent product Rotarix, researchers report (
pp. 503–12). Infants 5–37 weeks of age had these rates of intussusception after vaccine exposure in 2004 through mid-2011: “The analyses included 507,874 first doses and 1,277,556 total doses of RV5 and 53,638 first doses and 103,098 total doses of RV1. The statistical power for the analysis of RV1 was lower than that for the analysis of RV5. The number of excess cases of intussusception per 100,000 recipients of the first dose of RV5 was significantly elevated, both in the primary analysis (attributable risk, 1.1 [95% confidence interval, 0.3 to 2.7] for the 7-day risk window and 1.5 [95% CI, 0.2 to 3.2] for the 21-day risk window) and in the secondary analysis (attributable risk, 1.2 [95% CI, 0.2 to 3.2] for the 21-day risk window). No significant increase in risk was seen after dose 2 or 3. The results with respect to the primary analysis of RV1 were not significant, but the secondary analysis showed a significant risk after dose 2.” (W. K. Yih, katherine_yih@harvardpilgrim.org)
Significantly increased risk of intussusception with the monovalent vaccine was evident in a second study, one that used data from six integrated health care organizations in the Vaccine Safety Datalink (VSD) project (
pp. 513–9). Infants were 4–34 weeks old when vaccinated in 2008–13. Results showed: “During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated.” (E. S. Weintraub, eiw8@cdc.gov)
While lots of questions remain, editorialists conclude that the benefits of these second-generation rotavirus vaccines outweigh their risks even in developed countries (
pp. 568–70): “Given this low risk and the major impact that these vaccines have had on the reduction of hospitalizations, emergency department visits, and in some cases, deaths from diarrhea, policy makers have concluded that rotavirus vaccine remains a valuable addition to the national program for childhood immunizations. For example, in the U.S. cohort of 4.5 million babies born each year, vaccination is estimated to prevent approximately 53,000 hospitalizations and 170,000 emergency department visits for diarrhea, at the expense of causing 45 to 213 cases of intussusception nationwide.” (R. I. Glass)

>>>PNN NewsWatch
* Cigarettes and other tobacco products will be removed from the 7,600 CVS/pharmacy outlets by Oct. 1, the company said yesterday. “Ending the sale of cigarettes and tobacco products at CVS/pharmacy is the right thing for us to do for our customers and our company to help people on their path to better health,” said Larry J. Merlo, president and CEO, CVS Caremark. “Put simply, the sale of tobacco products is inconsistent with our purpose.”
*
FDA has announced the launch of a national public education campaign to prevent youth tobacco use and reduce the number of kids ages 12 to 17 who become regular smokers. “The Real Cost” campaign is the FDA’s first of several planned tobacco education campaigns using the new authority granted under the Family Smoking Prevention and Tobacco Control Act, signed into law by Pres. Obama in 2009.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 7, 2014 * Vol. 21, No. 26
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Feb. 11 issue of the Journal of the American College of Cardiology (2014; 63).
Monoclonal Antibody & LDL Cholesterol: In the LAPLACE–TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial Infarction 57) trial, more than 90% of high-risk patients achieved ATP III lipid goals when treated with AMG 145, a monoclonal antibody that targets proprotein convertase subtilisin kexin type 9 (PCSK9) (pp. 430–3). Participants had been unable to achieve the triple lipid goal (LDL cholesterol less than 70 mg/dL, non-HDL cholesterol less than 100 mg/dL, apolipoprotein B less than 80 mg/dL) despite high-potency statin therapy. Among 252 participants, attainment of lipid goals was observed with AMG 145 administered at either of two top doses given every 2 weeks or every 4 weeks. (N. R. Desai)
Polypills & Targeted Preventive Pharmacotherapy: Targeting of higher-risk patients for therapy with a cardioprotective polypill could reduce events while avoiding therapy in those unlikely to benefit, according to findings of MESA (Multi-Ethnic Study of Atherosclerosis) (pp. 434–43). Investigators used the criteria of four polypill studies (TIPS [The Indian Polycap Study], Poly-Iran, Wald, and the PILL [Program to Improve Life and Longevity] Collaboration) to stratify patients based on their coronary artery calcium (CAC) score. Cardiovascular disease (CVD) and coronary heart disease (CHD) event rates and 5-year numbers needed to treat (NNTs) after stratification showed these results: “Among MESA participants eligible for TIPS, Poly-Iran, Wald, and the PILL Collaboration, CAC = 0 was observed in 58.6%, 54.5%, 38.9%, and 40.8%, respectively. The rate of CHD events among those with CAC = 0 varied from 1.2 to 1.9 events per 1,000 person–years, those with CAC scores from 1 to 100 had event rates ranging from 4.1 to 5.5, and in those with CAC scores >100 the event rate ranged from 11.6 to 13.3. The estimated 5-year NNT to prevent 1 CVD event ranged from 81–130 for patients with CAC = 0, 38–54 for those with CAC scores from 1 to 100, and 18–20 for those with CAC scores >100.” (M. S. Bittencourt)
“Refining risk prediction by adding CAC to classic scores as proposed by Bittencourt et al. is an innovative approach to preventive strategies,” editorialists write (
pp. 444–6). “Unlike implementation of healthy diet and lifestyle modification, preventive pharmacotherapy in asymptomatic healthy subjects remains controversial. Because long-term drug prescription unavoidably comes with side effects, it is conceivable that the potential benefit of polypill prescription will be confounded. As a result, polypill trials may run the risk of showing neutral or even negative net effects. Using CAC to identify subjects at intermediate to high risk who carry the disease substrate at a pre-clinical state for inclusion in such trials seems like an attractive ‘de-risking’ strategy for preventive pharmacotherapy.” (W. Wijns)

>>>Circulation Report
Source:
Feb. 4 issue of Circulation (2014; 129).
LDL Cholesterol Discordance: Reflecting on results of an study showing that coronary risk may be underestimated or overestimated in women with discordant LDL-related measures (pp. 553–61; S. Mora, smora@partners.org), editorialists provide a bridge from the older LDL-centric approaches to the new risk-based assessments (pp. 539–41): “As emphasized by the latest American College of Cardiology (ACC)/American heart Association (AHA) guidelines, the baseline decisions about initiating statin treatment are more related to global risk prediction using lipid parameters in addition to other risk factors. For lipid parameter inputs, the risk calculator incorporates total cholesterol and HDL-C, rather than LDL-C, non–HDL-C, apoB, or LDL-P. In the future, it may become feasible and desirable to replace total cholesterol and HDL-C with other lipid parameters in the ACC/AHA risk calculator. If 1 of these atherogenic lipid parameters were used, this would allow one to understand the modifiable component to lipid related risk. A very clinically relevant question is what risk can be directly targeted with treatment? For this question, total cholesterol and HDL-C are not ideal because, to date, we have not identified a treatment that improves clinical outcomes by directly targeting HDL-C. Total cholesterol is a crude measure of atherogenic lipid and lipoprotein burden.” (E. D. Michos, edonnel1@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 10, 2014 * Vol. 21, No. 27
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 8 issue of Lancet (2014; 383).
A Cure for HCV-1? A fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir 400 mg and the hepatitis C virus (HCV) NS5A inhibitor ledipasvir 90 mg, administered with and without ribavirin, “has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis,” researchers report (pp. 515–23). In an open-label study, 100 adults in the U.S. were treated in late 2012 as two cohorts. Cohort A included 60 noncirrhotic, treatment-naive patients who received the two drugs for 8 (group 1) or 12 weeks (group 3) or with ribavirin for 8 weeks (group 2). Patients in cohort B had previous virologic failure after receiving a protease inhibitor; they received the two drugs for 12 weeks (group 4) or the two drugs plus ribavirin for 12 weeks (group 5).
Results showed: “In cohort A, [sustained virological response 12 weeks after treatment (SVR12)] was achieved by 19 (95%) of 20 patients (95% CI 75–100) in group 1, by 21 (100%) of 21 patients (84–100) in group 2, and by 18 (95%) of 19 patients (74–100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74–100) in group 4 and by all 21 (100%) of 21 patients (84–100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment.” (E. Lawitz,
lawitz@txliver.com)
Pimavanserin for Parkinson Disease Psychosis: In a Phase III trial with an innovative design, patients with psychosis related to Parkinson disease responded well to treatment with pimavanserin, a selective serotonin 5-HT2A inverse agonist (pp. 533–40). The trial used a 2-week nonpharmacologic lead-in phase to limit placebo response, the authors report, and included patients aged 40 years or older with Parkinson disease psychosis. Pimavanserin 40 mg/d or placebo showed these results over a 6-week period during which progress was assessed with the Parkinson disease–adapted scale for assessment of positive symptoms (SAPS-PD): “Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5.79 decrease in SAPS-PD scores compared with −2.73 for placebo (difference −3.06, 95% CI −4.91 to −1.20; p = 0.001; Cohen’s d 0.50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.” (C. Ballard, clive.ballard@kcl.ac.uk)

>>>PNN JournalWatch
* Pharmacological Treatments of Non-Substance-Withdrawal Delirium: A Systematic Review of Prospective Trials, in
American Journal of Psychiatry, 2014; 171: 151–9. (J. I. Friedman, jfriedman1@rcn.com)
* Clinical Applications of Targeted Temperature Management, in
Chest, 2014; 145: 386–93. (D. F. Gaieski, gaieskid@uphs.upenn.edu)
* Fecal Microbiota Transplantation: A Practical Update for the Infectious Disease Specialist, in
Clinical Infectious Diseases, 2014; 58: 541–5. (J. S. Bakken, jbakken1@d.umn.edu)
* Effectiveness of Seasonal Trivalent Influenza Vaccine for Preventing Influenza Virus Illness Among Pregnant Women: A Population-Based Case–Control Study During the 2010–2011 and 2011–2012 Influenza Seasons, in
Clinical Infectious Diseases, 2014; 58: 449–57. (M. G. Thompson, isq8@cdc.gov)
* Challenges and Opportunities in Pediatric Heart Failure and Transplantation: Update on Pharmacological Heart Failure Therapies in Children—Do Adult Medications Work in Children and if Not, Why Not?, in
Circulation, 2014; 129: 607–12. (J. W. Rossano, rossanoj@email.chop.edu)
* Dysnatremias in Patients With Kidney Disease, in
American Journal of Kidney Diseases, 2014; 63: 294–303. (T. Berl, tomas.berl@ucdenver.edu)
* ASA Failure [in lacunar stroke]: Does the Combination ASA/Clopidogrel Confer Better Long-Term Vascular Protection?, in
Neurology, 2014; 82: 382–9. (R. Côté, robert.cote@mcgill.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 11, 2014 * Vol. 21, No. 28
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Feb. issue of JAMA Internal Medicine (2014; 174).
Pharmacists, Team Improve Adherence After ACS: Pharmacist-led medication reconciliation and tailoring was part of a successful multidisciplinary intervention (INT) that increased medication adherence in the year following hospitalization for acute coronary syndrome (ACS), researchers report (pp. 186–93). At VA facilities in Denver, Seattle, Durham, NC, and Little Rock, patients admitted for ACS were randomized to the INT (pharmacist-led medication reconciliation and tailoring; patient education; collaborative care between pharmacist and a patient’s primary care clinician and/or cardiologist; and two types of voice messaging) or usual care (UC), with these results: “Of 253 patients, 241 (95.3%) completed the study (122 in INT and 119 in UC). In the INT group, 89.3% of patients were adherent compared with 73.9% in the UC group (P = .003). Mean [proportion of days covered] was higher in the INT group (0.94 vs 0.87; P< .001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs 70.7%; P = .03), statins (93.2% vs 71.3%; P < .001), and ACEI/ARB (93.1% vs 81.7%; P = .03) but not beta-blockers (88.1% vs 84.8%; P = .59). There were no statistically significant differences in the proportion of patients who achieved [blood pressure] and LDL-C level goals.” (P. M. Ho, Michael.ho@va.gov)
“This intervention would cost $360 per patient per year using relatively lower costs of services in the VA system, which if applied to every patient with ACS in the United States would add $1 billion annually to health care costs, on the basis of recent estimates of 2.5 million hospital discharges per year for patients with ACS,” writes a journal editor (
p. 193). Noting that improved indirect measures of adherence did not result in changes in blood pressure and LDL cholesterol, she adds, “For many reasons, the relatively modest increases in already high rates of medication regimen adherence in the patients studied may not translate into improved outcomes even if maintained for 3 to 5 years or longer. Of course, we hope that they do. But before recommending investment in this strategy, it would be prudent to know that patient outcomes will actually improve.” (R. F. Redberg)
Drugs & Weight Loss: The two drugs approved by FDA for weight loss during 2012—lorcaserin and phentermine/topiramate—add little to the pharmacologic options for patients with obesity, authors of a special communication write (10.1001/jamainternmed.2013.14629): “The approvals were based on 1-year trials showing that on top of recommendations to follow a calorie-restricted diet and to increase exercise, patients randomized to either drug lost more weight than patients randomized to placebo (3% [95% CI, 3%-4%] more weight lost with lorcaserin; 7% [95% CI, 3%-4%] more with phentermine/topiramate). The drugs have been associated with serious harms: Both drugs’ labels include warnings about memory, attention, or language problems and depression; for lorcaserin, the label also warns of valvular heart disease and euphoria; and for phentermine-topiramate, the label warns of metabolic acidosis, increased heart rate, anxiety, insomnia, and elevated creatinine levels. Neither medication is marketed in Europe because of safety concerns. The manufacturer withdrew its application for lorcaserin in Europe after the European Medicines Agency (EMA) said approval was unlikely, and the EMA rejected phentermine-topiramate. In the United States, the required postmarketing safety trials are behind schedule. Until there is more convincing evidence about the cardiovascular safety of these drugs, physicians and patients should approach them cautiously. Patients who do not lose at least 5% of their body weight within 12 weeks of starting to take either drug should stop taking it, as stated in the prescribing information.” (L. M. Schwartz, lisa.schwartz@dartmouth.edu)
Diuretics & Diarrhea: Prescribing of a diuretic during an appointment with a clinical pharmacist was not appropriate because the patient had chronic diarrhea from protease inhibitors, authors write in an article subtitled “a dangerous combination” (p. 182). “Although blood pressure control is a crucial component of primary care medicine, treating to targets without equal attention to the potential harms from overtreatment can be a risky endeavor.” (P. Liu, pai.liu@ucdenver.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 706/613-0200 (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
Feb. 12, 2014 * Vol. 21, No. 29
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 12 issue of JAMA (2014; 311).
Number of Required HPV Doses: Two doses of human papillomavirus (HPV) vaccines are nearly as effective in prevention of condylomas as the recommended three-dose series, authors conclude based on an open cohort study of Swedish women (pp. 597–603). Using national registries, 1,045,165 girls and women ages 10–24 were followed up in 2006–10 for HPV vaccination and first occurrence of condyloma. Results showed: “A total of 20,383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an [incidence rate ratio (IRR)] of 0.18 (95% CI, 0.15–0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21–0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20–0.49), which corresponds to an [incidence rate difference (IRD)] of 384 cases (95% CI, 305–464) per 100,000 person–years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346–454) and for 3 doses, 459 cases (95% CI, 437–482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2–117) per 100,000 person–years.” (L. Arnheim-Dahlström, lisen.arnheim.dahlstrom@ki.se)
Preterm Birth & Plasma Insulin Levels: Reacting to a study showing an inverse relationship between gestational age and plasma insulin levels (pp. 587–96; X. Wang, xiwang@jhsph.edu), an editorialist relates the findings to the “thrifty phenotype” hypothesis and other theories on the origins of diabetes (pp. 575–6): “The population … (ie, largely urban and minority) has a high risk of preterm birth and also of childhood obesity and later metabolic syndrome. The findings confirm the importance of the developmental origins of health and disease concept to such populations and raise questions about the relative effect size longer-term. However, such populations should not be viewed as special cases; they show a continuum of [noncommunicable disease] risk that is initiated by a range of environmental influences operating across the normal range of early development. The effects, small at the outset but potentially magnified later, may be comparable with the life course adaptive processes conditioned by developmental cues reported in a range of other species. Basic research in this area is beginning to unravel the underlying mechanisms and to suggest possible biomarkers of risk.” (M. Hanson, m.hanson@soton.ac.uk)

>>>Pediatrics Report
Source:
Feb. issue of Pediatrics (2014; ).
OTC Label Adherence: Marketed OTC liquid medications mostly adhere to FDA guidances and Consumer Healthcare Products Association recommendations regarding dosing directions and dosing devices, a study shows (pp. e283–90). Independent reviewers looking at product labels found the following: “Of 68 products, 91% of dosing directions and 62% of dosing devices adhered to all top tier recommendations; 57% of products adhered to every top tier recommendation, and 93% adhered to all or all but one. A dosing device was included with all products. No dosing directions used atypical volumetric units (eg, drams), and no devices used volumetric units that did not appear in dosing directions. Six products used trailing zeros or failed to use leading zeros with decimal doses; eight did not use small font for fractions. Product adherence to low tier recommendations ranged from 26% to 91%.” (D. S. Budnitz)
Maternal Self-Medication & Children’s OTC Analgesic Use: Children’s use of OTC analgesics is more influenced by maternal self-medication with these agents than by the pain itself, according to a survey of 131 Danish children ages 6–11 (pp. e291–8): “After adjusting for several sociodemographic and health parameters, maternal use of OTC analgesics was significantly associated with self-medication with OTC analgesics, particularly [acetaminophen], in our population of schoolchildren, even when the child’s pain was adjusted for (odds ratio 3.00, P = .008). A clear association between child pain and OTC analgesic use was not found. Additionally, maternal health (self-rated health, chronic pain, chronic disease, daily medicine intake) did not significantly influence child use of OTC analgesics.” (J. F. Jensen)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 13, 2014 * Vol. 21, No. 30
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 13 issue of the New England Journal of Medicine (2014; 370).
Oxantel Pamoate–Albendazole for Trichuris trichiura: Compared with standard therapy for Trichuris trichiura, the combination of oxantel pamoate and albendazole resulted in higher cure and egg-reduction rates in a study of children in Tanzania (pp. 610–20). The double-blind trial assigned patients to oxantel pamoate 20 mg/kg plus 400 mg of albendazole, administered on consecutive days; oxantel pamoate 20 mg/kg as a single dose; albendazole 400 mg as a single dose; or mebendazole 500 mg as a single dose. Results showed: “Complete data were available for 458 children, of whom 450 were infected with T. trichiura, 443 with hookworm, and 293 with [Ascaris] lumbricoides. The cure rate of T. trichiura infection was significantly higher with oxantel pamoate–albendazole than with mebendazole (31.2% vs. 11.8%, P = 0.001), as was the egg-reduction rate (96.0% [95% confidence interval {CI}, 93.5 to 97.6] vs. 75.0% [95% CI, 64.2 to 82.0]). The cure rate with albendazole (2.6%) and the egg-reduction rate with albendazole (45.0%; 95% CI, 32.0 to 56.4) were significantly lower than the rates with mebendazole (P = 0.02 for the comparison of cure rates). Oxantel pamoate had low efficacy against hookworm and A. lumbricoides. Adverse events (mainly mild) were reported by 30.9% of all children.” (J. Keiser, jennifer.keiser@unibas.ch)
“Research and development of new anthelmintic agents are urgently needed, such as that occurring with the anti-wolbachia consortium and the reformulation of flubendazole as macrofilaricides for onchocerciasis and lymphatic filariasis,” an editorialist writes (
pp. 665–6). “[Current research efforts] should be encouraged and expanded to include all helminthic infections that are neglected tropical diseases, and research-based companies, including those working on animal and human health, could help bridge knowledge gaps and facilitate the development of new treatments.” (L. Savioli)
Pregabalin v. Pramipexole for Restless Legs Syndrome: In a 52-week trial of patients with restless legs syndrome (RLS), pregabalin was more effective than pramipexole and produced lower proportions of patients who experienced augmentation, a complication thought to result from long-term dopaminergic treatment (pp. 621–31). Pregabalin 300 mg/d, pramipexole 0.25 or 0.5 mg/d, or placebo for 12 weeks followed by 40 weeks of randomly assigned active treatment produced these results: “A total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the [International RLS] scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P < 0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P < 0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P = 0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P = 0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.” (R. P. Allen, richardjhu@mac.com)
An editorialist writes of the “therapeutic dilemma” with RLS (
pp. 667–8): “The observation that augmentation can occur with different drugs … raises the question of whether augmentation is related to medication, is intrinsic to RLS, or is related to individual patient characteristics. Many other gaps exist in our knowledge of how to best treat patients with this condition. More head-to-head comparisons of treatments are needed, and future trials should include children and elderly patients, those with secondary RLS, and those with mild-to-moderate RLS. Studies should also include an objective assessment of sleep and an evaluation of the role of sleep disruption in morbidity. I hope that this latest progress in RLS research will spur the development of an ideal drug for the treatment of this challenging condition.” (S. Chokroverty)

>>>PNN NewsWatch
* FDA has expanded approved uses of ibrutinib (Imbruvica, Pharmacyclics) to include previously treated chronic lymphocytic leukemia.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 14, 2014 * Vol. 21, No. 31
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Mar. 1 issue of Clinical Infectious Diseases (2014; 58).
Whole-Genome Analysis of S. aureus ICU Transmission: Patient-to-patient transmission of Staphylococcus aureus explains only about one-fifth of acquired organisms in intensive-care units, according to investigators who analyzed isolates using whole-genome sequencing (pp. 609–18). In an adult ICU over a 14-month period, all admitted patients were screened for S. aureus. A total of 275 isolates were spa typed and sequenced, with these results: “Staphylococcus aureus was carried by 185 of 1,109 patients sampled within 24 hours of ICU admission (16.7%); 59 (5.3%) patients carried methicillin-resistant S. aureus (MRSA). Forty-four S. aureus (22 MRSA) acquisitions while on ICU were detected. Isolates were available for genetic analysis from 37 acquisitions. Whole-genome sequencing indicated that 7 of these 37 (18.9%) were transmissions from other colonized patients. Conventional methods (spa typing combined with overlapping patient stay) falsely identified 3 patient-to-patient transmissions (all MRSA) and failed to detect 2 acquisitions and 4 transmissions (2 MRSA).” (M. Llewelyn, m.j.llewelyn@bsms.ac.uk)
National Intervention for Carbapenem-Resistant Enterobacteriaceae: Cases of nosocomial carbapenem-resistant Enterobacteriaceae (CRE) were cut by more than 10-fold in Israel after the Ministry of Health initiated a nationwide intervention in 2007, a study shows (pp. 697–703). Authors report: “Guidelines were issued to the microbiology laboratories delineating procedures for identifying CRE and carbapenemase production. A protocol for ruling out continued carriage in known carriers was established. Compliance with national guidelines was overseen via site visits at healthcare facilities, routine reporting of carrier census and isolation status, and the establishment of a network of communications to facilitate reporting on identified carriage, contact tracing and screening, and outbreak investigations. During the intervention, nosocomial CRE acquisition in acute care declined from a monthly high of 55.5 to an annual low of 4.8 cases per 100,000 patient–days (P < .001).” (M. J. Schwaber, mitchells@tlvmc.gov.il)

>>>Oncology Highlights
Source:
Feb. 10 issue of the Journal of Clinical Oncology (2014; 32).
Preoperative Chemoradiotherapy in Upper GI Cancers: In patients with cancer of the esophagus or gastroesophageal junction, preoperative chemoradiotherapy (CRT) plus surgery reduced recurrence over surgery alone, according to findings of the CROSS trials (pp. 385–91). Five weekly courses of paclitaxel and carboplatin combined with concurrent radiation produced these results in 422 patients in 2001–08: “Of the 374 patients who underwent resection, 86% were allocated to surgery and 92% to CRT plus surgery. On January 1, 2011, after a minimum follow-up of 24 months (median, 45 months), the overall recurrence rate in the surgery arm was 58% versus 35% in the CRT plus surgery arm. Preoperative CRT reduced locoregional recurrence (LRR) from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the CRT group (35% v 29%; P = .025). LRR occurred in 5% within the target volume, in 2% in the margins, and in 6% outside the radiation target volume. In 1%, the exact site in relation to the target volume was unclear. Only 1% had an isolated infield recurrence after CRT plus surgery.” (M. C. C. M. Hulshof, m.c.hulshof@amc.uva.nl)
“The approach taken in the CROSS studies emphasizes the importance of controlling both systemic and local-regional disease,” editorialists write (
pp. 367–9). Combining radiation, chemotherapy, and surgery is likely “the most promising strategy for improving outcomes in esophageal cancer,” the writer concludes. (H. J. Mamon, hmamon@lroc.harvard.edu)

>>>PNN NewsWatch
* Shortages of intravenous saline solutions are affecting 76% of U.S. hospitals, ASHP reports based on a survey of pharmacy directors. While conservation strategies are working for 53% of respondents experiencing this shortage, 29% of respondents reporting a shortage have a supply inadequate to meet all patient needs.
*
PNN will not be published on Mon., Feb. 17, Presidents Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 18, 2014 * Vol. 21, No. 32
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 18 issue of the Annals of Internal Medicine (2014; 160).
Cost-effectiveness of Genotype-Guided Dual Antiplatelet Therapies in ACS: Analysis of the costs of five strategies for antiplatelet therapy after percutaneous coronary intervention for acute coronary syndrome (ACS) led authors to conclude, “Genotype-guided personalization may improve the cost-effectiveness of prasugrel and ticagrelor…, but ticagrelor for all patients may be an economically reasonable alternative in some settings” (pp. 221-32). With a lifetime horizon and societal perspective, the investigators used cost-effectiveness analysis to assess generic clopidogrel, prasugrel, ticagrelor, and genotyping for polymorphisms of CYP2C19 with carriers of loss-of-function alleles receiving either ticagrelor (genotyping with ticagrelor) or prasugrel (genotyping with prasugrel) and noncarriers receiving clopidogrel, with these results: “The clopidogrel strategy produced $179,301 in costs and 9.428 [quality-adjusted life–years (QALYs)]. Genotyping with prasugrel was superior to prasugrel alone, with an [incremental cost-effectiveness ratio] of $35,800 per QALY relative to clopidogrel. Genotyping with ticagrelor was more effective than genotyping with prasugrel ($30,200 per QALY relative to clopidogrel). Ticagrelor was the most effective strategy ($52,600 per QALY relative to genotyping with ticagrelor).” A sensitivity analysis showed the following: “Stronger associations between genotype and thrombotic outcomes rendered ticagrelor substantially less cost-effective ($104,800 per QALY). Genotyping with prasugrel was the preferred therapy among patients who could not tolerate ticagrelor.” (D. S. Kazi, kazi@alumni.stanford.edu)
Rituximab in Primary Sjögren Syndrome: Among 120 patients with the autoimmune disorder primary Sjögren syndrome (pSS), rituximab did not reduce symptoms or disease activity at 24 weeks, researchers report, although some benefits were evident at earlier time points in the randomized controlled trial (pp. 233–42). Conducted at 14 French university hospitals, the trial included patients with scores of 50 mm or greater on at least two of four visual analogue scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (<10 years) biologically active or systemic pSS. Based on a primary end point of improvement of at least 30 mm in two of four VASs by week 24, the investigators found: “No significant difference between groups in the primary end point was found (difference, 1.0% [95% CI, −16.7% to 18.7%]). The proportion of patients with at least 30-mm decreases in at least two of the four VAS scores was higher in the rituximab group at week 6 (22.4% vs. 9.1%; P = 0.036). An improvement of at least 30 mm in VAS fatigue score was more common with rituximab at weeks 6 (P < 0.001) and 16 (P = 0.012), and improvement in fatigue from baseline to week 24 was greater with rituximab. Adverse events were similar between groups except for a higher rate of infusion reactions with rituximab.” (A. Saraux, alain.saraux@chu-brest.fr)

>>>PNN NewsWatch
* FDA on Friday approved elosulfase alfa (Vimizim, BioMarin), the first approved treatment for Mucopolysaccharidosis Type IVA (Morquio A syndrome), a rare, autosomal recessive lysosomal storage disease caused by a deficiency in N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Elosulfase alfa replaces the missing GALNS enzyme and thereby avoids problems with bone development, growth, and mobility.

>>>
PNN JournalWatch
* Medical Management With or Without Interventional Therapy for Unruptured Brain Arteriovenous Malformations (ARUBA): A Multicentre, Non-Blinded, Randomised Trial, in
Lancet, 2014; 383: 614–21. (C. Stapf, christian.stapf@lrb.aphp.fr)
* State of the Art on Food Allergen Immunotherapy: Oral, Sublingual, and Epicutaneous, in
Journal of Allergy and Clinical Immunology, 2014; 133: 318–23. (S. M. Jones, jonesstaciem@uams.edu)
* Advances in Allergic Skin Disease, Anaphylaxis, and Hypersensitivity Reactions to Foods, Drugs, and Insects in 2013, in
Journal of Allergy and Clinical Immunology, 2014; 133: 324–34. (S. H. Sicherer, scott.sicherer@mssm.edu)
* Effect of Age on the Profile of Psychotropic Users: Results from the 2010 National Ambulatory Medical Care Survey, in
Journal of the American Geriatrics Society, 2014; 62: 358–64. (D. T. Maust, maustd@umich.edu)
* The Interleukin-23/Interleukin-17 Axis in Spondyloarthritis Pathogenesis: Th17 and Beyond, in
Arthritis & Rheumatology, 2014; 66: 231–41. (R. A. Colbert, colbertr@mail.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 19, 2014 * Vol. 21, No. 33
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 19 issue of JAMA (2014; 311).
Citalopram & Agitation in Alzheimer Disease: If cognitive and cardiac adverse effects are tolerated, citalopram may be a useful addition to psychosocial therapy of patients with Alzheimer disease, according to results of the Citalopram for Agitation in Alzheimer Disease Study (CitAD) (pp. 682–91). Participants had probable Alzheimer disease when they were randomized to placebo or citalopram 10 mg/d with titration to 30 mg/d over 3 weeks. Psychosocial therapy was provided to patients in both arms, and results showed: “Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The [18-point Neurobehavioral Rating Scale agitation subscale] estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the [modified Alzheimer Disease Cooperative Study–Clinical Global Impression of Change] showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given [Clinical Global Impression of Change] category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the [Cohen-Mansfield Agitation Inventory], total [Neuropsychiatric Inventory (NPI)], and caregiver distress scores but not on the NPI agitation subscale, [activities of daily living], or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1–30.1; P = .01) were seen in the citalopram group.” (A. P. Porsteinsson, anton_porsteinsson@urmc.rochester.edu)
“As demonstrated by the results of this study of citalopram, when behavioral interventions fail to improve agitation, multiple factors need consideration for selecting the best medication for an individual patient, including cardiac safety issues and evidence of efficacy from randomized controlled trials,” an editorialist writes (
pp. 677–8). “Until more definitive treatments are available, the careful selection and monitoring of pharmacologic agents may help optimize the level of functioning and quality of life for some patients with dementia.” (G. W. Small, gsmall@ucla.edu)
Drugs v. Ablation in AF: Lower rates of recurrence of paroxysmal atrial fibrillation (AF) were seen with radiofrequency ablation compared with medications in patients who had received no previous antiarrhythmic therapy, researchers report (pp. 692–700). In the RAAFT-2 trial, 127 treatment-naive patients at 16 centers in Europe and North America were randomized to medications or ablation, with these results based on time to the first documented atrial tachyarrhythmia of more than 30 seconds: “Forty-four patients (72.1%) in the antiarrhythmic group and in 36 patients (54.5%) in the ablation group experienced the primary efficacy outcome (hazard ratio [HR], 0.56 [95% CI, 0.35–0.90]; P = .02). For the secondary outcomes, 59% in the drug group and 47% in the ablation group experienced the first recurrence of symptomatic AF, atrial flutter, atrial tachycardia (HR, 0.56 [95% CI, 0.33–0.95]; P = .03). No deaths or strokes were reported in either group; 4 cases of cardiac tamponade were reported in the ablation group. In the standard treatment group, 26 patients (43%) underwent ablation after 1-year. Quality of life was moderately impaired at baseline in both groups and improved at the 1 year follow-up. However, improvement was not significantly different among groups.” (C. A. Morillo, morillo@hhsc.ca)
While few patients want to “undergo catheter ablation without at least 1 trial of an antiarrhythmic medication,” an editorialist writes that “first-line AF ablation is a preferred treatment strategy” in several subgroups of patients (
pp. 679–80). “One example is patients with both paroxysmal atrial fibrillation and significant sinus node dysfunction” (H. Calkins, hcalkins@jhmi.edu)

>>>PNN NewsWatch
* FDA yesterday approved droxidopa (Northera, Chelsea Therapeutics) for treatment of neurogenic orthostatic hypotension. The accelerated approval relied on short-term relief of dizziness as an indicator of improvement in the outcome of ultimate interest, relief of dizziness during chronic treatment.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 20, 2014 * Vol. 21, No. 34
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 20 issue of the New England Journal of Medicine (2014; 370).
Bevacizumab in Newly Diagnosed Glioblastoma: Two research studies and an editorial examine use of bevacizumab in patients with newly diagnosed glioblastoma.
Addition of bevacizumab to standard therapy did not improve overall survival in patients with newly diagnosed glioblastoma, according to results of a Phase III trial, RTOG 0825 (
pp. 699–708). In 637 patients, bevacizumab or placebo was started during the fourth week of radiotherapy and daily temozolomide. Based on risks of mortality and progression of disease, the investigators found: “There was no significant difference in the duration of overall survival between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months vs. 7.3 months; hazard ratio for progression or death, 0.79). There were modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.” (M. R. Gilbert)
Similar clinical results were observed in a second Phase III trial, with survival unchanged but progression-free survival, quality of life, and performance status improved (
pp. 709–22). Following an initial round of bevacizumab or placebo with radiotherapy and temozolomide and a 28-day break in therapy, maintenance bevacizumab was initiated with temozolomide for six 4-week cycles. This was followed by bevacizumab monotherapy or placebo until disease progressed or unacceptable toxic effects occurred. Results showed: “A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P < 0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P = 0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P = 0.049) and 33.9% and 30.1% at 2 years (P = 0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).” (O. L. Chinot, livier.chinot@ap-hm.fr">olivier.chinot@ap-hm.fr)
While there is “still much to learn” about bevacizumab use in glioblastoma, an editorialist remains positive about this agent (
pp. 764–5): “Despite its limitations, bevacizumab remains the single most important therapeutic agent for glioblastoma since temozolomide. Ongoing and future trials will better define how and when it should be used in this population of patients for whom so few treatment options currently exist.” (H. A. Fine)
Bevacizumab in Advanced Cervical Cancer: Median overall survival increased by 3.7 months when bevacizumab was added to combination chemotherapy in patients with advanced cervical cancer, researchers report (pp. 734–43). Women with recurrent, persistent, or metastatic cervical cancer received bevacizumab or placebo with chemotherapy. Results showed: “Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%).” (K. S. Tewari, ktewari@uci.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 21, 2014 * Vol. 21, No. 35
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Feb. issue of the Journal of Allergy and Clinical Immunology (2014; 133).
Choosing Optimal Step 3 Asthma Drugs: Post-hoc analysis of the Best Add-On Giving Effective Response (BADGER) shows that clinical and laboratory tests are useful for choosing among step-3 medication options of a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting beat-2-agonist (LABA step-up therapy) (pp. 350–6). “Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E4 levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy,” the authors conclude. “Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.” Results of the post-hoc analysis showed: “In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV1 response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E4 levels were marginally (P = .053) related to a differential FEV1 response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV1 and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses.” (N. Rabinovitch, rabinovitchn@njhealth.org)
Rare Genetic Variants Predict Bronchodilator Response: In 1,782 Latino children with asthma, a genomewide association study for bronchodilator response (BDR) shows that rare variants explain individual responses to albuterol, researchers report (pp. 370–8.e15). Genome data combined with replication studies in 531 Latinos showed these results: “We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10−8), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells.” (D. G. Torgerson, dara.torgerson@ucsf.edu)

>>>Rheumatology Highlights
Source:
Feb. issue of Arthritis & Rheumatology (2014; 66).
Glucocorticoid Dose Thresholds & Mortality in RA: At a threshold glucorticoid dose of 8 mg daily, patients with rheumatoid arthritis (RA) have significantly lower mortality rates, a study shows (pp. 264–72). Patients at rheumatology clinics were recruited for the study, which looked at glucocorticoid dose; demographic, socioeconomic, clinical, and laboratory features of RA; cardiovascular (CV) risk factors; and vital status. Results showed: “We studied 779 RA patients with a total of 7,203 person–years of observation, during which 237 of them died, yielding a mortality rate of 3.2 per 100 person–years (95% confidence interval [95% CI] 2.8–3.7). One hundred twenty of the deaths were due to CV causes, yielding a CV mortality rate of 1.8 (95% CI 1.5–2.1). Exposure to glucocorticoids was associated with a dose-dependent increase in death from all causes, with a ratio (HR) of 1.07 per mg of prednisone per day (95% CI 1.05–1.08). Compared to patients who were not receiving corticosteroids, the minimum daily prednisone dose threshold associated with an increase in all-cause mortality was 8–15 mg, with an adjusted HR of 1.78 (95% CI 1.22–2.60). For the cumulative dose of glucocorticoids, the minimum dosage associated with all-cause mortality was 40 g (HR 1.74 [95% CI 1.25–2.44]).” (I. del Rincón, delrincon@uthscsa.edu)

>>>PNN NewsWatch
* Young and middle-aged Americans have been hospitalized with influenza at unusually high rates this season, CDC said yesterday. Vaccination reduced Americans’ risk of seeing a physician for flu by 60% among all age groups this season.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 24, 2014 * Vol. 21, No. 36
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 22 issue of Lancet (2014; 383).
Reducing I.V. Acetylcysteine Adverse Effects: A modified 12-h regimen of intravenous acetylcysteine may reduce adverse effects that can occur when patients are being treated for paracetamol (acetaminophen) poisoning, researchers report (pp. 697–704). At three U.K. hospitals, patients with acute paracetamol overdose were randomized to standard intravenous acetylcysteine regimen (duration 20–25 h) or a shorter (12 h) modified protocol, with or without pretreatment with intravenous ondansetron 4 mg. Results showed: “Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0.26, 97.5% CI 0.13–0.52; p < 0.0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0.41, 0.20—0.80; p = 0.003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0.23, 97.5% CI 0.12–0.43; p < 0.0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0.60, 97.5% CI 0.20–1.83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3.30, 1.01–10.72; p = 0.024).” (D. N. Bateman, spib@luht.scot.nhs.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Opioid Prescribing by Multiple Medicare Providers: Based on patterns identified among 1.8 million Medicare beneficiaries who received at least one prescription for opioids during 2010, “concurrent opioid prescribing by multiple providers is common in Medicare patients and is associated with higher rates of hospital admission related to opioid use,” a study concludes (g1393). A 20% random sample of Medicare beneficiaries was studied using a retrospective cohort design, with these results: “Among 1,208,100 beneficiaries with [more than one] opioid prescription, 418,530 (34.6%) filled prescriptions from two providers, 171,420 (14.2%) from three providers, and 143,344 (11.9%) from four or more providers. Among beneficiaries with four or more opioid providers, 110,671 (77.2%) received concurrent opioid prescriptions from multiple providers, and the dominant provider prescribed less than half of the mean total prescriptions per beneficiary (7.9/15.2 prescriptions). Multiple provider prescribing was highest among beneficiaries who were also prescribed stimulants, non-narcotic analgesics, and central nervous system, neuromuscular, and antineoplastic drugs. Hospital admissions related to opioid use increased with multiple provider prescribing: the annual unadjusted rate of admission was 1.63% (95% confidence interval 1.58 to 1.67%) for beneficiaries with one provider, 2.08% (2.03% to 2.14%) for two providers, 2.87% (2.77% to 2.97%) for three providers, and 4.83% (4.70% to 4.96%) for four or more providers. Results were similar after covariate adjustment.” (A. B. Jena, jena@hcp.med.harvard.edu)

>>>PNN JournalWatch
* International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation, in
Journal of Clinical Oncology, 2014; 32: 587–600. (A. Palumbo, appalumbo@yahoo.com)
* The Pharmacogenetics of Type 2 Diabetes: A Systematic Review, in
Diabetes Care, 2014; 37: 876–86. (N. M. Maruthur, maruthur@jhmi.edu)
* Microalbuminuria as a Risk Predictor in Diabetes: The Continuing Saga, in
Diabetes Care, 2014; 37: 867–75. (G. L. Bakris, gbakris@gmail.com)
* Percutaneous Interventional Therapies for the Treatment of Patients With Severe Pulmonary Hypertension, in
Journal of the American College of Cardiology, 2014; 63: 611–8. (P. Bhamra-Ariza)
* Connected Health: A Review of Technologies and Strategies To Improve Patient Care With Telemedicine and Telehealth, in
Health Affairs, 2014; 33: 194–9. (W. Everett, weverett@nehi.net)
* Effects of Continuity of Care on Medication Duplication Among the Elderly, in
Medical Care, 2014; 52: 149–56. (S-H Cheng)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 25, 2014 * Vol. 21, No. 37
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; 160).
Intensified Lipid-Lowering Choices: In high-risk patients with elevated lipids for whom high-dose statins are effective or acceptable, a lower-dose statin regimen plus bile acid sequestrant is a reasonable alternative, according to authors of a systematic review (doi: 10.7326/M13-2526). This approach should be used with caution since long-term evidence of benefits and harms is lacking, the group writes based on a review of 36 trials: “Low-intensity statin plus bile acid sequestrant decreases LDL cholesterol 0% to 14% more than does mid-intensity monotherapy among high-risk hyperlipidemic patients. Mid-intensity statin plus ezetimibe decreases LDL cholesterol 5% to 15% and 3% to 21% more than does high-intensity monotherapy among patients with [atherosclerotic cardiovascular disease] and diabetes mellitus, respectively. Evidence was insufficient to evaluate LDL cholesterol for fibrates, niacin, and omega-3 fatty acids. Evidence was insufficient for long-term clinical outcomes, adherence, and harms for all regimens.” (K. Gudzune, gudzune@jhu.edu)
Vitamin, Mineral Supplements for Cardiovascular Disease and Cancer Prevention: After reviewing the evidence on efficacy of vitamin and mineral supplements for primary prevention of cardiovascular disease and cancer, the U.S. Preventive Services Task Force (USPSTF) reaches these conclusions (doi: 10.7326/M14-0198; www.uspreventiveservicestaskforce.org):
* The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins for the prevention of cardiovascular disease or cancer. (I statement)
* The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the use of single- or paired-nutrient supplements (except beta-carotene and vitamin E) for the prevention of cardiovascular disease or cancer. (I statement)
* The USPSTF recommends against the use of beta-carotene or vitamin E supplements for the prevention of cardiovascular disease or cancer. (D recommendation)

>>>Internal Medicine Report II
Source:
Early-release article from JAMA Internal Medicine (2014; 174).
Antihypertensive Medications & Serious Falls: Blood-pressure-lowering medications should be used with caution in older adults, particularly those with previous falls, because of an increased risk of falls with injuries, a study concludes (doi: 10.1001/jamainternmed.2013.14764). Among a nationally representative group of 4,961 community-living adults older than 70 with hypertension, investigators identified these frequencies of serious fall injuries and related them to doses of antihypertensive medications: “Of the 4,961 participants, 14.1% received no antihypertensive medications; 54.6% were in the moderate-intensity and 31.3% in the high-intensity antihypertensive groups. During follow-up, 446 participants (9.0%) experienced serious fall injuries, and 837 (16.9%) died. The adjusted hazard ratios for serious fall injury were 1.40 (95% CI, 1.03–1.90) in the moderate-intensity and 1.28 (95% CI, 0.91–1.80) in the high-intensity antihypertensive groups compared with nonusers. Although the difference in adjusted hazard ratios across the groups did not reach statistical significance, results were similar in the propensity score–matched subcohort. Among 503 participants with a previous fall injury, the adjusted hazard ratios were 2.17 (95% CI, 0.98–4.80) for the moderate-intensity and 2.31 (95% CI, 1.01–5.29) for the high-intensity antihypertensive groups.” (M. E. Tinetti, mary.tinetti@yale.edu)

>>>JAPhA Highlights
Source:
Early-release article from the Journal of the American Pharmacists Association (2014; 54).
Med Rec in Family Medicine Clinic: Pharmacist review of medications in an outpatient family medicine clinic resulted in identification of large numbers of medication discrepancies with the electronic health record, and researchers report that more than one-half of errors were clinically important (pp. e55–e61). Among 327 patients seen before physician visits, 2,167 discrepancies were identified (6.6 ± 4.5 total discrepancies and 3.4 ± 3.2 clinically important discrepancies per patient). The most common discrepancy was “not taking medication on list,” and pain medications were most commonly involved. (A. M. Philbrick, philb020@umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 26, 2014 * Vol. 21, No. 38
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 26 issue of JAMA (2014; 311).
Live MMR Vaccine & Hospitalizations for Other Infections: Findings from low-income countries showing reduced mortality from causes other than measles when children receive live measles vaccine are replicated in a study from Denmark with respect to hospitalizations (pp. 826–35). Using nationwide registries to conduct a population-based cohort study, investigators looked vaccinations and hospitalizations in 1997–2006. Children were assessed based on receipt as infants or at 15 months of live measles, mumps, and rubella (MMR) vaccine and/or inactivated vaccine against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib).
Results showed: “The study included 495,987 children contributing with 56,889 hospital admissions for any type of infection during 509,427 person–years (rate, 11.2 per 100 person–years). For the 456,043 children who followed the recommended schedule and received MMR after the third dose of DTaP-IPV-Hib, MMR (rate, 8.9 per 100 person–years) vs the third dose of DTaP-IPV-Hib (rate, 12.4 per 100 person–years) as the most recent vaccine was associated with an adjusted [incidence rate ratios (IRRs)] of 0.86 (95% CI, 0.84–0.88) for any admission for infection. There were 19,219 children immunized out of sequence. The adjusted IRR was 0.87 (95% CI, 0.80–0.95) for those receiving MMR (rate, 9.9 per 100 person–years) after the second dose of DTaP-IPV-Hib (rate, 15.1 per 100 person–years). However, in the 1,981 children who subsequently received the third dose of DTaP-IPV-Hib (rate, 12.8 per 100 person–years) after MMR, the IRR for hospital admissions for infection was significantly greater (adjusted IRR, 1.62 [95% CI, 1.28–2.05]). The risk of admission for an infection between ages 16 months and 24 months was 4.6% (95% CI, 4.5%–4.7%) for receiving MMR on time and 5.1% (95% CI, 5.0%–5.2%) for not receiving MMR on time. The risk difference was 0.5 percentage point (95% CI, 0.4–0.6), and the number needed to vaccinate with MMR before age 16 months to prevent 1 admission for any infection was 201 (95% CI, 159–272).” (S. Sørup,
sgs@ssi.dk)
Observational studies such as this one are important and contribute to the body of literature, an editorialist writes, but they are not enough (
pp. 804–5): “The ability to properly control for bias and confounding in observational studies is often limited, and without randomized controlled trials specifically designed to test the hypothesis, the issue of nonspecific effects of vaccines may remain subject to continuing debate.” (D. Goldblatt, d.goldblatt@ucl.ac.uk)
U.S. Obesity Trends: In the 2011–12 National Health and Nutrition Examination Survey, obesity among Americans remained at the high levels evident in the past four biennial surveys, researchers report (pp. 806–14). Obesity declined among young children, increased in older women, and remained about the same for other subgroups: “In 2011–2012, 8.1% (95% CI, 5.8%–11.1%) of infants and toddlers had high weight for recumbent length, and 16.9% (95% CI, 14.9%–19.2%) of 2– to 19-year-olds and 34.9% (95% CI, 32.0%–37.9%) of adults (age-adjusted) aged 20 years or older were obese. Overall, there was no significant change from 2003–2004 through 2011–2012 in high weight for recumbent length among infants and toddlers, obesity in 2- to 19-year-olds, or obesity in adults. Tests for an interaction between survey period and age found an interaction in children (P = .03) and women (P = .02). There was a significant decrease in obesity among 2- to 5-year-old children (from 13.9% to 8.4%; P = .03) and a significant increase in obesity among women aged 60 years and older (from 31.5% to 38.1%; P = .006).” (C. L. Ogden, cogden@cdc.gov)

>>>PNN NewsWatch
* FDA has approved metreleptin for injection (Myalept, Amylin) as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy. The product is available only through the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program because of the risks associated with the development of neutralizing antibodies and lymphoma. A Medication Guide should be provided to patients with each prescription fill of the product. FDA is requiring the company to conduct seven postmarketing studies of the drug.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 27, 2014 * Vol. 21, No. 39
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 27 issue of the New England Journal of Medicine (2014; 370).
ADHD Management: The case of a 9-year-old boy with attention-deficit/hyperactivity disorder (ADHD) provides the framework for a Clinical Practice article (pp. 838–46). The authors conclude: “The child described in the vignette has the core symptoms of ADHD—inattention, hyperactivity, and impulsivity—with functional impairment in academic performance and social relationships. He had improvement in core symptoms of ADHD when he received stimulant medication, as has been shown in randomized trials of these medications. However, the use of stimulants alone did not substantially improve his educational and social functioning. We recommend that the treating physician suggest a comprehensive psychoeducational assessment to determine whether he has learning disabilities. In addition, his academic productivity and social difficulties should be targeted for interventions; given the demonstrated benefits of these methods in clinical studies, we would recommend behavioral parental training, behavioral classroom management, peer intervention approaches, or a combination of these methods. Specific, individualized, measurable objectives should be established and progress toward those objectives carefully monitored in collaboration with his family and teachers, as well as counselors, coaches, and other advisors in the community.” (H. M. Feldman, hfeldman@stanford.edu)
Malaria, Fever in Tanzanian Children: Among outpatient children in Tanzania, viruses are more frequently implicated as causes of fever than are bacteria and parasites such as malaria, researchers report (pp. 809–17). At one urban and one rural clinic, these etiologies were identified using rapid diagnostic tests in children 2 months to 10 years of age with temperatures of 38 degrees Celsius or higher: “Analyses of data derived from clinical presentation and from 25,743 laboratory investigations yielded 1,232 diagnoses. Of 1,005 children (22.6% of whom had multiple diagnoses), 62.2% had an acute respiratory infection; 5.0% of these infections were radiologically confirmed pneumonia. A systemic bacterial, viral, or parasitic infection other than malaria or typhoid fever was found in 13.3% of children, nasopharyngeal viral infection (without respiratory symptoms or signs) in 11.9%, malaria in 10.5%, gastroenteritis in 10.3%, urinary tract infection in 5.9%, typhoid fever in 3.7%, skin or mucosal infection in 1.5%, and meningitis in 0.2%. The cause of fever was undetermined in 3.2% of the children. A total of 70.5% of the children had viral disease, 22.0% had bacterial disease, and 10.9% had parasitic disease.” (V. D’Acremont, valerie.dacremont@unibas.ch)
“New diagnostics have considerable potential to improve care, target treatment, and reduce the cost of unnecessary prescriptions and the downstream effects of antimicrobial resistance,” an editorialist responds (
pp. 875–7). “However, a trial investigating the effect of rapid, point-of-care malaria diagnostics on case-management decision making, in which pretrial training of clinical staff emphasized that a negative test result should lead to consideration of an alternative diagnosis, did not show reduced rates of malaria treatment. Ninety percent of antimalarial agents prescribed in the trial were for children with negative test results. As the epidemiologic landscape evolves, updated guidelines based on evidence such as that generated in the study by D’Acremont and colleagues are welcome; however, experience suggests that changing current practice will not be a straightforward process.” (K. Maitland)
Enterovirus 71 Vaccine: Two research studies from China show efficacy of a vaccine against enterovirus 71, the causative agent of hand, foot, and mouth disease and herpangina (pp. 818–28, N. Wang, wangnan@sinovac.com; pp. 829–37; Q. Li, liqihan@imbcams.com.cn). The first study, a Phase III trial, included 10,007 healthy infants and young children aged 6–35 months. Those receiving the Vero cell–based EV71 inactivated vaccine with aluminum hydroxide had significantly lower rates of EV71-associated disease (0.3% versus 2.1% in those receiving placebo). The other study, also a Phase III trial, showed that the EV71 vaccine produced EV71-specific immune responses and protection against hand, foot, and mouth disease in 12,000 children ages 6–71 months, with vaccine efficacy of 97.4%.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Feb. 28, 2014 * Vol. 21, No. 40
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (2014; 37).
Glycemic Control & GFR Estimates: In patients with diabetes, estimates of glomerular filtration rate (eGFR) become increasingly falsely elevated as glycemic control worsens, a study shows, but eGFR can be corrected to clinically useful values using hemoglobin A1c (pp. 596–603). In 80 participants (40 with and 40 without diabetes), GFR was evaluated using inulin clearance (Cin), and eGFR values were calculated using serum creatinine and/or serum cystatin C levels. Results showed: “Although Cin was not significantly different between the diabetic and nondiabetic subjects (P = 0.2866), each of three eGFR measures from the diabetic patients was significantly higher than that of the nondiabetic subjects (P < 0.01). There were significant and positive correlations between the ratio of each eGFR/Cin, hemoglobin A1c, and glycated albumin. The intraclass correlation coefficients in diabetic patients were weaker than those in the nondiabetic subjects, and the intercepts of the regression lines between each eGFR measure and Cin in the diabetic patients were significantly higher than those of the nondiabetic subjects. New formulae for the calculation of eGFR corrected by the glycemic control indices were better than the original eGFR, particularly in diabetic patients.” (E. Ishimura, ish@med.osaka-cu.ac.jp)
Patient-Managed Insulin Intensification: In patients with stable type 2 diabetes, a patient-managed insulin intensification strategy using insulin glargine and insulin glulisine was as effective as physician-managed care, researchers report (pp. 604–10). The study included patients with type 2 diabetes, HbA1c levels greater than 7%, and either nocturnal episodes of hypoglycemia or insufficient basal insulin glargine levels. Bolus insulin glulisine was added at breakfast, and patients were randomized to patient self-titration or physician management, with these results: “After a mean (SD) follow-up of 159.4 days (36.2 days), 28.4% of participants in the self-titration arm vs. 21.2% in the physician titration arm achieved an HbA1c level of ≤7% (53 mmol/mol) without severe hypoglycemia (between-group absolute difference 7.2%; 95% CI −3.2 to 17.7). The lower end of this 95% confidence interval was within the predetermined noninferiority boundary of −5% (P noninferiority = 0.011).” (S. B. Harris, sharris1@uwo.ca)
Age-Related Effects of Intensive Glucose Control: In the ACCORD trial, younger participants experienced benefits from intensive glucose control, while older participants had neutral effects on cardiovascular disease and total mortality, an analysis shows (pp. 634–43). Participants with type 2 diabetes had a mean age of 62 and duration of diabetes of 10 years when randomized to strategies that targeted A1c levels below 6.0% or 7.0–7.9%. Outcomes were as follows: “Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences. Within the older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45% intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard).” (M. E. Miller, mmiller@wakehealth.edu)

>>>PNN NewsWatch
* FDA yesterday proposed an update to the Nutrition Facts label for packaged foods to reflect the latest scientific information, including the link between diet and chronic diseases such as obesity and heart disease. The proposed label also would replace out-of-date serving sizes to better align with how much people really eat, and it would feature a fresh design to highlight key parts of the label such as calories and serving sizes. If adopted as proposed, the new label would inform consumers of the amount of added sugar in a product, have dual columns for per-serving and per-package portions, require declarations of potassium and vitamin D content, and remove the “calories from fat” information since some fats are beneficial.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 3, 2014 * Vol. 21, No. 41
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 1 issue of Lancet (2014; 383).
Antibiotics for Melioidosis: In northeast Thailand, trimethoprim-sulfamethoxaxole (TMP-SMX) was noninferior to TMP-SMX plus doxycycline for treatment of melioidosis, a difficult-to-cure infection of the gram-negative bacillus Burkholderia pseudomallei (pp. 807–14). The TMP-SMX regimen had a better safety profile and was better tolerated by patients. In the study, patients received TMP-SMX or TMP-SMX plus doxycycline for 20 weeks, and patients were followed every 4 months for 1 year and then annually, with these results based on culture-confirmed recurrent melioidosis and a noninferiority hazard-ratio margin of 1.7: “We enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0.81; 95% CI 0.42–1.55). The criterion for non-inferiority was met (p = 0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]).” (D. Limmathurotsakul, direk@tropmedres.ac)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Epilepsy Pharmacotherapy in Adults: For the nearly one-third of patients who have drug-resistant epilepsy, revitalization of the drug-development process is needed urgently, a review article concludes (g254). “Antiepileptogenic compounds that prevent epilepsy before the first seizure in at risk patients are needed, as well as disease modifying drugs to control ongoing severe epilepsy and its comorbidities,” the authors write, based on these findings: “About two in three adults with new onset epilepsy will achieve lasting seizure remission on or off these drugs, although around half will experience mild to moderately severe adverse effects. Patients with epilepsy, especially the 20–30% whose seizures are not fully controlled with available drugs (drug resistant epilepsy), have a significantly increased risk of death, as well as psychiatric and somatic comorbidities, and adverse effects from antiepileptic drugs. Newer drugs have brought more treatment options, and some such as levetiracetam cause fewer drug interactions and less hypersensitivity than older ones. However, they do not reduce the prevalence of drug resistant epilepsy or prevent the development of epilepsy in patients at high risk, such as those with a traumatic brain injury. The development of antiepileptic drugs urgently needs to be revitalized so that we can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms. Antiepileptogenic agents to prevent epilepsy before the first seizure in at risk patients and disease modifying agents to control ongoing severe epilepsy associated with progressive underlying disease are also needed.” (D. Schmidt, dbschmidt@t-online.de)

>>>PNN NewsWatch
* ASHP’s 2-day inaugural Ambulatory Care Conference and Summit starts today in Dallas. In addition to educational sessions, attendees “will have a unique and valuable opportunity to influence the future of practice through consensus-building activities,” ASHP said. “As a next step in the Pharmacy Practice Model Initiative, our goal is to create a vision for forward-thinking pharmacy practice models that will ensure pharmacists are members of the ambulatory health care team who are responsible and accountable for patient and health care system outcomes.”

>>>PNN JournalWatch
* Chemotherapy Drug Shortages in Pediatric Oncology: A Consensus Statement, in
Pediatrics, 2014; 133: e716–24. (Working Group on Chemotherapy Drug Shortages in Pediatric Oncology)
* Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analysis, in
Pediatrics, 2014; 133: 493–9. (G. E. Keeney)
* A Word to the Wise About Ketamine, in
American Journal of Psychiatry, 2014; 171: 262–4. (A. F. Schatzberg, afschatz@stanford.edu)
* Improving Adherence to Oral Cancer Therapy in Clinical Practice, in
Pharmacotherapy, 2014; 34: 10.1002/phar.1399. (D. McCue, dblamble@mdanderson.org)
*
CYP2C19 Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics?, in Pharmacotherapy, 2014; 34: 10.1002/phar.1400. (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 706/613-0200 (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
Mar. 4, 2014 * Vol. 21, No. 42
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 4 issue of the Annals of Internal Medicine (2014; 160).
Single-Patient Trials for Statin Myalgia: N-of-1 trials can be useful for evaluating “selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate,” a study concludes (pp. 301–10). At a tertiary care lipid clinic, patients underwent N-of-1 trials with three double-blind crossover rechallenges with statins or placebo separated by 3-week washout periods. Results based on weekly visual analogue scale (VAS) scores for myalgia and specific symptoms showed: “Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months.” (T. R. Joy, tisjoy@hotmail.com)
HCV Infection Trends in the U.S.: About 2.7 million people living in the U.S. have infections of hepatitis C virus (HCV), according to data from the nationally representative National Health and Nutrition Examination Surveys conducted in 2003 and 2010 (pp. 293–300). While the figure is 500,000 fewer than a 1999–2002 estimate, researchers conclude, “These data underscore the urgency of identifying the millions of persons who remain infected and linking them to appropriate care and treatment.” Among the 30,074 survey participants whose experiences were projected in the article, the investigators found: “Based on 273 participants who tested positive for HCV RNA, the estimated prevalence of HCV infection was 1.0% (95% CI, 0.8% to 1.2%), corresponding to 2.7 million chronically infected persons (CI, 2.2 to 3.2 million persons) in the U.S. noninstitutionalized civilian population. Infected persons were more likely to be aged 40 to 59 years, male, and non-Hispanic black and to have less education and lower family income. Factors significantly associated with chronic HCV infection were illicit drug use (including injection drugs) and receipt of a blood transfusion before 1992; 49% of persons with HCV infection did not report either risk factor.” (S. D. Holmberg, sdh1@cdc.gov)
Lung Cancer Screening Strategies: Among patients with 30 or more pack–years’ exposure to smoking, annual screening for lung cancer using computed tomography (CT) imaging has more benefits than harms, according to a comparative modeling study conducted for the U.S. Preventive Services Task Force (pp. 311–20). “The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack–years and ex-smokers with less than 15 years since quitting,” the authors write. “It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5,250 life–years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]).” (H. J. de Koning, h.dekoning@erasmusmc.nl)
Based on these data, the Task Force recommended “annual screening for lung cancer with low-dose computed tomography in adults aged 55 to 80 years who have a 30 pack–year smoking history and currently smoke or have quit within the past 15 years” (
pp. 330–8). “Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.” (www.uspreventiveservicestaskforce.org)

>>>PNN NewsWatch
* With 22 corporate and association members—including all three major chains—the newly formed Patient Access to Pharmacists’ Care Coalition “will lead the effort to develop and help enact a federal policy proposal to increase patient access to pharmacists’ patient care services,” APhA announced in a CEO blog yesterday. “We are off and running” toward provider status, added ASHP in a similar CEO blog.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 5, 2014 * Vol. 21, No. 43
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 5 issue of JAMA (2014; 311).
Warfarin & Renal Function in MI, AF: In consecutive patients with acute myocardial infarction (MI) and atrial fibrillation, warfarin therapy lowered a composite measure of death, MI, and ischemic stroke, researchers report, and benefits were unrelated to the severity of patients’ chronic kidney disease (CKD) as reflected in estimated glomerular filtration rates (GFRs) (pp. 919–28). Data from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry show these patterns in 2003–10: “A total of 5,292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9,002 events) in each CKD stratum for event rates per 100 person–years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30–60: event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15–30: event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR≤15: event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37–0.86). The risk of bleeding (n = 1,202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person–years.… Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9,592 events) for event rates per 100 person–years.…” (J. J. Carrero, juan.jesus.carrero@ki.se)
This study “provides the best evidence to date that vitamin K antagonists are associated with improved clinical outcomes and no significant increased risk of bleeding in patients with myocardial infarction and atrial fibrillation with advanced CKD, editorialists write (
pp. 913–5). “These data support the use and continuation of warfarin therapy among patients with CKD with excellent INR control. In situations of suboptimal [time in therapeutic range (TTR)] (probably below 70%–75% until better thresholds are defined), clinicians should be motivated to find ways to improve TTR; perhaps this should be the next lesson from Sweden’s exceptional anticoagulation care system. Until then, the question of warfarin treatment in patients with atrial fibrillation and advanced CKD whose achievable TTR is subpar remains one of a sin of omission vs commission.” (W. C. Winkelmayer, wcw1@stanford.edu)

>>>Pediatrics Report
Source:
Mar. issue of Pediatrics (2014; 133).
Vaccine Financing: The uncertainty of payments for vaccine administration is frustrating primary care physicians, according to a national survey conducted in 2011 (pp. 367–74). Physicians were using a variety of strategies to deal with the situation: “Response rates were 69% (190/277) for pediatricians and 70% (181/260) for family physicians. Level of dissatisfaction varied significantly by payer type for payment for vaccine administration (Medicaid, 63%; Children’s Health Insurance Program, 56%; managed care organizations, 48%; preferred provider organizations, 38%; fee for service, 37%; P < .001), but not for payment for vaccine purchase (health maintenance organization or managed care organization, 52%; Child Health Insurance Program, 47%; preferred provider organization, 45%; fee for service, 41%; P = .11). Ten percent of physicians had seriously considered discontinuing providing all childhood vaccines to privately insured patients because of cost issues. The most commonly used strategy for handling uncertainty about insurance coverage for new vaccines was to inform parents that they may be billed for the vaccine; 67% of physicians reported using 3 or more strategies to handle this uncertainty.” (S. T. O’Leary)
Outpatient Antibiotic Use: Among infants and children 3–23 months old, antibiotic prescribing has plateaued at a level lower than in 2000 but still of concern in some conditions, analysis of claims data shows (pp. 375–85). In 2000–10, 5.0%, 9.3%, and 7.2% annual declines were noted among three plans early in the decade; these figures were 2.4%, 2.1%, and 0.5% at the end. Use of third-generation cephalosporins for otitis media climbed by 1.5-, 15-, and 5.5-fold in the three plans. (L. E. Vaz)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 6, 2014 * Vol. 21, No. 44
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 6 issue of the New England Journal of Medicine (2014; 370).
Gene Editing in HIV Infection: Site-specific modification of the CCR5 gene was safe in patients with chronic aviremic HIV infection, and the intervention reduced CD4 susceptibility to viral action, a study shows (pp. 901–10). In an open-label study, 6 of the 12 patients who were aviremic during highly active antiretroviral therapy were randomized to treatment interruption 4 weeks after infusion of 10 billion autologous CD4 T cells. The CCR5 gene had been rendered permanently dysfunctional by zinc-finger nuclease (ZFN) in 11% and 28% of the infused cells. Compared with patients not receiving the genetically modified cells, treated patients had these responses to treatment interruption: “One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1,517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P < 0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (−1.81 cells per day) was significantly less than the decline in unmodified cells (−7.25 cells per day) (P = 0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients.” (P. Tebas, pablo.tebas@uphs.upenn.edu)
“This proof-of-principle study is an important first step, not just in the treatment of those infected with HIV but also for genome editing in a broader sense,” editorialists write (
pp. 968–9). “The potential future of gene knockout by ZFNs and other techniques is not restricted to HIV infection. There are now methods that can be used not only to inactivate a gene but also to make specific nucleotide changes in a specific site in the genome and gene addition. These methods will be useful in fixing genes that contain harmful mutations and in supplying therapeutic proteins. Through repeated trips from bedside to bench and back again, it is likely that these approaches represent a basis for effective future therapeutic interventions.” (M. A. Kay)
Loss-of-Function Mutations & Stroke, Vasculopathy: Genetic analysis of nine patients with similar and unusual symptoms, researchers found that “loss-of-function mutations in [cat eye syndrome chromosome region, candidate 1 (CECR1)] were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis” (pp. 911–20). Using a variety of genetic tests, enzyme assays, and immunologic-profiling tools, the authors determined: “All nine patients carried recessively inherited mutations in CECR1 … encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia—phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers.” (I. Aksentijevich, askentii@exchange.nih.gov)
Global Shortages of Physicians, Nurses: After reviewing data showing worldwide shortages and maldistributions of physicians and nurses, authors explore how massive open online courses (MOOCs) could transform the education of health professionals (pp. 950–7): “Educators of health professionals must grasp the opportunity to produce transformative leaders who have the motivation and capability to shape the future— or themselves be shaped by it.” (N. Crisp)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 7, 2014 * Vol. 21, No. 45
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
March issue of and early-release articles from Pharmacotherapy (2014; 34).
Physical Activity & Warfarin Dose: Patients who exercise regularly require higher warfarin doses and have lower risk of hemorrhage, researchers report (10.1002/phar.1401). Based on self-reports of regular physical activity at more than 80% of visits at an anticoagulation clinic, 1,272 patients on long-term warfarin therapy had these outcomes: “There were 683 (53.7%) patients who were regularly physically active (≥ 30 min ≥ 3 times/week). Physically active patients required warfarin doses that were 6.9% higher (p = 0.006) than in physically inactive patients after controlling for sociodemographic factors, vitamin K intake, clinical factors, and genetic variations.
“The overall incidence of major hemorrhagic events was 7.6/100 person–years (p-yrs, 95% confidence interval [CI] 6.4–8.9) in our population. The incidence was lower for physically active patients (5.6/100 p-yrs, 95% CI 4.2–7.2) than in inactive patients (10.3/100 p-yrs, 95% CI 8.2–12.9, p = 0.0004). Active patients had a 38% lower risk of hemorrhage (hazard ratio 0.62, 95% CI 0.42–0.98, p = 0.03) compared with inactive patients.” (N. A. Limdi,
nlimdi@uab.edu)
Flecainide-Associated Cardiac Arrest: A case is presented in which flecainide therapy was associated with QT prolongation and cardiac arrest (10.1002/phar.1403): “A 32-year-old man with a structurally normal heart and persistent AF … was started on diltiazem and flecainide 50 mg twice/day approximately a year prior to presentation. Due to persistent and bothersome symptoms, his dose was increased to 150 mg twice/day, which was associated with a progressive lengthening of his corrected QT interval. On the day of presentation, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. An automated external defibrillator was available that displayed polymorphic ventricular tachycardia. The patient was successfully resuscitated. Although rare, this case suggests that flecainide can induce QT prolongation leading to torsades de pointes. Clinicians should be aware and consider periodic evaluations with electrocardiograms.” (K. Oguayo, koguayo@sw.org)
Drug Interactions in Intensive Care: In a retrospective observational study, investigators find that patients in medical intensive-care units have potential drug interactions (pDDIs) twice as often as patients on general wards (pp. 213–9). Records in the Dutch national drug database, the G Standaard, for 2009–10 were analyzed for pDDIs; 35,784 medication episodes were identified, yielding 2,887 pDDIs in 1,659 patients (1.7 pDDIs per patient [95% CI, 1.6–1.9]): “Overall, 54% of the patients experienced at least one pDDI with pDDIs present during 27% of all ICU admission days. All pDDIs could be reconstructed using 81 of the 358 (23%) relevant unique pDDI pairs described in the G-Standaard. The most frequently occurring potential clinical consequence was an increased risk of side effects or toxicity (91% of the pDDIs) such as electrolyte disturbances and masking of hypoglycemia. The most important advised management strategy was monitoring (81%), consisting of monitoring of laboratory values (52%), clinical monitoring of toxicity or effectiveness (48%), or monitoring of physical parameters such as electrocardiogram and blood pressure (11%).” (E. V. Uijtendaal, e.v.uijtendaal@umcutrecht.nl)
Cholinesterase Inhibitors & Pisa Syndrome: A form of dystonia, Pisa syndrome (PS) may be the result of a dopaminergic–cholinergic imbalance, an analysis of cases in the FDA adverse event database shows (pp. 272–8). Women were involved in twice as many cases as men, and about one-half of patients were taking both cholinesterase inhibitors and antipsychotic agents. Awareness of the potential cause can increase early identification and treatment, the authors noted. (A. S. Zannas, antonios.zannas@duke.edu)

>>>PNN NewsWatch
* FDA yesterday said the doripenem (Doribax, Shionogi) labeling has been changed to warn that the drug, when used off label to treat pneumonia, has an increased mortality risk and lower clinical cure rates, compared with imipenem and cilastatin. Doripenem is not approved to treat any type of pneumonia, FDA added.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 10, 2014 * Vol. 21, No. 46
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Delayed Antibiotic Prescribing for Respiratory Infections: Among 889 patients 3 years of age or older, strategies for reducing antibiotic prescribing for respiratory tract infections resulted in fewer than 40% receiving such prescriptions, a study shows (g1606). Outcomes were similar between those prescribed antibiotics and those who were not. The study, conducted in 25 U.K. primary care practices in 2010–12 with 53 health professionals, randomized patients with no immediate need for antibiotics to no prescription or one of four delay strategies: recontact for prescription, postdated prescription, collection of the prescription, and patient-led decision regarding prescription.
Results showed: “Mean symptom severity had minimal differences between the strategies involving no prescription and delayed prescription (recontact, post-date, collection, patient led; 1.62, 1.60, 1.82, 1.68, 1.75, respectively; likelihood ratio test chi square 2.61, P = 0.625). Duration of symptoms rated moderately bad or worse also did not differ between no prescription and delayed prescription strategies combined (median 3 days v 4 days; 4.29, P=0.368). There were modest and non-significant differences in patients very satisfied with the consultation between the randomised groups (79%, 74%, 80%, 88%, 89%, respectively; likelihood ratio test chi square 2.38, P = 0.667), belief in antibiotics (71%, 74%, 73%, 72%, 66%; 1.62, P = 0.805), or antibiotic use (26%, 37%, 37%, 33%, 39%; 4.96, P = 0.292). By contrast, most patients given immediate antibiotics used antibiotics (97%) and strongly believed in them (93%), but with no benefit for symptom severity (score 1.76) or duration (median 4 days).” (P. Little, p.little@soton.ac.uk)
HPV Vaccine & Cervical Abnormalities: Administered to young women in Australia, the quadrivalent human papillomavirus (HPV) vaccine provided protection against development of cervical abnormalities, researchers report (g1458). Study participants, all 12–26 years of age in 2007, had not yet begun cervical screening when the vaccine program was implemented. Those with high-grade cervical abnormalities at their first screening (n = 1,062) were compared with those with other abnormalities (n = 10,887 and control patients with normal cytology (n = 96,404). Results showed: “The adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%.” (E. Crowe, e.crowe1@uq.edu.au)

>>>PNN NewsWatch
* After a pharmacist found a Tikosyn (dofetilide) capsule in a bottle of Effoxor XR, Pfizer recalled one lot of 30-count Effexor XR (venlafaxine hydrochloride) 150 mg extended-release capsules, one lot of 90-count Effexor XR 150 mg extended-release capsules, and one lot of 90-count Greenstone LLC-branded Venlafaxine hydrochloride 150 mg extended-release capsules.
*
Baxter International is recalling a lot of DIANEAL PD-2 Peritoneal Dialysis Solution with 1.5% Dextrose 6000 mL to the hospital/user level because of complaints of presence of particulate matter.

>>>PNN JournalWatch
* Current Evidence on Treatment of Patients With Chronic Systolic Heart Failure and Renal Insufficiency: Practical Considerations From Published Data, in
Journal of the American College of Cardiology, 2014; 63: 853–71. (K. Damman)
* Lomitapide and Mipomersen: Two First-in-Class Drugs for Reducing Low-Density Lipoprotein Cholesterol in Patients With Homozygous Familial Hypercholesterolemia, in
Circulation, 2014; 129: 1022–32. (D. J. Rader, rader@mail.med.upenn.edu)
* Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions: A Scientific Statement From the American Heart Association, in
Circulation, 2014; 129: 1049–78. (J. W. Olin)
* Copy, Paste, and Cloned Notes in Electronic Health Records: Prevalence, Benefits, Risks, and Best Practice Recommendations, in
Chest, 2014; 145: 632–8. (J. M. Weis, justin_weis@urmc.rochester.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 11, 2014 * Vol. 21, No. 47
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. issue of JAMA Internal Medicine (2014; 174).
CNS Function, Structure After Intensive Blood Pressure, Lipid Lowering: In the ACCORD-MIND study, intensive therapy to lower blood pressure (BP) and lipids did not alter cognitive decline at 40 months, and a greater decline in total brain volume (TBV) was noted with intensive BP control (pp. 324–33). A total of 2,977 North American participants with type 2 diabetes mellitus (T2DM) and no baseline evidence of cognitive impairment or dementia were randomized in 2003–05 to systolic BP goals of less than 120 or 140 mm Hg or to fibrate or placebo with LDL cholesterol goals of less than 100 mg/dL. Follow-up in 2009 showed the following: “Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, −4.4 [95% CI, −7.8 to −1.1] cm3; P = .01). Fibrate therapy had no effect on TBV compared with placebo.” (J. D. Williamson, jwilliam@wakehealth.edu)
“The expectation that short-term interventions at relatively young ages will reveal major changes in brain structure and function might be too optimistic,” authors of an invited Commentary conclude (
pp. 333–5). They also note, “An important outcome of the ACCORD MIND substudy, which was also reported for the phase 3 antiamyloid trials, is the apparent discordant therapeutic actions of the treatment on function (no effect) and structure (harmful effect of intensive BP-lowering treatment, which is different from the glycemic arm of the study that revealed protection from brain atrophy with tight glycemic control). Treatment effects are first seen on structure and then on function if the follow-up of participants is long enough. This possibility has not been convincingly demonstrated, and the validity of magnetic resonance imaging biomarkers as surrogate markers of dementia has not been established.” (C. Brayne, carol.brayne@medschl.cam.ac.uk)
Warfarin–Antibiotic–Disease Interactions in Ambulatory Care: While antibiotics do increase the risk of excessive anticoagulation when used in patients taking warfarin, acute upper respiratory infections can increase the risk independently of antibiotic use, researchers report (pp. 409–16). In ambulatory patients on stable warfarin therapy, neither the drugs nor the condition result in “clinically relevant increases in INR,” the investigators conclude. At Kaiser Permanente Colorado, retrospective longitudinal cohort evaluation of 5,857, 5,579, and 570 patients in antibiotic, stable control, and sick control groups, respectively, showed the following: “The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more.” (N. P. Clark, nathan.clark@kp.org)
“Nudges” in Antibiotic Prescribing Guideline Adherence: A simple, low-cost intervention—poster-sized commitment letters in examination rooms—increased adherence to antibiotic-prescribing guidelines to a similar degree as previously reported, more expensive interventions, a study shows (pp. 425–31). Behavioral “nudges” can be highly effective through subtle cognitive mechanisms, the authors explain. Randomized assignment of patients at five ambulatory primary care clinics had the following effects on care of 954 adults with acute respiratory infections (ARIs): “Baseline [antibiotic prescribing] rates were 43.5% and 42.8% for control and poster, respectively. During the intervention period, inappropriate prescribing rates increased to 52.7% for controls but decreased to 33.7% in the posted commitment letter condition. Controlling for baseline prescribing rates, we found that the posted commitment letter resulted in a 19.7 absolute percentage reduction in inappropriate antibiotic prescribing rate relative to control (P = .02). There was no evidence of diagnostic coding shift, and rates of appropriate antibiotic prescriptions did not diminish over time.” (D. Meeker, dmeeker@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 706/613-0200 (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
Mar. 12, 2014 * Vol. 21, No. 48
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Mar. 15 issue of Clinical Infectious Diseases (2014; 58).
Sustained Injection-Drug-Use Changes After HCV Seroconversion: Over the long term, persons who inject drugs (PWID) reduce their drug use following notification of hepatitis C virus (HCV) seroconversion, according to data gathered in Montreal from 2004 to 2011 (pp. 755–61). Looking into the possibility of sustained changes in drug use based on previously noted short-term reductions, study authors analyzed semiannual screening visit data, including blood samples and responses to an interviewer-administered questionnaire. Results showed: “Of the 208 participants (83% male; mean age, 34.7 years, mean follow-up time, 39 months), 69 (33.2%) seroconverted to HCV. A linear decrease in syringe sharing behavior was observed over time after HCV and status notification, whereas a 10% decrease for each additional 3 months of follow-up was observed for injection cocaine and heroin use among HCV seroconverters but not among HCV-seronegative PWID (P < .05). No significant changes were observed in alcohol use.” (J. Bruneau, julie.bruneau@umontreal.ca)
Readmissions After Discharge on Injectable Antibiotics: Patients discharged from hospitals on injectable antibiotics who are at high risk of readmission can be identified through “easily obtainable clinical characteristics,” researchers report (pp. 812–9). Using a database of 782 patients prescribed outpatient parenteral antibiotic therapy (OPAT) at hospital discharge in 2009–11 at an academic medical center, the authors developed and tested a model for predicting readmissions: “Mean patient age was 58 years (range, 18–95 years), 43% were women, and the most common diagnoses were bacteremia (24%), osteomyelitis (20%), and pyelonephritis (13%). The unplanned 30-day readmission rate was 26%. The leading indications for readmission were non–infection related (30%), worsening infection (29%), and new infection (19%). The final regression model consisted of age (odds ratio [OR], 1.09 per decade; 95% confidence interval [CI], 0.99–1.21), aminoglycoside use (OR, 2.33; 95% CI, 1.17–4.57), resistant organisms (OR, 1.57; 95% CI, 1.03–2.36), and number of prior hospital discharges without intravenous antibiotics in the past 12 months (OR, 1.20 per prior admission; 95% CI, 1.09–1.32). The c-statistic was 0.61 and the highest-risk quintile of patients had almost a 3-fold higher rate of readmission compared to the lowest.” (G. M. Allison, gallison@tuftsmedicalcenter.org)

>>>PNN NewsWatch
* A bill granting pharmacists provider status under the Social Security Act was introduced into the House of Representatives yesterday, APhA and other organizations report. If enacted, the legislation would recognize state-licensed pharmacists’ patient care services under Medicare Part B in medically underserved communities. Reps. Brett Guthrie (R–KY), G. K. Butterfield (D–NC), and Todd Young (R–IN) introduced the bill. The recently formed Patient Access to Pharmacists Care Coalition is working to gain passage of the bill; members include 9 national membership and trade associations, 11 chain pharmacies, and 2 drug wholesalers.
* Today’s
JAMA contains articles on fair distribution of shared savings in accountable care organizations (pp. 1011–2, M. DeCamp, mdecamp1@jhmi.edu) and reports from last year’s International Congress on Peer Review and Biomedical Publication (pp. 1019–20, A. Flanagin, annette.flanagin@jamanetwork.org; pp. 1045–52, M. Briel, matthias.briel@usb.ch; pp. 1063–5, J. S. Ross, joseph.ross@yale.edu; pp. 1065–7, A. Marušić, ana.marusic@mefst.hr)
*
FDA yesterday allowed marketing of a transcutaneous electrical nerve stimulation (TENS) device for prevention of migraine headaches. Cefaly (STX-Med) is a small, portable, battery-powered, prescription device that resembles a plastic headband worn across the forehead and atop the ears. The user positions the device in the center of the forehead, just above the eyes, using a self-adhesive electrode. The device applies an electric current to the skin and underlying body tissues to stimulate branches of the trigeminal nerve, which has been associated with migraine headaches. The user may feel a tingling or massaging sensation where the electrode is applied. Cefaly is indicated for patients 18 years of age and older and should only be used once per day for 20 minutes.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 13, 2014 * Vol. 21, No. 49
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 13 issue of the New England Journal of Medicine (2014; 370).
Idelalisib in Relapsed Leukemia and Lymphoma: Two research studies and an editorial detail use of idelalisib, an orally administered phosphatidylinositol 3-kinase–delta (PI3K-delta) inhibitor, in patients with relapsed leukemia or lymphoma.
The addition of idelalisib to rituximab improved several clinical outcomes in 220 patients with relapsed chronic lymphocytic leukemia (CLL) who also had clinically significant coexisting medical conditions that prevented them from receiving standard chemotherapy, according to results of a Phase III study (
pp. 997–1007). Participants had decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses when they received rituximab and either placebo or idelalisib. Results showed: “The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P <0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P <0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab.” (R. R. Furman, rrfurman@med.cornell.edu)
In an open-label, Phase II study of 125 patients with indolent non-Hodgkin’s lymphomas, “idelalisib showed antitumor activity with an acceptable safety profile,” researchers report (
pp. 1008–18). Study participants had either not responded to rituximab and an alkylating agent or had relapsed within 6 months of chemotherapy. Given idelalisib 150 mg twice daily until the disease progressed or study withdrawal, the patients had these responses: “The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin’s lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström’s macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin’s lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%).” (A. K. Gopal, agopal@u.washington.edu)
“Along with ibrutinib, which targets Bruton’s tyrosine kinase (BTK), idelalisib represents a new class of agents that target signal transduction downstream of the B-cell receptor (BCR) in malignant B cells,” editorialists write (
pp. 1061–2). “As with most anticancer agents, idelalisib and ibrutinib do not produce durable responses in all patients. Identifying and overcoming resistance mechanisms will be crucial for the most effective use of these agents. Since the two agents have acceptable side-effect profiles, it makes sense to test the combination of idelalisib and ibrutinib. This approach should suppress the emergence of rare clones with point mutations in the kinase domains of PI3K-delta or BTK. It will also be informative to monitor AKT activation as a possible resistance mechanism. AKT is a prosurvival kinase that binds PIP3 and plays a key role in many solid tumors. Selective inhibitors of AKT are in development and might be tested in combination with PI3K-delta or BTK inhibitors. Although most clinical trials with PI3K inhibitors have focused on solid tumors with PI3K mutations or PTEN loss, it is likely that the first approval of a PI3K inhibitor will be in a disease in which neither PI3K nor PTEN is mutated but in which there is a cell-lineage–specific requirement for a specific PI3K isoform.” (D. A. Fruman)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 14, 2014 * Vol. 21, No. 50
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Mar. 18 issue of the Journal of the American College of Cardiology (2014; 63).
Uninterrupted Rivaroxaban During AF Ablation: Patients taking rivaroxaban can undergo radiofrequency ablation for atrial fibrillation without drug interruption as safely as when warfarin therapy is not stopped. a study shows (pp. 982–8). At eight North American centers, 642 patients on warfarin or rivaroxaban were assessed prospectively in an observational study, with these results: “Mean age was 63 ± 10 years, with 442 (69%) males and 328 (51%) patients with paroxysmal AF equally distributed between the 2 groups. Patients in the warfarin group had a slightly higher mean HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score (1.70 ± 1.0 vs. 1.47 ± 0.9, respectively; p = 0.032). Bleeding and embolic complications occurred in 47 (7.3%) and 2 (0.3%) patients (both had transient ischemic attacks) respectively. There were no differences in the number of major bleeding complications (5 [1.6%] vs. 7 [1.9%], respectively; p = 0.772), minor bleeding complications (16 [5.0%] vs. 19 [5.9%], respectively; p = 0.602), or embolic complications (1 [0.3%] vs. 1 [0.3%], respectively; p = 1.0) between the rivaroxaban and warfarin groups in the first 30 days.” (D. Lakkireddy)
Atrial Fibrillation in Cancer: Pathophysiology and management of atrial fibrillation (AF) in patients with cancer are reviewed in a state-of-the-art paper (pp. 945–53): “AF has been found to occur with an increased frequency in patients with malignancies, particularly in those undergoing cancer surgery. The occurrence of AF in cancer may be related to comorbid states or a direct tumor effect or may represent a complication of cancer surgical or medical therapy, whereas inflammation may be a common denominator for both conditions. Treating AF in patients with malignancies is a challenge, especially in terms of antithrombotic therapy, because cancer may result in an increased risk of either thrombosis or hemorrhage and an unpredictable anticoagulation response, whereas thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke&hellipWinking may not be applicable. The general lack of evidence imposes an individualized approach to the management of AF in those patients, although some general recommendations based on current guidelines in noncancer patients and the existing evidence in cancer patients, where available, may be outlined.” (D. Farmakis)

>>>Oncology Report
Source:
Mar. 10 issue of the Journal of Clinical Oncology (2014; 32).
Timing of Adjuvant Chemotherapy in Breast Cancer: Worse outcomes occurred with delayed initiation of adjuvant chemotherapy among 6,827 women with breast cancer (BC) seen at one institution in 1997–2011, researchers report (pp. 735–44). Patients were categorized by time to initiation of adjuvant chemotherapy (TTC) after surgery, with these results: “The 5-year overall survival (OS), relapse-free survival (RFS), and distant RFS (DRFS) estimates were similar for the different TTC categories. Initiation of chemotherapy ≥61 days after surgery was associated with adverse outcomes among patients with stage II (DRFS: hazard ratio [HR], 1.20; 95% CI, 1.02 to 1.43) and stage III (OS: HR, 1.76; 95% CI, 1.26 to 2.46; RFS: HR, 1.34; 95% CI, 1.01 to 1.76; and DRFS: HR, 1.36; 95% CI, 1.02 to 1.80) BC. Patients with triple-negative BC (TNBC) tumors and those with human epidermal growth factor receptor 2 (HER2) –positive tumors treated with trastuzumab who started chemotherapy ≥61 days after surgery had worse survival (HR, 1.54; 95% CI, 1.09 to 2.18 and HR, 3.09; 95% CI, 1.49 to 6.39, respectively) compared with those who initiated treatment in the first 30 days after surgery.” (M. Chavez-MacGregor, mchavez1@mdanderson.org)
“Evolving evidence indicates that it is unlikely that early commencement of chemotherapy makes a difference for the majority of patients,” editorialists note (
pp. 717–9). “Although the evidence is weak due to the potential biases and inconsistent outcomes, the current report suggests that unnecessary delay in initiation of chemotherapy may be unwise for patients in whom the effect of adjuvant chemotherapy is expected to be significant.” (M. Colleoni, marco.colleoni@ieo.it)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 17, 2014 * Vol. 21, No. 51
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 15 issue of Lancet (2014; 383).
Newer Oral Anticoagulants in AF: Other than an increased rate of gastrointestinal bleeding, four new oral anticoagulants outperformed warfarin on efficacy and safety parameters in a meta-analysis of data from pivotal Phase III trials of the drugs (pp. 955–62). Investigators looked at the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF–TIMI 48 trials, which included a total of 71,683 participants. Main outcome and subgroup analyses showed the following, “New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0.81, 95% CI 0.73–0.91; p <0.0001), mainly driven by a reduction in haemorrhagic stroke (0.49, 0.38–0.64; p <0.0001). New oral anticoagulants also significantly reduced all-cause mortality (0.90, 0.85–0.95; p = 0.0003) and intracranial haemorrhage (0.48, 0.39–0.59; p <0.0001), but increased gastrointestinal bleeding (1.25, 1.01–1.55; p = 0.04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0.69, 0.59–0.81 vs 0.93, 0.76–1.13; p for interaction 0.022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1.03, 0.84–1.27; p = 0.74), and a more favourable bleeding profile (0.65, 0.43–1.00; p = 0.05), but significantly more ischaemic strokes (1.28, 1.02–1.60; p = 0.045).” (C. T. Ruff, cruff@partners.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2014; 348).
Nicotine Patches in Pregnant Smokers: In 476 pregnant smokers at 23 maternity wards in France, provision of nicotine patches—even in higher-than-normal doses and amounts that produced nicotine levels similar to those attained by smoking tobacco—did not increase cessation rates or birth weights, compared with placebo, researchers report (g1622). The women were randomized to nicotine or placebo patches from their quit day to time of delivery. In the active group, doses were adjusted to achieve salivary cotinine levels observed when the patient was smoking. Results showed: “Complete abstinence was achieved by 5.5% (n = 11) of women in the nicotine patch group and 5.1% (n = 10) in the placebo patch group (odds ratio 1.08, 95% confidence interval 0.45 to 2.60). The median time to the first cigarette smoked after target quit day was 15 days in both groups (interquartile range 13–18 in the nicotine patch group, 13–20 in the placebo patch group). The point prevalence abstinence ranged from 8% to 12.5% in the nicotine patch group and 8% to 9.5% in the placebo patch group without statistically significant differences. The nicotine substitution rate did not differ from 100%, and the self reported median compliance rate was 85% (interquartile range 56–99%) in the nicotine patch group and 83% (56-95%) in the placebo patch group, assessed at 1,016 visits. The mean birth weight was 3,065 g (SE 44 g) in the nicotine patch group and 3,015 g (SE 44 g) in the placebo patch group (P = 0.41). Diastolic blood pressure was significantly higher in the nicotine patch group than in the placebo patch group. The frequency of serious adverse events was similar between the groups, although more non-serious adverse reactions, mainly of skin, occurred in the nicotine patch group.” (I. Berlin, ivan.berlin@psl.aphp.fr)

>>>PNN NewsWatch
* Mar. 16–22 is National Poison Prevention Week in the U.S., Pres. Obama noted in a proclamation issued Friday. He reminded Americans that the national toll-free Poison Help Line is 800/222-1222.

>>>PNN JournalWatch
* Preliminary Data from a Pharmacist-Managed Anticoagulation Clinic Embedded in a Multidisciplinary Patient-Centered Medical Home: A Coordinated Quality, Cost-Savings Model, in
Journal of the American Geriatrics Society, 2014; 62: 536–40. (C. L. Garwood, cgarwood@wayne.edu)
* Alterations in Platelet Function During Aging: Clinical Correlations With Thromboinflammatory Disease in Older Adults, in
Journal of the American Geriatrics Society, 2014; 62: 529–35. (M. T. Rondina, matt.rondina@u2m2.utah.edu)
* Immunotherapy: What Lies Beyond, in
Journal of Allergy and Clinical Immunology, 2014; 133: 612–9. (T. B. Casale, tbcasale@health.usf.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 706/613-0200 (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
Mar. 18, 2014 * Vol. 21, No. 52
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 18 issue of the Annals of Internal Medicine (2014; 160).
Hepatic Decompensation in Antiretroviral-Treated HIV and Hepatitis C Virus: In patients coinfected with HIV and hepatitis C virus (HCV), hepatic function continues to decline despite antiretroviral therapy (ART), compared with those infected only with HCV, a study shows (pp. 369–79). A retrospective cohort study of 4,280 VA patients coinfected with the two viruses and 6,079 patients with HCV monoinfections showed these rates of hepatic decompensation: “The incidence of hepatic decompensation was greater among co-infected than monoinfected patients (7.4% vs. 4.8% at 10 years; P < 0.001). Compared with HCV-monoinfected patients, co-infected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% CI, 1.31 to 1.86]). Co-infected patients who maintained HIV RNA levels less than 1,000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [CI, 1.05 to 1.99]). Baseline advanced hepatic fibrosis (FIB-4 score >3.25) (HR, 5.45 [CI, 3.79 to 7.84]), baseline hemoglobin level less than 100 g/L (HR, 2.24 [CI, 1.20 to 4.20]), diabetes mellitus (HR, 1.88 [CI, 1.38 to 2.56]), and nonblack race (HR, 2.12 [CI, 1.65 to 2.72]) were each associated with higher rates of decompensation among co-infected patients.” (V. Lo Re III)
Cardiovascular Guidelines for Fatty Acids: Available evidence is unclear as to what fatty acid intake is best for cardiovascular health, report authors of a systematic review and meta-analysis (pp. 398–406). Nutritional guidelines generally encourage low consumption of saturated fats, high consumption of omega-3 polyunsaturated fatty acids, and avoidance of trans fats, the investigators note, adding these findings: “There were 32 observational studies (530,525 participants) of fatty acids from dietary intake; 17 observational studies (25,721 participants) of fatty acid biomarkers; and 27 randomized, controlled trials (103,052 participants) of fatty acid supplementation. In observational studies, relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain omega-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for omega-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids when the top and bottom thirds of baseline dietary fatty acid intake were compared. Corresponding estimates for circulating fatty acids were 1.06 (CI, 0.86 to 1.30), 1.06 (CI, 0.97 to 1.17), 0.84 (CI, 0.63 to 1.11), 0.94 (CI, 0.84 to 1.06), and 1.05 (CI, 0.76 to 1.44), respectively. There was heterogeneity of the associations among individual circulating fatty acids and coronary disease. In randomized, controlled trials, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for alpha-linolenic, 0.94 (CI, 0.86 to 1.03) for long-chain omega-3 polyunsaturated, and 0.89 (CI, 0.71 to 1.12) for omega-6 polyunsaturated fatty acid supplementations.” (R. Chowdhury, rajiv.chowdhury@phpc.cam.ac.uk)
Middle East Respiratory Syndrome Coronavirus Infection: Severe acute hypoxemic respiratory failure, extrapulmonary organ dysfunction, and high mortality are features of Middle East respiratory syndrome coronavirus (MERS-CoV), authors of a case series from three intensive-care units in Saudi Arabia report (pp. 389–97): “Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care–associated cluster that also included 3 [health care workers (HCWs)]. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive.” (Y. M. Arabi, arabi@ngha.med.sa)

>>>PNN NewsWatch
* Provider status for pharmacists legislation was emphasized during last week’s RxIMPACT Day on Capitol Hill. The NACDS event reached more than 80% of Members of Congress, including 136 of 139 members who serve on health-care–related committees.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 19, 2014 * Vol. 21, No. 53
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 19 issue of JAMA (2014; 311).
Infections During Pregnancy & Adverse Fetal Outcomes: Pregnancy is associated with a greater risk of infection with Haemophilus influenzae, and those infections are associated with poorer outcomes, according to data collected in England and Wales (pp. 1125–32). Using national surveillance data from Public Health England, investigators identified 171 women with laboratory-confirmed invasive H. influenzae infection: “Overall, 75 of 171 women (43.9%; 95% CI, 36.3%–51.6%) were pregnant at the time of infection, most of whom were previously healthy and presented with unencapsulated H influenzae bacteremia. The incidence rate of invasive unencapsulated H influenzae disease was 17.2 (95% CI, 12.2–24.1; P < .001) times greater among pregnant women (2.98/100,000 woman–years) compared with nonpregnant women (0.17/100,000 woman–years). Unencapsulated H influenzae infection during the first 24 weeks of pregnancy was associated with fetal loss (44/47; 93.6% [95% CI, 82.5%–98.7%]) and extremely premature birth (3/47; 6.4% [95% CI, 1.3%–17.5%]). Unencapsulated H influenzae infection during the second half of pregnancy was associated with premature birth in 8 of 28 cases (28.6%; 95% CI, 13.2%–48.7%) and stillbirth in 2 of 28 cases (7.1%; 95% CI, 0.9%–23.5%). The incidence rate ratio for pregnancy loss was 2.91 (95% CI, 2.13–3.88) for all serotypes of H influenzae and 2.90 (95% CI, 2.11–3.89) for unencapsulated H influenzae compared with the background rate for pregnant women.” (S. N. Ladhani, shamez.ladhani@phe.gov.uk)
“Infectious diseases are a potentially preventable cause of adverse pregnancy outcomes,” an editorialist writes (
pp. 1115–6). “On a broader scale, design of guidelines to ensure that blood cultures and other appropriate samples are obtained in febrile pregnant women, especially during later stages of pregnancy, should be undertaken to clarify the contribution of bacterial infections (including H influenzae) to fetal loss, stillbirth, and premature delivery. Resources should be allocated to foster implementation of such practices. Infrastructure (eg, the enhanced reporting system in the study by Collins et al.) should be developed to better understand infectious causes of fetal loss and prematurity. Although challenging to undertake, gathering such information is a necessary prelude to designing interventions to prevent these adverse outcomes whether by improving maternal health, prolonging pregnancy to reduce preterm birth, or preventing infection by chemoprophylaxis or immunization. Reaching these goals would go a long way toward improving child and maternal health globally.” (M. S. Edwards, morvene@bcm.edu)
Psychiatric Diagnoses & Critical Illness: Patients with psychiatric diagnoses are more likely to need critical care, and patients requiring intensive care with intubation are more likely to receive new psychiatric diagnoses and psychoactive medications for several months following discharge, a study from Denmark shows (pp. 1133–42). Adjusted prevalence ratios (PRs) for 5 years before and 1 year after critical illness showed these patterns: “Among 24,179 critically ill patients, 6.2% had 1 or more psychiatric diagnoses in the prior 5 years vs 5.4% for hospitalized patients (adjusted PR, 1.31; 95% CI, 1.22–1.42; P <.001) and 2.4% for the general population (adjusted PR, 2.57; 95% CI, 2.41–2.73; P <.001). Five-year preadmission psychoactive prescription rates were similar to hospitalized patients: 48.7% vs 48.8% (adjusted PR, 0.97; 95% CI, 0.95–0.99; P <.001) but were higher than the general population (33.2%; adjusted PR, 1.40; 95% CI, 1.38–1.42; P <.001). Among the 9,912 critical illness survivors with no psychiatric history, the absolute risk of new psychiatric diagnoses was low but higher than hospitalized patients: 0.5% vs 0.2% over the first 3 months (adjusted HR, 3.42; 95% CI, 1.96–5.99; P <.001), and the general population cohort (0.02%; adjusted HR, 21.77; 95% CI, 9.23–51.36; P <.001). Risk of new psychoactive medication prescriptions was also increased in the first 3 months: 12.7% vs 5.0% for the hospital cohort (adjusted HR, 2.45; 95% CI, 2.19–2.74; P <.001) and 0.7% for the general population (adjusted HR, 21.09; 95% CI, 17.92–24.82; P <.001). These differences had largely resolved by 9 to 12 months after discharge.” (C. F. Christiansen, cc@dce.au.dk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 20, 2014 * Vol. 21, No. 54
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 20 issue of the New England Journal of Medicine (2014; 370).
Obinutuzumab in Chronic Lymphocytic Leukemia: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, the combination of a monoclonal anti-CD20 antibody plus chlorambucil improved progression-free survival, compared with chlorambucil alone (pp. 1101–10). The type 2, glycoengineered antibody obinutuzumab outperformed the anti-CD20 agent rituximab, the authors report, among 781 patients: “The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and [Cumulative Illness Rating Scale] score of 8 at baseline. Treatment with obinutuzumab–chlorambucil or rituximab–chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab–chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P <0.001; and 16.3 months with rituximab–chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P <0.001). Treatment with obinutuzumab–chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P = 0.002). Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P <0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab–chlorambucil than with rituximab–chlorambucil, but the risk of infection was not increased.” (M. Hallek, michael.hallek@uni-koeln.de)
“Obinutuzumab is an anti-CD20 monoclonal antibody that differs from previous anti-CD20 monoclonal antibodies in its glycoengineered Fc region and type 2 CD20-binding mode,” editorialists write (
pp. 1160–2). “The rational targeting of dysregulated pathways in CLL has just started. New targeted agents, such as ABT-199 (an inhibitor of the antiapoptotic B-cell lymphoma 2 [BCL2] protein), are showing antitumor activity, including complete remissions, in high-risk relapsed or refractory CLL. The [above study] will certainly encourage future combination strategies of obinutuzumab with targeted agents such as ibrutinib, idelalisib, and ABT-199. These exciting new discoveries will indisputably shape the clinical landscape of CLL in the next decade.” (K. R. Rai)
Ribavirin in Chronic Hepatitis E Virus Infection: Among transplant recipients with chronic hepatitis E virus (HEV) infections, ribavirin as monotherapy may be effective in 3-month courses, according to results of a retrospective multicenter study (pp. 1111–20). Examination of the records of 59 patients with a variety of solid-organ transplants showed these responses to ribavirin initiated at a median of 9 months after HEV diagnosis and at median doses of 600 mg/d: “All the patients had HEV viremia when ribavirin was initiated (all 54 in whom genotyping was performed had HEV genotype 3). At the end of therapy, HEV clearance was observed in 95% of the patients. A recurrence of HEV replication occurred in 10 patients after ribavirin was stopped. A sustained virologic response, defined as an undetectable serum HEV RNA level at least 6 months after cessation of ribavirin therapy, occurred in 46 of the 59 patients (78%). A sustained virologic response was also observed in 4 patients who had a recurrence and were re-treated for a longer period. A higher lymphocyte count when ribavirin therapy was initiated was associated with a greater likelihood of a sustained virologic response. Anemia was the main identified side effect and required a reduction in ribavirin dose in 29% of the patients, the use of erythropoietin in 54%, and blood transfusions in 12%.” (N. Kamar, kamar.n@chu-toulouse.fr)

>>>PNN NewsWatch
* FDA yesterday approved miltefosine (Impavido, Paladin Therapeutics) to treat leishmaniasis. The parasite, transmitted through the bites of sand flies, causes three types of leishmaniasis—visceral, cutaneous, and mucosal. Miltefosine is approved for treatment of all three forms, and it is the first agent approved for treatment of cutaneous or mucosal leishmaniasis.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 21, 2014 * Vol. 21, No. 55
Providing news and information about medications and their proper use

>>>Nephrology Report
Source:
Mar. American Journal of Kidney Diseases (2014; 63).
Drug Prescribing in Renal Disease: In older patients with chronic kidney disease (CKD) whose estimated glomerular filtration rates (eGFR) were 30 mL/min/1.73 sq m or less, prescribing errors were “exceedingly common” in southwestern Ontario databases (pp. 422–8). Investigators looked at prescribed antibiotics for ambulatory patients 66 years or older in 2003–10, finding: “1,464 prescriptions were filled for study antibiotics throughout the study period. Prior to eGFR reporting, the average rate of antibiotic prescriptions dosed in excess of guidelines was 64 per 100 antibiotic prescriptions. The introduction of eGFR reporting had no impact on this rate (68 per 100 antibiotic prescriptions; P = 0.9). Nitrofurantoin, which is contraindicated in patients with CKD, was prescribed 169 times throughout the study period.” (A. K. Jain, arsh.jain@lhsc.on.ca)
“Can’t we do better” with drug prescribing in kidney disease, editorialists ask (
pp. 382–3). “The nephrology community has had vigorous debates regarding the best way to estimate kidney function for drug dosing and which set of dosing recommendations should be the standard for prescribing. In 2010, KDIGO (Kidney Disease: Improving Global Outcomes) brought together 50 international experts to articulate the state of knowledge of drug disposition in patients with kidney disease and make recommendations for the improvement of drug dosing. We identified significant gaps in knowledge of the pharmacokinetics and pharmacodynamics of many drugs in patients with impaired kidney function. However, we were barking up the wrong tree. We did not recognize that the greatest barrier to appropriate drug dosing would be prescribers failing to apply guidelines that are already widely available. [Authors of the above study] have shown us that we cannot rely on physicians to recognize that kidney function is impaired and that drug doses need to be altered accordingly. To improve drug prescribing in patients with kidney disease, we must develop systems of care in which the default action is the correct dose.” (G. R. Aronoff, gra@louisville.edu)

>>>Health Affairs Highlights
Source:
Mar. issue of Health Affairs (2014; 33).
Insurance Design & Medication Adherence: Evaluation of 76 value-based insurance design (VBID) plans introduced in 2007–10 reveal five factors that increase medication adherence (pp. 493–501). VBID plans “selectively lower cost sharing to increase medication adherence,” the authors note. “Existing plans have been structured in a variety of ways, and these variations could influence the effectiveness of VBID plans.… We found that after we adjusted for the other features and baseline trends, VBID plans that were more generous, targeted high-risk patients, offered wellness programs, did not offer disease management programs, and made the benefit available only for medication ordered by mail had a significantly greater impact on adherence than plans without these features. The effects were as large as 4–5 percentage points.” (N. K. Choudhry, nchoudhry@partners.org)

>>>Medical Care Report
Source:
Apr. issue of Medical Care (2014; 52).
“Activated” Patient Medication Requests: Using video-based scenarios presented to 192 primary care physicians in six states, investigators determined that patients making specific requests for medication significantly influenced prescribing patterns (pp. 294–9). The study sought to determine the influence of patient activation through Web searches, advice of friends, and direct-to-consumer pharmaceutical advertising. Results showed: “19.8% of sciatica patients requesting oxycodone would receive a prescription for oxycodone, compared with 1% of those making no specific request (P = 0.001). Fifty-three percent of knee osteoarthritis patients requesting Celebrex would receive it, compared with 24% of patients making no request (P = 0.001). Patients requesting oxycodone were more likely to receive a strong narcotic (P = 0.001) and less likely to receive a weak narcotic (P = 0.01). Patients requesting Celebrex were much less likely to receive a nonselective nonsteroidal anti-inflammatory drugs (P = 0.008). No patient attributes, physician, or organizational factors influenced a physician’s willingness to accede to a patient’s medication request.” (J. B. McKinlay)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 24, 2014 * Vol. 21, No. 56
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 22 issue of Lancet (2014; 383).
Prophylactic Anastrozole in Postmenopausal Women: In postmenopausal women at high risk, anastrozole 1 mg/d for 5 years significantly reduced breast cancer, compared with placebo (pp. 1041–8). The findings provide “support for the use of anastrozole in postmenopausal women at high risk of breast cancer,” the authors conclude based on these results: “1,920 women were randomly assigned to receive anastrozole and 1,944 to placebo. After a median follow-up of 5.0 years (IQR 3.0–7.1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0.47, 95% CI 0.32–0.68, p <0.0001). The predicted cumulative incidence of all breast cancers after 7 years was 5.6% in the placebo group and 2.8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p = 0.836)” (J. Cuzick, j.cuzick@qmul.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2014; 348).
Agomelatine in Depression: “Agomelatine is an effective antidepressant with similar efficacy to standard antidepressants,” according to these results of a meta-analysis of published and unpublished studies of the 5HT2C antagonist/ melatonergic MT1/MT2 agonist (g1888): “We identified 20 trials with 7,460 participants meeting inclusion criteria (11 in the published literature, four from the European Medicines Agency file, and five from the manufacturer). Almost all studies used the 17 item Hamilton depression rating scale (score 0–50). Agomelatine was significantly more effective than placebo with an effect size (SMD) of 0.24 (95% confidence interval 0.12 to 0.35) and relative risk of response 1.25 (1.11 to 1.4). Compared with other antidepressants, agomelatine showed equal efficacy (SMD 0.00, −0.09 to 0.10). Significant heterogeneity was uncovered in most analyses, though risk of bias was low. Published studies were more likely than unpublished studies to have results that suggested advantages for agomelatine.” (D. Taylor, david.taylor@slam.nhs.uk)
Anxiolytic/Hypnotic Drug Use & Mortality: Over a 7-year period, investigators found about 4 excess deaths per 100 patients taking anxiolytic and hypnotic agents in a retrospective analysis of data from the U.K. General Practice Research Database (g1996). All-cause mortality figures for 34,727 patients seen at 273 primary care practices showed these patterns: “Physical and psychiatric comorbidities and prescribing of non-study drugs were significantly more prevalent among those prescribed study drugs than among controls. The age adjusted hazard ratio for mortality during the whole follow-up period for use of any study drug in the first year after recruitment was 3.46 (95% confidence interval 3.34 to 3.59) and 3.32 (3.19 to 3.45) after adjusting for other potential confounders. Dose-response associations were found for all three classes of study drugs (benzodiazepines, Z drugs (zaleplon, zolpidem, and zopiclone), and other drugs). After excluding deaths in the first year, there were approximately four excess deaths linked to drug use per 100 people followed for an average of 7.6 years after their first prescription.” (S. Weich, s.weich@warwick.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved apremilast (Otezla, Celgene) to treat adults with active psoriatic arthritis (PsA). The phosphodiesterase-4 inhibitor improved signs and symptoms of PsA in 1,493 patients in three clinical trials. Adverse effects of the drug include weight loss, possible association with depression, diarrhea, nausea, and headache.

>>>PNN JournalWatch
* Genetics of Essential Tremor: Meta-analysis and Review, in
Neurology, 2014; 82: 1000–7. (G. Kuhlenbäumer, g.kuhlenbaeumer@neurologie.uni-kiel.de)
* Features of the Synovium of Individuals at Risk of Developing Rheumatoid Arthritis: Implications for Understanding Preclinical Rheumatoid Arthritis, in
Arthritis & Rheumatology, 2014; 66: 513–22. (P.P. Tak, paul-peter.x.tak@gsk.com)
* Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives, in
Gastroenterology, 2014; 146: 914–928.e1. (R. J. Fontana, rfontana@med.umich.edu)
* Medicaid and Marketplace Eligibility Changes Will Occur Often in All States; Policy Options Can Ease Impact, in
Health Affairs, 2014; 10.1377/hlthaff.2013.1023. (B. D. Sommers, bsommers@hsph.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 25, 2014 * Vol. 21, No. 57
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from JAMA Internal Medicine (2014; 174).
Omega Fatty Acids, Supplements & Cardiovascular Outcomes: In older patients with age-related macular degeneration, daily supplementation for a median of 4.8 years with long-chain omega-3 polyunsaturated fatty acids or with macular xanthophylls in addition to minerals and vitamins had no effects on risks of cardiovascular disease (CVD), researchers report (10.1001/jamainternmed.2014.328). In the Cardiovascular Outcome Study (COS)—an ancillary study of the Age-Related Eye Disease Study 2 (AREDS2)—4,203 patients ages 50–85 years at 82 U.S. academic and community received the AREDS vitamin and mineral formulation for macular degeneration plus daily omega-3 polyunsaturated fatty acids (docosahexaenoic acid [DHA] 350 mg + eicosapentaenoic acid [EPA] 650 mg), macular xanthophylls (lutein 10 mg and zeaxanthin 2 mg), both supplements, or neither. Results showed: “Study participants were primarily white, married, and highly educated, with a median age at baseline of 74 years. A total of 602 cardiovascular events were adjudicated, and 459 were found to meet 1 of the study definitions for a CVD outcome. In intention-to-treat analysis, no reduction in the risk of CVD or secondary CVD outcomes was seen for the DHA + EPA (primary outcome: hazard ratio [HR], 0.95; 95% CI, 0.78–1.17) or lutein + zeaxanthin (primary outcome: HR, 0.94; 95% CI, 0.77–1.15) groups. No differences in adverse events or serious adverse event were seen by treatment group. The sample size was sufficient to detect a 25% reduction in CVD events with 80% power.” (D. E. Bonds, bondsde@nhlbi.nih.gov)
“After many years of randomized evidence accumulated on various outcomes across a variety of diseases, omega-3 supplementation still fails to find its place in everyday clinical practice,” write authors of an invited commentary (
10.1001/jamainternmed.2013.13734). “What is evident so far is that omega-3 supplementation with daily doses close to 1 g in patients with or without established CVD shows no clear, considerable benefit. Continuing to conduct more [randomized controlled trials] seems unjustified. The time is ripe for a meta-analysis of individual participant data where investigators will have the valuable opportunity to carry out time-to-event and subgroup analyses uniformly across all studies and draw conclusions on the postulated omega-3 varying effects based on the participants’ characteristics. The design of future trials should focus on the remaining gaps of knowledge such as high-dose omega-3 supplementation (definitely more than 1 g daily) with various EPA/DHA ratios in subjects with [triglyceride (TG)] levels above 200 mg/dL (to convert to millimoles per liter, multiply by 0.0113). Until then, omega-3 should be considered only as TG-lowering agents for those with severe hypertriglyceridemia (an extreme minority of the general population). Patients raising the question of taking omega-3 supplements should be informed of the uncertainty surrounding their choice, and regular dietary consumption of (whole) fish should be preferentially encouraged as a source of omega-3 (not supplements) based on the wealth of the available epidemiological evidence.” (E. C. Rizos, vagrizos@gmail.com)
E-cigarettes & Smoking Cessation: “E-cigarettes may not increase rates of smoking cessation,” conclude authors of longitudinal analysis of 1,189 smokers recruited from the Knowledge Networks (now GfK) probability-based Web-enabled panel in 2011–12 (10.1001/jamainternmed.2014.187). Self-reported use of e-cigarettes and smoking cessation experiences showed the following: “E-cigarette use at baseline did not significantly predict quitting 1 year later (OR, 0.71 [95% CI, 0.35–1.46]; P = .35). A second model including intent, consumption, and dependence covariates found that intention to quit (OR, 5.59 [95% CI, 2.41–12.98]; P < .001) and cigarettes smoked per day (OR, 0.97 [95% CI, 0.94–0.99]; P = .02) significantly predicted quit status; past 30-day e-cigarette use did not (OR, 0.76 [95% CI, 0.36–1.60]; P = .46).
“Among participants who reported smoking at both baseline and follow-up (n = 821), e-cigarette use at baseline was not associated with a change in cigarette consumption (P = .25), controlling for baseline cigarette consumption.” (P. M. Ling,
pling@medicine.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 706/613-0200 (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
Mar. 26, 2014 * Vol. 21, No. 58
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 26 issue of JAMA (2014; 311).
Web-Based Alcohol Screening & Brief Intervention: A national Web-based alcohol screening and brief intervention program conducted among university students in New Zealand failed to generate significant reductions in frequency or volume of drinking or in academic problems, researchers report (pp. 1218–24). At seven universities in 2010, invitations with hyperlinks were e-mailed to 14,991 students ages 17–24 years. Those responding were screened using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), with these results: “Of 5,135 students screened, 3,422 scored 4 or greater and were randomized, and 83% were followed up. There was a significant effect on 1 of the 6 prespecified outcomes. Relative to control participants, those who received intervention consumed less alcohol per typical drinking occasion (median 4 drinks [interquartile range {IQR}, 2-8] vs 5 drinks [IQR 2-8]; rate ratio [RR], 0.93 [99.17% CI, 0.86–1.00]; P = .005) but not less often (RR, 0.95 [99.17% CI, 0.88–1.03]; P = .08) or less overall (RR, 0.95 [99.17% CI, 0.81–1.10]; P = .33). Academic problem scores were not lower (RR, 0.91 [99.17% CI, 0.76–1.08]; P = .14) and effects on the risks of binge drinking (odds ratio [OR], 0.84 [99.17% CI, 0.67–1.05]; P = .04) and heavy drinking (OR, 0.77 [99.17% CI, 0.56–1.05]; P = .03) were not significantly significant. In a sensitivity analysis accounting for attrition, the effect on alcohol per typical drinking occasion was no longer statistically significant.” (K. Kypri, kypros.kypri@newcastle.edu)
A1C & CVD: Addition of glycated hemoglobin measurements to conventional cardiovascular disease (CVD) tests provides little additional insight into CVD risk, according to an analysis of 73 prospective studies of 294,998 participants (pp. 1225–33): “During a median follow-up of 9.9 (interquartile range, 7.6–13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7,603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517).” (J. Danesh, erfc@phpc.cam.ac.uk)
Using RCT Data in Developing Practice Guidelines: Identifying relevant data from randomized controlled trials (RCTs) is not always sufficient in developing clinical practice guidelines for chronic cardiovascular disorders, according to Viewpoint authors (pp. 1195–6): “Because RCTs are less subject to bias and confounding, they are considered the preferred source for evidence reviews. It is important to critically assess the ability of a set of RCTs to provide reliable signals of an effect of an intervention on health outcomes. Features of trial design that influence the number of events observed include the definition of events, the duration of follow-up, and the sample size. Patient factors (age, comorbid conditions, position along the disease-process continuum) and aspects of the test intervention (potency of treatment, dose, drug interactions) also influence the relative difference in events in the treatment groups of the RCT. Thus, the critical issue is not that randomization was used but rather the adequacy of the number of events observed in the various treatment groups.” (E. M. Antman, eantman@rics.bwh.harvard.edu)
Hospital Alarms & Patient Safety: Reflecting on the recognition of hospital alarms as a major problem in patient safety, Viewpoint authors call for improvements in this area (pp. 1199–200): “Existing hospital alarms no longer provide an umbrella of safety. The scope and design of these systems must shift from the status quo to a biologically valid, clinically relevant, patient-centered model. Existing technology allows integration and intelligent assessment of patient data to create advanced alarm systems. Changes to design and implementation of alarms are necessary to improve patient safety. No longer should hospitals be alarmed and potentially dangerous.” (V. Chopra, vineetc@med.umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 27, 2014 * Vol. 21, No. 59
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 27 issue of the New England Journal of Medicine (2014; 370).
Ceritinib in Non–Small-Cell Lung Cancer: Ceritinib (LDK378), an investigational inhibitor of the anaplastic lymphoma kinase gene (ALK), was effective against non–small-cell lung cancer (NSCLC) in patients whose disease had progressed during crizotinib treatment, a Phase I study shows (pp. 1189–97). Administered in doses ranging from 50 to 750 mg daily, ceritinib produced these effects: “A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).” (A. T. Shaw, ashaw1@mgh.harvard.edu)
While this study “is good news for patients with
ALK-rearranged lung cancer,” an editorialist writes that “some questions remain” (pp. 1250–1): “For example, what was the drug exposure and degree of target inhibition in patients with a response, as compared with those without a response? In addition, given the indirect measure of ALK fusions by means of fluorescence in situ hybridization with the use of break-apart probes, it would be helpful to determine the presence or absence of the fusion in patients with a response and in those without a response by means of direct sequencing in order to validate the true performance of this critical test. Finally, were responses also observed in patients with primary crizotinib resistance?” (R. K. Thomas)
Health Care–Associated Infections: Clostridium difficile is the most common pathogen in health care–associated infections, according to a prevalence survey conducted in 10 geographically diverse states (pp. 1198–208). Device-associated infections are declining, note authors who conclude that “consideration should be given to expanding surveillance and prevention activities to include other health care–associated infections.” The total numbers of health care–associated infections and affected inpatients in U.S. acute care hospitals in 2011 were as follows: “Surveys were conducted in 183 hospitals. Of 11,282 patients, 452 had 1 or more health care–associated infections (4.0%; 95% confidence interval, 3.7 to 4.4). Of 504 such infections, the most common types were pneumonia (21.8%), surgical-site infections (21.8%), and gastrointestinal infections (17.1%). Clostridium difficile was the most commonly reported pathogen (causing 12.1% of health care–associated infections). Device-associated infections (i.e., central-catheter–associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia), which have traditionally been the focus of programs to prevent health care–associated infections, accounted for 25.6% of such infections. We estimated that there were 648,000 patients with 721,800 health care–associated infections in U.S. acute care hospitals in 2011.” (S. S. Magill, smagill@cdc.gov)
Nutrition in Acute Phase of Critical Illness: “It does not appear to be desirable to interfere with the early catabolic response to critical illness, either with macronutrients or, as shown previously, with anabolic hormones,” conclude authors of a review (pp. 1227–36). “Although the unfavorable effect of large amounts of macronutrients and growth factors during acute illness might be explained by their suppressive effects on pathways of cell-damage removal that recycle substrates from clearing debris, more research is needed to unravel the exact underlying mechanisms. In addition, research focusing on biomarkers and on scoring systems should aim to identify patients who are able to effectively use macronutrients for recovery and thus are likely to benefit from more aggressive earlier nutrition.” (G. Van den Berghe, greet.vandenberghe@med.kuleuven.be)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (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
Mar. 28, 2014 * Vol. 21, No. 60
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (2014; ).
Ambulatory Treatment of Type 2 Diabetes: Changes in treatments for type 2 diabetes are quantified in an analysis of cross-sectional data from the 1997–2012 IMS Health National Disease and Therapeutic Index (pp. 985–92): “Ambulatory diabetes visits increased from 23 million treatment visits in 1997 (95% CI 21–25) to 35 million (32–37) in 2007 and declined to 31 million visits by 2012 (27–31). Between 1997 and 2012 biguanide use increased, from 23% (20–26) to 53% (50–56) of treatment visits. Glitazone use grew from 6% (4–8) in 1997 (41% [39–43] of all visits in 2005), but declined to 16% (14–18) by 2012. Since 2005, dipeptidyl peptidase-4 (DPP-4) inhibitor use increased steadily, representing 21% (18–23) of treatment visits by 2012. Glucagon-like peptide 1 (GLP-1) agonists accounted for 4% of treatment visits in 2012. Visits where two or more drug compounds were used increased nearly 40% from 1997 to 2012. Between 2008 and 2012, drug expenditures increased 61%, driven primarily by use of insulin glargine and DPP-4 inhibitors.” (G. C. Alexander, galexand@jhsph.edu)
Costimulation Modulation With Abatacept in Type 1 Diabetes: In 112 patients with recent-onset type 1 diabetes, costimulation modulation with abatacept slowed decline of beta-cell function and improved glycosylated hemoglobin levels, researchers report (pp. 1069–75). Study participants, ages 6–36 years, received abatacept or placebo infusions intravenously 27 times over 2 years, with these effects on baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years: “C-peptide [area under the curve] means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168–0.268) and 0.141 nmol/L (95% CI 0.071–0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.” (J. S. Skyler, jskyler@miami.edu)
Ocular Anti-VEGF Therapy for Diabetic Retinopathy: Two bench-to-clinic symposia articles describe advances in understanding the role of vascular endothelial growth factor (VEGF) in development of diabetic macular edema (DME). In one article (pp. 893–9), authors write: “Intravitreal anti-VEGF agents have emerged as new treatments.… To provide an understanding of the rationale for use and clinical efficacy of anti-VEGF treatment … we provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy, the molecular characteristics of anti-VEGF agents currently used, and future perspectives and challenges in this area.” (R. Simó, rafael.simo@vhir.org)
“Ocular anti-vascular endothelial growth factor (VEGF) therapy represents one of the most significant advances in modern medicine,” write authors of the second article (
pp. 900–5). “The introduction and widespread use of ocular anti-VEGF therapy for age-related macular degeneration heralded a new era in the treatment of vascular and exudative diseases of the retina. Its expanding indications now include diabetic macular edema and proliferative diabetic retinopathy, two vision-threatening forms of diabetic retinopathy. It is widely anticipated that ocular anti-VEGF therapy could spark a dramatic shift in the treatment paradigm for diabetic retinopathy. However, despite its clear efficacy shown in clinical trials, the dynamic landscape of evolving medical, ethical, and economic issues related to this new treatment suggests significant challenges ahead.” (N. Cheung, dannycheung@hotmail.com)

>>>PNN NewsWatch
* APhA2014 gets under way today in Orlando. Pharmacy’s only professionwide deliberative body, the APhA House of Delegates, will take up three policies: care transitions, audits of health care practices, and use of social media. U. Minn. Dean Marilyn K. Speedie, BSPharm, PhD, will receive the 2014 Remington Honor Medal for her work in gaining NIH recognition of PharmD’s as principal investigators and helping establish practice environments in Minnesota where pharmacists are compensated for medication therapy management 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 706/613-0200 (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
Mar. 31, 2014 * Vol. 21, No. 61
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 29 issue of Lancet (2014; 383).
Retinal Gene Therapy for Choroideremia: A Phase I/II trial provides support for further research into retinal gene therapy of the X-linked recessive disorder choroideremia and other diseases, such as age-related macular degeneration, in which early intervention is needed (pp. 1129–37). In six men who received this treatment, these results were noted: “Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3.8 letters (SE 4.1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23.0 dB (SE 1.1) at baseline to 25.3 dB (1.3) after treatment (increase 2.3 dB [95% CI 0.8–3.8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1.7 [SE 1.0]) was correlated with the vector dose administered per mm2 of surviving retina (r = 0.82, p = 0.04). By contrast, small non-significant reductions (p > 0.05) were noted in the control eyes in both maximal sensitivity (–0.8 dB [1.5]) and mean sensitivity (–1.6 dB [0.9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector.” (R. E. MacLaren, enquiries@eye.ox.ac.uk)
Gene Therapy for Parkinson Disease: In patients with advanced Parkinson disease, a lentiviral vector–based gene therapy was safe and well tolerated, researchers report (pp. 1138–46). Participants received one of three doses of ProSavin. Results showed: “15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on–off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean [Unified Parkinson’s Disease Rating Scale] part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n = 15, p = 0.0001) and 12 months (38 vs 27 [8]; n = 15, p = 0.0001) compared with baseline.” (S. Palfi, stephane.palfi@hmn.aphp.fr)

>>>PNN NewsWatch
* FDA on Friday approved Coagulation Factor IX (Recombinant), Fc Fusion Protein (Alprolix, Biogen) for use in adults and children who have hemophilia B. This is the first treatment for this condition that requires less frequent injections when used to prevent or reduce the frequency of bleeding. Alprolix, an orphan product, consists of the Factor IX molecule linked to the Fc portion of antibodies, which makes the product last longer in circulation.
*
FDA on Friday also for the first time approved a drug for prevention of migraine headaches in adolescents ages 12–17. Topiramate (Topamax, Janssen) reduced the frequency of migraine by 72%, compared with 44% with placebo, in a clinical trial of 103 participants.
* GlaxoSmithKline has withdrawn all lots of
Alli from the U.S. market because some packages were tampered with and may contain other kinds of pills, FDA said on Friday. FDA advises consumers not to purchase Alli at this time. Consumers who have purchased Alli should check the capsules inside the bottle to ensure that they are authentic. Alli is a turquoise blue capsule with a dark blue band imprinted with the text “60 Orlistat.”

PNN JournalWatch
* Fungal Nail Infection: Diagnosis and Management, in
BMJ, 2014; 348: g1800. (R. Sinclair, rodney.sinclair@epworthdermatology.com.au)
* Chronic Migraine, in
BMJ, 2014; 348: g1416. (T. J. Schwedt, schwedt.todd@mayo.edu)
* Diagnostic Tests and Treatment Options in Glomerular Disease: 2014 Update, in
American Journal of Kidney Diseases, 2014; 63: 656–66. (G. B. Appel, nephroman@msn.com)
* Ten Common Mistakes in the Management of Lupus Nephritis, in
American Journal of Kidney Diseases, 2014; 63: 667–76. (J. M. Bargman, joanne.bargman@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 706/613-0200 (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.