Dec 2011

PNN Quarterly File—Fourth Quarter 2011

PNN Pharmacotherapy Line
Oct. 3, 2011 * Vol. 18, No. 191
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 1 issue of Lancet (2011; 378).
Diagnosing High Blood Pressure in Primary Care: A cost-effectiveness analysis of options for diagnosing high blood pressure in the primary care setting shows that ambulatory monitoring would “reduce misdiagnosis and save costs” following an initially high clinic reading (pp. 1219–30). Using a Markov model, researchers estimated lifetime costs, quality-adjusted life years, and cost-effectiveness for three diagnostic strategies: further blood pressure measurement in the clinic or at home, or with an ambulatory monitor: “Ambulatory monitoring was the most cost-effective strategy for the diagnosis of hypertension for men and women of all ages. It was cost-saving for all groups (from −£56 [95% CI –105 to –10] in men aged 75 years to –£323 [–389 to –222] in women aged 40 years) and resulted in more quality-adjusted life years for men and women older than 50 years (from 0.006 [0.000 to 0.015] for women aged 60 years to 0.022 [0.012 to 0.035] for men aged 70 years). This finding was robust when assessed with a wide range of deterministic sensitivity analyses around the base case, but was sensitive if home monitoring was judged to have equal test performance to ambulatory monitoring or if treatment was judged effective irrespective of whether an individual was hypertensive.” (S. Jowett, s.jowett@bham.ac.uk)
Worldwide Use of Secondary CVD Prevention Meds: “Systematic approaches are needed to improve the long-term use of basic, inexpensive, and effective drugs” for secondary prevention of cardiovascular disease, the Prospective Urban Rural Epidemiological (PURE) study shows, based on usage patterns identified in rural and urban settings in countries at various stages of economic development (pp. 1231–43). Questionnaires, telephone interviews, and home visits for adults aged 35–70 years showed the following: “We enrolled 153,996 adults from 628 urban and rural communities in countries with incomes classified as high (three countries), upper-middle (seven), lower-middle (three), or low (four) between January, 2003, and December, 2009. 5,650 participants had a self-reported coronary heart disease event (median 5.0 years previously [IQR 2.0–10.0]) and 2,292 had stroke (4.0 years previously [2.0–8.0]). Overall, few individuals with cardiovascular disease took antiplatelet drugs (25.3%), beta blockers (17.4%), ACE inhibitors or ARBs (19.5%), or statins (14.6%). Use was highest in high-income countries (antiplatelet drugs 62.0%, beta blockers 40.0%, ACE inhibitors or ARBs 49.8%, and statins 66.5%), lowest in low-income countries (8.8%, 9.7%, 5.2%, and 3.3%, respectively), and decreased in line with reduction of country economic status (Ptrend < 0.0001 for every drug type). Fewest patients received no drugs in high-income countries (11.2%), compared with 45.1% in upper middle-income countries, 69.3% in lower middle-income countries, and 80.2% in low-income countries. Drug use was higher in urban than rural areas (antiplatelet drugs 28.7% urban vs 21.3% rural, beta blockers 23.5% vs 15.6%, ACE inhibitors or ARBs 22.8% vs 15.5%, and statins 19.9% vs 11.6%; all P < 0.0001), with greatest variation in poorest countries (Pinteraction < 0.0001 for urban vs rural differences by country economic status). Country-level factors (eg, economic status) affected rates of drug use more than did individual-level factors (eg, age, sex, education, smoking status, body-mass index, and hypertension and diabetes statuses).” (S. Yusuf, yusufs@mcmaster.ca)

>>>PNN JournalWatch
* Comparing Bivalent and Quadrivalent Human Papillomavirus Vaccines: Economic Evaluation Based on Transmission Model, in BMJ, 2011; 343: d5575. (M. Jit, mark.jit@hpa.org.uk)
* Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials, in
Pediatrics, 2011; 128: 729–39. (L. M. Askie)
* Nonpharmacologic Treatments for Childhood Constipation: Systematic Review, in
Pediatrics, 2011; 128: 753–61. (M. M. Tabbers)
* Telaprevir: A Novel NS3/4 Protease Inhibitor for the Treatment of Hepatitis C, in
Pharmacotherapy, 2011; 3: 951–74. (O. M. Klibanov)
* New and Emerging Anticoagulant Therapy for Atrial Fibrillation and Acute Coronary Syndrome, in
Pharmacotherapy, 2011; 31: 975–1016. (E. M. Davis)
* Efficacy, Safety, and Cost of Thrombolytic Agents for the Management of Dysfunctional Hemodialysis Catheters: A Systematic Review, in
Pharmacotherapy, 2011; 31: 1031–40. (D. Hilleman)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 4, 2011 * Vol. 18, No. 192
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Oct. 4 issue of the Annals of Internal Medicine (2011; 155).
2001 Anthrax Attacks: In the weeks after the Sept. 11 terrorist attacks, the deliberate release of anthrax through the U.S. Postal Service “disrupt[ed] our way of life and reveal[ed] our vulnerability,” writes a pair of physicians who were involved in diagnosing the index case and alerting authorities (early release): “Even though such attacks had been the subject of much writing and had been planned for, detection of and the appropriate response to an attack with an agent from the so-called ‘Category ‘A’ List’ had only been considered in theoretical terms. What transpired during the following difficult weeks, including how public health and federal government agencies performed, has been both praised and criticized. An intertwined epidemiologic and criminal investigation of such magnitude was unprecedented in U.S. history. To address the question of whether we as a nation are now better prepared for future threats involving biologic agents, it is important to learn from the lessons of the 2001 anthrax attacks, including the critical role of clinicians in surveillance. As physicians involved in diagnosing anthrax in the index case and alerting authorities, we offer our perspective on these events a decade after their occurrence.” (L. M. Bush)
Colchicine for Recurrent Pericarditis: In 120 patients with a first episode of pericarditis at four Italian hospitals, colchicine was a safe and effective means of secondary prevention, according to data from the CORP (COlchicine for Recurrent Pericarditis) study (pp. 409–14). Patients were randomized to placebo or colchicine 1.0–2.0 mg on the first day followed by 0.5–1.0 mg/d for 6 months, with these results: “At 18 months, the recurrence rate was 24% in the colchicine group and 55% in the placebo group (absolute risk reduction, 0.31 [95% CI, 0.13 to 0.46]; relative risk reduction, 0.56 [CI, 0.27 to 0.73]; number needed to treat, 3 [CI, 2 to 7]). Colchicine reduced the persistence of symptoms at 72 hours (absolute risk reduction, 0.30 [CI, 0.13 to 0.45]; relative risk reduction, 0.56 [CI, 0.27 to 0.74]) and mean number of recurrences, increased the remission rate at 1 week, and prolonged the time to subsequent recurrence. The study groups had similar rates of side effects and drug withdrawal.” (M. Imazio)
Treatments for Obesity in Primary Care: Evidence is lacking for behavioral and pharmacologic treatments for obesity that can be used in primary care, according to a systematic review of trials of overweight and obese adults (pp. 434–7). “Medication trials had high attrition, lacked postdiscontinuation data, and were inadequately powered for rare adverse effects,” the authors wrote, adding these details: “Behaviorally based treatment resulted in 3-kg (6.6-lb) greater weight loss in intervention than control participants after 12 to 18 months, with more treatment sessions associated with greater loss. Limited data suggest weight-loss maintenance for 1 year or more. Orlistat plus behavioral intervention resulted in 3-kg (6.6-lb) more weight loss than did placebo after 12 months. Metformin resulted in less weight loss. Data on effects of weight-loss treatment on long-term health outcomes (for example, death and cardiovascular disease) were insufficient. Weight-loss treatment reduced diabetes incidence in participants with prediabetes. Effects on intermediate outcomes (for example, lipids and blood pressure) were mixed and small. Data on serious medication harms were insufficient. Medications commonly caused withdrawals due to gastrointestinal symptoms.” (E. S. LeBlanc)
Health Care Reform in the U.K.: Proposals for reforming the U.K. National Health Service by placing general practitioners at the center of the system and giving them control of 80% of the £100 billion budget are under scrutiny, authors report (pp. 465–9). Proposed in a white paper that was issued about 6 weeks after the May 2010 election of a new government, “the proposals were greeted with considerable concern by many health care professionals, patient representatives, and the media,” the authors write. “In response, the government organized an independent review, and proposals have been altered in response. This article outlines the current organization of the National Health Service, the rationale for change, and government proposals.” (N. O’Flynn)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 5, 2011 * Vol. 18, No. 193
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Oct. 11 issue of the Journal of the American College of Cardiology (2011; 58).
Early Statin Therapy with Extremely Low LDL Cholesterol: In a study from South Korea, 1,054 patients with acute myocardial infarction and LDL cholesterol levels below 70 mg/dL benefited from early initiation of statin therapy (pp. 1664–71). Patients who were prescribed statins at discharge in 2005–07 were compared with those who did not receive the agents, and these results were noted based on a primary endpoint of 1-year major adverse cardiac events, including death, recurrent MI, target vessel revascularization, and coronary artery bypass grafting: “Statin therapy significantly reduced the risk of the composite primary endpoint (adjusted hazard ratio [HR]: 0.56; 95% confidence interval [CI]: 0.34 to 0.89; p = 0.015). Statin therapy reduced the risk of cardiac death (HR: 0.47; 95% CI: 0.23 to 0.93; p = 0.031) and coronary revascularization (HR: 0.45, 95% CI: 0.24 to 0.85; p = 0.013). However, there were no differences in the risk of the composite of all-cause death, recurrent MI, and repeated percutaneous coronary intervention rate.” (M. Ho Jeong, myungho@chollian.net)
Since this study was observational, relying on retrospective data, it cannot prove causality, an editorialist notes (
pp. 1672–3). With this and other studies showing benefits of statins even in patients with very low LDL cholesterol levels, the writer notes that it would be ethically challenging to design a prospective study in which patients are assigned to placebo. If such a trial can be conducted, it would shed important light on this question, the writer notes, including the following: “Such a trial could also address the lingering concern that very low LDL levels might themselves be a risk for the development of some other serious, nonvascular disorders. Currently, the impressive success of statins in vascular disease trials has made it much more difficult to study any potential drawbacks to aggressive LDL lowering.…
“Such a trial might address the interesting question of whether achievement of very low LDL levels would obviate the need to aggressively modify other risk factors. If, as Roberts suggested some time ago, LDL is the necessary substrate for atherogenesis, without which atherosclerosis does not progress, then achievement of extremely low LDL levels might be worthwhile, particularly if it can be done without significant risk. In this regard, it is interesting that in both the TNT (Treating to New Targets) and JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) studies), high-density lipoprotein levels ceased to be predictors of vascular risk in those with very low LDL levels.” (J. C. LaRosa)
Testosterone & Cardiovascular Events: In the prospective population-based MrOS (Osteoporotic Fractures in Men) Sweden study of 2,416 men aged 69–81 years, high serum testosterone levels were a significant predictor of reduced 5-year risk of cardiovascular events (pp. 1674–81). Correlation of testosterone levels, sex hormone–binding globulin (SHBG) levels, presence of polymorphisms in the SHBG gene, and CV events as recorded in Swedish registers showed the following: “During a median 5-year follow-up, 485 CV events occurred. Both total testosterone and SHBG levels were inversely associated with the risk of CV events (trend over quartiles: p = 0.009 and p = 0.012, respectively). Men in the highest quartile of testosterone (550 ng/dl) had a lower risk of CV events compared with men in the 3 lower quartiles (hazard ratio: 0.70, 95% confidence interval: 0.56 to 0.88). This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline (hazard ratio: 0.71, 95% confidence interval: 0.53 to 0.95). In models that included both testosterone and SHBG, testosterone but not SHBG predicted CV risk.” (Å. Tivesten, asa.tivesten@medic.gu.se)

>>>PNN NewsWatch
* FDA yesterday announced approval of a reverse thermosensitive polymer gel used to temporarily occlude blood vessels during vascular surgery. LeGoo (PluroMed) replaces clamps and loops that can damage blood vessels and is better for providing a bloodless surgical field, FDA said. The gel will dissolve after 15 minutes on its own or can be quickly dissolved by applying a cold pack.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 6, 2011 * Vol. 18, No. 194
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 6 issue of the New England Journal of Medicine (2011; 365).
Oral Acyclovir & Neurodevelopment After Neonatal Herpes: Orally administered acyclovir for 6 months improved 12-month neurodevelopmental outcomes in neonates who had herpes simplex virus (HSV) disease with CNS involvement, researchers report (pp. 1284–92). In two parallel, identical studies, neonates with CNS involvement or skin, eye, and mouth involvement received 14–21 days of parenteral acyclovir. Infants were then randomized to placebo or oral acyclovir 300 mg/sq m three times daily for 6 months, with these results: “A total of 74 neonates were enrolled—45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P = 0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P = 0.09).” (D. W. Kimberlin, dkimberlin@peds.uab.edu)
“Extended oral acyclovir therapy should improve the lives of babies who have survived neonatal HSV,” writes an editorialist (
pp. 1338–9). Drawing on the story of the Three Musketeers as a metaphor for defenses against viral pathogens, she adds, “It is hoped that specific antiviral therapy will be joined by the active immunization ‘Musketeer’ to prevent maternal HSV infections. As with measles, even when there is a vaccine, we need effective specific antiviral therapy. HSV seems unlikely to disappear even with a vaccine. We too need synergy: ‘one for all and all for one.’”
Teriflunomide for Relapsing Multiple Sclerosis: The active metabolite of leflunomide, teriflunomide was significantly better than placebo in a trial of 1,088 patients with multiple sclerosis, reducing relapse rates, disability progression at a higher dose, and MRI evidence of disease (pp. 1293–303). Patients aged 18–55 years received teriflunomide 7 or 14 mg or placebo for 108 weeks, with this impact on a primary end point of annualized relapse rate: “Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P < 0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P = 0.08), and 20.2% with teriflunomide at 14 mg (P = 0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by… MRI. Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred.” (P. O’Connor, connorp@smh.ca">oconnorp@smh.ca)
Adjuvant Trastuzumab in HER2-Positive Breast Cancer: Reacting to a study that shows improved disease-free and overall survival with adjuvant trastuzumab in women with HER2-positive breast cancer (pp. 1273–83; D. Slamon, dslamon@mednet.ucla.edu), an editorialist writes that “the present is clearly brighter” for these patients but that “the future promises to shine even more” (pp. 1336–8): “Pilot studies suggest that the combination of trastuzumab and lapatinib, a small oral HER2 tyrosine kinase inhibitor, may be more effective than either drug alone. A large, international clinical trial addressing this question has been completed, and results are pending. Newer agents that target HER2 in different ways or target complementary pathways are under investigation.” (D. F. Hayes)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 7, 2011 * Vol. 18, No. 195
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Oct. issue of Chest (2011; 140).
Timing of Oseltamivir in Pandemic Influenza: Patients hospitalized with pandemic 2009 influenza A/H1N1 benefitted from oseltamivir administration even if onset of symptoms was more than 48 hours previously, researchers report (pp. 1025–32). Observational analysis of 538 patients with confirmed cases at 13 Spanish hospitals showed these patterns in time from onset of symptoms to oseltamivir administration and other outcomes: “The median time from onset of symptoms to oseltamivir administration was 3 days (interquartile range [IQR], 2–5 days). With regard to outcomes, the median duration of fever was 2 days (IQR, 1–3 days), the median [hospital length of stay (LOS)] was 5 days (IQR, 3–8 days), 49 patients (9.1%) underwent mechanical ventilation, and 11 patients (2%) died during hospitalization. In univariate analysis, prolonged duration of fever (above the median), prolonged LOS (above the median), need for mechanical ventilation, and mortality all increased with time to oseltamivir administration (chi-square test for trend P = .001, P ≤ .001, P = .008, and P = .001, respectively). After adjustment for confounding factors, time from onset of symptoms to oseltamivir administration (+1-day increase) was associated with a prolonged duration of fever (OR, 1.10; 95% CI, 1.02–1.19), prolonged LOS (OR, 1.07; 95% CI, 1.00–1.15), and higher mortality (OR, 1.20; 95% CI, 1.06–1.35).” (J. Carratalà, jcarratala@ub.edu)

>>>Psychiatry Highlights
Source:
Oct. issue of the American Journal of Psychiatry (2011; 168).
Lithium, Valproate in Suicide Attempters with Bipolar Disorder: No significant difference in suicidal behaviors was identified between lithium and valproate during a 2.5-year trial of 98 patients with bipolar disorder and histories of suicidal acts (pp. 1050–6). The double-blind study showed these results for time to suicide attempt and time to suicide event: “There were 45 suicide events in 35 participants, including 18 suicide attempts made by 14 participants, six from the lithium group and eight from the valproate group. There were no suicides. Intent-to-treat analysis using the log-rank test showed no differences between treatment groups in time to suicide attempt or to suicide event. Post hoc power calculations revealed that the modest sample size, reflective of challenges in recruitment, only permits detection of a relative risk of 5 or greater.” (M. A. Oquendo)
Use of Antipsychotics in Anxiety Disorders: Despite little evidence supporting the use, antipsychotic medications are increasingly prescribed by U.S. office-based psychiatrists for patients with anxiety disorders, an analysis of data from the 1996–2007 National Ambulatory Medical Care Surveys shows (pp. 1057–65). In a nationally representative sample of 4,166 visits, these prescribing patterns were identified: “Across the 12-year period, antipsychotic prescriptions in visits for anxiety disorders increased from 10.6% (1996–1999) to 21.3% (2004–2007). Over the study period, the largest increase in antipsychotic prescribing occurred among new patient visits. Antipsychotic prescribing also significantly increased among privately insured visits and visits in which neither antidepressants nor sedative/hypnotics were prescribed. Among the common anxiety disorder diagnoses, the largest increase in antipsychotic medication treatment was observed in visits for panic disorder. Antipsychotic prescribing rose from 6.9% (1996–1999) to 14.5% (2004–2007) among visits for anxiety disorders in which there were no co-occurring diagnoses with an indication approved by the Food and Drug Administration for antipsychotic medications.” (J. S. Comer)
“Perhaps the greatest value of the Comer et al. study is that it calls attention to the pressing need for more research to evaluate antipsychotics for use in patients with anxiety disorders given the high and growing use of these agents in this patient group,” an editorialist writes (
pp. 1012–4; A. Breier, abreier@iupui.edu)

>>>PNN NewsWatch
* CMS is proposing a separation of the consultant and dispensing services to U.S. long-term care facilities, ASCP reports. If finalized as written, the rule could have a major impact on consultant pharmacists, who now work primarily for three large national companies that provide integrated services.
*
PNN will not be published on Mon., Oct. 10, Columbus 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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 11, 2011 * Vol. 18, No. 196
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 10 issue of the Archives of Internal Medicine (2011; 171).
Dietary Supplements & Total Mortality in Older Women: Use of several dietary supplements is linked to increased total mortality risk in older women, a study shows (pp. 1625–33). The authors described the association with supplemental iron as the strongest, while calcium lowered the risk in this study, which differs from other research in that respect. Other data from 38,772 older women in the Iowa Women’s Health Study show the following usage patterns in the 15,594 women who died: “In multivariable adjusted proportional hazards regression models, the use of multivitamins (hazard ratio, 1.06; 95% CI, 1.02–1.10; absolute risk increase, 2.4%), vitamin B6 (1.10; 1.01–1.21; 4.1%), folic acid (1.15; 1.00–1.32; 5.9%), iron (1.10; 1.03–1.17; 3.9%), magnesium (1.08; 1.01–1.15; 3.6%), zinc (1.08; 1.01–1.15; 3.0%), and copper (1.45; 1.20–1.75; 18.0%) were associated with increased risk of total mortality when compared with corresponding nonuse. Use of calcium was inversely related (hazard ratio, 0.91; 95% confidence interval, 0.88–0.94; absolute risk reduction, 3.8%). Findings for iron and calcium were replicated in separate, shorter-term analyses (10-year, 6-year, and 4-year follow-up), each with approximately 15% of the original participants having died, starting in 1986, 1997, and 2004.” (J. Mursu, jaakko.mursu@uef.fi)
“Dietary supplementation has shifted from preventing deficiency to trying to promote wellness and prevent diseases,” writes a commentator (
pp. 1633–4). “Consumers believe that vitamin and mineral supplements are safe and use them without the supervision of their physicians. Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong. One should consider the likely U-shaped relationship between micronutrient status and health. We believe that for all micronutrients, risks are associated with insufficient and too-large intake. Low levels of intake increase the risk of deficiency. High levels of intake increase the risk of toxic effects and disease. Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market.” (G. Bjelakovic, g.bjelakovic@ctu.rh.dk)

>>>Lancet Highlights
Source:
Oct. 8 issue of Lancet (2011; 378).
Treatments for Acute Mania: For treating acute mania, antipsychotic drugs are more effective than mood stabilizers, researchers report, with risperidone, olanzapine, and haloperidol “among the best of the available options” (pp. 1306–15). From 68 randomized controlled trials of 16,073 participants, the authors found these overall results in a multiple-treatments meta-analysis: “Haloperidol (standardised mean difference [SMD] –0.56 [95% CI –0.69 to –0.43]), risperidone (–0.50 [—0.63 to –0.38), olanzapine –0.43 [—0.54 to –0.32], lithium (–0.37 [—0.63 to –0.11]), quetiapine (–0.37 [—0.51 to –0.23]), aripiprazole (–0.37 [—0.51 to –0.23]), carbamazepine (–0.36 [—0.60 to –0.11], asenapine (–0.30 [—0.53 to –0.07]), valproate (–0.20 [—0.37 to –0.04]), and ziprasidone (–0.20 [—0.37 to –0.03]) were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium (SMD –0.19 [95% CI –0.36 to –0.01]), quetiapine (–0.19 [—0.37 to 0.01]), aripiprazole (–0.19 [—0.36 to –0.02]), carbamazepine (–0.20 [—0.36 to –0.01]), asenapine (–0.26 [—0.52 to 0.01]), valproate (–0.36 [—0.56 to –0.15]), ziprasidone –0.36 [–0.56 to –0.15]), lamotrigine (–0.48 [—0.77 to –0.19]), topiramate (–0.63 [—0.84 to –0.43]), and gabapentin (–0.88 [–1.40 to –0.36]). Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin.” (A. Cipriani, andrea.cipriani@univr.it)

>>>PNN JournalWatch
* Genetics and Phenotyping in Chronic Sinusitis, in Journal of Allergy and Clinical Immunology, 2011; 128: 710–20. (L. Borrish, lb4m@virginia.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 12, 2011 * Vol. 18, No. 197
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 12 issue of JAMA (2011; 306).
Vitamin E & Prostate Cancer Risk: Among 35,533 men at 427 study sites in the U.S., Canada, and Puerto Rico, dietary supplementation with vitamin E significantly increased risk of prostate cancer, according to findings from SELECT, the Selenium and Vitamin E Cancer Prevention Trial (pp. 1549–56). Participants received oral selenium 200 µg/d, vitamin E 400 IU/d, both agents, or matching placebos for 7–12 years, with these results: “Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004–1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93–1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89–1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1,000 person–years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.”
Discussing their results, SELECT investigators advise caution with use of factorial designs in future trials of micronutrients, given the interaction observed here between vitamin E and selenium. They add this caution about the likelihood that vitamin E and other supplements have a U-shaped benefits curve: “Although modest benefits for vitamin E supplementation have been observed in a limited number of randomized clinical trials for Alzheimer disease and (as 1 part of a combination of oral antioxidants) for age-related macular degeneration, no benefits were demonstrated for prevention of cardiac events or mortality, colorectal adenomas, respiratory infections in elderly individuals, pre-eclampsia in women with type 1 diabetes, or prevention or progression of cataracts or macular degeneration. Moreover, the increased incidence of prostate cancer seen in SELECT, the previously reported increased incidence of lung cancer with high-dose beta carotene in both [the Alpha-Tocopherol, Beta Carotene (ATBC) trial] and the Beta-Carotene and Retinol Efficacy Trial (CARET), and the increased risk of colon polyps seen in a trial administering high-dose folate, suggest that caution should be used when recommending or studying high doses of micronutrients. As opposed to synthetic pharmaceuticals, these naturally occurring dietary constituents are part of normal physiology, and a U-shaped-dose response curve may exist where either deficiency or supraphysiological doses are harmful.” (E. A. Klein,
kleine@ccf.org)
Folic Acid & Severe Language Delay: Use of folic acid supplements from 4 weeks before to 8 weeks after conception significantly reduced risk of severe language delay in children at 3 years, researchers report (pp. 1566–73). Noting that the agent may benefit neurodevelopment in ways that extend beyond the neural tube, the investigators add these details from the prospective observational Norwegian Mother and Child Cohort Study: “Among 38,954 children, 204 (0.5%) had severe language delay. Children whose mothers took no dietary supplements in the specified exposure interval were the reference group (n = 9,052 [24.0%], with severe language delay in 81 children [0.9%]). Adjusted ORs for 3 patterns of exposure to maternal dietary supplements were (1) other supplements, but no folic acid (n = 2480 [6.6%], with severe language delay in 22 children [0.9%]; OR, 1.04; 95% CI, 0.62–1.74); (2) folic acid only (n = 7,127 [18.9%], with severe language delay in 28 children [0.4%]; OR, 0.55; 95% CI, 0.35–0.86); and (3) folic acid in combination with other supplements (n = 19,005 [50.5%], with severe language delay in 73 children [0.4%]; OR, 0.55; 95% CI, 0.39–0.78).” (C. Roth, christine.roth@fhi.no)
Dietary Supplements & Acute Lung Injury: Outcomes were significantly worse among patients with acute lung injury who received omega-3 fatty acids, gamma-linoleic acid, and antioxidants, compared with isocaloric control, the OMEGA study shows (pp. 1574–81). The study was stopped early after interim analysis showed fewer ventilator-free and ICU-free days among those on supplements. Higher 60-day mortality rates approached significance in the supplement group. (T. W. Rice, todd.rice@vanderbilt.edu)

>>>PNN NewsWatch
* Dasatinib (Sprycel, Bristol-Myers Squibb) increases patients’ risk of developing pulmonary arterial hypertension, FDA warned yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 13, 2011 * Vol. 18, No. 198
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 13 issue of the New England Journal of Medicine (2011; 365).
Adjuvant Zoledronic Acid in Breast Cancer: Disease-free survival was not improved when zoledronic acid was added to standard adjuvant systemic therapy in 3,360 patients with early-stage breast cancer, a study shows (pp. 1396–405). Open-label zoledronic acid was administered every 3–4 weeks for 6 doses and then every 3–6 months for 5 years of treatment, with these results: “At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P = 0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths—243 in the zoledronic acid group and 276 in the control group—were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P = 0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P < 0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.” (R. E. Coleman, r.e.coleman@sheffield.ac.uk)
Oil-in-Water Emulsion Adjuvant for Influenza Vaccine: Use of adjuvant MF59, an oil-in-water emulsion, improved the efficacy of trivalent inactivated influenza vaccine (TIV) in 4,707 health children aged 6 to 71 months, researchers report (pp. 1406–16). In two consecutive influenza seasons, two groups of children received two doses of age-appropriate TIV with or without MF59, while a control group was given noninfluenza vaccines. Using polymerase chain reaction (PCR) assay to confirm influenza cases, the investigators found: “Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, −6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups.” (T. Vesikari, timo.vesikari@uta.fi)
Adult Care of Patients with Acute Lymphoblastic Leukemia: After discussing the case of a 26-year-old woman who had acute lymphoblastic leukemia (ALL) at age 3 years, an author reaches several conclusions the primary care she needs as an adult (pp. 1417–24): “Given increased rates of obesity and associated metabolic abnormalities among survivors, they should be assessed for obesity; screened for hypertension, dyslipidemia, and glucose intolerance; and educated regarding diet, exercise, and avoidance of smoking. Hepatitis C screening should be performed in all survivors of leukemia treated before 1992. Survivors should have regular dental and ophthalmologic evaluations. Given reduced bone accretion associated with treatment for childhood cancer, bone-density assessment is recommended at entry into adult primary care. Optimal nutrition and exercise to promote bone mineralization should be encouraged. Survivors who were exposed to anthracycline therapy should have a baseline echocardiographic evaluation, with the follow-up frequency dependent on the findings.…” (L. Diller, lisa_diller@dfci.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 14, 2011 * Vol. 18, No. 199
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Nov. 1 issue of Clinical Infectious Diseases (2011; 53).
Nosocomial MRSA Transmission in Critically Ill Children: Colonization with methicillin-resistant Staphylococcus aureus puts children at risk for subsequent infection during periods of critical illness, a study shows, making prevention of transmission in this age group just as important as in adults (pp. 853–9). Children admitted to the pediatric intensive care unit of an academic medical center in 2007–10 showed these prevalence and infection patterns: “The MRSA admission prevalence among 3,140 children was 4.9%. Overall, 56 children (1.8%) developed an MRSA infection, including 13 (8.5%) colonized on admission and 43 (1.4%) not colonized on admission (relative risk [RR], 5.9; 95% confidence interval [CI], 3.4–10.1). Of those, 10 children (0.3%) developed an MRSA infection during their hospitalization, including 3 of 153 children (1.9%) colonized on admission and 7 of 2,987 children (0.2%) not colonized on admission (RR, 8.4; 95% CI, 2.7–25.8). African-Americans and those with public health insurance were more likely to get a subsequent infection (P < .01 and P = .03, respectively). We found that 15 children acquired MRSA colonization in the pediatric intensive care unit, and 7 (47%) developed a subsequent MRSA infection.” (A. M. Milstone, amilsto1@jhmi.edu)
Colistin-Associated Nephrotoxicity: In a retrospective cohort of patients treated with colistin over a 5-year period at an academic teaching hospital, nephrotoxicity occurred in 43% of patients treated in a dose-dependent manner, researchers report (pp. 879–84). The data “raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens,” the authors add, noting that they used “higher colistin doses similar to those commonly used in the United States.” Results showed the following: “Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P < .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3–103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42–10.2), and coadministration of ≥3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42–32.49).” (J. M. Pogue, jpogue@dmc.org)

>>>Oncology Highlights
Source:
Oct. 10 issue of the Journal of Clinical Oncology (2011; 29).
Venlafaxine/Clonidine for Hot Flashes from Breast Cancer Treatments: In 102 patients with hot flashes secondary to treatments for breast cancer, venlafaxine and clonidine were effective treatments (pp. 3862–8). Random assignment of participants to venlafaxine 75 mg, clonidine 0.1 mg, or placebo daily for 12 weeks showed these effects on questionnaire responses regarding daily hot flash scores, sexual function, sleep quality, anxiety, and depression: “After 12 weeks, a total of 80 patients were evaluable for the primary end point. During week 12, hot flash scores were significantly lower in the clonidine group versus placebo (P = .03); for venlafaxine versus placebo, the difference was borderline not significant (P = .07). However, hot flash scores were equal in the clonidine and venlafaxine groups. Over the course of 12 weeks, the differences between both treatments and placebo were significant (P < .001 for venlafaxine v placebo; P = .045 for clonidine v placebo). Frequencies of treatment-related adverse effects of nausea (P = .02), constipation (P = .04), and severe appetite loss were higher in the venlafaxine group.” (J. H. M. Schellens, j.schellens@nki.nl)
Adding men with androgen-deprivation therapy–related symptoms to the discussion, editorialists write that these results make it “reasonable to try each of the effective regimens in both women and men, as we pursue improvements in the quality of life for these patients” (
pp. 3842–6). “Accepting that there are some differences between the treatment of hot flashes in men and women, the available data suggest that there are many more similarities than differences.” (C. L. Loprinzi, cloprinzi@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 17, 2011 * Vol. 18, No. 200
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 15 issue of Lancet (2011; 378).
Outcomes with Surgery for Epilepsy: Neurosurgery provides a reasonable option for patients with refractory focal epilepsy, according to an assessment of 615 adults who were followed for a median of 8 years (pp. 1388–95). Most patients (n = 497) had anterior temporal resections, and long-term outcomes were as follows: “We used survival methods to estimate that 52% (95% CI 48–56) of patients remained seizure free (apart from simple partial seizures [SPS]) at 5 years after surgery, and 47% (42–51) at 10 years. Patients who had extratemporal resections were more likely to have seizure recurrence than were those who had anterior temporal resections (hazard ratio [HR] 2.0, 1.1–3.6; p = 0.02); whereas for those having lesionectomies, no difference from anterior lobe resection was recorded. Those with SPS in the first 2 years after temporal lobe surgery had a greater chance of subsequent seizures with impaired awareness than did those with no SPS (2.4, 1.5–3.9). Relapse was less likely the longer a person was seizure free and, conversely, remission was less likely the longer seizures continued. In 18 (19%) of 93 people, late remission was associated with introduction of a previously untried antiepileptic drug. 104 of 365 (28%) seizure-free individuals had discontinued drugs at latest follow-up.” (J. S. Duncan, j.duncan@ucl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Adverse Pregnancy Outcomes in Polycystic Ovary Syndrome: Occurrence of gestational diabetes, pre-eclampsia, preterm and still births, and other adverse pregnancy outcomes—known to be more common in women with polycystic ovary syndrome—cannot be explained by use of assistive reproductive technology alone, researchers report (d6309). All singleton births in Sweden in 1995–2007 were reviewed, with these relationships identified among various adverse pregnancy outcomes and maternal characteristics: “Women with polycystic ovary syndrome were more often obese and more commonly used assisted reproductive technology than women without such a diagnosis (60.6% v 34.8% and 13.7% v 1.5%). Polycystic ovary syndrome was strongly associated with pre-eclampsia (adjusted odds ratio 1.45, 95% confidence interval 1.24 to 1.69) and very preterm birth (2.21, 1.69 to 2.90) and the risk of gestational diabetes was more than doubled (2.32, 1.88 to 2.88). Infants born to mothers with polycystic ovary syndrome were more prone to be large for gestational age (1.39, 1.19 to 1.62) and were at increased risk of meconium aspiration (2.02, 1.13 to 3.61) and having a low Apgar score (<7) at five minutes (1.41, 1.09 to 1.83).” (N. Roos. nathalie.roos@karolinska.se)

>>>PNN NewsWatch
* FDA on Friday granted accelerated approval to deferiprone (Ferriprox, ApoPharma) for treatment of patients with thalassemia with iron overload due to blood transfusions who had an inadequate response to prior chelation therapy. The safety and effectiveness of the drug were established in 12 clinical trials of 236 such patients. About one-half of those receiving deferiprone has at least a 20% decrease in serum ferritin levels. The most common adverse effects in patients on deferiprone were nausea, vomiting, abdominal and joint pain, chromaturia (urine discoloration), neutropenia, and an increase in serum levels of a liver enzyme. Agranulocytosis occurred in about 2% of patients on the drug. The approval brings the number of FDA’s 2011 new molecular entity approvals to 26.

>>>PNN JournalWatch
* Biosimilars: The Debate Continues, in Arthritis & Rheumatism, 2011; 63: 2848–50. (R. A. Colbert, colbertr@mail.nih.gov)
* Transforming Growth Factor-beta in the Gastrointestinal and Hepatic Tumor Microenvironment, in
Gastroenterology, 2011; 141: 1167–78. (L. Yang, yangl3@mail.nih.gov)
* Chronic Rhinosinusitis: Epidemiology and Medical Management, in
Journal of Allergy and Clinical Immunology, 2011; 128: 693–707. (D. L. Hamilos, dhamilos@partners.org)
* Addressing the Ethical, Policy, and Social Challenges of Preclinical Alzheimer Disease, in
Neurology, 2011; 77: 1487–93. (J. Karlawish, Jason.Karlawish@uphs.upenn.edu)
* Podocytopathy in Diabetes: A Metabolic and Endocrine Disorder, in
American Journal of Kidney Diseases, 2011; 58: 637–46. (A. Fornoni, afornoni@med.miami.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 18, 2011 * Vol. 18, No. 201
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 18 issue of the Annals of Internal Medicine (2011; 155).
Interventions Targeting 30-Day Rehospitalization Rates: A review of a wide variety of interventions aimed at reducing the 20% rate at which Medicare fee-for-service patients are rehospitalized within 30 days failed to identify a specific approach that worked consistently, researchers report (pp. 520–8). Pharmacist services—including medication reconciliation, a discharge medication teaching service, and clinical pharmacy services for patients with heart failure and acute coronary syndrome—were among the interventions studied in 43 trials from the literature: “A taxonomy was developed to categorize interventions into 3 domains that encompassed 12 distinct activities. Predischarge interventions included patient education, medication reconciliation, discharge planning, and scheduling of a follow-up appointment before discharge. Postdischarge interventions included follow-up telephone calls, patient-activated hotlines, timely communication with ambulatory providers, timely ambulatory provider follow-up, and postdischarge home visits. Bridging interventions included transition coaches, physician continuity across the inpatient and outpatient setting, and patient-centered discharge instruction.”
The authors conclude: “Given the paucity of high-quality trials evaluating various interventions to reduce 30-day readmissions (for example, we found only 4 randomized, controlled trials enrolling >400 participants) and the impending hospital reimbursement penalty for excess rehospitalization, additional patient-centered outcomes research on remedies for avoidable rehospitalization and characteristics of successful implementation is clearly needed. Although rehospitalization represents a large burden to patients and the health care system, the current evidence base may not be adequate to facilitate change even for highly incentivized hospitals, and reconsideration of planned penalties may be reasonable.” (L. O. Hansen,
l-hansen@northwestern.edu)

>>>Nephrology Report
Source:
Oct. issue of the American Journal of Kidney Diseases (2011; 58).
Vitamin D Levels & Mortality in Nondialysis-Dependent CKD: Levels of 25-hydroxyvitamin D (25[OH]D) below 15 ng/mL were associated with increased mortality in a study of a large population of patients with nondialysis-dependent chronic kidney disease (CKD) (pp. 536–43). Patients with stages 3 or 4 CKD at the Cleveland Clinic had these outcomes when grouped in three 25(OH)D concentration ranges: “Of 12,763 patients with CKD, 15% (n = 1,970) had 25(OH)D levels <15 ng/mL, whereas 45% (n = 5,749) had 25(OH)D levels of 15–29 ng/mL. Male sex, African American race, diabetes, coronary artery disease, and lower estimated glomerular filtration rate were associated significantly with 25(OH)D level <30 ng/mL. A graded increase in risk of 25(OH)D level <30 ng/mL was evident across increasing body mass index levels. Patients who had 25(OH)D levels measured in fall through spring had higher odds for 25(OH)D levels <30 ng/mL. After covariate adjustment, patients with CKD with 25(OH)D levels <15 ng/mL had a 33% increased risk of mortality (95% CI, 1.07–1.65). The group with 25(OH)D levels of 15–29 ng/mL did not show a significantly increased risk of mortality (HR, 1.03; 95% CI, 0.86–1.22) compared with patients with 25(OH)D levels ≥30 ng/mL.” (S. D. Navaneethan, navanes@ccf.org)
Vitamin D Levels & Renal Clearance in CKD: Among 1,026 adults with all-stage CKD, 25(OH)D deficiency was independently related to impaired measured glomerular filtration rates (mGFRs) (pp. 544–53). For mGFR determined with labeled EDTA, “the prevalence of 25(OH)D deficiency was associated inversely with mGFR, ranging from 28% [to] 51% for mGFR ≥60 [to] <15 mL/min/1.73 m2,” the authors report. “It was higher in patients of African origin; those with obesity, diabetes, hypertension, macroalbuminuria, and hypoalbuminemia; and during winter. After adjusting for these factors, ORs for 25(OH)D deficiency increased from 1.4 (95% CI, 0.9–2.3) to 1.4 (95% CI, 0.9–2.1), 1.7 (95% CI, 1.1–2.7), and 1.9 (95% CI, 1.1–3.6) as mGFR decreased from 45–59 to 30–44, 15–29, and <15 (reference, ≥60) mL/min/1.73 m2 (P for trend = 0.02).” Factors associated with 25(OH)D deficiency in those with very low levels are also studied. (B. Stengel, benedicte.stengel@inserm.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 19, 2011 * Vol. 18, No. 202
Providing news and information about medications and their proper use

>>>JAMA Report
Source:
Oct. 19 issue of JAMA (2011; 306).
Heart Failure Hospitalization & Mortality Rates: Recent declines in ischemic heart disease and its risk factors among Americans appear to have led to a dramatic decline in hospitalizations for heart failure in 1998–2008, a study shows (pp. 1669–78). In the study of 55 million fee-for-service Medicare beneficiaries, declines were smaller among black men, and the overall 1-year mortality rate “declined slightly over the past decade but remains high,” the investigators note, adding these details: “The HF hospitalization rate adjusted for age, sex, and race declined from 2,845 per 100,000 person–years in 1998 to 2007 per 100,000 person–years in 2008 (P < .001), a relative decline of 29.5%. Age-adjusted HF hospitalization rates declined over the study period for all race-sex categories. Black men had the lowest rate of decline (4,142 to 3,201 per 100,000 person–years) among all race–sex categories, which persisted after adjusting for age (incidence rate ratio, 0.81; 95% CI, 0.79–0.84). Heart failure hospitalization rates declined significantly faster than the national mean in 16 states and significantly slower in 3 states. Risk-adjusted 1-year mortality decreased from 31.7% in 1999 to 29.6% in 2008 (P < .001), a relative decline of 6.6%. One-year mortality rates declined significantly in 4 states but increased in 5 states.” (J. Chen, jersey.chen@yale.edu)
Editorialists explored the under-use of agents proven to reduce hospitalizations (
pp. 1705–6): “The use of digoxin is on a steep decline and mineralocorticoid antagonists are underused in patients with HF in the United States. The DIG [Digitalis Investigation Group] trial showed that use of digoxin reduced overall hospitalization rate by almost 30%, whereas the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial revealed that compared with placebo, use of eplerenone reduced all-cause hospitalization by almost 25%. These rates of reduction in HF admission were comparable with that of ‘life-saving’ therapies available in chronic HF such as angiotensin-converting enzyme inhibitors or beta-blockers.” (M. Gheorghiade, m-gheorghiade@northwestern.edu)
Predicting Risk of Rehospitalization: Models for predicting risk of hospital readmission were developed for comparative or clinical purposes, limiting their use to specific settings, authors of a systematic review report (pp. 1688–98). Published studies of validated risk prediction models showed the following: “Of 7,843 citations reviewed, 30 studies of 26 unique models met the inclusion criteria. The most common outcome used was 30-day readmission; only 1 model specifically addressed preventable readmissions. Fourteen models that relied on retrospective administrative data could be potentially used to risk-adjust readmission rates for hospital comparison; of these, 9 were tested in large US populations and had poor discriminative ability (c statistic range: 0.55–0.65). Seven models could potentially be used to identify high-risk patients for intervention early during a hospitalization (c statistic range: 0.56–0.72), and 5 could be used at hospital discharge (c statistic range: 0.68–0.83). Six studies compared different models in the same population and 2 of these found that functional and social variables improved model discrimination. Although most models incorporated variables for medical comorbidity and use of prior medical services, few examined variables associated with overall health and function, illness severity, or social determinants of health.” (D. Kansagara, kansagar@ohsu.edu)
Politics & Mandatory HPV Vaccine: Addressing presidential candidate Michelle Bachmann’s claims that human papillomavirus (HPV) vaccine is “a dangerous drug,” authors of a Commentary write (pp. 1699–700): “Comments such as these could cause parents to decide not to have their children vaccinated, thereby potentially leading to preventable illness and perhaps even death. The scientific evidence demonstrates that population-based HPV vaccination is safe and effective, justifying widespread adoption of the vaccine. The question is whether a state mandate would increase vaccination rates or result in a backlash not only against HPV vaccination but also wider childhood vaccinations. Given the political divisiveness, states should launch health education campaigns before resorting to compulsion.” (L. O. Gostin, gostin@law.georgetown.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 20, 2011 * Vol. 18, No. 203
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 20 issue of the New England Journal of Medicine (2011; 365).
Timing of Antiretroviral Therapy in Patients Coinfected with HIV/Tubeculosis: In HIV-infected adults patients who are newly diagnosed with tuberculosis and have low CD4+ T-cell counts (less than 200 cells per cu mm), starting antiretroviral (ART) therapy 2 weeks after antitubercular therapy improves survival, according to the CAMELIA (Cambodian Early versus Late Introduction of Antiretrovirals) study team (pp. 1471–81). Participants began standard 6-month treatment for tuberculosis followed by open-label antiretroviral therapy either 2 or 6 months later, with these results: “A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log10 copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P = 0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P < 0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients.” (F-X Blanc, xavier.blanc@bct.aphp.fr)
Commenting on this and two related studies (
pp. 1482–91, D. V. Havlir, dhavlir@php.ucsf.edu; pp. 1492–501, S. S. Abdool Karim, caprisa@ukzn.ac.za), editorialists agree with early initiation of ART but provides these caveats to consider outside the research setting (pp. 1538–40): “First, diagnosing tuberculosis in this patient population is difficult, since confirmation still often relies on microscopy to detect acid-fast bacilli (the sensitivity of which is low), and smear-negative tuberculosis is common. Thus, antituberculosis therapy is often initiated on clinical grounds, before the diagnosis of tuberculosis is confirmed by means of culture (a test that is rarely performed in regions with scarce resources). Conversely, the initiation of ART in HIV-infected patients with undiagnosed tuberculosis may unmask the underlying mycobacterial infection. Second, the high pill burden associated with treatment with four antituberculosis drugs, three antiretroviral drugs, and antimicrobial prophylaxis (e.g., with cotrimoxazole and fluconazole) against opportunistic infections, as well as possible drug interactions and toxic effects, may jeopardize the patient’s adherence to treatment. Third, treatment may be complicated further by the need to treat multidrug-resistant or extensively drug-resistant tuberculosis, drug-resistant HIV infection, or both, which would require even more complex regimens that may be less well tolerated.” (M. E. Török)
Effects of Neighborhoods on Obesity & Diabetes: Results of a study of shifting women with children from low-income public housing projects to low-poverty neighborhoods points to community-level solutions to the U.S. obesity and diabetes epidemic (pp. 1509–19). Research has identified a number of factors in impoverished areas that can contribute to obesity and diabetes, including exercise level, diet, and level of stress. In 1994–98, the U.S. Dept. of Housing and Urban Development randomly assigned 4,498 women with children living in public housing in high-poverty urban census tracts to receive housing vouchers redeemable only if they moved to a low-poverty census tract and counseling on moving; unrestricted, traditional vouchers with no special counseling on moving; or a control group offered neither of these opportunities. Ten years later, these outcomes were found in participants whose body mass index (BMI) figures (84.2% of participants) and hemoglobin A1C level data (71.3%) were available: “The prevalences of a BMI of 35 or more, a BMI of 40 or more, and a glycated hemoglobin level of 6.5% or more were lower in the group receiving the low-poverty vouchers than in the control group, with an absolute difference of 4.61 percentage points (95% confidence interval [CI], −8.54 to −0.69), 3.38 percentage points (95% CI, −6.39 to −0.36), and 4.31 percentage points (95% CI, −7.82 to −0.80), respectively. The differences between the group receiving traditional vouchers and the control group were not significant.” (J. Ludwig, jludwig@uchicago.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 21, 2011 * Vol. 18, No. 204
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Oct. issue of the Journal of the American Geriatrics Society (2011; 59).
Vitamin D in Older Adults: Two research studies examine the relationships between older adults’ vitamin D levels and their blood glucose and physical function levels.
Among 2,038 community-dwelling adults who participated in the Health Survey for England in 2005, vitamin D levels below 50 nmol/L were independently associated with hyperglycemia (
pp. 1786–92). Concluding that this findings are “important public health concerns for older populations living in northern latitudes because both are common, and both have substantial adverse health consequences,” the investigators add these details about their data: “Hyperglycemia was independently associated with low vitamin D levels (odds ratio (OR) = 2.30, 95% confidence interval (CI) = 1.20–4.42 for 25(OH)D <25.0 nmol/L and OR = 2.09, 95% CI = 1.22–3.58 for 25(OH)D 25.0–49.9 nmol/L) but not for 25(OH)D between 50.0 and 74.9 nmol/L (OR = 1.49, 95% CI = 0.85–2.62).” (V. Hirani, v.hirani@ucl.ac.uk)
In the Cardiovascular Health Study All Stars, 988 community-dwelling adults aged 77 to 100 years commonly had vitamin D deficiency, and this was linked to poorer physical performance, lower muscle strength, and more frequent problems with mobility and activities of daily living (ADLs), researchers report (
pp. 1793–801). The study, which had both cross-sectional and longitudinal elements, showed these patterns in vitamin D levels, the Short Physical Performance Battery (SPPB), and grip and knee extensor strength at baseline, and mobility disability and ADL disability over a 3-year period: “Almost one-third (30.8%) of participants were deficient in 25(OH)D (<20 ng/mL). SPPB scores were lower in those with deficient 25(OH)D (mean (standard error) 6.53 (0.24)) than in those with sufficient 25(OH)D (≥30 ng/mL) (7.15 (0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions (P = .006). Grip strength adjusted for body size was also lower in those with deficient 25(OH)D than in those with sufficient 25(OH)D (24.7 (0.6) kg vs 26.0 (0.6) kg, P = .02). Participants with deficient 25(OH)D were more likely to have prevalent mobility (OR = 1.44, 95% confidence interval (CI)) = 0.96–2.14) and ADL disability (OR = 1.51, 95% CI = 1.01–2.25) at baseline than those with sufficient 25(OH)D. Furthermore, participants with deficient 25(OH)D were at greater risk of incident mobility disability over 3 years of follow-up (hazard ratio = 1.56, 95% CI = 1.06–2.30).” (D. K. Houston, dhouston@wakehealth.edu)

>>>Health Affairs Report
Source:
Oct. issue of Health Affairs (2011; 30).
Racial Differences in Nursing Home Flu Vaccination Rates: In 2006–09, influenza vaccination rates improved slightly in U.S. nursing homes, but they remained “well below” the 90% target level, and blacks continued to lag whites, according to data from the Minimum Data Sets for those years (pp. 1939–46). Blacks refused influenza vaccination more frequently than did whites, and they were more likely to live in nursing homes with lower vaccination rates, the study shows. “Unfortunately, we lack information about why blacks are less likely to be offered flu vaccinations compared with whites,” the authors write. “Unconscious provider bias has been suggested as one of the potential explanations for the racial differences in flu vaccination rates. This bias might help account for the racial differences within facilities.
“To completely eliminate racial differences in flu vaccination rates, educational programs that focus on elderly blacks and their families may be necessary. Appropriate incentives may also be important in motivating nursing homes to provide such educational programs.” (S. Cai,
shubing_cai@brown.edu)
“Meaningful Use” & Clinical Outcomes: The initial meaningful-use threshold for hospitals, requiring use of electronic orders for 30% of eligible patients, is too low to improve patient outcomes for heart failure and myocardial infarction among hospitalized Medicare beneficiaries, an analysis shows (pp. 2005–12). Researchers project that the proposed next level of health information technology integration, requiring coverage of 60% of patients, would be more likely “to produce the improved patient outcomes at the heart of the federal health information technology initiative” (S. S. Jones, sjones1@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 24, 2011 * Vol. 18, No. 205
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 22 issue of Lancet (2011; 378).
Primary Care Referral for Weight Loss: Referral of overweight and obese patients to the Weight Watchers program by primary care professionals is viable way to achieve “clinically useful early intervention for weight management,” concludes a study from Australia, Germany, and the U.K. (pp. 1485–92). Weight Watchers, a commercial program, offers regular weighing, advice about diet and physical activity, motivation, and group support. Among 772 adults with overweight or obesity, 12 months of standard care and free membership in Weight Watchers yielded these outcomes: “377 participants were assigned to the commercial programme, of whom 230 (61%) completed the 12-month assessment; and 395 were assigned to standard care, of whom 214 (54%) completed the 12-month assessment. In all analyses, participants in the commercial programme group lost twice as much weight as did those in the standard care group. Mean weight change at 12 months was –5.06 kg (SE 0.31) for those in the commercial programme versus –2.25 kg (0.21) for those receiving standard care (adjusted difference –2.77 kg, 95% CI –3.50 to –2.03) with LOCF; –4.06 kg (0.31) versus –1.77 kg (0.19; adjusted difference –2.29 kg, –2.99 to –1.58) with BOCF; and –6.65 kg (0.43) versus –3.26 kg (0.33; adjusted difference –3.16 kg, –4.23 to –2.11) for those who completed the 12-month assessment. Participants reported no adverse events related to trial participation.” (S. A. Jebb, susan.jebb@mrc-hnr.cam.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
ACE Inhibitors in Early Pregnancy & Congenital Malformations: The risk of congenital malformations in offspring of mothers taking ACE inhibitors during the first trimester of pregnancy is similar to that of other antihypertensives, researchers report, indicating that the underlying hypertension is the likely cause rather than any teratogenicity of the drugs (d5931). In 465,754 mother–child pairs born in the Kaiser Permanente Northern California region, these patterns were noted in 1995–2008: “The prevalence of ACE inhibitor use in the first trimester only was 0.9/1000, and the use of other antihypertensive medications was 2.4/1000. After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors during the first trimester only seemed to be associated with increased risk of congenital heart defects in offspring compared with normal controls (those with neither hypertension nor use of any antihypertensives during pregnancy) (15/381 (3.9%) v 6,232/400,021 (1.6%) cases, odds ratio 1.54 (95% confidence interval 0.90 to 2.62)). A similar association was observed for use of other antihypertensives (28/1090 (2.6%) cases of congenital heart defects, odds ratio 1.52 (1.04 to 2.21)). However, compared with hypertension controls (those with a diagnosis of hypertension but without use of antihypertensives) (708/29,735 (2.4%) cases of congenital heart defects), neither use of ACE inhibitors or of other antihypertensives in the first trimester was associated with increased congenital heart defects risk (odds ratios 1.14 (0.65 to 1.98) and1.12 (0.76 to 1.64) respectively).” (D-K Li, de-kun.li@kp.org)

>>>PNN NewsWatch
* The increased risk of serotonin syndrome in patients receiving methylene blue or linezolid while taking serotonergic psychiatric medications has been further clarified by FDA. The situation occurs most frequently when patients undergo parathyroid surgery, during which methylene blue is used as a visualizing agent, or when they receive linezolid, while taking specific psychiatric drugs: a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, or clomipramine.

>>>PNN JournalWatch
* Flushing Oral Oncology Drugs Down the Toilet, in Journal of Clinical Oncology, 2011; 29: 3958–9. (M. J. Ratain)
* Nitric Oxide: A Pleiotropic Signal in the Nervous System, in
Neurology, 2011; 77: 1568–76. (E. E. Benarroch)
* A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry, in
American Journal of Psychiatry, 2011; 168: 1041–9. (L. E. Duncan)
* Integrating Pharmacogenomics into Pharmacy Practice via Medication Therapy Management, in
Journal of the American Pharmacists Association, 2011; 51: e64–e74. (J. A. Owen, jowen@aphanet.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 25, 2011 * Vol. 18, No. 206
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 24 issue of the Archives of Internal Medicine (2011; 171).
Cardiovascular Risk Prediction: Two articles and an editorial explore cardiovascular risk prediction.
Several factors independently predict risk of sudden cardiac death (SCD) in women with coronary artery disease (CAD), the Heart and Estrogen/progestin Replacement Study shows (
pp. 1703–9). While studying hormone-replacement therapy in 2,763 postmenopausal women with CAD, investigators identified these SCD predictive factors over a mean follow-up of 6.8 years based on 136 SCDs among 254 cardiac deaths: “The annual SCD event rate was 0.79% (95% confidence interval, 0.67–0.94). The following variables were independently associated with SCD in the multivariate model: myocardial infarction, heart failure, an estimated glomerular filtration rate of less than 40 mL/min/1.73 m2, atrial fibrillation, physical inactivity, and diabetes. The incidences of SCD among women with 0 (n = 683), 1 (n = 1,224), 2 (n = 610), and 3 plus (n = 246) risk factors at baseline were 0.3%, 0.5%, 1.2%, and 2.9% per year, respectively. The combination of clinical risk factors and [left ventricular ejection fraction (LVEF)] (C-index, 0.681) were better predictors of SCD than LVEF alone (C-index, 0.600) and resulted in a net reclassification improvement of 0.20 (P < .001).” (R. Deo, Rajat.Deo@uphs.upenn.edu)
Incorporation of hemoglobin A1c into models of cardiovascular disease (CVD) risk improves predictive ability compared with classification of diabetes as a cardiovascular risk equivalent, researchers report (
pp. 1712–8). Among 24,674 women and 11,280 men (including 685 and 563 patients with diabetes at baseline, respectively), 125 CVD events occurred in women with diabetes (666 in other women), and 170 CVD events occurred in men with diabetes (1,382 in other men). Applying models for CVD risk, the investigators determined: “In women, the models including HbA1c levels in diabetic participants improved the C statistic by 0.177 (P < .001) over the risk equivalence model and showed improved reclassification (net reclassification improvement [NRI] of 26.7% [P = .001]). In men, the improvements were more modest but still statistically significant (C statistic change of 0.039 [P = .02]; NRI of 9.2% [P = .04]). Including HbA1c levels also improved prediction over a dichotomous term for diabetes in women (NRI of 11.8% [P = .03]) but not in men.” (N. P. Paynter, npaynter@partners.org)
With an eye on the “tempo of translation” of clinical research into practice parameters, a commentator writes (
pp. 1718–20): “As guideline committees grapple with whether to endorse using HbA1c measurement for diabetic patients, C-reactive protein and the Reynolds Risk Score, coronary calcium scanning for intermediate risk persons, treatment thresholds for aspirin and statin use, and other important specifics of CVD risk prediction, they should also consider the more general issue of how to translate CVD risk discoveries more quickly into better population health. Updating guidelines once per decade is not conducive, by itself, to rapid translation. However, guideline committees or their sponsors could develop a systematic approach to evaluating new information about CVD risk prediction, a standing committee to make case-by-case decisions between once-per-decade guideline releases, and flexible intuitive tools for clinicians to implement approved approaches. Though any such approach would be subject to a myriad of criticisms (as are omnibus guidelines), speeding up the tempo of translation from CVD risk discovery into better clinical decisions could have very large public health benefits.” (M. J. Pletcher, mpletcher@epi.ucsf.edu)

>>>PNN NewsWatch
* FDA yesterday approved clobazam (Onfi, Lundbeck) for adjunctive treatment of Lennox–Gastaut syndrome in patients aged 2 years or older. The benzodiazepine was approved as an orphan drug, as this condition affects fewer than 200,000 patients in the U.S. Efficacy was established in two multicenter trials. They showed a reduction in drop seizures (atonic, clonic, or myoclonic) during drug therapy, compared with a 4-week baseline period. Seizure control was better with active drug than with control drugs. Common adverse reactions include somnolence, sedation, fever, drooling, constipation, cough, urinary tract infection, insomnia, aggression, fatigue, upper respiratory tract infection, irritability, vomiting, dysphagia, ataxia, bronchitis, and pneumonia.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 26, 2011 * Vol. 18, No. 207
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (2011; 34).
Insulin Resistance & Poor Thrombolytic Response in Stroke: Patients with high insulin resistance (IR) do not respond as well as other patients to intravenous thrombolytics used in the treatment of acute ischemic stroke, researchers report (pp. 2413–7). In a study of patients with middle cerebral artery (MCA) occlusions who received thrombolytics, more persistent arterial occlusions and worse long-term outcomes were noted in patients with higher IR as determined by the homeostatic model assessment index (HOMA-IR): “A total of 109 thrombolysed MCA ischemic stroke patients were included (43.1% women, mean age 71 years). The HOMA-IR was higher in the group of patients with poor outcome (P = 0.02). The probability of good outcome decreased gradually with increasing HOMA-IR tertiles (80.6%, 1st tertile; 71.4%, 2nd tertile; and 55.3%, upper tertile). A HOMA-IR in the upper tertile was independently associated with poor outcome when compared with the lower tertile (odds ratio [OR] 8.54 [95% CI 1.67–43.55]; P = 0.01) and was associated with more persistent MCA occlusions (OR 8.2 [1.23–54.44]; P = 0.029).” (A. I. Calleja, aicsanz@hotmail.com)
DPP-4 Inhibitors & Bone Fractures: The risk of bone fractures may be reduced with use of dipeptidyl peptidase-4 (DPP-4) inhibitors, according to a meta-analysis of randomized controlled trials lasting at least 24 weeks (pp. 2474–6). Patients with type 2 diabetes had these fracture rates when DPP-4 inhibitors were compared with placebo or active drugs: “Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026).” (E. Mannucci, edoardo.mannucci@unifi.it)
CKD-EPI, MDRD Equations Underestimate GFRs: Glomerular filtration rates are underestimated by two commonly used equations in type 2 diabetes, accroding to a study of 105 patients (pp. 2353–5). Compared with GFR values measured using isotope-labeled EDTA, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations provided these values: “The mean age of patients was 57 ± 8 years; 53 (50%) were men and 90 (86%) were white. Forty-six (44%) patients had microalbuminuria, and 14 (13%) had macroalbuminuria. 51Cr-EDTA GFR was 103 ± 23, CKD-EPI GFR was 83 ± 15, and MDRD-GFR was 78 ± 17 mL/min/1.73 m2 (P < 0.001). Accuracy (95% CI) was 67% (58–74) for CKD-EPI and 64% (56–75) for MDRD. Precision was 21 and 22, respectively.” (S. P. Silveiro, sandrasilveiro@terra.com.br)

>>>PNN NewsWatch
* New patients should not be started on drotrecogin alfa (activated) (Xigris, Lilly), and treatment of patients on the agent should be stopped, FDA said yesterday after Lilly announced a worldwide market withdrawal of the drug. The action followed release of data from the recently completed PROWESS-SHOCK trial, which showed a 28-day, all-cause mortality rate of 26.4% of patients on active drug and 24.2% in placebo-treated patients, a nonsignificant difference. The trial was conducted as a condition for continued market authorization by European authorities, Lilly said. More information is available at online at www.Lilly.com and by calling 800-LillyRx.
* Meeting in Atlanta on Tuesday, the CDC’s Advisory Committee on Immunization Practices (ACIP) approved recommendations for routine vaccination of boys 11 or 12 years old with 3 doses of
HPV4 vaccine (Gardasil, Merck) to protect against human papilloma virus. The HPV vaccine will afford protection against certain HPV-related conditions and cancers in males, CDC said, and vaccination of males with HPV may also provide indirect protection of women by reducing transmission of HPV. Gardasil was licensed by FDA in 2009 for use in males aged 9–26 for prevention of genital warts, and it was previously licensed for girls in that age group for prevention of HPV complications.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 27, 2011 * Vol. 18, No. 208
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online content and the Oct. 27 issue of the New England Journal of Medicine (2011; 365).
Briakinumab v, Methotrexate for Psoriasis: Briakinumab, a monoclonal antibody that targets the p40 molecule on both interleukin-12 and 23, was significantly more effective than methotrexate for reducing symptoms of moderate to severe psoriasis, researchers report (pp. 1586–96). Patients receiving the monoclonal antibody had higher rates of serious infections and cancers, but not significantly so. The 52-week trial included 317 participants and used primary end points of at least 75% improvement in psoriasis area-and-severity index (PASI) scores at weeks 24 and 52 and a score on the physician’s global assessment of 0 (clear; no apparent disease) or 1 (minimal disease) at weeks 24 and 52.
Results showed: “At week 24, a total of 81.8% of the patients in the briakinumab group versus 39.9% in the methotrexate group had at least 75% improvement in the PASI score, and 80.5% versus 34.4% had a score of 0 or 1 on the physician’s global assessment. The corresponding percentages at week 52 were 66.2% versus 23.9% with at least a 75% improvement in the PASI score and 63.0% versus 20.2% with a score of 0 or 1 on the physician’s global assessment (P < 0.001 for all comparisons). During the 52-week study, serious adverse events occurred in 9.1% of the patients in the briakinumab group (12.9 events per 100 patient–years) and in 6.1% in the methotrexate group (10.6 events per 100 patient–years). Serious infections occurred in 2.6% of the patients in the briakinumab group (4.1 events per 100 patient–years) and in 1.8% in the methotrexate group (2.7 events per 100 patient–years); cancers occurred in 1.9% (2.0 events per 100 patient–years) versus 0%.” (K. Reich,
kreich@dermatologikum.de)
Hormonal Adaptations After Weight Loss: Levels of hormones that promote weight gain remain altered 1 year after diet-induced weight loss, a study shows, providing targets for helping people keep off lost pounds (pp. 1597–604). The hormones—leptin, ghrelin, cholecystokinin, peptide YY, insulin, pancreatic polypeptide, and glucagon-like peptide 1—are secreted by the gastrointestinal tract, pancreas, and adipose tissues, and their effects are integrated in the hypothalamus to regulate food intake and energy expenditure, the authors explain.
In the study, 50 overweight or obese patients without diabetes dieted for 10 weeks. Hormone levels measured at baseline, 10 weeks, and 62 weeks showed these patterns: “Weight loss (mean [±SE], 13.5 ± 0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P < 0.001 for all comparisons), and amylin (P = 0.002) and to increases in levels of ghrelin (P < 0.001), gastric inhibitory polypeptide (P = 0.004), and pancreatic polypeptide (P = 0.008). There was also a significant increase in subjective appetite (P < 0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P < 0.001), peptide YY (P < 0.001), cholecystokinin (P = 0.04), insulin (P = 0.01), ghrelin (P < 0.001), gastric inhibitory polypeptide (P < 0.001), and pancreatic polypeptide (P = 0.002), as well as hunger (P < 0.001).” (J. Proietto,
j.proietto@unimelb.edu.au)
PSA: Test or Not? Recommendations of the U.S. Preventive Services Task Force against PSA-based screening are debated in four online Commentaries. In one, authors make three points about what the “task force left out” (10.1056/NEJMp1112191). In addition to the difficulty of explaining contradictory literature to patients in a way that they can make an informed decision about whether to be tested and the general stewardship of health care resources, the writers make these points about “the variable and often idiosyncratic management of PSA levels in primary care and urology practices”: “Many PSA levels fall near the commonly used action thresholds in the range of 2.5 to 4.0 ng per milliliter. Men are tested and retested—sometimes several times per year—hoping to hear that their PSA levels ‘went down’ or at least ‘didn’t go up’ Patients undergo repeated biopsies, often at arbitrary intervals, after small spikes in PSA levels. PSA screening has even contributed to overuse of quinolone antibiotics, which many clinicians prescribe for lowering mildly elevated PSA levels in asymptomatic men with presumed prostatitis, even though a recent trial showed no difference between the PSA response to antibiotics and placebo.” (A. S. Brett)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 28, 2011 * Vol. 18, No. 209
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Nov. issue of Pharmacotherapy (2011; 31).
Atorvastatin in Plaque-Type Psoriasis: Atorvastatin in doses of 40 mg/d produced no significant benefits in 42 patients with plaque-type psoriasis with body surface area (BSA) involvement of 10% or more, researchers report (pp. 1045–50). Reviews in the literature tout statins for treatment of psoriasis, the authors explain, but this is the first randomized controlled trial of a statin for this indication. The 12-week trial showed these changes in Psoriasis Area and Severity Index (PASI) and percentage BSA involvement: “Mean ± SD baseline PASI scores were 7.42 ± 1.90 and 6.92 ± 1.76 in the atorvastatin and placebo groups, respectively. The primary outcomes were the degree of change in PASI scores and percentage BSA involvement from baseline to week 12. Significant improvement in psoriasis lesions was observed in both the atorvastatin and placebo groups (p < 0.001 for both groups). A 75% improvement in PASI score (PASI 75) was achieved in 8 patients (40%) in the atorvastatin group and 7 patients (35%) in the placebo group. However, no statistically significant differences were noted between the two treatment groups in mean PASI score, percentage BSA involvement, and PASI 75. In terms of adverse effects, atorvastatin was well tolerated.” (M. Radfar, radfarma@tums.ac.ir)
Statin Prevention of Atrial Fibrillation: Statin therapy is useful in prevention of atrial fibrillation, conclude authors of a meta-analysis and systematic review (pp. 1051–62). Benefits of statins were seen in both primary and secondary prevention, and atorvastatin was more effective than pravastatin for this use, the authors report, adding: “Of the 20 trials, atorvastatin was studied in 11, pravastatin in five, rosuvastatin in three, and simvastatin in one. Overall, among the 32,311 patients in these trials, the risk of atrial fibrillation was significantly reduced by statins (OR 0.59, 95% CI 0.45–0.76), and the drugs were effective for both primary prevention (OR 0.67, 95% CI 0.51–0.88) and secondary prevention (OR 0.40, 95% CI 0.20–0.83). Secondary prevention was not superior to primary prevention, however. A significant benefit was observed in the atorvastatin-treated subgroup (OR 0.43, 95% CI 0.27–0.66), especially in the dose range of 10–40 mg/day (OR 0.29, 95% CI 0.19–0.45). No protective effect was observed in the pravastatin subgroup (OR 1.03, 95% CI 0.77–1.37).” (Y. Hou, houyinglong2010@hotmail.com)

>>>PNN NewsWatch
* Distribution of investigational pentavalent (ABCDE) botulinum toxoid vaccine (PBT) will end on Nov. 30, CDC said in an MMWR article released yesterday. The product has been used primarily in workers with potential occupational exposure to botulinum toxin or neurotoxin-producing species of Clostridium. These include workers at public health laboratories, research facilities, and manufacturing institutions, CDC said. PBT has been available since 1965 under an IND application, and the lots in current use were made more than 30 years ago. Because of declining potency of the product, vaccination schedules had been modified in recent years with the addition of a 6-month injection to the three needed in the first 12 weeks. Combined with the need for annual boosters and increasing rate of moderate local reactions with these boosters, CDC decided to stop distribution. No replacement product is currently available, but the Dept. of Defense is working on a vaccine produced with recombinant technologies.
*
FDA has released a final report of an agency-funded study of the risk of blood clots in women taking various hormonal contraceptives. Results of the study, with a focus on drospirenone-containing oral contraceptives, will be presented at an advisory committee meeting on Dec. 8. The study used data from the two Kaiser Permanente programs in southern California and the Tennessee and Washington state Medicaid programs. Three contraceptives—drospirenone/ethinyl estradiol tablets, norelgestromin/ethinyl estradiol transdermal patches, and etonogestrel/estradiol vaginal rings—had significantly higher risks of venous thromboembolic events, compared with low-estrogen comparators (respective risks of 1.74 [95% CI, 1.42–2.14], 1.55 [1.17–2.07], and 1.56 [1.02–2.37]). In an analysis of new users, drospirenone/ethinyl estradiol showed a significantly higher risk of both arterial thrombotic events (2.01 [1.06–3.81]) and venous thromboembolic events (1.77 [1.33–2.35]).

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Oct. 31, 2011 * Vol. 18, No. 210
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 29 issue of Lancet (2011; 378).
Dalcetrapib & Atherosclerotic Disease: Used for 24 months to increase HDL cholesterol, dalcetrapib showed no atherosclerotic effects, as monitored using novel noninvasive multimodality imaging in the dal-PLAQUE trial (pp. 1547–59). Because of detrimental effects of the cholesteryl ester transfer protein (CETP) modulator torcetrapib, researchers focused on safety of dalcetrapib in a Phase IIb trial. Patients were monitored for a coprimary endpoint of MRI-assessed indices of arterial function at 24 months and radionuclide PET/CT assessment of arterial function with the carotid arteries or the ascending aorta at 6 months, with these results: “189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was –4.01 mm2 (90% CI –7.23 to –0.80; nominal p = 0.04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7.3 [90% CI –13.5 to –0.8]; nominal p = 0.07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.” (Z. A. Fayad, zahi.fayad@mssm.edu)
Point-of-Care CD4 Testing & Retention of Patients with HIV: Treatment and retention of patients with HIV are improved with point-of-care CD4 testing and prompt initiation of antiretroviral therapy, researchers report (pp. 1572–9). In an observational cohort study, retrospective evaluation of patient records at four primary health clinics that provide HIV treatment and point-of-care CD4 services showed these results: “After the introduction of point-of-care CD4 the proportion of patients lost to follow-up before completion of CD4 staging dropped from 57% (278 of 492) to 21% (92 of 437) (adjusted odds ratio [OR] 0.2, 95% CI 0.15–0.27). Total loss to follow-up before initiation of antiretroviral treatment fell from 64% (314 of 492) to 33% (142 of 437) (OR 0.27, 95% CI 0.21–0.36) and the proportion of enrolled patients initiating antiretroviral therapy increased from 12% (57 of 492) to 22% (94 of 437) (OR 2.05, 95% CI 1.42–2.96). The median time from enrolment to antiretroviral therapy initiation reduced from 48 days to 20 days (p < 0.0001), primarily because of a reduction in the median time taken to complete CD4 staging, which decreased from 32 days to 3 days (p < 0.0001). Loss to follow-up between staging and antiretroviral therapy initiation did not change significantly (OR 0.84, 95% CI 0.49–1.45).” (I. V. Jani, ilesh.jani@gmail.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
VTE with Oral Contraceptives: The risk of venous thromboembolism is at least twice as high with certain progestogen types, a study shows (d6423). Data from four Danish registries were evaluated for patterns of oral contraceptive use and event risk during 8 million women–years of use. Based on 4,307 first-ever VTE events, the researchers found relative risk of confirmed venous thromboembolism of 2.9, 6.6, 6.2, and 6.6 in users of oral contraceptives containing 30–40 µg ethinyl estradiol with levonorgestrel, desogestrel, gestodene, and drospirenone, respectively. The absolute risk of VTE in current users of desogestrel, gestodene, or drospirenone is about 10 per 10,000 women–years, the authors noted, meaning 2,000 women would need to be changed to levonorgestrel to prevent a single event of venous thromboembolism in 1 year. (Ø. Lidegaard, Lidegaard@rh.regionh.dk)

>>>PNN JournalWatch
* Genomics and the Multifactorial Nature of Human Autoimmune Disease, in New England Journal of Medicine, 2011; 365: 1612–23. (J. H. Cho, judy.cho@yale.edu)
* Strategies to Reduce the Cost of Renal Complications in Patients with Type 2 Diabetes, in
Diabetes Care, 2011; 34: 2486–7. (T. P. Gilmer, tgilmer@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 1, 2011 * Vol. 18, No. 211
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 1 issue of the Annals of Internal Medicine (2011; 155).
Clopidogrel Plus Aspirin in AF When Warfarin Cannot Be Used: Among 7,554 patients with atrial fibrillation for whom warfarin was unsuitable, addition of clopidogrel to aspirin therapy provided a modest benefit, one likely to be clinically beneficial in some patients, according to results of the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials (pp. 579–86). Data from the randomized trial were assessed for net benefit of dual antiplatelet therapy as expressed by ischemic stroke equivalents prevented per 100 patient–years (sum of the weighted event incidence with dual therapy minus the weighted event incidence on control treatment). Results showed: “Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, −0.12 to 1.24) per 100 patient–years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, −0.03 to 1.18) when weighted by death or disability after ischemia or hemorrhage.” (S. J. Connolly)
VTE Prophylaxis in Hospitalized Patients: Prevention of venous thromboembolism among hospitalized patients is explored in a review article, clinical guidelines, and an editorial (pp. 636–7; M. C. Fang).
Neither heparin nor mechanical prophylaxis provided overall benefits in hospitalized adult medical patients or in those with acute stroke, authors of a systematic review report (
pp. 602–15). Providing background for the below clinical practice guideline, the review shows that heparin prophylaxis did not lower mortality, may have reduced pulmonary embolism (PE) in medical patients and in all patients, but led to bleeding episodes that negated any beneficial effects. This finding applied to all heparins, the authors conclude, adding these details: “In medical patients, heparin prophylaxis did not reduce total mortality but did result in fewer … PEs (odds ratio [OR], 0.69 [95% CI, 0.52 to 0.90], but with evidence of publication bias) and an increase in all bleeding events (risk ratio [RR], 1.34 [CI, 1.08 to 1.66]). Heparin prophylaxis had no statistically significant effect on any outcome in patients with acute stroke except for an increase in major bleeding events (OR, 1.66 [CI, 1.20 to 2.28]). When trials of medical patients and those with stroke were considered together (18 studies; 36,122 patients), heparin prophylaxis reduced the incidence of PE (OR, 0.70 [CI, 0.56 to 0.87]; absolute reduction, 3 events per 1,000 patients treated [CI, 1 to 5 events]) but increased the incidence of all bleeding (RR, 1.28 [CI, 1.05 to 1.56]) and major bleeding events (OR, 1.61 [CI, 1.23 to 2.10]), with an absolute increase of 9 bleeding events per 1,000 patients treated (CI, 2 to 18 events), 4 of which were major (CI, 1 to 7 events). A reduction in total mortality approached statistical significance (RR, 0.93 [CI, 0.86 to 1.00]; P = 0.056; absolute decrease, 6 deaths per 1,000 patients treated [CI, 0 to 11 deaths]). No statistically significant differences in clinical outcomes were observed in the 14 trials that compared unfractionated heparin with low-molecular-weight heparin. No improvements in clinical outcomes were seen in the 3 studies of mechanical prophylaxis in patients with stroke, but more patients had lower-extremity skin damage (RR, 4.02 [CI, 2.34 to 6.91])—an increase of 39 events per 1,000 patients treated (CI, 17 to 77 events).” (F. A. Lederle)
In the clinical guideline, the American College of Physicians Clinical Guidelines Committee maintains support heparin for prophylaxis of venous thromboembolism for hospitalized nonsurgical patients (medical patients and patients with acute stroke) (
pp. 625–32). Specifically, ACP recommends:
* Assessment of risk for thromboembolism and bleeding in medical (including stroke) patients before initiation of prophylaxis of venous thromboembolism (strong recommendation, moderate-quality evidence)
* Pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (strong recommendation, moderate-quality evidence)
* Against use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (strong recommendation, moderate-quality evidence)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 2, 2011 * Vol. 18, No. 212
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and Nov. 1 issue of JAMA (2011; 306).
Alcohol Use & Breast Cancer Risk: Data from the Nurses’ Health Study strongly link low levels of alcohol consumption with a small increase in risk of breast cancer, with cumulative levels of alcohol intake throughout the adult life being the strongest risk factor (pp. 1884–90). The prospective observational study included 105,986 women who were followed from 1980 until 2008. Based on an early adult alcohol assessment and eight later updates, the investigators found: “During 2.4 million person–years of follow-up, 7,690 cases of invasive breast cancer were diagnosed. Increasing alcohol consumption was associated with increased breast cancer risk that was statistically significant at levels as low as 5.0 to 9.9 g per day, equivalent to 3 to 6 drinks per week (relative risk, 1.15; 95% CI, 1.06–1.24; 333 cases/100,000 person–years). Binge drinking, but not frequency of drinking, was associated with breast cancer risk after controlling for cumulative alcohol intake. Alcohol intake both earlier and later in adult life was independently associated with risk.” (W. Y. Chen, wendy.chen@channing.harvard.edu)
Hematopoietic Cell Transplantation in Older Patients: A minimally toxic nonmyeloablative regimen for allogeneic hematopoietic cell transplantation (HCT) in patients aged 60–75 produced generally positive results, with 5-year overall and progression-free survivals of 35% and 32%, respectively, researchers report (pp. 1874–83). Procedures requiring HCT have historically been provided only for hematologic malignancies if patients were 55–60 or younger, the authors explain, because of higher mortality following high-dose HCT in older patients. Using low-dose total body irradiation alone or combined with fludarabine 90 mg/sq m, patients receiving related or unrelated donor transplants had these outcomes: “Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%–32%) and 41% (95% CI, 36%–46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%–40%) and 32% (95% CI, 27%–37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08–2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38–2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10–2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43–3.43]) were associated with worse survival compared with low relapse risk (P < .001 overall).” (M. L. Sorror, msorror@fhcrc.org)
Barriers to Personalized Medicine: Writing of “detours on the road to personalized medicine,” authors of a Commentary article write (pp. 1914–5): “A new era of discovery is possible using huge databases of genetic information. Understanding the value of genomic information in clinical decision making will require an equal investment by creating large databases of carefully curated phenotype information with continuous outcome measurement during the course of routine treatment. Proactive support by the payers of health care would ensure that modifications of timely new markers would be incorporated.” (L. D. Fiore, louis.fiore@va.gov)
Hospital Conditions for Participation: CMS officials provide background information on a major revision of the federal Conditions for Participation that defines quality and safety standards hospitals must follow to receive payments from the Medicare and Medicaid programs (10.1001/jama.2011.1611). “The proposed rule also encourages a stronger patient-centered culture and engagement in the hospital,” the authors write. “For example, it encourages hospitals to take a patient-centered approach and permit self-administration of home medications by patients or administration by their support persons. Hospitals have the flexibility to establish this as a standing policy for all hospitalized patients or to tailor the policy (eg, for certain medications or with physician approval).” In addition to quality/safety standards and patient-centered approach to care, the short Commentary article covers simplification of governance and care coordination, removal of unnecessary costly regulations, and next steps. (P. H. Conway, Patrick.Conway@cms.hhs.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 3, 2011 * Vol. 18, No. 213
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online-only articles and Nov. 3 issue of the New England Journal of Medicine (2011; 365).
ADHD Drugs & Serious Cardiovascular Events: An FDA-funded analysis shows no significant association between current use of attention-deficit/hyperactivity drugs and serious cardiovascular events such as sudden cardiac death, acute myocardial infarction, and stroke (10.1056/NEJMoa1110212). FDA reacted to release of the data by saying that two other funded studies are under way and that it will reassess the drugs’ black-box warning once all data are available.
The current study analyzes data from four health plans: the Tennessee and Washington State Medicaid programs, Kaiser Permanente California (northern and southern), and OptumInsight Epidemiology (national data). Relative risks for current and former users and nonusers of methylphenidate, dexmethylphenidate, dextroamphetamines, amphetamine salts, atomoxetine, or pemoline showed the following: “Cohort members had 81 serious cardiovascular events (3.1 per 100,000 person–years). Current users of ADHD drugs were not at increased risk for serious cardiovascular events (adjusted hazard ratio, 0.75; 95% confidence interval [CI], 0.31 to 1.85). Risk was not increased for any of the individual end points, or for current users as compared with former users (adjusted hazard ratio, 0.70; 95% CI, 0.29 to 1.72). Alternative analyses addressing several study assumptions also showed no significant association between the use of an ADHD drug and the risk of a study end point.” (W. O. Cooper,
william.cooper@vanderbilt.edu)
Shortages of Generic Drugs: Released in conjunction with Pres. Obama’s signing of an executive order regarding drug shortages, a Perspective article focuses on generic manufacturers (10.1056/NEJMp1112633): “The origins of drug shortages are multifactorial, but simply stated, the problem for cancer treatment stems from a confluence of factors: consolidation of generic-drug production in the hands of a few manufacturers (Teva, Bedford, APP Pharmaceuticals, Hospira), who in turn have experienced both increased demand for drugs and production ‘problems.’ In general, generic drugs are sold for very limited profit, as fixed by Medicare legislation, and therefore are produced as inexpensively as possible, using older and less efficient production facilities, and with limited inventories to reduce carrying costs for the company. Contamination of commercial drug vials with particulate or biologic matter has led to the closure of several key plants (Bedford and Hospira).” (B. A. Chabner)
CFTR Potentiation in Cystic Fibrosis: Ivacaftor (VX-770; a potentiator of the cystic fibrosis transmembrane conductance regulator [CFTR] protein) improved lung function from 2 through 48 weeks in a study of 161 patients with cystic fibrosis and at least one G551D-CFTR mutation (pp. 1663–72). The patients, aged 12 years or older, received placebo or 150 mg of the drug every 12 hours. A primary end point of estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1) showed the following: “The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P < 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P < 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire–revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient’s quality of life) (P < 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P < 0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was −48.1 mmol per liter (P < 0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).” (B. W. Ramsey, bonnie.ramsey@seattlechildrens.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 4, 2011 * Vol. 18, No. 214
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (2011; 128).
H1N1 Influenza Vaccine Effectiveness: In infants and children aged 6 months to 9 years, a single dose of the 2009 A/H1N1 influenza vaccine was highly effective, protecting young patients against hospitalization as soon as 10–14 days after vaccination, a study shows (e1084–91). Using matched case–control design, investigators paired children hospitalized in Quebec during fall 2009 for confirmed pandemic H1N1 infection with nonhospitalized children, with these results: “The overall effectiveness of a single pediatric dose of vaccine administered ≥14 days before illness onset was 85% (95% confidence interval [CI]: 61% to 94%), varying according to age category but with wide and overlapping CIs: 92% (95% CI: 51% to 99%) in 6–23 month-old children, 89% (95% CI: 34% to 98%) in 2–4 year-olds, and 79% (95% CI: −31% to 96%) in 5–9 year-olds. Overall vaccine effectiveness for immunization ≥10 days before illness onset was slightly lower at 80% (95% CI: 60% to 90%), with similar variation according to age.” (R. Gilca)
Increasing Influenza Vaccination Rates Among Adolescents: A multicomponent intervention among predominantly black middle- and high-school students increased rates of vaccination against influenza, researchers report (e1092–9). The nonrandomized study had three arms. In three different counties, school-based interventions were compared with interventions at the provider level and standard-of-care conditions, with these results: “During the 2008–2009 influenza season, 70 (19%) of 370 students were vaccinated in the school-based county and 110 (15%) of 736 students were vaccinated in the provider-based county, compared with 71 (8%) of 889 students in the standard-of-care county (risk ratio [RR]school: 2.4 [95% confidence interval (CI): 1.7–3.2]; RRprovider: 1.9 [95% CI: 1.4–2.5]). During 2009–2010, seasonal influenza vaccination coverage was 114 (30.4%) of 375 of students in the school-based county, 122 (16.9%) of 663 of students in the provider-based county, and 131 (15.2%) of 861 students in the standard-of-care county (RRschool: 2.3 [95% CI: 1.9–2.9]; RRprovider: 1.2 [95% CI: 0.97–1.5]).” (L. M. Gargano)
HPV Vaccinations Among Girls: National data show that the vaccination rates among American girls against human papillomavirus (HPV) are increasing but well below target levels (pp. 830–9). In 2008–09, HPV vaccinations among 18,228 girls 13 to 17 years of age showed these patterns: “Overall, 40.5% of girls had received ≥1 HPV vaccine dose, and 53.3% of those girls completed the series. Factors independently associated with vaccination initiation included older age, having an 11- to 12-year preventive visit, insurance status, mother’s age and marital status, not receiving all vaccines at public facilities, and provider recommendation, which was the factor most strongly associated with initiation (prevalence ratio: 2.6 [95% confidence interval: 2.4–2.9]). Compared with white girls (60.4%), black (46.0%) and Hispanic (40.3%) girls were less likely to complete the series. Lack of knowledge of the vaccine (19.4%), vaccination was not needed (18.8%), the daughter was not sexually active (18.3%), and a provider did not recommend (13.1%) were the most common reasons for parents’ nonintent to have their daughters vaccinated.” (C. G. Dorell)

>>>PNN NewsWatch
* In an update on its ongoing safety review of tumor necrosis factor (TNF) blockers and malignancy in children, adolescents, and adults younger than 30 years, FDA said yesterday that it is requiring manufacturers to begin conducting in-depth follow-up of reports of malignancy cases and submitting all reports of malignancy to FDA as expedited reports (within 15 days). Annual summaries and assessments of malignancies and TNF blocker utilization data will also be required.
* Depending on which group you listen to, November is
American Diabetes Month, National Diabetes Month, or National Diabetes Awareness Month. All provide an excellent chance for pharmacists to connect with patients about the disease, and a video that can help in this process, “Our Voices: Type 2 Diabetes,” has been produced by Harvard medical student Eric Lu. It presents the stories of patients in their own words: “I’m just hoping that I can beat the diabetes somehow.”

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 7, 2011 * Vol. 18, No. 215
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Medical Receptionists & Medication Safety: Important “hidden” contributions to quality and safety of electronic medication prescribing are made by receptionists and other administrative personnel in physician offices, a study shows (d6788). During 395 hours of observation of 25 physicians, 20 nurses and health care assistants, 6 managers, and 56 reception and administrative staff, these patterns were observed with regard to repeat prescribing: “Repeat prescribing was a complex, technology-supported social practice requiring collaboration between clinical and administrative staff, with important implications for patient safety. More than half of requests for repeat prescriptions were classed as ‘exceptions’ by receptionists (most commonly because the drug, dose, or timing differed from what was on the electronic repeat list). They managed these exceptions by making situated judgments that enabled them (sometimes but not always) to bridge the gap between the idealised assumptions about tasks, roles, and interactions that were built into the electronic patient record and formal protocols, and the actual repeat prescribing routine as it played out in practice. This work was creative and demanded both explicit and tacit knowledge. Clinicians were often unaware of this input and it did not feature in policy documents or previous research. Yet it was sometimes critical to getting the job done and contributed in subtle ways to safeguarding patients.” (D. Swinglehurst, d.swinglehurst@qmul.ac.uk)

>>>Lancet Highlights
Source:
Early-release article from Lancet (2011; 378).
Androgen Deprivation Therapy Plus Radiation Therapy in Prostate Cancer: In men with locally advanced prostate cancer (T3 or T4), addition of radiation therapy (RT) to androgen-replacement therapy (ADT) improved survival at 7 years, researchers report (10.1016/S0140-6736(11)61095-7). The study also included men with organ-confined disease (T2) whose PSA levels were more than 40 ng/mL or more than 20 mg/mL with Gleason scores of 8 or higher. Overall survival rates were as follows when patients received lifelong ADT plus RT or ADT only: “Between 1995 and 2005, 1,205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6.0 years (IQR 4.4–8.0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70–78 vs 66%, 60–70; hazard ratio [HR] 0.77, 95% CI 0.61–0.98, p = 0.033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0.5%) in the ADT only group, two (0.3%) in the ADT and RT group; diarrhoea grade >3, four patients (0.7%) vs eight (1.3%); urinary toxicity grade >3, 14 patients (2.3%) in both groups).” (P. Warde, padraig.warde@rmp.uhn.on.ca)

>>>PNN NewsWatch
* Rivaroxaban (Xarelto, Janssen) was approved on Friday for reducing the risk of stroke in patients with nonvalvular atrial fibrillation, FDA said. The agent was initially approved in July of this year for reducing thrombic complications following hip- and knee-replacement surgery.

>>>PNN JournalWatch
* 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients with Peripheral Artery Disease (Updating the 2005 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, in Circulation, 2011; 124: 2020–45. (available at www.cardiosource.org and my.americanheart.org)
* NIAID-Sponsored 2010 Guidelines for Managing Food Allergy: Applications in the Pediatric Population, in
Pediatrics, 2011; 128: 955–65. (A. W. Burks)
* Essential Components of Effective HIV Care: A Policy Paper of the HIV Medicine Association of the Infectious Diseases Society of America and the Ryan White Medical Providers Coalition, in
Clinical Infectious Diseases, 2011; 53: 1043–50. (J. Gallant, jgallant@jhmi.edu)
* Combination Antibiotic Therapy for Empiric and Definitive Treatment of Gram-Negative Infections: Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2011; 31:1073–84. (M. D. Nailor, mnailor@harthosp.org)
* Treatment of Fever After Stroke: Conflicting Evidence, in
Pharmacotherapy, 2011; 31: 1085–91. (S. C. Fagan, sfagan@georgiahealth.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 8, 2011 * Vol. 18, No. 216
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
Nov. 8 issue of Circulation (2011; 124).
Insomnia & AMI: Patients with insomnia are at increased risk of acute myocardial infarction, according to a population-based study of 52,610 men and women in one county in Norway who were followed for a mean of 11.4 years (pp. 2073–81). A total of 2,368 incident AMIs occurred, according to data from the National Cause of Death Registry and hospitals. The investigators found these patterns of insomnia in association with AMIs: “Difficulties initiating and maintaining sleep and having a feeling of nonrestorative sleep were associated with a moderate increase in AMI risk. The multiadjusted hazard ratios for AMI were 1.45 (95% confidence interval 1.18–1.80) for people with difficulties initiating sleep almost every night, 1.30 (1.01–1.68) for those with difficulties maintaining sleep almost every night, and 1.27 (1.03–1.57) for those with a feeling of nonrestorative sleep more than once a week compared with people who never experienced these sleep difficulties. When we combined the symptoms, a dose-dependent association was seen between the number of insomnia symptoms and AMI risk (P for trend 0.003). Alternative multivariable models and different sensitivity analyses suggest that the results were robust, especially concerning difficulties initiating sleep.” (L. E. Laugsand, lars.e.laugsand@ntnu.no)
Gender Differences in Preventive Cardiology/Lifestyle Medicine: The understanding and public awareness of the importance of preventing cardiovascular disease in women increased greatly over the past decade, authors of a “recent advances” article report (pp. 2145–54): “Over the past decade, scientists, healthcare providers, the public, and policy makers have made substantial efforts to improve understanding of the sex/gender*differences in cardiovascular disease (CVD) and to recognize the importance of heart disease in women.… There was a near doubling of the rate of awareness of heart disease as the leading cause of death in women between 1997, when the [the American Heart Association] launched its first campaign for women, and 2009; during that same period, the death rate resulting from CVD decreased by nearly half. The extent to which efforts to close research gaps and to heighten awareness of heart disease in women are causally linked to lower CVD mortality or have resulted in improved clinical outcomes for women is not established. The purposes of this article are to evaluate contemporary sex/gender differences in the burden of CVD, to assess the impact of recent clinical trials on recommendations for the prevention of CVD in women, and to examine factors that may facilitate or impede quality CVD preventive care in women. Recommendations for the design and analyses of future CVD clinical trials in women are also provided.” (L. Mosca, ljm10@columbia.edu)

>>>Cardiology Highlights
Source:
Nov. 15 issue of the Journal of the American College of Cardiology (2011; 58).
Birth Prevalence of Congenital Heart Disease: In a focus issue of JACC on structural heart disease, authors of a systematic review and meta-analysis quantify the worldwide prevalence of congential heart disease (pp. 2241–7): “Reported total CHD birth prevalence increased substantially over time, from 0.6 per 1,000 live births (95% confidence interval [CI]: 0.4 to 0.8) in 1930 to 1934 to 9.1 per 1,000 live births (95% CI: 9.0 to 9.2) after 1995. Over the last 15 years, stabilization occurred, corresponding to 1.35 million newborns with CHD every year. Significant geographical differences were found. Asia reported the highest CHD birth prevalence, with 9.3 per 1,000 live births (95% CI: 8.9 to 9.7), with relatively more pulmonary outflow obstructions and fewer left ventricular outflow tract obstructions. Reported total CHD birth prevalence in Europe was significantly higher than in North America (8.2 per 1,000 live births [95% CI: 8.1 to 8.3] vs. 6.9 per 1,000 live births [95% CI: 6.7 to 7.1]; p < 0.001).” (J. W. Roos-Hesselink, j.roos@erasmusmc.nl)

>>>PNN NewsWatch
* FDA has extended to 4 months the time that patients have to use dabigatran (Pradaxa, Boehringer Ingelheim) after opening the manufacturer-supplied bottle, ASHP reports on its website.
*
Cetuximab (Erbitux, Bristol-Myers Squibb, Lilly) is now approved in patients with metastatic head and neck cancer, FDA said yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 9, 2011 * Vol. 18, No. 217
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from JAMA (2011; 306).
TNF-alpha Antagonists & Hospitalization for Infections: Patients with autoimmune disorders are at no greater risk for hospitalization for serious infections if they are treated with tumor necrosis factor (TNF)–alpha antagonists or alternative agents, researchers report (10.1001/jama.2011.1692). Retrospective cohorts assembled from the databases of Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare showed these associations for patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies): “Study cohorts included 10,484 RA, 2,323 IBD, and 3,215 psoriasis and spondyloarthropathies matched pairs using TNF-alpha antagonists and comparator medications. Overall, we identified 1,172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-alpha antagonists) and 7.78 (comparator regimens) per 100 person–years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91–1.21]). Among patients with IBD, rates were 10.91 (TNF-alpha antagonists) and 9.60 (comparator) per 100 person–years (aHR, 1.10 [95% CI, 0.83–1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-alpha antagonists) and 5.37 (comparator) per 100 person–years (aHR, 1.05 [95% CI, 0.76–1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07–1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02–1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections.” (C. G. Grijalva, carlos.grijalva@vanderbilt.edu)
This study “raises important questions about the comparative safety of immunosuppressant and biologic therapy and may prompt a reevaluation of anti-TNF safety,” write editorialists, noting that the data “question the accepted notion that anti-TNF therapy confers an increased risk of serious infection” (
10.1001/jama.2011.1705; D. T. Felson, dfelson@bu.edu).
Etanercept in Juvenile Idiopathic Arthritis: A study of 262 Dutch patients with juvenile idiopathic arthritis (JIA) who were treated with biologic agents shows that about one-third had excellent responses, one-third had intermediate responses, and one-third poor responses after 15 months of therapy (10.1001/jama.2011.1671). Using data from the Arthritis and Biologicals in Children Register, investigators looked at outcomes of all biologically naive patients who started etanercept before Oct. 2009: “Compared with an intermediate or poor response, an excellent response was associated with lower baseline disability score (range, 0–3 points, with 0 being the best score; adjusted odds ratio [OR] per point increase, 0.49; 95% CI, 0.33–0.74); fewer disease-modifying antirheumatic drugs (DMARD) (including methotrexate) used before initiating etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43–0.95), and younger age at onset (adjusted OR per year increase, 0.92; 95% CI, 0.84–0.99). Compared with an intermediate or excellent response, a poor response was associated with systemic JIA (adjusted OR systemic vs nonsystemic categories, 2.92; 95% CI, 1.26–6.80), and female sex (adjusted OR female vs male, 2.16; 95% CI, 1.12–4.18). Within the first 15 months of etanercept treatment, 119 patients experienced 1 or more infectious, noninfectious, or serious adverse events, including 37 among those with an excellent response, 36 with an intermediate response, and 46 with a poor response. Within the first 15 months of treatment, 61 patients discontinued etanercept treatment, including 4 with an excellent response, 0 with an intermediate response, and 57 with a poor response. In a secondary analysis of 262 patients with a median follow-up of 35.6 months after initiation of etanercept, a range of 37% to 49% of patients reached inactive disease. The mean adherence to etanercept was 49.2 months (95% CI, 46.4–52.0) for patients with an excellent response after 15 months, 47.5 months (95% CI, 44.9–50.1) for patients with an intermediate response, and 17.4 months (95% CI, 13.6–21.2) for patients with a poor response.” (M. H. Otten, m.otten@erasmusmc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 10, 2011 * Vol. 18, No. 218
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Nov. 10 issue of the New England Journal of Medicine (2011; 365).
Glucocorticoids, NAC in Severe Alcoholic Hepatitis: While short-term outcomes were improved when glucocorticoids plus N-acetylcysteine were used in 174 patients with severe alcoholic hepatitis, 6-month survival rates were unaffected, a study shows (pp. 1781–9). All patients received prednisolone for 4 weeks, and the dual-therapy group also received N-acetylcysteine on days 1–5, with these results: “Mortality was not significantly lower in the prednisolone–N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone–N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P < 0.001), a shorter prothrombin time (P < 0.001), a lower level of bilirubin at baseline (P < 0.001), and a decrease in bilirubin on day 14 (P < 0.001). Infections were less frequent in the prednisolone–N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups.” (E. Nguyen-Khac, nguyen-khac.eric@chu-amiens.fr)
It may be time to rethink the 6-month “rule” regarding the abstinent period required for liver transplants in patients with alcoholic hepatitis, an editorialist writes (
pp. 1836–8): “When we approach these decisions, we need to balance issues of utility and justice. Certainly from a utility standpoint, we can justify liver transplantation for alcoholic liver disease, probably even with an abstinence period of shorter than 6 months in selected individuals. The outcomes for alcoholic liver disease are better than those for the natural history of the disease without liver transplantation and are as good as or superior to those for other indications for liver transplantation.
“The issue of justice is more complex. The argument of self-inflicted disease is not a valid one. When one looks at the causes of liver disease, much of it could be perceived as self-inflicted, such as prior drug use resulting in viral hepatitis or obesity leading to nonalcoholic fatty liver disease. Alcoholism is a disease, and it should not be used to exclude patients from transplantation. However, there are important issues regarding the selection of appropriate candidates, and this is where the justice concept becomes more difficult. Without a good objective tool to predict risk of recidivism that can be applied fairly and equally across candidates, we are likely to have bias in our selection of candidates.” (R. S. Brown)
Medicaid at the Supreme Court: Analyzing the oral arguments in the Supreme Court case involving California Medicaid reimbursement rates, an attorney notes (10.1056/NEJMp1111428): “Justice Elena Kagan may have made the ultimate point: if the federal enforcement system were properly structured and funded, California’s proposal would have been reviewed before payments were cut. Had the DHHS approved the payment reductions, its decision would have been upheld out of judicial deference to complex agency decisions; had it decided not to approve the plan, that presumably would have ended the matter.
“Unfortunately, that’s not how Medicaid works. Given its size, the volume of daily administration decisions, and inadequate federal oversight capacity, states act first and seek permission later. Even when federal officials say no, federal funds continue to flow while the state appeals. Cutting off federal funding is unheard of, even when the state action is deemed unlawful. While this failed enforcement scheme unfolds, the health of millions of people may be at stake. Under these circumstances, it’s easy to see why even conservative justices have difficulty closing the courthouse doors; it’s also evident why the courts’ injunctive power is so basic to a system of fundamental fairness.” (S. Rosenbaum)

>>>PNN NewsWatch
* Fenofibric acid (Trilipix, Abbott) may not lower patients’ risk of myocardial infarction or stroke, FDA said yesterday after reviewing the results of the ACCORD trial. FDA is adding study information to the product label and requiring a clinical trial in high-risk patients on statins.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 11, 2011 * Vol. 18, No. 219
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Nov. issue of the Journal of Allergy and Clinical Immunology (2011; 128).
Primary Prevention of Asthma: “Surrogate therapeutic interventions that activate … mechanisms in young children at high risk for asthma” similar to those seen on farms could make primary prevention possible, writes the author of a review article (pp. 939–45): “Recent studies of the natural history of asthma have shifted attention toward viral respiratory tract illness in early life as a major risk factor associated with the development of the most persistent forms of the disease. Although early aeroallergen sensitization is strongly associated with chronic asthma, several trials in which single-aeroallergen exposure in pregnancy and early childhood was successfully accomplished and compared with sham avoidance have failed to show any decrease in asthma incidence. New evidence suggests that complex interactions occur between viral infection and aeroallergen sensitization in genetically susceptible subjects that trigger the immune responses and airway changes that are characteristic of persistent asthma. The finding that exposure to bacterial products among children raised on farms is associated with diminished asthma prevalence during the school years has now been replicated, and experimental studies have suggested that these effects are mediated by the activation of regulatory T cells in the airway.” (F. D. Martinez, fernando@arc.arizona.edu)
Cord Blood Vitamin D & Aeroallergen Sensitization: In children younger than 5 years in Tucson, AZ, low and high levels of cord blood 25-hydroxyvitamin D (25[OH]D) were associated with increased aeroallergen sensitization, researchers report (pp. 1093–9.e5). In the Tucson Infant Immune Study, plasma total IgE and specific IgE levels to 6 aeroallergens were measured at 1, 2, 3, and 5 years. Longitudinal data on diagnosed allergic rhinitis and asthma and skin prick test (SPT) positivity showed these patterns: “The median cord blood 25(OH)D level was 64 nmol/L (interquartile range, 49–81 nmol/L). Relative to the reference group (50–74.9 nmol/L), both low (<50 nmol/L) and high (≥100 nmol/L) levels were associated with increased total IgE (coefficient = 0.27, P = .006 and coefficient = 0.27, P = .04, respectively) and detectable inhalant allergen-specific IgE (odds ratio = 2.4, P = .03 and odds ratio = 4.0, P = .01, respectively) through age 5 years. High 25(OH)D levels were also associated with increased SPT positivity (odds ratio = 4.0, P = .02). By contrast, the 25(OH)D level was not significantly associated with allergic rhinitis or asthma.” (A. L. Wright, awright@arc.arizona.edu)

>>>Infectious Disease Report
Source:
Dec. 1 issue of Clinical Infectious Diseases (2011; 53).
Acute Care Hospital Requirement for Personnel Influenza Vaccination: A 2011 survey of 998 acute care U.S. hospitals shows that influenza vaccination of health care personnel (HCP) is required in facilities of varying size and location (pp. 1051–9): “Of responding hospitals (n = 808; 81.0%), 440 (55.6%) reported institutional requirements for influenza vaccination. Although employees were uniformly subject to requirements, nonemployees often were not. The proportion of requirements with consequences for vaccine refusal was 44.4% (n = 194); where consequences were imposed, nonmedical exemptions were often granted (69.3%). Wearing a mask was the most common consequence (74.2% of 194 requirements); by contrast, 29 hospitals (14.4%) terminated unvaccinated HCP. After adjustment for demographic factors, the following characteristics remained significantly associated with requirements: location in a state requiring HCP to receive or decline influenza vaccine, caring for inpatients that are potentially vulnerable to influenza, use of ≥9 Advisory Committee on Immunization Practices–recommended, evidence-based influenza vaccination campaign strategies, and for-profit ownership.” (B. L. Miller, bradymil@med.umich.edu)

>>>PNN NewsWatch
* FDA yesterday approved Hemacord (New York Blood Center), the first licensed hematopoietic progenitor cells-cord (HPC-C) cell therapy. The product is indicated for use in hematopoietic stem cell transplantation procedures in patients with disorders affecting the hematopoietic system.A boxed warning notes risks of graft versus host disease, engraftment syndrome, graft failure, and infusion reactions.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 14, 2011 * Vol. 18, No. 220
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 12 issue of Lancet (2011; 378).
Evidence-Based Symptom Management After Stroke: Nurse management of fever, hyperglycemia, and swallowing dysfunction in patients after acute stroke produced significantly better outcomes when evidence-based protocols were followed, a study shows (pp. 1699–706). In 19 cluster-randomized acute stroke units (ASUs) in Australia, data from 6,564 patients showed these benefits with use of protocols supported by multidisciplinary teams, as measured with the modified Rankin scale (mRS): “Irrespective of stroke severity, intervention ASU patients were significantly less likely to be dead or dependent (mRS ≥2) at 90 days than control ASU patients (236 [42%] of 558 patients in the intervention group vs 259 [58%] of 449 in the control group, p = 0.002; number needed to treat 6.4; adjusted absolute difference 15.7% [95% CI 5.8–25.4]). They also had a better SF-36 mean physical component summary score (45.6 [SD 10.2] in the intervention group vs 42.5 [10.5] in the control group, p = 0.002; adjusted absolute difference 3.4 [95% CI 1.2–5.5]) but no improvement was recorded in mortality (21 [4%] of 558 in intervention group and 24 [5%] of 451 in the control group, p = 0.36), SF-36 mean mental component summary score (49.5 [10.9] in the intervention group vs 49.4 [10.6] in the control group, p = 0.69) or functional dependency (Barthel Index ≥60: 487 [92%] of 532 patients vs 380 [90%] of 423 patients; p = 0.44).” (S. Middleton, sandy.middleton@acu.edu.au)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 343).
HIV Monitoring in Resource-Limited Settings: Two articles examine utility of CD4 monitoring of patients with HIV.
In Uganda, patients with HIV who were being treated with antiretroviral therapy (ART) had improved health and survival outcomes when laboratory monitoring of CD4 counts was used in addition to routine clinical monitoring, researchers report (
d6792). Three study arms compared viral load monitoring, CD4 monitoring, and clinical monitoring alone, with these results: “1,094 participants started ART; median CD4 count at baseline was 129 cells × 106/L. Median follow-up was three years. In total, 126 participants died (12%), 148 (14%) experienced new AIDS defining illnesses, and 61(6%) experienced virological failure, defined as two consecutive viral loads >500 copies/mL occurring more than three months after the start of ART. After adjustment for age, sex, baseline CD4 count, viral load, and body mass index, the rate of new AIDS defining events or death was higher in the clinical arm than the viral load arm (adjusted hazard ratio 1.83, P = 0.002) or the CD4 arm (1.49, P = 0.032). There was no significant difference between the CD4 arm and the viral load arm (1.23, P = 0.31).” (D. M. Moore, dmoore@cfenet.ubc.ca)
In a 15-year analysis of disability-adjusted life–years (DALYs) and incremental cost-effectiveness ratios (ICER; $ per DALY averted), routine CD4 monitoring proved to be “considerably more cost effective than additionally including routine viral load testing in the monitoring strategy and … more cost effective than ART” (
d6884). “With the intention to treat (ITT) results per 100 individuals starting ART, we found that clinical/CD4 monitoring compared with clinical monitoring alone increases costs by $20,458 (£12,780, 14,707 euros) and averts 117.3 DALYs (ICER=$174 per DALY). Clinical/CD4/viral load monitoring compared with clinical/CD4 monitoring adds $142,458, and averts 27.5 DALYs ($5,181 per DALY). The superior ICER for clinical/CD4 monitoring is robust to uncertainties in input values, and that strategy is dominant (less expensive and more effective) compared with clinical/CD4/viral load monitoring in one quarter of simulations. If clinical inputs are based on the as treated analysis starting at 90 days (after laboratory monitoring was initiated), then clinical/CD4/viral load monitoring is dominated by other strategies.” (J. G. Kahn, jgkahn@ucsf.edu)

>>>PNN JournalWatch
* Gray Matter Volume Abnormalities in ADHD: Voxel-Based Meta-Analysis Exploring the Effects of Age and Stimulant Medication, in American Journal of Psychiatry, 2011; 168: 1154–63. (T. Nakao)
* The Role of Phosphorus in the Development and Progression of Vascular Calcification, in
American Journal of Kidney Diseases, 2011; 58: 826–34. (J. Kendrick, jessica.kendrick@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 15, 2011 * Vol. 18, No. 221
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
Nov. 15 issue of the Annals of Internal Medicine (2011; 155).
INR Frequency in Warfarin Dosing: Patients on long-term warfarin therapy do just as well with INR testing every 12 weeks as with monthly assessments, report investigators who studied 226 patients for 12 months (pp. 653–9). Using a primary outcome of percentage of time in therapeutic range, the authors found these outcomes: “The percentage of time in the therapeutic range was 74.1% (SD, 18.8%) in the 4-week group compared with 71.6% (SD, 20.0%) in the 12-week group (absolute difference, 2.5 percentage points [1-sided 97.5% upper confidence bound, 7.3 percentage points]; noninferiority P = 0.020 for a 7.5–percentage point margin). Fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs. 55.6%; absolute difference, 18.5 percentage points [95% CI, 6.1 to 30.0 percentage points]; P = 0.004). Secondary outcomes did not differ between groups.” (S. Schulman, schulms@mcmaster.ca)
Discussing this and the below dabigatran study, editorialists note that these “patients have a 2% to 3% annual risk for stroke or systemic embolism, a nearly 5% risk for major bleeding, and a nearly 6% risk for death,” regardless of whether they are on warfarin or dabigatran 150 mg daily (
pp. 714–5). “Most patients with CHADS2 scores of 3 or higher are aged 75 years or older, the population in whom dabigatran was associated with a higher rate of major bleeding than warfarin,” the authors continue, adding, “Many patients who receive a stable dose of warfarin seem able to undergo assessment of warfarin dosing every 3 months. If less frequent INR monitoring can also safely keep patients within the therapeutic range of warfarin at least 70% of the time, warfarin may remain the preferred anticoagulant therapy, especially in patients aged 75 years or older or with CHADS2 scores of 3 or higher.” (C. S. Landefeld)
Outcomes in Patients with AF: Among 18,112 patients with atrial fibrillation who were receiving oral anticoagulants, higher CHADS2 score (1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke) were associated with increased risks for stroke or systemic embolism, bleeding, and death, researchers report (pp. 660–7). An analysis of data from the RE-LY trial showed the following: “Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS2 score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS2 scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P < 0.001 for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS2 score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS2 scores.” (J. Oldgren)

>>>Internal Medicine Report II
Source:
Nov. 14 issue of the Archives of Internal Medicine (2011; 171).
Lifestyle Modification, CV Risk Reduction & Erectile Dysfunction: Lifestyle modification and pharmacotherapy for cardiovascular (CV) risk factors improve sexual health and reduce erectile dysfunction, according to results of a systematic review and meta-analysis of 6 clinical trials of 740 men (pp. 1797–803). Randomized controlled trials of at least 6 weeks of lifestyle modification intervention or pharmacotherapy for CV risk factor reduction showed the following: “Lifestyle modifications and pharmacotherapy for CV risk factors were associated with statistically significant improvement in sexual function (IIEF-5 score): weighted mean difference, 2.66 (95% CI, 1.86–3.47). If the trials with statin intervention (n = 143) are excluded, the remaining 4 trials of lifestyle modification interventions (n = 597) demonstrate statistically significant improvement in sexual function: weighted mean difference, 2.40 (95% CI, 1.19–3.61).” (B. P. Gupta, gupta.bhanu@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 16, 2011 * Vol. 18, No. 222
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Nov. 16 issue of JAMA (2011; 306).
New-Onset Atrial Fibrillation in Severe Sepsis: Management strategies are needed to address underrecognized stroke and death secondary to new-onset atrial fibrillation (AF) in patients with severe sepsis, authors conclude (10.1001/jama.2011.1615). A retrospective population-based cohort study of California State Inpatient Database claims data from nonfederal acute care hospitals in 2007 showed the following for patients with ICD-9 codes for in-hospital ischemic stroke: “Patients with severe sepsis were a mean age of 69 (SD, 16) years and 48% were women. New-onset AF occurred in 5.9% of patients with severe sepsis vs 0.65% of patients without severe sepsis (multivariable-adjusted odds ratio [OR], 6.82; 95% CI, 6.54–7.11; P < .001). Severe sepsis was present in 14% of all new-onset AF in hospitalized adults. Compared with severe sepsis patients without new-onset AF, patients with new-onset AF during severe sepsis had greater risks of in-hospital stroke (75/2,896 [2.6%] vs 306/46,186 [0.6%] strokes; adjusted OR, 2.70; 95% CI, 2.05–3.57; P < .001) and in-hospital mortality (1629 [56%] vs 18 027 [39%] deaths; adjusted relative risk, 1.07; 95% CI, 1.04–1.11; P < .001).” (A. J. Walkey, alwalkey@bu.edu)
Editorialists add that, if these observational data are confirmed in another large cohort study, clinicians consider intervening “with the hope of preventing this complication, such as with acute cardioversion, anticoagulation, or both” (
10.1001/jama.2011.1730): “It is difficult to maintain successful cardioversion as long as severe sepsis persists, perhaps because acute risk factors such as high catecholamine states have not yet resolved. Anticoagulation presents additional risks for patients with severe sepsis due to coagulation abnormalities and frequent invasive procedures. Given the limitations of these observational data, current practice should not change in favor of interventions that could involve additional risk. Given the small event rate, a randomized trial of anticoagulation for new-onset atrial fibrillation in severe sepsis would be logically difficult. However, further observational studies with large databases assessing how interventions might modify the risk of stroke could provide more useful information.” (C. H. Goss, goss@u.washington.edu)
Evacetrapib for Dyslipidemia: The cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, used as monotherapy or in combination with statins, produced beneficial changes in lipid profiles without the increased mortality seen with the first agent in this class, torcetrapib (pp. 2099–109). The study included 398 patients with elevated LDL cholesterol or low HDL cholesterol levels. They received placebo; evacetrapib 30, 100, or 500 mg/d; or statin therapy with or without evacetrapib, with these results: “The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of −0.7 mg/dL (−3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of −20.5 to −51.4 mg/dL (−13.6% to −35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of −67.1 to −75.8 mg/dL (−11.2% to −13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed.” (S. J. Nicholls, nichols1@ccf.org)
Describing HDL cholesterol as the “Holy Grail” for cardiovascular researchers, an editorialist notes (
pp. 2153–5): “Further interventions await data from the large randomized trials of current therapies (eg, niacin) and emerging therapies like the CETP inhibitors, including dalcetrapib, anacetrapib, and, likely, evacetrapib. As such, the quest for the Holy Grail in coronary disease has many worthy knights on the trail.” (C. P. Cannon, cpcannon@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 17, 2011 * Vol. 18, No. 223
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 17 issue of the New England Journal of Medicine (2011; 365).
Malaria Vaccine in Children: In an ongoing Phase III trial, the candidate malaria vaccine RTS,S/AS01 provided protection against clinical and severe malaria among 15,460 children in seven African countries, researchers report (pp. 1863–75). Children in two initial age ranges, 6–12 weeks and 5–17 months, were assessed following three doses of the candidate or nonmalaria comparator vaccine: “In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6,000 children in the older age category was 0.32 episodes per person–year in the RTS,S/AS01 group and 0.55 episodes per person–year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1,000 doses (95% CI, 0.62 to 1.64).” (K. Mertes, kmertes@path.org)
An editorialist, lauding investigators who have worked to develop a vaccine for malaria, points to these potential benefits of “the control and elimination of malaria” (
pp. 1926–7): “In places where effective interventions (insecticide-treated bed nets, insecticides, and artemisinin-combination treatments) are being intensively deployed, malaria morbidity and mortality are falling. Several new, simple, affordable interventions, such as seasonal chemoprevention among young children in areas of seasonally high malaria transmission and the use of artesunate in patients with severe malaria, can also provide substantial reductions in mortality. The very low rate of death from malaria in this large trial (only 10 deaths directly attributed to malaria) testifies to the benefits of providing early diagnosis and effective antimalarial treatment. But there are real dangers ahead. How will the necessary funding be sustained in the face of a global economic downturn, along with a reduction in political pressure associated with declining mortality from malaria? In addition, artemisinin resistance in malaria parasites and pyrethroid resistance in anopheline mosquito vectors pose very serious threats.” (N. J. White)
Mycophenolate in Lupus Nephritis: In 227 patients with lupus nephritis, mycophenolate mofetil was superior to azathioprine for maintaining a renal response to treatment and preventing relapse, a study shows (pp. 1886–95). In the 36-month Phase III trial, mycophenolate reduced the time to treatment failure (hazard ratio, 0.44; 95% CI, 0.25–0.77; P = 0.003), time to renal flare and time to rescue therapy (HR < 1.00, P < 0.05), and rate of treatment failure (16.4% versus 32.4%), compared with azathioprine. Serious adverse effects occurred in 23.5% of those on mycophenolate and 33.3% of azathioprine patients (P = 0.11). (N. Solomons, neil.solomons@viforpharma.com)

>>>PNN NewsWatch
* The first drug specifically indicated for treatment of the rare disease myelofibrosis, ruxolitinib (Jakafi, Incyte) was approved yesterday by FDA. Ruxolitinib is also the first agent in a new class of monoclonal antibodies, the Janus kinase (JAK) inhibitors. Myelofibrosis is thought to develop as a result of dysregulated signaling in this pathway, leading to bone marrow failure, splenomegaly, and debilitating symptoms including fatigue, pruritus, night sweats, bone pain, and early satiety. In two clinical trials, ruxolitinib reduced spleen volume by 35% or more at 24 weeks in significantly more patients than did placebo (41.9% versus 0.7% in the COMFORT-1 trial; 28.5% versus 0% in the COMFORT-2 trial). The most common adverse reactions in the studies were thrombocytopenia and anemia. These events were manageable and rarely led to discontinuation of ruxolitinib treatment. The most common nonhematologic adverse reactions were bruising, dizziness, and headache.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 18, 2011 * Vol. 18, No. 224
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Nov. issue of Chest (2011; 140).
Short-Course Steroids in COPD Patients with RSV Infections: Viral load and shedding were unaffected when hospitalized patients with chronic obstructive pulmonary disease were treated with short-course steroids for acute respiratory syncytial virus (RSV) infections (pp. 1155–61). Serum assays and nasal secretion analysis at 2 days, 2 weeks, and 1 month showed: “Thirty-three of 50 (66%) patients hospitalized with RSV received systemic steroids for a mean duration of 11 days. Those who received steroids more frequently wheezed and were less often febrile. There were no serious adverse events related to steroids and no significant differences in peak viral load, duration of RSV shedding, nasal cytokines, or lymphocyte subsets in patients treated with steroids and patients untreated with steroids. Antibody responses to RSV were slightly blunted in the steroid-treated group.” (A. R. Falsey, ann.falsey@rochestergeneral.org)
Long-term Sildenafil in Pulmonary Arterial Hypertension: Generally positive outcomes are noted in a long-term study of 259 patients using sildenafil citrate for pulmonary arterial hypertension (PAH) (pp. 1274–83). An open-label extension of the 12-week SUPER-1 trial, the SUPER-2 study continued until the last patient had completed 3 years of sildenafil treatment. Patients were titrated to sildenafil 80 mg three times daily, with one dose reduction allowed for tolerability: “The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1–1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n = 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related.” (L. J. Rubin, ljrubin@ucsd.edu)

>>>Geriatrics Highlights
Source:
Nov. supplement on delirium to the Journal of the American Geriatrics Society (2011; 59).
Antipsychotics for Delirium in Older Hospitalized Adults: Evidence does not support use of antipsychotic agents for treating delirium in older hospitalized adults, authors of a systematic review conclude (pp. S269–76). Citing “severe methodological limitations in the studies, the writers note: “Of the comparison studies, five (71%) used randomization, but only one of these (a placebo-controlled study) used adequate allocation concealment methods, and only one other study (comparing two antipsychotics) described a double-blind method in detail. In the only placebo-controlled study (which was stopped early), no statistically significant differences in mean delirium severity scores were found at individual time points (Days 2, 3, 4, 7, 10). The other 12 studies reported improvements in delirium severity or resolution of delirium based on cutoff scores of the scales, but it is not clear from any of these studies what the natural course of delirium would have been without use of antipsychotics.” (J. Flaherty, Flaherty@slu.edu)
Anticholinergics & Incident Delirium: Prospective studies are needed to examine the relationship between use of anticholinergic medications and development of delirium in hospitalized older adults, authors report (pp. S277–81). An observational cohort study of 147 patients aged 65 or older with cognitive impairment had these outcomes during hospitalization: “Fifty-seven percent of the cohort received at least one order for possible anticholinergic medications, and 28% received at least one order for definite anticholinergic medications. The incident rate for delirium was 22% of the entire cohort.… The odds ratio (OR) for developing delirium in those with orders for possible anticholinergic medications was 0.33 (95% confidence interval (CI) = 0.10–1.03). The OR for developing delirium among those with orders for definite anticholinergic medications was 0.43 (95% CI = 0.11–1.63).” (N. L. Campbell, noll.campbell@wishard.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 21, 2011 * Vol. 18, No. 225
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 19 issue of Lancet (2011; 378).
Ocrelizumab in Multiple Sclerosis: Effects of a monoclonal antibody on relapsing–remitting multiple sclerosis support further investigation into the role of B lymphocytes in the disease, researchers report (pp. 1779–87). At 79 centers in 20 countries, patients aged 18–55 received placebo, a low or high dose of the humanized anti-CD20 agent ocrelizumab, or interferon beta-1a, with these effects on a primary endpoint of total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24: “218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68–97; p < 0.0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89–99; p < 0.0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3.0–4.4) patients in the placebo group, one of 55 (2%; 1.3–2.3) in the 600 mg ocrelizumab group, three of 55 (5%; 4.6–6.3) in the 2000 mg group, and two of 54 (4%; 3.0–4.4) in the interferon beta-1a group.” (L. Kappos, lkappos@uhbs.ch)
Community Case Management of Severe Pneumonia with Oral Amoxicillin: A study from Pakistan shows that community case management by lady health workers (LHWs) is feasible for children with severe pneumonia (pp. 1796–803). The approach can also reduce the time to treatment and costs for families and health systems, the investigators add, noting these results when LWHs administered a first dose of oral co-trimoxazole and mothers were provided with oral amoxicillin and instructions on its use in their children, aged 2–29 months: “We assigned 1,995 children to treatment in 14 intervention clusters and 1,477 in 14 control clusters, and we analysed 1,857 and 1,354 children, respectively. Cluster-adjusted treatment failure rates by day 6 were significantly reduced in the intervention clusters (165 [9%] vs 241 [18%], risk difference –8.9%, 95% CI –12.4 to –5.4). Further adjustment for baseline covariates made little difference (–7.3%, –10.1 to –4.5). Two deaths were reported in the control clusters and one in the intervention cluster. Most of the risk reduction was in the occurrence of fever and lower chest indrawing on day 3 (–6.7%, –10.0 to –3.3). Adverse events were diarrhoea (n = 4) and skin rash (n = 1) in the intervention clusters and diarrhoea (n = 3) in the control clusters.” (S, Sadruddinm, ssadruddin@savechildren.org)

>>>PNN NewsWatch
* FDA on Friday announced approval of two new drugs. Afilbercept (Eylea, Regeneron) is indicated for treating patients with neovascular (wet) age-related macular degeneration. Pivotal clinical studies of 2,412 adult patients showed afilbercept to be noninferior to ranbizumab, with maintenance of vision rates of about 95% in all treatment groups. Common adverse effects of the new drug include eye pain, conjunctival hemorrhage at injection sites, vitreous floaters, cataracts, and increased eye pressure. The second newly approved drug is asparaginase Erwinia chrysanthemi (Erwinaze, EUSA Pharma), an orphan drug approved for treatment of acute lymphocytic leukemia in children with hypersensitivity to Escherichia coli–derived asparaginase.

>>>PNN JournalWatch
* Phosphatidylinositol 3-Kinase and Antiestrogen Resistance in Breast Cancer, in Journal of Clinical Oncology, 2011; 29: 4452–61. (C. L. Arteaga, carlos.arteaga@vanderbilt.edu)
* Pilot Induction Regimen Incorporating Pharmacokinetically Guided Topotecan for Treatment of Newly Diagnosed High-Risk Neuroblastoma: A Children’s Oncology Group Study, in
Journal of Clinical Oncology, 2011; 29: 4351–7. (J. R. Park, julie.park@seattlechildrens.org)
* Response to Rituximab in Patients with Rheumatoid Arthritis in Different Compartments of the Immune System, in
Arthritis & Rheumatism, 2011; 63: 3187–94. (P. P. Tak, p.p.tak@amc.uva.nl)
* Toxicology in the ICU. Part 3: Natural Toxins, in
Chest, 2011; 140: 1357–70. (M. Levine, michael.levine@bannerhealth.com)
* Pharmacist-Provided Immunization Compensation and Recognition: White Paper Summarizing APhA/AMCP Stakeholder Meeting, in
Journal of the American Pharmacists Association, 2011; 51: 704–12. (M. C. Rothholz, mrothholz@aphanet.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 22, 2011 * Vol. 18, No. 226
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Nov. issue of Health Affairs, a theme issue on “Linking Community Development & Health” (2011; 30).
Health & Community Development Partnerships: Health organizations are beginning to address some of the root causes of poor health in low-income neighborhoods, including “lack of access to health care, limited food choices, and exposure to environmental hazards,” researchers report (pp. 2042–51): “The health sector has begun to collaborate with the community development sector, which for decades has been working in low-income neighborhoods. Encouraging local and national examples of these new partnerships abound. They include an effort in Seattle, Washington, to reduce exposure to allergens and irritants among low-income asthmatic children, and a $500 million federal program to finance the operation of grocery stores in what have previously been urban ‘food deserts.’ To nurture such efforts, the Robert Wood Johnson Foundation, the Federal Reserve System, and others have sponsored a series of ‘healthy community’ forums in US cities. In this article we explore the growing partnerships between the health and community development sectors as well as the challenges they face, and we offer policy recommendations that might help them succeed.” (S. Braunstein, sandy.braunstein@frb.gov)
Hatch–Waxman Revision Needed: Changes in pharmaceutical competition since the 1984 passage of the Hatch–Waxman Act raise “raises questions about whether the act’s intended balance of incentives for cost savings and continued innovation has been achieved,” authors write (pp. 2157–66): “Generic drug usage and challenges to brand-name drugs’ patents have increased markedly, resulting in greatly increased cost savings but also potentially reduced incentives for innovators. Congress should review whether Hatch–Waxman is achieving its intended purpose of balancing incentives for generics and innovation. It also should consider whether the law should be amended so that some of its provisions are brought more in line with recently enacted legislation governing approval of so-called biosimilars, or the corollary for biologics of generic competition for small-molecule drugs.” (H. G. Grabowski, grabow@econ.duke.edu)

>>>Medical Care Report
Source:
Dec. issue of Medical Care (2011; 49).
Quantifying Dangers in the Hospital: Just how dangerous is a day in the hospital? That question is posed and answered based on administrative hospital episode data for 206,489 medical inpatients at all public hospitals in the Australian state of Victoria (pp. 1068–75): “A hospital stay carries a 5.5% risk of an adverse drug reaction, 17.6% risk of infection, and 3.1% risk of ulcer for an average episode, and each additional night in hospital increases the risk by 0.5% for adverse drug reactions, 1.6% for infections, and 0.5% for ulcers. Length of stay is endogenous in models of adverse events, and risks would be underestimated if length of stay was treated as exogenous.” (K. Hauck)
Nursing Staffing/Education & Inpatient Deaths: Increasing percentages of nurses with baccalaureate degrees and decreasing patient-to-nurse ratios have positive effects on 30-day inpatient mortality rates and failure-to-rescue rates in average and high-performing hospitals, but only better education helps in facilities with poor work environments, a study shows (pp. 1047–53). Outcomes at 665 hospitals in four large states were assessed using hospital discharge abstracts for 1.2 million inpatients, a random sample of 39,038 hospital staff nurses, and data from the American Hospital Association: “The effect of decreasing workloads by 1 patient/nurse on deaths and failure-to-rescue is virtually nil in hospitals with poor work environments, but decreases the odds on both deaths and failures in hospitals with average environments by 4%, and in hospitals with the best environments by 9% and 10%, respectively. The effect of 10% more Bachelors of Science in Nursing Degree nurses decreases the odds on both outcomes in all hospitals, regardless of their work environment, by roughly 4%.” (L. H. Aiken)

>>>PNN NewsWatch
* Cuts in health programs are imminent following failure of the “super committee” to reach a budget-deficit deal, Kaiser Health News reports.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 23, 2011 * Vol. 18, No. 227
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and Nov. 23 issue of JAMA, a theme issue on cardiovascular disease (2011; 306).
Genetic Dosing of Clopidogrel: Patients who are carriers of one copy of the CYP2C19*2 loss-of-function gene have similar platelet reactivity to clopidogrel doses of 225 mg as noncarriers do to 75 mg, a study shows (10.1001/jama.2011.1703). For patients with two copies of the defective gene, doses up to 300 mg fail to reach similar levels of platelet reactivity, according to ELEVATE-TIMI data. The analysis included 333 patients, including 247 noncarriers of CYP2C19*2, 80 heterozygotes, and 6 homozygotes.
During four treatment periods of 14 days each, daily clopidogrel doses of 75 and 150 mg were given to noncarriers, and 75, 150, 225, and 330 mg were given to carriers, with these effects on platelet function tests (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y
12 assays) and adverse events: “With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% CI, 66.0%–74.0%, vs 57.5%; 95% CI, 55.1%–59.9%, and VerifyNow P2Y12 reaction units [PRU]: mean, 225.6; 95% CI, 207.7–243.4, vs 163.6; 95% CI, 154.4–173.9; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity, with VASP PRI decreasing to 48.9% (95% CI, 44.6%–53.2%) and PRU to 127.5 (95% CI, 109.9–145.2) (P < .001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (≥230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 or 300 mg (P < .001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85–0.99, and PRU, 0.94; 90% CI, 0.84–1.04). In CYP2C19*2 homozygotes, even with 300 mg daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%–91.6%) and mean PRU, 287.0 (95% CI, 170.2–403.8).” (J. L. Mega, jmega@partners.org)
“Normal” Systolic Blood Pressures & Recurrent Stroke: Very low, high, and very high systolic blood pressures (SBPs) within the normal range are associated with recurrent stroke in patients with recent noncardioembolic ischemic stroke, researchers report (pp. 2137–44). Post hoc observational analysis of a multicenter trial of 20,330 such patients with mean SBPs that were very low-normal (<120 mm Hg), low-normal (120–<130 mm Hg), high-normal (130–<140 mm Hg), high (140–<150 mm Hg), and very high (≥150 mm Hg) showed: “The recurrent stroke rates were 8.0% (95% CI, 6.8%–9.2%) for the very low-normal SBP level group, 7.2% (95% CI, 6.4%–8.0%) for the low-normal SBP group, 6.8% (95% CI, 6.1%–7.4%) for the high-normal SBP group, 8.7% (95% CI, 7.9%–9.5%) for the high SBP group, and 14.1% (95% CI, 13.0%–15.2%) for the very high SBP group. Compared with patients in the high-normal SBP group, the risk of the primary outcome was higher for patients in the very low-normal SBP group (adjusted hazard ratio [AHR], 1.29; 95% CI, 1.07–1.56), in the high SBP group (AHR, 1.23; 95% CI, 1.07–1.41), and in the very high SBP group (AHR, 2.08; 95% CI, 1.83–2.37). Compared with patients in the high-normal SBP group, the risk of secondary outcome was higher for patients in the very low-normal SBP group (AHR, 1.31; 95% CI, 1.13–1.52), in the low-normal SBP group (AHR, 1.16; 95% CI, 1.03–1.31), in the high SBP group (AHR, 1.24; 95% CI, 1.11–1.39), and in the very high SBP group (AHR, 1.94; 95% CI, 1.74–2.16).” (B. Ovbiagele, Ovibes@ucsd.edu)

>>>PNN NewsWatch
* More than one third of primary care providers have agreed to adopt electronic health records, pharmacist.com reports. At last week’s annual meeting of the Office of the National Coordinator for Health Information Technology, Farzad Mostashari, MD, ScM, ONC head, said that “100,000 primary care providers … have committed to adopting EHRs, including those in rural areas. He described funds to support Medicaid providers and training people for tens of thousands of job openings.”
*
PNN will not be published on Thurs. and Fri., Nov. 24–25, Thanksgiving.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 28, 2011 * Vol. 18, No. 228
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 24 issue of the New England Journal of Medicine (2011; 365).
Emergency Hospitalizations of Older Americans for Adverse Drug Events: Warfarin, insulins, and oral antiplatelet and hypoglycemic agents account for two thirds of drug-related emergency hospitalizations of older Americans, according to an analysis of data from the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance project in 2007–09 (pp. 2002–12). Medications considered high risk or inappropriate in criteria such those developed by Beers were infrequently implicated in emergency department visits by older adults, the investigators found, adding: “On the basis of 5,077 cases identified in our sample, there were an estimated 99,628 emergency hospitalizations (95% confidence interval [CI], 55,531 to 143,724) for adverse drug events in U.S. adults 65 years of age or older each year from 2007 through 2009. Nearly half of these hospitalizations were among adults 80 years of age or older (48.1%; 95% CI, 44.6 to 51.6). Nearly two thirds of hospitalizations were due to unintentional overdoses (65.7%; 95% CI, 60.1 to 71.3). Four medications or medication classes were implicated alone or in combination in 67.0% (95% CI, 60.0 to 74.1) of hospitalizations: warfarin (33.3%), insulins (13.9%), oral antiplatelet agents (13.3%), and oral hypoglycemic agents (10.7%). High-risk medications were implicated in only 1.2% (95% CI, 0.7 to 1.7) of hospitalizations.” (D. S. Budnitz, dbudnitz@cdc.gov)
Abciximab/Heparin Versus Bivalirudin for NSTEMI: Compared with bivalirudin in 1,721 patients with acute non–ST-segment elevation myocardial infarction, the combination of abciximab plus heparin failed to provide added clinical benefits and produced significantly more episodes of serious bleeding, researchers report (pp. 1980–9). Using a primary end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days, the investigators found: “The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P = 0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P = 0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P = 0.02).” (A. Kastrati, kastrati@dhm.mhn.de)

>>>PNN NewsWatch
* On Wednesday, FDA approved zolpidem tartrate sublingual tablets (Intermezzo, Transcept Pharmaceuticals) for treatment of insomnia characterized by middle-of-the-night awakenings followed by difficulty returning to sleep. This is the first FDA approval for this type of insomnia. In clinical trials of 370 people, sublingual zolpidem was significantly more effective than placebo for returning patients to sleep following such awakenings. The product label cautions patients not to use the drug if fewer than 4 hours remain until expected awakening.
* At
FDA’s request the Dept. of Justice on Wednesday filed a permanent injunction against ATF Fitness Products, Manufacturing ATF Dedicated Excellence (MADE), and the owner and operator of both companies, James G. Vercelotti of Oakmont, PA. FDA said the dietary supplement manufacturer failed to comply with current Good Manufacturing Practices by adulterating or misbranding final products and failing to report serious adverse events, including one patient who the agency said had a spike in blood pressure and mild heart attack after use of an ATF/MADE products.

>>>PNN JournalWatch
* Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing, in New England Journal of Medicine, 2011; 365: 1990–2001. (R. S. Zeiger, robert.s.zeiger@kp.org)
* Intensified Chemotherapy with ACVBP plus Rituximab Versus Standard CHOP plus Rituximab for the Treatment of Diffuse Large B-Cell Lymphoma (LNH03-2B): An Open-Label Randomised Phase 3 Trial, in
Lancet, 2011; 378: 1858–67. (H. Tilly, herve.tilly@rouen.fnclcc.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 29, 2011 * Vol. 18, No. 229
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 28 issue of the Archives of Internal Medicine (2011; 171).
Nicotine Therapy Sampling in Smoking Cessation: Provision of samples of nicotine lozenges significantly increased quit attempts among smokers who were otherwise unmotivated to stop tobacco use, researchers report (pp. 1901–7). In 849 patients in a nationwide randomized trial, a practice quit attempt (PQA) alone was compared with nicotine replacement therapy sampling of OTC lozenges within the context of a PQA, with these results: “Compared with PQA intervention, nicotine therapy sampling was associated with a significantly higher incidence of any quit attempt (49% vs 40%; relative risk [RR], 1.2; 95% CI, 1.1–1.4) and any 24-hour quit attempt (43% vs 34%; 1.3; 1.1–1.5). Nicotine therapy sampling was marginally more likely to promote floating abstinence (19% vs 15%; RR, 1.3; 95% CI, 1.0–1.7); 6-month point prevalence abstinence rates were no different between groups (16% vs 14%; 1.2; 0.9–1.6).” (M. J. Carpenter, carpente@musc.edu)
Chronic Disease Management for Tobacco Dependence: A 1-year, telephone-based intervention was significantly more effective than usual care in helping 443 patients stop smoking, according to a randomized controlled trial (pp. 1894–900). The telephone-based chronic disease management approach with 1 year of longitudinal care (LC) included 8 weeks of evidence-based treatment, repeated quit attempts, and interim smoking reduction for relapsers. It was compared with usual care (UC), which included one additional telephone call after an initial run-in phase when patients in both groups were contacted before quitting, 1–3 days after quitting, and at 1, 2, and 4 weeks after quitting. Results showed: “At 18 months, 30.2% of LC participants reported 6 months of abstinence from smoking, compared with 23.5% in UC (unadjusted, P = .13). Multivariate analysis showed that LC (adjusted odds ratio, 1.74; 95% CI, 1.08–2.80), quit attempts in past year (1.75; 1.06–2.89), baseline cigarettes per day (0.95; 0.92–0.99), and smoking in the 14- to 21-day interval post-quit (0.23; 0.14–0.38) predicted prolonged abstinence at 18 months. The LC participants who did not quit reduced smoking more than UC participants (significant only at 12 months). The LC participants received more counseling calls than UC participants (mean, 16.5 vs 5.8 calls; P < .001), longer total duration of counseling (283 vs 117 minutes; P < .001), and more nicotine replacement therapy (4.7 vs 2.4 boxes of patches; P < .001).” (A. M. Joseph, amjoseph@umn.edu)
Chronic disease management makes sense for tobacco-dependent patients, a commentator writes (
pp. 1907–9): “In a chronic disease management program tobacco addiction would be managed as one treats hypertension, hyperlipidemia, or diabetes mellitus. Chronic disease management programs for hypertension and diabetes have been accepted as effective and are used and supported by some insurance programs. Cigarette addiction is a chronic relapsing disorder, and a chronic disease management approach should also become the standard of care for its treatment. More research is needed to establish the cost vs benefit for such an approach, so that such treatment will be considered for funding by insurers who make coverage decisions based on cost-effectiveness.” (N. L. Benowitz, NBenowitz@MedSFGH.ucsf.edu)
Steroids During Ventilator-Supported COPD Therapy: Systemic corticosteroid therapy in 354 patients with chronic obstructive pulmonary disease significantly improved outcomes during exacerbations that required mechanical ventilation (pp. 1939–46). Increases were noted among intervention patients in both success of noninvasive mechanical ventilation and reduction in the duration of mechanical ventilation with IV methylprednisolone in declining doses over a 10-day period: “There were no significant differences between the groups in demographics, severity of illness, reasons for COPD exacerbation, gas exchange variables, and corticosteroid rescue treatment. Corticosteroid treatment was associated with a significant reduction in the median duration of mechanical ventilation (3 days vs 4 days; P = .04), a trend toward a shorter median length of ICU stay (6 days vs 7 days; P = .09), and significant reduction in the rate of [noninvasive] failure (0% vs 37%; P = .04).” (A. Esteban, aesteban@ucigetafe.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Nov. 30, 2011 * Vol. 18, No. 230
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 30 issue of JAMA (2011; 306).
Urinary Sodium/Potassium Excretion & Cardiovascular Risks: An assessment of urinary excretion patterns demonstrates a J-shaped curve for sodium in relation to cardiovascular (CV) events and an association of high potassium excretion with reduced stroke risk (pp. 2229–38). In cohorts of 28,880 people in the ONTARGET and TRANSCEND trials, a composite outcome of CV death, myocardial infarction (MI), stroke, and hospitalization for congestive heart failure (CHF) occurred in 4,729 (16.5%) of participants during the study period of 2001–08.
Based on estimated 24-hour urinary sodium and potassium excretion as determined from a pretrial morning fasting urine sample using the Kawasaki formula, the researchers determined: “Compared with the reference group with estimated baseline sodium excretion of 4 to 5.99 g per day (n = 14,156; 6.3% participants with CV death, 4.6% with MI, 4.2% with stroke, and 3.8% admitted to hospital with CHF), higher baseline sodium excretion was associated with an increased risk of CV death (9.7% for 7–8 g/day; hazard ratio [HR], 1.53; 95% CI, 1.26–1.86; and 11.2% for >8 g/day; HR, 1.66; 95% CI, 1.31–2.10), MI (6.8%; HR, 1.48; 95% CI, 1.11–1.98 for >8 g/day), stroke (6.6%; HR, 1.48; 95% CI, 1.09–2.01 for >8 g/day), and hospitalization for CHF (6.5%; HR, 1.51; 1.12–2.05 for >8 g/day). Lower sodium excretion was associated with an increased risk of CV death (8.6%; HR, 1.19; 95% CI, 1.02–1.39 for 2–2.99 g/day; 10.6%; HR, 1.37; 95% CI, 1.09–1.73 for <2 g/day), and hospitalization for CHF (5.2%; HR, 1.23; 95% CI, 1.01–1.49 for 2–2.99 g/day) on multivariable analysis. Compared with an estimated potassium excretion of less than 1.5 g per day (n = 2194; 6.2% with stroke), higher potassium excretion was associated with a reduced risk of stroke (4.7% [HR, 0.77; 95% CI, 0.63–0.94] for 1.5–1.99 g/day; 4.3% [HR, 0.73; 95% CI, 0.59–0.90] for 2–2.49 g/day; 3.9% [HR, 0.71; 95% CI, 0.56–0.91] for 2.5–3 g/day; and 3.5% [HR, 0.68; 95% CI, 0.49–0.92] for >3 g/day) on multivariable analysis.” (M. J. O’Donnell,
donnm@mcmaster.ca">odonnm@mcmaster.ca)
An editorialist notes that the identified curve is J rather than U shaped, minimizing the impact if patients overdo sodium restrictions in response to public health or provider messages (
pp. 2262–4): “Although the inverse relationship between urinary potassium excretion and stroke is consistent with many previous reports and meta-analyses, the possible causal relationship between urinary sodium excretion and CVD events would have to be probed more carefully, especially at the lower end of the J curve. Prior experience, such as in the context of body mass index, cholesterol levels, [blood pressure], alcohol intake, or other factors, suggests that preexisting disease is an important potential confounding factor that must be considered in the uptick in risk observed at the bottom end of a J-shaped curve. Moreover, the curve reported by O’Donnell et al is J-shaped rather than U-shaped, and as such, a relatively small proportion of study participants were in the sodium intake categories at the lower end of the curve (ie, only 3% in the group identified with urinary sodium excretion of <2 g/d and 29% in the 2–3.99 g/d group). The CVD risk among this group was far less than that among the groups in the longer end of the J-shaped curve with higher levels of urinary sodium excretion.” (P. K. Whelton, pkwhelton@gmail.com)
Prescription Drug Monitoring Programs for Limiting Opioid Abuse: State programs for monitoring prescribing of opioids reduce the number of prescriptions for these drugs, but that may not reduce associated deaths, writes a Commentary author (pp. 2258–9). “Whether prescription drug monitoring programs are associated with reduced opioid-related mortality is uncertain. Statistical modeling performed in 2006 by the Department of Justice found that drug monitoring programs are associated with reductions in the volume of Schedule II opioids in communities and suggested that this result should ‘reduce the probability of opioid abuse.’ In contrast, a 2011 analysis of US opioid analgesic–induced deaths including opioids from all Drug Enforcement Administration schedules found no statistical difference in opioid overdose mortality between states with and without prescription drug monitoring programs, concluding that these programs require significant modification to have an effect on mortality.” (H. M. Gugelmann, hallamg@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 1, 2011 * Vol. 18, No. 231
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 1 New England Journal of Medicine (2011; 365).
Intensive Statins & Progression of Coronary Disease: In a comparison of rosuvastatin and atorvastatin, maximum doses of the agents produced statistically similar levels of regression in coronary atherosclerosis, researchers report (pp. 2078–87). However, regression of a key indicator was noted despite achievement of LDL and HDL cholesterol levels in this study of 1,039 patients with coronary disease: “After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P < 0.001), and higher levels of … HDL cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P = 0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], −1.19 to −0.63) with atorvastatin and by 1.22% (95% CI, −1.52 to −0.90) with rosuvastatin (P = 0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: −6.39 mm3 (95% CI, −7.52 to −5.12), as compared with −4.42 mm3 (95% CI, −5.98 to −3.26) (P = 0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P = 0.07) and 64.7% and 71.3%, respectively, for TAV (P = 0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events.” (S. J. Nicholls, nichols1@ccf.org)
Prescription Drug Coverage of Preventive Drugs After MI: Despite no significant improvement in adherence, patients discharged after myocardial infarction had better outcomes with full coverage of preventive medications than with usual pharmacy benefits, according to the Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) trial (pp. 2088–97). Using block randomization at the plan-sponsor level, 2,845 patients were assigned to full prescription coverage, with no cost sharing for brand-name or generic statins, beta-blockers, ACE inhibitors, or angiotensin-receptor blockers. Compared with 3,010 patients with usual prescription coverage, full coverage yielded these results: “Rates of adherence ranged from 35.9 to 49.0% in the usual-coverage group and were 4 to 6 percentage points higher in the full-coverage group (P < 0.001 for all comparisons). There was no significant between-group difference in the primary outcome (17.6 per 100 person–years in the full-coverage group vs. 18.8 in the usual-coverage group; hazard ratio, 0.93; 95% confidence interval [CI], 0.82 to 1.04; P = 0.21). The rates of total major vascular events or revascularization were significantly reduced in the full-coverage group (21.5 vs. 23.3; hazard ratio, 0.89; 95% CI, 0.90 to 0.99; P = 0.03), as was the rate of the first major vascular event (11.0 vs. 12.8; hazard ratio, 0.86; 95% CI, 0.74 to 0.99; P = 0.03). The elimination of copayments did not increase total spending ($66,008 for the full-coverage group and $71,778 for the usual-coverage group; relative spending, 0.89; 95% CI, 0.50 to 1.56; P = 0.68). Patient costs were reduced for drugs and other services (relative spending, 0.74; 95% CI, 0.68 to 0.80; P < 0.001).” (N. K. Choudhry, nchoudhry@partners.org)
“Reducing or eliminating the costs of highly beneficial medicines is almost certainly one key component of increasing adherence, even if its absolute benefit is distressingly modest,” editorialists write (
pp. 2131–3). “More comprehensive insurance coverage also has appeal, but it is likely to raise the costs of care. For patients who have had a myocardial infarction, currently available generic formulations are already far less expensive than the average copayments faced by patients in the study by Choudhry et al. For example, generic statins cost $4 per month, as compared with their average copayment of $25 per month. Pharmaceutical companies should not expect that the elimination of copayments for costly proprietary preparations will be considered a sensible alternative when low-cost generics are available.” (L. Goldman)

>>>PNN NewsWatch
* Two generic atorvastatin products came onto the U.S. market yesterday. FDA approved Ranbaxy’s product for what is usually a 6-month exclusive period. But Pfizer apparently trumped that by authorizing Watson to produce a competing generic product using tablets supplied by the Lipitor manufacturer.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 2, 2011 * Vol. 18, No. 232
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. issue of Diabetes Care (2011; 34).
Kinetics/Dynamics of High-Dose Regular U-500 Insulin: In 24 healthy obese participants, high doses of human regular U-500 insulin (as used in patients with high levels of insulin resistance) had similar pharmacokinetics and pharmacodynamics as U-100 products (pp. 2496–501). Subcutaneous injections of the two products, tested in crossover fashion, revealed that U-500R had blunted peak concentrations and actions profiles and prolonged effects after peaks, the authors noted, adding these details from their euglycemic clamp study: “Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05).” (A. de la Peña, de_la_pena_amparo@lilly.com)
Lifestyle Interventions in Obese Pregnant Women: Gestational weight gain (GWG) can be limited through lifestyle interventions in women with obesity, a study shows, but the overall effect on obstetric outcomes is limited (pp. 2502–7). In the LiP (Lifestyle in Pregnancy) study, women with obesity and in early pregnancy were allocated to lifestyle intervention—which included dietary guidance, free membership in fitness centers, physical training, and personal coaching—or usual care, with these results: “A total of 360 obese pregnant women were included, and 304 (84%) were followed up until delivery. The intervention group had a significantly lower median (range) GWG compared with the control group of 7.0 (4.7–10.6) vs. 8.6 kg (5.7–11.5; P = 0.01). The Institute of Medicine (IOM) recommendations on GWG were exceeded in 35.4% of women in the intervention group compared with 46.6% in the control group (P = 0.058). Overall, the obstetric outcomes between the two groups were not significantly different.” (C. A. Vinter, c.vinter@dadlnet.dk)
Depressive Symptoms, Antidepressants, & Insulin Resistance: Depressive symptoms occur more commonly in patients with insulin resistance (IR), regardless of whether they have diabetes, but correction of IR has little effect on the depressive symptoms, according to a study of 4,419 patients who had oral glucose tolerance tests (OGTTs) (pp. 2545–7). Based on a homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR), self-reported depressive symptoms and antidepressant use showed these relationships: “After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations.” (K. Räikkönen, katri.raikkonen@helsinki.fi)

>>>PNN NewsWatch
* Products at a Wisconsin dietary supplements company were seized yesterday by federal marshals acting on an FDA request. Syntec Inc. has “claimed in videos and promotional materials that some of its products could be used to prevent, treat, or cure diseases such as asthma, cardiovascular disease, cataracts, glaucoma and infections,” the government alleges.
*
FDA yesterday issued draft guidance for investigators and manufacturers who are developing and seeking approval for artificial pancreas device systems. An artificial pancreas system combines an insulin pump and a continuous glucose monitor (CGM) that receives information on glucose levels from a sensor placed under the patient’s skin, FDA said. The guidance recommends a three-phase clinical study progression so that studies may move to an outpatient setting as quickly as possible. To further streamline clinical studies, the guidance suggests ways sponsors may leverage existing safety and effectiveness data for components that may make up an artificial pancreas system, as well as data gathered from non–U.S. clinical studies.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 5, 2011 * Vol. 18, No. 233
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from and Dec. 3 issue of Lancet (2011; 378).
Self-monitoring of Oral Anticoagulation: Self-monitoring and self-management of oral anticoagulation is “a safe option for suitable patients of all ages,” conclude authors of a systematic review and meta-analysis (10.1016/S0140-6736(11)61294-4). Using primary outcomes of time to death, first major hemorrhage, and first thromboembolic event to compare self-monitoring with clinic or primary care, the authors found these trends: “Of 1,357 abstracts, we included 11 trials with data for 6,417 participants and 12,800 person–years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0.51; 95% CI 0.31–0.85) but not for major haemorrhagic events (0.88, 0.74–1.06) or death (0.82, 0.62–1.09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0.33, 95% CI 0.17–0.66), as did participants with mechanical heart valve (0.52, 0.35–0.77). Analysis of major outcomes in the very elderly (age ≥85 years, n = 99) showed no significant adverse effects of the intervention for all outcomes.” (C. Heneghan, carl.heneghan@phc.ox.ac.uk)
Axitinib v. Sorafenib in Advanced Renal Cell Carcinoma: In 723 patients with advanced renal cell carcinoma, progression-free survival (PFS) was significantly longer with the second-generation agent axitinib, compared with sorafenib, an approved inhibitor of vascular endothelial growth factor (VEGF; pp. 1931–9): “The median PFS was 6.7 months with axitinib compared to 4.7 months with sorafenib (hazard ratio 0.665; 95% CI 0.544–0.812; one-sided p < 0.0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar–plantar erythrodysaesthesia, and alopecia in the sorafenib arm.” (B. I. Rini, rinib2@ccf.org)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 343).
Statins & Infections: Statins do not reduce the risk of infections, according to a systematic review and meta-analysis of 22 trials of 30,947 participants (d7281). The possibility that these agents might affect infection rates comes from their pleiotropic effects, specifically anti-inflammatory and immunomodulatory properties, the authors explained, adding these details from their study: “4,655 of the participants (2,368 assigned to statins and 2,287 assigned to placebo) reported an infection during treatment. Meta-analysis showed no effect of statins on the risk of infections (relative risk 1.00, 95% confidence interval 0.96 to 1.05) or on infection related deaths (0.97, 0.83 to 1.13).” (E. M. W. van de Garde, e.van.de.garde@antoniusziekenhuis.nl)
Intensive Glycemic Control in Type 2 Diabetes: The risk of severe hypoglycemia is increased by 30% in patients undergoing intensive glycemic control, according to a systematic review and meta-analysis of 14 trials of 28,614 participants (d6898). Benefits were unclear or equivocal overall: “The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P = 0.004; 28,111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P = 0.01; 25,600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P = 0.009; 10,793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27,769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27,844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia.” (B. Hemmingsen, bh@ctu.rh.dk)

>>>PNN JournalWatch
* Anticoagulation Patient Self-monitoring in the United States: Considerations for Clinical Practice Adoption, in Pharmacotherapy, 2011; 31: 1161–74. (E. A. Nutescu)
* Emerging Applications of Metabolomic and Genomic Profiling in Diabetic Clinical Medicine, in
Diabetes Care, 2011; 34: 2624–30. (A. M. McKillop, am.mckillop@ulster.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 6, 2011 * Vol. 18, No. 234
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 6 issue of the Annals of Internal Medicine (2011; 155).
Comparison of Second-Generation Antidepressants: Based on efficacy, no second-generation antidepressant can be recommended over any other for treatment of major depressive disorder (MDD), according to an updated meta-analysis (pp. 772–85). Onsets of action and side effects profiles differ among the agents, and this could inform medication selection, the authors write, adding these details from randomized trials of at least 6 weeks’ duration and observational harm studies with at least 1,000 participants: “Meta-analyses and mixed-treatment comparisons of response to treatment and weighted mean differences were conducted on specific scales to rate depression. On the basis of 234 studies, no clinically relevant differences in efficacy or effectiveness were detected for the treatment of acute, continuation, and maintenance phases of MDD. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions. Individual drugs differed in onset of action, adverse events, and some measures of health-related quality of life.”
These findings provide guidance to practitioners, the authors conclude: “Given the difficulty in predicting what medication will be both efficacious for and tolerated by an individual patient, familiarity with a broad spectrum of antidepressants is prudent. Existing evidence of efficacy, however, does not warrant choosing a particular second-generation antidepressant as first-line therapy for acute-phase MDD or as a subsequent treatment in patients who do not respond to therapy or experience remission. Because of differences in adverse events and dosing regimens, engaging in informed decision making can help physicians to take patient preferences into consideration.” (G. Gartlehner,
gerald.gartlehner@donau-uni.ac.at)
Immunogenicity of A/H1N1 Influenza Vaccine in Pregnancy: Strong immune responses in pregnant women and high levels of seroprotection in infants resulted from single doses of the 2009 pandemic influenza A/H1N1 vaccine, researchers report (pp. 733–41). At five perinatal centers in France, 107 pregnant women received 1 intramuscular dose of the vaccine between the 22nd and 32nd gestational weeks, with these results: “At baseline, 19% of the women had an antibody titer of 1:40 or greater. At day 21, 98% of the women had an antibody titer of 1:40 or greater, the seroconversion rate was 93%, and the fold increase in geometric mean titer was 67.4. At day 42, delivery, and 3 months after delivery, 98%, 92%, and 90% of the women, respectively, had an antibody titer of 1:40 or greater. Ninety-five percent of the cord serum samples obtained from 88 neonates showed an antibody titer of 1:40 or greater. The median neonate–mother antibody titer ratio was 1.4.” (O. Launay, dile.launay@cch.aphp.fr">odile.launay@cch.aphp.fr)
Prevalence of Knee Pain and Symptomatic Knee Osteoarthritis: Knee pain and symptomatic knee osteoarthritis has increased in prevalence significantly over the past 20 years among Americans, affecting both white and Hispanic men and women and black women, a study shows (pp. 725–32). According to data from the 6 NHANES (National Health and Nutrition Examination Survey) surveys between 1971 and 2004 and from 3 examination periods in the FOA (Framingham Osteoarthritis) Study between 1983 through 2005, these changes in prevalence explain observed increases in knee-replacement surgeries and a larger burden of knee pain among Americans: “Age- and BMI-adjusted prevalence of knee pain increased by about 65% in NHANES from 1974 to 1994 among non-Hispanic white and Mexican American men and women and among African American women. In the FOA Study, the age- and BMI-adjusted prevalence of knee pain and symptomatic knee osteoarthritis approximately doubled in women and tripled in men over 20 years. No such trend was observed in the prevalence of radiographic knee osteoarthritis in FOA Study participants. After age adjustment, additional adjustment for BMI resulted in a 10% to 25% decrease in the prevalence ratios for knee pain and symptomatic knee osteoarthritis.” (D. T. Felson)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 7, 2011 * Vol. 18, No. 235
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 7 issue of JAMA (2011; 306).
Antenatal Steroids & Infant Outcomes: Lower rates of death or neurodevelopmental impairment were observed at 18–22 months in infants born at 23–25 weeks’ gestation when their mothers had received corticosteroids for preterm labor, researchers report (pp. 2348–58). Children in the cohort study weighed 401–1000 g when they were born prematurely in 1993–2009. Based on mortality and neurodevelopmental impairment at 18–22 months’ corrected age, the researchers found these effects of antenatal exposure to corticosteroids: “Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks’ gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42–0.80]), at 24 weeks’ gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49–0.78]), and at 25 weeks’ gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50–0.74]) but not in those infants born at 22 weeks’ gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29–2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks’ gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks’ gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30–0.97]).” (W. A. Carlo, wcarlo@peds.uab.edu)
Androgen Deprivation in Prostate Cancer: In a meta-analysis of 8 randomized trials of 4,141 patients, use of androgen deprivation therapy (ADT) was associated with a lower risk of prostate cancer–specific mortality (PCSM) and all-cause mortality (pp. 2359–66). ADT was not linked to an increased risk of cardiovascular death, the authors stated: “Cardiovascular death in patients receiving ADT vs control was not significantly different (255/2,200 vs 252/1,941 events; incidence, 11.0%; 95% CI, 8.3%–14.5%; vs 11.2%; 95% CI, 8.3%–15.0%; RR, 0.93; 95% CI, 0.79–1.10; P = .41). ADT was not associated with excess cardiovascular death in trials of at least 3 years (long duration) of ADT (11.5%; 95% CI, 8.1%–16.0%; vs 11.5%; 95% CI, 7.5%–17.3%; RR, 0.91; 95% CI, 0.75–1.10; P = .34) or in trials of 6 months or less (short duration) of ADT (10.5%; 95% CI, 6.3%–17.0%; vs 10.3%; 95% CI, 8.2%–13.0%; RR, 1.00; 95% CI, 0.73–1.37; P = .99). Among 4,805 patients from 11 trials with overall death data, ADT was associated with lower PCSM (443/2,527 vs 552/2,278 events; 13.5%; 95% CI, 8.8%–20.3%; vs 22.1%; 95% CI, 15.1%–31.1%; RR, 0.69; 95% CI, 0.56–0.84; P < .001) and lower all-cause mortality (1,140/2,527 vs 1,213/2,278 events; 37.7%; 95% CI, 27.3%–49.4%; vs 44.4%; 95% CI, 32.5%–57.0%; RR, 0.86; 95% CI, 0.80–0.93; P < .001).” (P. L. Nguyen, pnguyen@LROC.harvard.edu)
Antiplatelet/Anticoagulation with GI Bleeding: Upper gastrointestinal bleeding during antiplatelet/anticoagulation therapy is reviewed within the context of the case of an 86-year-old woman (pp. 2367–74): “Bleeding in the upper gastrointestinal tract is a common medical problem, with an incidence of 48 to 160 cases per 1,000 adults per year and a mortality rate of 5% to 14%. The risk of gastrointestinal bleeding is increased with the use of antiplatelet medications including aspirin and clopidogrel, as well as warfarin or a combination of these medications. The recurrence rate for bleeding in patients who continue to take aspirin after an episode of peptic ulcer disease–related bleeding can reach up to 300 cases per 1,000 person–years and varies by age, sex, and the use of nonsteroidal anti-inflammatory medications.” (A. Barkun, alan.barkun@muhc.mcgill.ca)

>>>PNN NewsWatch
* REMS requirements, including the need to register with national programs, have been relaxed for romiplastin (Nplate, Amgen; and eltrombopag (Promacta, Glaxo-SmithKline), FDA said yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 8, 2011 * Vol. 18, No. 236
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 8 issue of the New England Journal of Medicine (2011; 365).
Short Rifapentine/Isoniazid Regimens for Latent Tuberculosis: In an open-label noninferiority trial, a 3-month regimen of directly observed rifapentine and isonizid was as effective as 9 months of self-administered isoniazid in patients at high risk for Mycobacterium tuberculosis infection (pp. 2155–66). Using a noninferiority margin of 0.75%, investigators found these results in patients from the U.S., Canada, Brazil, and Spain: “In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3,986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3,745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P < 0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P = 0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P < 0.001).” (T. R. Sterling, timothy.sterling@vanderbilt.edu)
Results of this trial, performed in countries with low incidences of tuberculosis, “suggest that isoniazid plus rifapentine is as good as the principal competing regimens—notably, 3 months of isoniazid plus rifampin or 4 months of rifampin monotherapy in places where the use of isoniazid is not recommended,” an editorialist writes (
pp. 2230–1). “However, a head-to-head comparison of these three options remains to be performed.” (C. Dye)
Apixaban v. Enoxaparin for Thromboprophylaxis: In 4,495 evaluable medically ill patients, posthospitalization extension of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin, researchers report (pp. 2167–77). Study participants were acutely ill patients with congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism; all were hospitalized with an expected stay of at least 3 days. They were randomized to oral apixaban 2.5 mg twice daily for 30 days or subcutaneous enoxaparin 40 mg once daily for 6–14 days. Using a primary efficacy outcome of the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis and a primary safety outcome of bleeding, the investigators found: “Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P = 0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3,184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3,217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P = 0.04).” (S. Z. Goldhaber, sgoldhaber@partners.org)

>>>PNN NewsWatch
* In a controversial decision that smacks of election-year politics, HHS Secretary Kathleen Sebelius overruled an FDA decision that would have permitted the emergency contraceptive product Plan B to be sold without a prescription to girls and women of any age. Plan B is currently available OTC to those aged 17 years or older. FDA, acting on an application from Plan B manufacturer Teva, was prepared to remove the age restrictions on OTC sales. The Secretary and FDA Commissioner Margaret Hamburg issued dueling news release explaining their positions. FDA officials told the New York Times that this is the first time in history that the HHS secretary has publicly overruled the scientists, physicians, and Commissioner at FDA.
* Seven warning letters have been issued by
FDA and FTC to companies marketing products labeled for homeopathic weight loss but containing human chorionic gonadotropin.
* Postmarketing reports of serious bleeding with
dabigatran etexilate mesylate (Pradaxa, Boehringer Ingelheim) have prompted FDA to look at whether these events are occurring more frequently than expected based on pivotal trial data. In a safety communication, FDA yesterday said that it believes the benefits of the drug continue to outweigh risks.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 9, 2011 * Vol. 18, No. 237
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Dec. 13/30 issue of the Journal of the American College of Cardiology (2011; 58).
Prediction of Cardiovascular Events After Stent Implantation: In a study of monitoring parameters for patients who have received drug-eluting stents (DESs) during percutaneous coronary interventions (PCIs), high on-treatment platelet reactivity (HTPR) on clopidogrel was not significantly associated with long-term atherothrombotic risks, but elevated C-reactive protein (CRP) was linked to worse outcomes and showed incremental predictive values over conventional risk factors (pp. 2630–9). HTPR was measured with post-PCI VerifyNow P2Y12 assays in 2,849 patients, 2,546 of whom also had CRP levels.
Using a primary endpoint of a composite of all-cause death, nonfatal myocardial infarction, stent thrombosis, and stroke, the investigators found: “During follow-up (median, 2.2 years), the occurrence of the primary endpoint did not significantly differ among patients with and without HTPR (2.8% vs. 2.4% at 2 years; hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 0.88 to 2.01; p = 0.18). By contrast, patients with elevated CRP levels were at significantly higher risk for the primary endpoint, as compared with those with nonelevated CRP levels (5.6% vs. 1.7% at 2 years; HR: 2.81, 95% CI:, 1.83 to 4.31; p < 0.001). The VerifyNow test had no incremental usefulness to classify long-term risk. However, the incorporation of CRP into a model with conventional clinical and procedural risk factors significantly improved the C-statistic for the prediction of the primary endpoint (0.729 to 0.759; p = 0.03).” (S-J Park,
sjpark@amc.seoul.kr)
Extreme Obesity & In-Hospital Outcomes in STEMI: Patients with extreme obesity—defined as body mass index (BMI) of 40 kg/sq m or more—who present with ST-segment elevation myocardial infarction (STEMI) have higher in-hospital mortality despite presence of less extensive coronary artery disease and better left ventricular systolic function, compared with patients of normal weight, researchers report (pp. 2642–50). Of 50,149 patients with STEMI whose information was included in the National Cardiovascular Data Registry (NCDR) ACTION Registry–GWTG, 5.1% were in the extreme obesity (class III) category, while 23.5% of patients had normal BMIs of 18.5–25 kg/ sq m, and their in-hospital experiences showed the following patterns: “Extreme obesity was associated with younger age at STEMI presentation (median age 55 years for class III obese vs. 66 years for normal weight); a higher prevalence of diabetes, hypertension, and dyslipidemia; a lower prevalence of smoking; and less extensive coronary artery disease and higher left ventricular ejection fraction. Process-of-care measures were similar across BMI categories, including the extremely obese. Using class I obesity as the referent, risk-adjusted in-hospital mortality rates were significantly higher only for class III obese patients (adjusted odds ratio: 1.64; 95% confidence interval: 1.32 to 2.03).” (S. R. Das, sandeep.das@utsouthwestern.edu)

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (2011; 31).
Dancing with Anticoagulation Care: Reflecting on numerous articles on anticoagulation management in this issue, an editorialist focuses on three areas of change (patient self-monitoring, novel oral anticoagulants, and pharmacogenomics) before providing this conclusion (pp. 1151–5): “Anticoagulation therapy with both warfarin and heparin were launched into this world at about the same time that I was, and progress over that interval has been limited and slow. Similarly, I have been slow to change the clinical tenets that I have held dear. But we now have new information technology capabilities, new pharmacologic agents, the evolving brave new world of pharmacogenomics, and opportunities for synergistic collaboration that have never existed before. After more than 50 years of limited change and progress, we are on the brink of a transformational change in anticoagulation and we should all work together to make sure that such change achieves as much progress as possible.
“The 20th century British philosopher, Alan Watts, once said, ‘The only way to make sense out of change is to plunge into it, move with it, and join the dance.’ Let’s all dance!” (Henry I. Bussey,
bussey@clotcare.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 12, 2011 * Vol. 18, No. 238
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 10 issue of Lancet (2011; 378).
Everolimus/Octreotide for Advanced Neuroendocrine Tumors: Progression-free survival was improved significantly among patients with advanced neuroendocrine tumors who were treated with everolimus plus octreotide, compared with octreotide alone, according to RADIANT-2 researchers (pp. 2005–12). In the Phase III trial, oral everolimus 10 mg/day produced these results when given with octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumors (carcinoid): “429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16.4 (95% CI 13.7–21.2) months in the everolimus plus octreotide LAR group and 11.3 (8.4–14.6) months in the placebo plus octreotide LAR group (hazard ratio 0.77, 95% CI 0.59–1.00; one-sided log-rank test p = 0.026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%).” (J. C. Yao, jyao@mdanderson.org)
Long-Term and Prolonged Benefits of Simvastatin Lowering of LDL Cholesterol: In 20,536 patients at high risk of vascular and nonvascular outcomes, lowering of LDL cholesterol with simvastatin 40 mg daily for a mean of 5.3 years produced benefits that persisted for at least 5 years after the Heart Protection Study ended, researchers report (pp. 2013–20). Further, benefits were enhanced with earlier therapy as well as more prolonged treatment. Based on a primary outcome of first postrandomization major vascular event, the investigators found: “During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1.0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19–28; p < 0.0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0.95 [0.89–1.02]) or vascular mortality (0.98 [0.90–1.07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0.98 [0.92–1.05]) or any particular site, or in mortality attributed to cancer (1.01 [0.92–1.11]) or to non-vascular causes (0.96 [0.89–1.03]).” (Heart Protection Study Collaborative Group, hps@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Bisphosphonates After Total Knee or Hip Arthroplasty: Implant survival time was almost doubled in patients who received bisphosphonates after total knee or hip arthroplasty in a population-based, retrospective cohort study in 1986–2006 (d7222): “Of 41,995 patients undergoing primary hip or knee arthroplasty, we identified 1,912 bisphosphonate users, who had a lower rate of revision at five years than non-users (0.93% (95% confidence interval 0.52% to 1.68%) v 1.96% (1.80% to 2.14%)). Implant survival was significantly longer in bisphosphonate users than in non-users in propensity adjusted models (hazard ratio 0.54 (0.29 to 0.99); P = 0.047) and had an almost twofold increase in time to revision after hip or knee arthroplasty (time ratio 1.96 (1.01 to 3.82)). Assuming 2% failure over five years, we estimated that the number to treat to avoid one revision was 107 for oral bisphosphonates.” (N. Arden, nigel.arden@ndorms.ox.ac.uk)

>>>PNN JournalWatch
* Biomaterials for the Treatment of Myocardial Infarction, in Journal of the American College of Cardiology, 2011; 58: 2615–29. (K. L. Christman, christman@bioeng.ucsd.edu)
*
Clostridium difficile in the ICU: The Struggle Continues, in Chest, 2011; 140: 1643–53. (L. D. Bobo, linda.bobo@sih.net)
* Implementing Medication Reconciliation in Outpatient Pediatrics, in
Pediatrics, 2011; 128: e1600–7. (D. I. Rappaport)
* Improving Reporting of Outpatient Pediatric Medical Errors, in
Pediatrics, 2011; 128: e1608–13. (D. R. Neuspiel)
* Positioning and Integrating Medication Therapy Management, in
Journal of the American Pharmacists Association, 2012; 52: e1–13. (J. S. Schommer, schom010@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 13, 2011 * Vol. 18, No. 239
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 12/26 Archives of Internal Medicine (2011; 171).
Behavioral Interventions & Patient Education in Diabetes: Three research studies and an editorial examine the effectiveness of patient-centered interventions when diabetes is poorly controlled.
For improving glycemia in adults with long-duration diabetes, a structured, cognitive behavioral program was more effective than educator-led attention control group education or unlimited individual nurse and dietitian education sessions for 6 months, a study shows (
pp. 1990–9). Included in the study were 222 adults, 49% of whom had type 1 diabetes, with a mean age of 53 years and a mean A1C level of 9.0%. Five sessions provided to those in the structured behavioral arm produced these results: “Linear mixed modeling found that all groups showed improved HbA1c levels (P < .001). However, the structured behavioral arm showed greater improvements than the group and individual control arms (3-month HbA1c concentration changes: –0.8% vs –0.4% and –0.4%, respectively (P = .04 for group X time interaction). Furthermore, participants with type 2 disease showed greater improvement than those with type 1 (P = .04 for type of diabetes x time interaction). Quality of life, glucose monitoring, and frequency of diabetes self-care did not differ by intervention over time.” (K. Weinger, Katie.Weinger@joslin.harvard.edu)
In 623 adults with type 2 diabetes and A1C levels above 7.0%, individual education was more effective than group education using U.S. Diabetes Conversation Maps, and there was a trend toward better psychosocial and behavioral outcomes with individual education, researchers report (
pp. 2001–10). Compared with usual care (UC), interventions produced these outcomes in 2008–09: “Mean HbA1c concentration decreased in all groups but significantly more with individual (–0.51%) than group education (–0.27%) (P = .01) and UC (–0.24%) (P = .01). The proportion of subjects with follow-up HbA1c concentration lower than 7% was greater for individual education (21.2%) than for group (13.9%) and UC (12.8%) (P = .03). Compared with UC, individual education (but not group) improved SF-12 physical component score (+1.88) (P = .04), [physical activity] (+42.95 min/wk) (P = .03), and [Recommended Food Score] (+0.63) (P = .05). Compared with group education, individual education reduced [Problem Areas in Diabetes scores] (–3.62) (P = .02) and increased self-efficacy (+0.1) (P = .04).” (J. Sperl–Hillen, joann.m.sperlhillen@healthpartners.com)
Behavioral support using a 24-min video and 5 sessions of telephone coaching failed to improve outcomes in 201 patients with poorly controlled type 2 diabetes (
pp. 2011–7). Study participants had annual incomes of less than $15,000 and were racially diverse (72% black or Latino). Coaching was provided by a trained diabetes nurse, and participants also received a 20-page brochure, with these results: “Most participants in both groups (94%) reviewed the intervention provided, and 73% of participants assigned to the experimental group completed 5 sessions of telephone coaching. There was a significant overall reduction in mean (SD) hemoglobin A1c value from baseline (9.6% [2.0%]) to 6 months (9.1% [1.9%]) (P < .001), but differences between groups were nonsignificant. Differences on other clinical measures (lipid levels and blood pressure) and measures of diabetes knowledge and self-care behaviors were also nonsignificant.” (D. L. Frosch, froschd@pamfri.org)
Editorialists point to factors that might have improved results in these studies (
pp. 1999–2000). “How can these interventions make it easier to eat better, exercise more, and take medications regularly? Some examples that can be aided or enabled with counseling are scheduling appointments for preventive care or screening services, medication reconciliation or intensification, and physical activity action plans that are developed over time with patients to adjust to the environmental context for patients. Motivational interviewing helps patients identify barriers and solutions, but its success depends heavily on the behavior and the ability of the counselor to identify resources with the patient that are accessible and appealing. Other instrumental barriers, such as food insecurity and access, built environment, social chaos, competing priorities, and severe comorbidities, may overcome these enabling factors if they are only focused at the individual level.” (R. Gonzales, ralphg@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 14, 2011 * Vol. 18, No. 240
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 14 issue of JAMA (2011; 306).
ADHD Meds & Cardiovascular Events in Adults: Use of medications for attention-deficit/hyperactivity disorder is not associated with an increased risk of serious cardiovascular events in young or middle-aged adults, researchers report (10.1001/jama.2011.1830). Using data from 1986 to 2005 and additional survey data from 2007, investigators determined these patterns of myocardial infarction (MI), sudden cardiac death (SCD), or stroke in patients aged 25–64 years in four systems (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network): “During 806,182 person–years of follow-up (median, 1.3 years per person), 1,357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person–years of current use (median, 0.33 years), with a crude incidence per 1,000 person–years of 1.34 (95% CI, 1.14–1.57) for MI, 0.30 (95% CI, 0.20–0.42) for SCD, and 0.56 (95% CI, 0.43–0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72–0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63–0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86–1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82–1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1,000 person–years at ages 25–44 years and 0.77 events per 1,000 person–years at ages 45–64 years.” (L. A. Habel, laurel.habel@kp.org)
These results provide “heartening news,” writes an editorialist (
10.1001/jama.2011.1866): “The importance of this study is apparent when viewed in light of recent events. The most commonly used ADHD medications—psychostimulants and atomoxetine—may increase blood pressure and heart rate, which some studies have linked with serious cardiovascular events. These concerns received glaring attention in 2006, when a US Food and Drug Administration advisory committee proposed placing a black box warning concerning sudden death on psychostimulants in response to adverse event reports. Shortly thereafter, 1 class of psychostimulant (mixed amphetamine salts) was briefly withdrawn in Canada, and the American College of Cardiology recommended considering routine electrocardiograms prior to starting use of psychostimulants in children. Subsequent epidemiologic studies quantifying this risk generally did not support an association, but the concerns have lingered.” (P. Shaw, shawp@mail.nih.gov)
Despite these and other recently published data (see PNN, Nov. 3),
FDA said yesterday that its recommendations on ADHD drugs have not changed. The agency continues to monitor emerging evidence, it added.
Consumer Preferences in Health Care: “Medications and surgical procedures are preferred over clinical strategies that involve behavioral changes (eg, diet or smoking cessation) or exercise regimens,” writes the author of a Commentary article that describes “what patients really want from health care” (pp. 2500–1). Noting that in 2012 “perhaps the most widely scrutinized sector of the economy in North America will be the health care industry,” the writer reaches this conclusion: “Policy makers in the United States and Canada have serious concerns about the sustainability of the health care sector, especially the part funded by tax revenues. However, predictions that the health care sector will overwhelm the entire economy are likely overstated. Health care is perhaps society’s most valued service. Patients want to know that over time their chances of being restored to good health when ill are continuously improving. As a result, consumers understand that they are going to have to devote more resources to health care. Preferences for immediate care and elimination of uncertainty make excess capacity and waste tolerable to the public. It may be more rational to spend resources on interventions that are of more value, like efforts to combat obesity, but most of the public cares more about treating illness. Changing attitudes about priorities would require a public health strategy, much like the efforts to make smoking or putting children at risk while playing sports socially unacceptable.” (A. S. Detsky, adetsky@mtsinai.on.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 15, 2011 * Vol. 18, No. 241
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 15 issue of the New England Journal of Medicine (2011; 365).
Niacin plus Statins for Low HDL Cholesterol: Added to intensive statin therapy in patients with atherosclerotic disease and LDL cholesterol levels below 70 mg/dL, niacin provided no additional benefit despite raising HDL cholesterol and lowering triglyceride levels, according to the AIM-HIGH study (pp. 2255–67). Extended-release niacin 1500–2000 mg/day or placebo was added to simvastatin 40–80 mg/day plus if-needed ezetimibe 10 mg/day, with these results: “A total of 3,414 patients were randomly assigned to receive niacin (1,718) or placebo (1,696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P = 0.79 by the log-rank test).” (R. McBride, ruthm@axioresearch.com)
After 56 years of niacin research and use for hypercholesterolemia, is it time for an early retirement? An editorialist poses that question and provides this response (
pp. 2318–20): “The disappointing results of AIM-HIGH do not provide support for the use of niacin as an add-on therapy to statins in patients with preexisting stable cardiovascular disease who have well-controlled LDL cholesterol levels. Given the lack of efficacy shown in this trial, the frequent occurrence of flushing with niacin therapy that some patients find intolerable, and the unresolved question of an increased risk of ischemic stroke, one can hardly justify the continued expenditure of nearly $800 million per year in the United States for branded extended-release niacin. However, before holding a final retirement party for niacin, it would appear to be more prudent to assign it to occasional part-time work, such as in statin-intolerant patients …, while we await the results from the much larger Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events trial…, which is targeted to be completed in 2013. Regardless of whether niacin is ultimately retired or not, one should not abandon the HDL-raising hypothesis altogether. Several ongoing studies with other promising drugs that raise HDL cholesterol levels substantially (by as much as 150%) by means of different mechanisms, and that in some cases can lower LDL cholesterol levels by as much as 40%, are well under way.” (R. P. Giugliano)
Dronedarone in High-Risk Permanent Atrial Fibrillation: Dronedarone should not be used in patients with permanent atrial fibrillation who are at high risk of vascular events, conclude investigators in the PALLAS trial (pp. 2268–76). Compared with placebo, the drug increased rates of heart failure, stroke, and death in study participants, who were 65 years or older with at least a 6-month history of permanent atrial fibrillation and had risk factors for major vascular events: “After the enrollment of 3,236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P = 0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P = 0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P = 0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P = 0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P = 0.02).” (S. J. Connolly, connostu@phri.ca)

>>>PNN NewsWatch
* Eugene V. White, the Berryville, VA, pharmacist credited with the first incorporation of patient profiles into community pharmacy practice, died on Dec. 9, pharmacist.com and the Washington Post 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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 16, 2011 * Vol. 18, No. 242
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Dec. issue of the Journal of Allergy and Clinical Immunology (2011; 128).
Biomarketer for Carbamazepine Sensitivity: Certain T-cell receptors (TCRs) are critical in recognition of small drug/peptide–HLA complexes, and these play a role in development of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) following exposure to carbamazepine (CBZ), researchers report (pp. 1266–76.e11). These findings explain “why some HLA-B*1502 carriers are tolerant to CBZ and [provide] a biomarker profile for drug hypersensitivity,” the authors add. The data come from analysis of peripheral blood mononuclear cells (PBMCs) and cultured CBZ-specific T-cells from patients with CBZ-SJS/TEN, tolerant control patients, and healthy subjects: “On drug stimulation, CBZ-specific CD8+ T cells were expanded in vitro and activated to release granulysin. Notably, VB-11-ISGSY was identified as the most predominant clonotype and shared among different subjects. This clonotype was present in 16 (84%) of 19 patients with SJS/TEN, absent in all 17 tolerant patients, and present at a low frequency in healthy subjects (4/29 [14%]). CBZ-specific cytotoxicity could be primed in vitro in the PBMCs of healthy subjects who are carriers of HLA-B*1502 and VB-11-ISGSY; this cytotoxicity could be blocked by an anti–TCR-VB-11 antibody. Furthermore, a single T-cell clone expressing VA-22-FISGTY/VB-11-ISGSY showed significant cytotoxicity against HLA-B*1502–positive antigen-presenting cells and CBZ.” (T. Chen, chen0010@ibms.sinica.edu.tw)
A Century of Antihistamines: Reflecting on a “century of progress” in research into the role of histamine in disease processes and 70 years of clinical use of antihistamines, authors provide these insights into future developments in research on these compounds (pp. 1139–50.e4): “We discuss histamine and clinically relevant information about the molecular mechanisms of action of H1-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)–generation H1-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)–generation H1-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H1-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H1-antihistamines for chronic urticaria treatment. New H1-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H3-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H4-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.” (F. E. R. Simons, lmcniven@hsc.mb.ca)

>>>PNN NewsWatch
* While not changing its advice that depression in pregnant women be treated when the risk–benefit analysis justifies it, FDA has updated a 2006 warning about the potential risk of persistent pulmonary hypertension of the newborn in babies born to mothers who took SSRIs during pregnancy. Since publication of a single study preceding a July 2006 FDA warning, conflicting results have been published, the agency said. It is “unclear whether use of SSRIs during pregnancy can cause PPHN,” FDA said.
*
FDA has reversed a recommendation made in June regarding maximum doses of simvastatin in patients taking amiodarone. FDA now says that the maximum dose is again 20 mg per day in this situation. The agency had lowered the maximum simvastatin daily dose in all patients from 80 mg to 40 mg in June, and it said that it proportionally lowered other recommended doses at that time. It has reconsidered this decision with regard to amiodarone, leading to the reversal.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 19, 2011 * Vol. 18, No. 243
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 17 issue of Lancet (2011; 378).
Aspirin & Hereditary Colorectal Cancer Risk: In a randomized controlled trial, aspirin in daily doses of 600 mg for a mean of 25 months significantly reduced cancer incidence after a mean of 55.7 months in patients who were carriers of Lynch syndrome, the major form of hereditary colorectal cancer (pp. 2081–7). The CAPP2 trials used a 2 X 2 factorial design to test the effects of aspirin, which has previously been studied mostly in observational trials. Randomization in blocks of 16 patients to aspirin or resistant starch 30 g for up to 4 years showed these outcomes: “At a mean follow-up of 55.7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0.63 (95% CI 0.35–1.13, p = 0.12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0.56 (95% CI 0.32–0.99, p = 0.05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0.41 (0.19–0.86, p = 0.02) and an IRR of 0.37 (0.18–0.78, p = 0.008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups.” (J. Burn, john.burn@ncl.ac.uk)
Vaginal Prostaglandin E2 Gel for Labor Induction: In women at term whose cervix was not opening sufficiently for delivery, use of a Foley catheter for mechanical intervention was just as effective as application of vaginal prostaglandin E2 gel and produced fewer maternal and neonatal adverse effects, researchers report (pp. 2095–103). At 12 Dutch hospitals, open-label randomization to gel or catheter produced these results in 824women with singleton pregnancies in cephalic presentation, intact membranes, an unfavorable cervix, an indication for induction of labor, and no prior cesarean section: “Caesarean section rates were much the same between the two groups (23% vs 20%, risk ratio [RR] 1.13, 95% CI 0.87–1.47). A meta-analysis including our trial data confirmed that a Foley catheter did not reduce caesarean section rates. We recorded two serious maternal adverse events, both in the prostaglandin group: one uterine perforation and one uterine rupture.” (K. W. M. Bloemenkamp, k.w.m.bloemenkamp@lumc.nl)
Anemia in Low- and Middle-Income Countries: Focusing on resource-challenged countries, authors of a review article make these observations about the causes and potential treatments for anemia (pp. 2123–35): “Anaemia affects a quarter of the global population, including 293 million (47%) children younger than 5 years and 468 million (30%) non-pregnant women. In addition to anaemia’s adverse health consequences, the economic effect of anaemia on human capital results in the loss of billions of dollars annually.… Our analysis shows that anaemia is disproportionately concentrated in low socioeconomic groups, and that maternal anaemia is strongly associated with child anaemia. Anaemia has multifactorial causes involving complex interaction between nutrition, infectious diseases, and other factors, and this complexity presents a challenge to effectively address the population determinants of anaemia. Reduction of knowledge gaps in research and policy and improvement of the implementation of effective population-level strategies will help to alleviate the anaemia burden in low-resource settings.” (S.V. Subramanian, svsubram@hsph.harvard.edu)

>>>PNN JournalWatch
* Antidepressant Clinical Trials and Subject Recruitment: Just Who Are Symptomatic Volunteers?, in
American Journal of Psychiatry, 2011; 168: 1245–7. (B. Brody)
* Cancer Immunotherapy Comes of Age, in
Journal of Clinical Oncology, 2011; 29: 4828–36. (S. L. Topalian, stopali1@jhmi.edu)
* Asthma Exacerbations: Origin, Effect, and Prevention, in
Journal of Allergy and Clinical Immunology, 2011; 1258: 1165–74. (S. L. Johnston, s.johnston@imperial.ac.uk)
* Risk-Sharing Arrangements That Link Payment for Drugs to Health Outcomes Are Proving Hard to Implement, in
Health Affairs, 2011; 30: 2329–37. (P. J. Neumann, pneumann@tuftsmedicalcenter.org)
* The Use and Misuse of Thrombolytic Therapy Within the Veterans Health Administration, in
Medical Care, 2012; 50: 66–73. (S. Keyhani)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 20, 2011 * Vol. 18, No. 244
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 20 issue of the Annals of Internal Medicine (2011; 155).
Vitamin D & Cardiovascular Disease: Nonhormonal actions of vitamin D are reviewed within the cardiovascular context (pp. 820–6): “Vitamin D deficiency has been linked with hypertension, myocardial infarction, and stroke, as well as other cardiovascular-related diseases, such as diabetes, congestive heart failure, peripheral vascular disease, atherosclerosis, and endothelial dysfunction.
“This review discusses the physiology and definition of vitamin D deficiency, evaluates the worldwide prevalence of vitamin D deficiency, and discusses recent evidence for the association between hypovitaminosis D and cardiovascular disease. Few randomized, controlled trials have evaluated the effect of vitamin D replacement on cardiovascular outcomes, and the results have been inconclusive or contradictory. Carefully designed randomized, controlled trials are essential to evaluate the role of vitamin D supplementation in reducing cardiovascular disease.” (C. McGreevy)
Vitamin D for Prevention of Cancer and Fractures: Evidence for efficacy of vitamin D and calcium supplementation is strong for prevention of fractures, but supplementation with the vitamin for prevention of cancer is “not sufficiently robust to draw conclusions regarding the benefits or harms,” researchers report (pp. 827–38). An updated meta-analysis conducted for the U.S. Preventive Services Task Force shows the following: “19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose–response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose–response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones.” (M. Chung)
Comparative Effectiveness of Treatments of C. difficile: No specific antimicrobial agent is “clearly superior” for initial cure of infections of Clostridium difficile, according to results of a comparative effectiveness review, but fidaxomicin proved better than vancomycin for prevention of recurrence (pp. 839–47). Based on 11 trials with 1,463 participants, the researchers found: “Three trials compared metronidazole with vancomycin; 8 compared metronidazole or vancomycin with another agent, combined agents, or placebo. Strain was analyzed in 1 trial and 2 cohort studies. No study comparing 2 antimicrobial agents demonstrated a statistically significant difference for initial cure; all comparisons were of low to moderate strength of evidence. Moderate-strength evidence from 1 study demonstrated that recurrence was decreased with fidaxomicin versus vancomycin (15% vs. 25%; difference, −10 percentage points [95% CI, −17 to −3 percentage points]; P = 0.005). Subgroup analysis of a single study comparing metronidazole with vancomycin for patients who have severe C. difficile infection showed no difference by intention-to-treat analysis; this was rated as insufficient-strength evidence. Harms, when reported, did not differ between treatments in any study.” (D. M. Drekonja)

>>>PNN NewsWatch
* Dronedarone (Multaq, Sanofi Aventis) should not be used in patients with permanent atrial fibrillation, FDA said yesterday. Product labeling has been revised to warn of a doubled rate of cardiovascular death, stroke, and heart failure in patients with AF who cannot or will not be converted into normal sinus rhythm. Patients on the drug should be monitored quarterly for abnormal sinus rhythms, FDA said, and cardioverted if clinically indicated.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 21, 2011 * Vol. 18, No. 245
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Dec. 21 issue of JAMA (2011; 306).
Chlorthalidone, Systolic Hypertension, & Survival: In older patients with systolic hypertension, chlorthalidone-based stepped-care therapy for 4.5 years significantly lowered mortality after 22 years of follow-up, according to an analysis of data from the Systolic Hypertension in the Elderly Program (SHEP) trial (pp. 2588–93). Participants in the 1985–90 study were advised to continue active therapy at completion of the trial. Using National Death Index data through the end of 2006, researchers found these patterns in all-cause and cardiovascular-related mortality: “At the 22-year follow-up, life expectancy gain, expressed as the area between active (n = 2,365) and placebo (n = 2,371) survival curves, was 105 days (95% CI, −39 to 242; P = .07) for all-cause mortality and 158 days (95% CI, 36–287; P = .009) for cardiovascular death. Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy. The active treatment group had higher survival free from cardiovascular death vs the placebo group (hazard ratio [HR], 0.89; 95% CI, 0.80–0.99; P = .03) but similar survival for all-cause mortality (HR, 0.97; 95% CI, 0.90–1.04; P = .42). There were 1,416 deaths (59.9%) in the active treatment group and 1,435 deaths (60.5%) in the placebo group (log-rank P = .38, Wilcoxon P = .24). Cardiovascular death was lower in the active treatment group (669 deaths [28.3%]) vs the placebo group (735 deaths [31.0%]; log-rank P = .03, Wilcoxon P = .02). Time to 70th percentile survival was 0.56 years (95% CI, −0.14 to 1.23) longer in the active treatment group vs the placebo group (11.53 vs 10.98 years; P = .03) for all-cause mortality and 1.41 years (95% CI, 0.34–2.61; 17.81 vs 16.39 years; P = .01) for survival free from cardiovascular death.” (J. B. Kostis, kostis@umdnj.edu)
Pharmacy Access to Adolescent Emergency Contraception: In a study of U.S. pharmacies located in 5 large U.S. cities, 19% of “teenagers” were told they could not purchase emergency contraception under any circumstance (10.1001/jama.2011.1949). Such responses occurred more often in low-income areas, researchers report, adding these details about telephone inquiries during 2010 by female research assistants posing as adolescents who had recently had unprotected intercourse: “The availability of emergency contraception did not differ based on neighborhood income. However, in 19% (n = 138) of calls, the adolescent was told she could not obtain emergency contraception under any circumstance. This misinformation occurred more often (23.7% vs 14.6%) among pharmacies in low-income neighborhoods (adjusted odds ratio [AOR], 1.93; 95% CI, 1.53–2.43). When callers queried the age threshold for over-the-counter access, they were given the correct age less often by pharmacies in low-income neighborhoods (50.0% vs 62.8%; AOR, 0.59 [95% CI, 0.45–0.79]). In all but 11 calls, the incorrect age was stated as erroneously too high, potentially restricting access. Adjusting analyses for pharmacy chain as a fixed effect yielded virtually identical results.” (T. A. Wilkinson, tracey.wilkinson@bmc.org)
In a viewpoint article, a writer is critical of the Dec. 7 decision by HHS Secretary Kathleen Sebelius to overrule an FDA decision permitting nonprescription access to Teva’s Plan B emergency contraceptive product (
10.1001/jama.2011.1957). After noting Pres. Obama’s promise in his Jan. 2009 inaugural address to “return science to its rightful place” in government, the author writes that the Plan B decision renews “concerns about the relation between science and politics in the federal government, regardless of the party in office”: “As the presidential election of November 2012 approaches, it is perhaps not surprising that HHS Secretary Sebelius and President Obama are now part of the continuing saga of over-the-counter emergency contraception in the United States. Teva Women’s Health is determining its next steps in responding to Secretary Sebelius’s decision. The decision has set an unfortunate precedent. The controversies about Plan B One-Step and the intrusion of science into politics in the federal government will continue.” (R. Steinbrook, rsteinbrook@attglobal.net)

>>>PNN NewsWatch
* FDA launched a safety evaluation after a report of death in a patient less than 24 hours after a first dose of fingolimod (Gilenya, Novartis).

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 22, 2011 * Vol. 18, No. 246
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 22 New England Journal of Medicine (2011; 365).
Gene Therapy for Hemophilia B: Transfer of a Factor IX (FIX) gene into patients with hemophilia B reduced bleeding with few adverse effects, researchers report (pp. 2357–65). The primary concern that arose during the trial was an immune-mediated clearance of adenovirus-associated virus (AAV)–transduced hepatocytes, but that can be controlled with a short course of glucocorticoids without loss of gene expression, the investigators wrote.
Six patients with severe hemophilia B received a single peripheral infusion of high, intermediate, or low doses of serotype-8–pseudotyped, self-complementary AAV vector expressing a codon-optimized human FIX transgene (scAAV2/8-LP1-hFIXco), with these results: “AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values.” (A. C. Nathwani,
a.nathwani@ucl.ac.uk)
It’s a “merry Christmas” for patients with hemophilia B—named Christmas disease after the 10-year-old boy in whom the disease was first reported—writes an editorialist, adding (
pp. 2424–5): “This gene therapy trial with an [AAV] vector for hemophilia B is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels. If further studies determine that this approach is safe, it may replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B. This technology may soon translate into applications for other disorders, such as lysosomal storage diseases, alpha1-antitrypsin deficiency, and hyperlipidemias.” (K. P. Ponder)
Kidney Function with Intensive Diabetes Therapy: In 1,375 patients with type 1 diabetes, long-term risk of impaired glomerular filtration rates (GFRs) was reduced by a mean of 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations, according to results of the Diabetes Control and Complications Trial (DCCT) and the follow-up observational Epidemiology of Diabetes Interventions and Complications (EDIC) study (pp. 2366–76). Compared with patients who received conventional diabetes therapy aimed at preventing hyperglycemic symptoms, intensive therapy produced these results: “Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P = 0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m2 during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m2 (P < 0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates.” (I. de Boer, deboer@u.washington.edu)
Tobacco & the First Amendment: The trend toward greater protection of commercial speech threatens FDA regulation of tobacco, an author writes. (pp. 2351–3). Instead of warnings and graphic images on tobacco packages, public health advocates should focus on areas free from First Amendment concerns, including “bans on smoking in public places, increased taxes to discourage consumption, raising the legal age for tobacco use, smoking-cessation programs including health insurance incentives, and outright bans on tobacco use.” (K. Outterson)

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 23, 2011 * Vol. 18, No. 247
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Jan. 1 issue of Clinical Infectious Diseases (2012; 54).
PPIs & Community-Acquired Pneumonia: While overall use of PPIs was not associated with community-acquired pneumonia in a study of veterans, some significant relationships, researchers report (pp. 33–42). More inquiry is merited based on an analysis of 71,895 outpatients who were newly prescribed PPIs in 1998–2007. Comparing 1,544 patients who developed CAP with 15,440 matched controls, the researchers found: “Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15–1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI–CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks.” (J. A. Hermos, john.hermos@va.gov)
Daptomycin v. Vancomycin in Highly Resistant MRSA: Daptomycin was associated with better outcomes in a retrospective case–control comparison of patients with septicemia caused by methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentrations (MICs) of 1–2 mcg/mL (pp. 51-8): “A total of 118 vancomycin-treated subjects were compared with 59 daptomycin-treated subjects. Clinical failure, defined compositely as mortality, microbiologic failure, and/or recurrence of infection, was numerically lower in daptomycin-treated subjects (31% vs 17%; P = .084) and was mainly driven by a lower incidence of mortality in the daptomycin group (20% vs 9%; P = .046). Factors independently associated with clinical failure included acute renal failure (odds ratio [OR], 3.91 [95% confidence interval {CI}, 1.05–14.56]) and vancomycin treatment group (OR, 3.13 [95%, CI, 1.00–9.76]). Right-sided endocarditis was independently associated with clinical success (OR, 0.07 [95% CI, .01–.83]). A comparison of 60-day mortality between vancomycin- and daptomycin-treated subjects found a higher probability of survival in the daptomycin-treated group (P = .022).” (M. J. Zervos, mzervos1@hfhs.org)
Antibiotic Implications of Chronic Rhinosinusitis: Prolonged courses of antibiotics may be unnecessary in patients with chronic rhinosinusitis (CRS), a 125-patient observational study shows (pp. 62–8): “The patients were classified into 2 groups: (1) those with radiographic evidence of sinusitis by CT (Sx + CT) (75) and (2) those with normal CT scans of the sinus (Sx – CT) (50). Decreased smell was significantly more common in Sx + CT than in Sx – CT patients, (P = .003). Paradoxically, headache, facial pain, and sleep disturbance occurred significantly more frequently in patients with Sx – CT than in patients with Sx + CT (P < .05). The absence of mucopurulence on endoscopy proved to be highly specific for Sx – CT patients (100%). On the other hand, sensitivity was low; only 24% of Sx + CT patients demonstrated mucopurulence by endoscopy. Improvement in response to antibiotics was similar between both CRS categories.” (V. L. Yu, vly@pitt.edu)

>>>PNN NewsWatch
* Raltegravir (Isentress, Merck) is now approved for combination use in younger patients with HIV-1 infection (ages 2–18). In a clinical trial of 96 children and adolescents with previously treated HIV-1 infection, 53% of patients had an undetectable amount of HIV in their blood after 24 weeks of treatment.
* Parents and caregivers need to be reminded about the new, more dilute concentration of
acetaminophen in products now on the U.S. market, FDA said. Two concentrations are currently available, 80 and 160 mg/5 mL. Parents and caregivers should read Drug Facts labels carefully and use only dosing devices that come with the product they are giving, FDA said. The new concentration is part of manufacturers’ commitment to switch to a single strength of acetaminophen and thereby avoid confusion and overdoses, according to pharmacist.com. FDA has issued a list of questions and answers and a consumer guide to help deal with the situation.
*
PNN will not be published on Mon., Dec. 26, Christmas.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 27, 2011 * Vol. 18, No. 248
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Dec. issue of the Journal of the American Geriatrics Society (2011; 59).
Overactive Bladder Treatments: Behavioral treatment has an important place in therapy of overactive bladder in men, according to results of the Male Overactive Bladder Treatment in Veterans (MOTIVE) trial (pp. 2209–16). Eight weeks of pelvic floor muscle exercises, urge suppression techniques, and delayed voiding showed these results when compared with antimuscarinic and alpha-blocker drugs: “Mean voids per day decreased from 11.3 to 9.1 (−18.8%) with behavioral treatment and 11.5 to 9.5 (−16.9%) with drug therapy. Equivalence analysis indicated that posttreatment means were equivalent (P < .01). After treatment, 85% of participants rated themselves as much better or better; more than 90% were completely or somewhat satisfied, with no between-group differences. The behavioral group showed greater reductions in nocturia (mean = −0.70 vs −0.32 episodes/night; P = .05). The drug group showed greater reductions in maximum urgency scores (mean = −0.44 vs −0.12; P = .02). Other between-group differences were nonsignificant.” (K. L. Burgio, kburgio@aging.uab.edu)
Mobility & Drug Use: The mobility of older community-dwelling adults is not lowered by use of ACE inhibitors or statins, report researchers in the Health, Aging and Body Composition (Health ABC) study (pp. 2226–32). The longitudinal cohort study included 3,055 patients who had no mobility limitations at baseline. Assessment of mobility limitations every 6 months showed these results in relation to drug use: “At baseline, 15.2% used ACE inhibitors and 12.9% used statins; use of both was greater than 25% by Year 6. Over 6.5 years of follow-up, 49.8% had developed mobility limitation. In separate multivariable models, neither ACE inhibitor (multivariate hazard ratio (HR) = 0.95, 95% confidence interval (CI) = 0.82–1.09) nor statin use (multivariate HR = 1.02, 95% CI = 0.87–1.17) was associated with lower risk of mobility limitation. Similar findings were seen in analyses examining dose–response and duration–response relationships and a sensitivity analysis restricted to those with hypertension.” (S. L. Gray, slgray@u.washington.edu)

>>>Rheumatology Report
Source:
Dec. issue of Arthritis & Rheumatism (2011; 63).
Golimumab Effects in RA: Inflammation improvements were significantly greater when 637 patients with rheumatoid arthritis were treated with golimumab plus methotrexate (MTX) than with MTX alone, researchers report (pp. 3712–22). In a 24-week study, the patients, all MTX naive, had lower scores for synovitis/osteitis and bone erosion using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) system for MRI studies and modified Sharp/van der Heijde (SvdH) scoring system for radiographs after 12 weeks of golimumab 100 mg subcutaneously every 4 weeks: “At weeks 12 and 24, combined therapy with golimumab plus MTX versus placebo plus MTX significantly improved RAMRIS scores for synovitis (mean −1.92 versus 0.14 [P < 0.001] at week 12; −2.45 versus −1.04 [P < 0.001] at week 24), osteitis (mean −1.82 versus 0.56 [P < 0.001] at week 12; −2.27 versus −0.32 [P < 0.001] at week 24), and bone erosion (mean −0.40 versus 0.24 [P = 0.016] at week 12; −0.40 versus −0.24 [P = 0.010] at week 24). Results of sensitivity analyses (no missing doses/data and using linear extrapolation) were generally consistent with results of the primary analyses. Changes in SvdH scores among the MRI substudy patients at week 28 showed no significant difference between golimumab plus MTX therapy and placebo plus MTX (mean 0.49 versus 0.92; P = 0.19). Radiographic SvdH scores demonstrated inhibition of structural damage progression by treatment with golimumab plus MTX as compared with placebo plus MTX in the overall study population but required double the number of patients (637 versus 318) and double the length of followup (28 versus 12 weeks) as needed for MRI to demonstrate this.” (M. Østergaard, mo@dadlnet.dk)

>>>PNN JournalWatch
* Bisphosphonates and Osteonecrosis of the Jaw, in
Journal of the American Geriatrics Society, 2011; 59: 2350–5. (A. A. Grippo, agrippo@astate.edu)
* Quality Measurement and Improvement in Rheumatology: Rheumatoid Arthritis as a Case Study, in
Arthritis & Rheumatism, 2011; 63: 3649–60. (S. P. Desai, sdesai5@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 28, 2011 * Vol. 18, No. 249
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 28 issue of JAMA (2011; 306).
Pharmacogenomics of Clopidogrel: The controversy over whether patients should be genotyped for CYP2C19 before clopidogrel therapy is examined in a Clinician’s Corner review (pp. 2704–14). Investigators found an association between genotype and clopidogrel responsiveness but no link between which allele was present and cardiovascular disease (CVD) events: “We retrieved 32 studies of 42,016 patients reporting 3,545 CVD events, 579 stent thromboses, and 1,413 bleeding events. Six studies were randomized trials (‘effect-modification’ design) and the remaining 26 reported individuals exposed to clopidogrel (‘treatment-only’ design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75–0.94; absolute risk reduction of 5–8 events per 1,000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09–1.28; absolute risk increase of 8–12 events per 1,000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86–1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes.” (M. V. Holmes, mvholmes@gmail.com)
Questioning whether genomics is “irrational exuberance” when it comes to clopidogrel, an editorialist writes (
pp. 2727–8): “A large randomized controlled trial is needed to adequately test the clopidogrel pharmacogenomic hypothesis. In the absence of such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution. It is still likely that pharmacogenomics has a bright future in cardiovascular medicine, but the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies. Overzealous adoption based on limited biochemical data does not serve the public interest.” (S. E. Nissen, nissens@ccf.org)
Troponin I & Early MI Diagnosis: Blood tests of highly sensitive troponin I (hsTnI) can be used to rule out myocardial infarction (MI) 3 hours after hospital admission, researchers report (pp. 2684–93). By comparing 3-hour values with those of a contemporary troponin I (cTnI) assay (taken on admission), clinicians can improve diagnostic accuracy, according to this study of 1,818 patients with suspected acute myocardial infarction (AMI): “For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95–0.97) for hsTnI on admission and 0.92 (95% CI, 0.90–0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours.” (S. Blankenberg, s.blankenberg@uke.de)

>>>PNN NewsWatch
* The 2012 Clinical Practice Recommendations of the American Diabetes Association are now available on the Diabetes Care website.
*
Correction: In Friday’s PNN, the concentration of acetaminophen infant drops was incorrectly stated as 80 mg/5 mL. The sentence should have read: Three concentrations are currently available: 80 mg/0.8 mL, 80 mg/mL, and 160 mg/5 mL.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 29, 2011 * Vol. 18, No. 250
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 29 New England Journal of Medicine (2011; 365).
LMWHs & Mortality in Acutely Ill Patients: In acutely ill medical patients, all-cause mortality rates were similar when enoxaparin was added to treatment with elastic stockings with graduated compression, researchers report (pp. 2463–72). Venous thromboembolism has been reduced by thromboprophylaxis in such patients, and this study sought to determine whether those benefits decrease mortality from any cause. At hospitals in Asia, Mexico, and of Tunisia, acutely ill patients were treated with elastic stockings with graduated compression with or without enoxaparin 40 mg daily for an average of 10 days, with these results: “A total of 8,307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4,171 patients) or placebo plus elastic stockings with graduated compression (4,136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P = 0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P = 0.35).” (A. K. Kakkar, akkakkar@tri-london.ac.uk)
Bevacizumab in Ovarian Cancer: Two clinical trials examine bevacizumab in ovarian cancer.
Added to carboplatin and paclitaxel chemotherapy, bevacizumab increased median progression-free survival by about 4 months in 1,873 patients with advanced epithelial ovarian cancer, according to a Phase III trial (
pp. 2473–83). Participants had Stage III or IV epithelial ovarian cancer and received chemotherapy during the first 6 cycles and a study treatment during cycles 2 through 22. Bevacizumab-initiation treatment was added in cycles 2 through 6, and for those in a bevacizumab-throughout group, the drug was given in cycles 2 through 22. Results showed: “The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group. Relative to control treatment, the hazard ratio for progression or death was 0.908 (95% confidence interval [CI], 0.795 to 1.040; P = 0.16) with bevacizumab initiation and 0.717 (95% CI, 0.625 to 0.824; P < 0.001) with bevacizumab throughout. At the time of analysis, 76.3% of patients were alive, with no significant differences in overall survival among the three groups. The rate of hypertension requiring medical therapy was higher in the bevacizumab-initiation group (16.5%) and the bevacizumab-throughout group (22.9%) than in the control group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2%, 2.8%, and 2.6% of patients in the control group, the bevacizumab-initiation group, and the bevacizumab-throughout group, respectively.” (R. A. Burger, robert.a.burger@fccc.edu)
In a second Phase III trial, bevacizumab improved progression-free survival in 1,528 women with ovarian cancer, with benefits greater among patients at greatest risk for disease progression (
pp. 2484–96). Added to a chemotherapy regimen of 6 cycles of carboplatin/paclitaxel, bevacizumab for up to a total of 18 cycles had these effects: “Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P = 0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P < 0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P = 0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.” (M. K.B. Parmar, mp@ctu.mrc.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Dec. 30, 2011 * Vol. 18, No. 251
Providing news and information about medications and their proper use

>>>PNN’s Top 10 for 2011
A year of dichotomies, 2011 saw a large number of new drug approvals—many of them important advances (Oct. 17)—but also drug shortages that are compromising therapy (Nov. 3). The 30th anniversary of AIDS epidemic (June 7) passed as clinicians continued debating just when antiretroviral therapy should be started (Aug. 11). Genomics and personalized medicine advanced even as staffing at anticoagulation clinics was reduced by new anticoagulants (Dec. 9) and research showing that warfarin self-monitoring is feasible (Apr. 4, Dec. 5). With those extremes in mind, here’s how 2011 looked through the lens of PNN:
1 New Drugs Galore: FDA approved some three dozen new chemical/biologic entities, including important new agents for cancers and orphan diseases. Two drugs, crizotinib (Aug. 29) for lung cancer and vemurafenib (Aug. 18) for metastatic or unresectable melanoma, were “breakthrough products for personalized medicine,” FDA said.
2 Medication Problems/FDA Reactions: FDA reacted to medication problems with near-daily announcements of warnings and alerts. Important actions included lowering of daily acetaminophen doses to 3 g (July 29), restricting the amount of that agent in combination prescription products (Jan. 13), monitoring the safety of drospirenone (Oct. 28, 31), and restricting use of rosiglitazone (May 19) and doses of simvastatin (June 9).
3 Health Care on the Docket: Important new parts of the health care reform law were implemented, including the closing the Medicare Part D doughnut hole (Feb. 17). With the law headed for the U.S. Supreme Court, the justices dealt with an unusually large number of cases involving pharmacy and drugs—prescription data mining (Jan. 10, May 26, Aug. 4), manufacturer duty to warn about adverse effects of generic drugs (Aug. 11), and Medicaid policies (Nov. 10).
4 Genomics & Personalized Medicine: Cancers (Jan. 27), asthma (Sept. 1, 12, 29), sinusitis (Oct. 11), and even Helicobacter pylori infections (Mar. 4) were among the conditions for which pharmacogenomic approaches and personalized medicine were studied. But the deal is not done, as barriers remain (Nov. 2).
5 Rx Drug Overdose Epidemic: The growing number of deaths and hospitalizations caused by prescription drug overdoses constitute an epidemic, the CDC (Feb. 18) and White House (Apr. 20) said. Long-term opioid therapy should be rethought (Sept. 6) and prescriptions monitored (Nov. 30), various authors wrote.
6 Antibiotic Resistance: Another CDC call to action (Apr. 8) was for conservation of antibiotics in the face of growing resistance (Feb. 23, Feb. 25, May 13, Aug. 23, Sept. 7).
7 Ups & Downs of Dietary Supplements: Vitamin D continued to surprise, playing a role in a wide variety of conditions (Jan. 31, Apr. 29, June 6, Sept. 16, Oct 18, Oct. 21, Nov. 11, Dec. 20). Many other dietary supplements faltered as controlled trials tested their effects and editorialists called for better regulation of these products (July 6). Even saw palmetto failed to hold up in clinical studies of the herb’s urologic effects (Sept. 28).
8 Putting on the Pounds: The obesity epidemic continued to worsen (Feb. 14, 24), and a disconcerting study of hormonal changes in people who have lost weight (Oct. 27) showed how difficult it is to keep extra pounds off.
9 Pharmacists’ Future Roles: Whether future pharmacists will practice in medical homes is not yet clear (Mar, 11), but the need for medication therapy management by a drug therapy expert was evident in many studies. Pharmacist care was effective for blood pressure control (Jan 14), cardiovascular disease and diabetes (Sept. 13), and intensive care (Feb. 4, Aug. 24). Numerous studies looked at services to older patients (Mar. 1, Aug. 19, Nov. 28), nursing home residents (Apr. 22, Oct. 7), and Medicare Part D beneficiaries (July 15, 27; Aug. 26).
10 Vaccines a Key: Immunization services have become a mainstay of offerings in community pharmacies of all types. In vaccine research, cell-cultured influenza vaccine may soon be a reality (Feb. 26), influenza vaccine can help patients with asthma (Jan. 21), varicella vaccine has virtually eliminated related deaths (Aug. 12), but politics could derail use of human papillomavirus vaccine (Oct. 19).

>>>PNN NewsWatch
* PNN will not be published on Mon., Jan. 2, New Year’s.

PNN Pharmacotherapy Line is published via e-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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.