Sep 2010

PNN Quarterly File—Third Quarter 2010

PNN Pharmacotherapy Line
July 1, 2010 * Vol. 17, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and July 1 issue of the New England Journal of Medicine (2010; 363).
Adverse Events with Testosterone Gel: In a small group of older men with limitations in mobility and low serum testosterone levels, daily application of testosterone gel for 6 months was associated with an increased risk of cardiovascular events, researchers report (10.1056/NEJMoa1000485). The study participants, all 65 years of age or older and having difficulty walking two blocks on a level surface or climbing 10 steps and having a score between 4 and 9 on the Short Physical Performance Battery, had these experiences during the study: “A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.” (S. Bhasin, bhasin@bu.edu)
Triptan Therapy During Migraine: Based on the case of a 23-year-old woman whose migraine symptoms were relieved by triptan therapy but who also felt chest pressure after drug administration, the author of a Clinical Therapeutics article provides these recommendations (pp. 63–70): “It is reasonable to recommend the use of an oral triptan. [The patient] has not had a consistent benefit from NSAIDs or combination analgesics but obtained complete relief of headache and associated nausea with subcutaneous sumatriptan. There is a good chance that her headaches will also respond to an oral triptan. The chest symptoms she reported are entirely consistent with nonserious triptan sensations and will be less likely to occur with an oral formulation. In young, healthy patients who are at low risk for cardiovascular disease according to risk-factor stratification, there is no need to perform baseline cardiovascular testing before prescribing triptans.
“Because it is the least expensive option, I would prescribe a dose of 50 mg or 100 mg of generic oral sumatriptan and advise the patient to take it early in the course of a headache, before the pain becomes severe. I would ask her to limit use of the medication to 2 days a week and to keep a diary of headache frequency, characteristics, and response to treatment. I would see the patient in a follow-up visit several months later to assess treatment results. If sumatriptan causes unpleasant side effects or is not helpful, I would consider trying a different triptan.” (E. Loder,
eloder@partners.org)

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (2010; 30).
Opioid Harm Reduction Through Intranasal Naloxone Use: Increased availability of intranasal naloxone to narcotic addicts could help in preventing some of the 20,000 overdose deaths occurring annually in the U.S., an editorialist writes (pp. 627–31). Studies have shown that addicts have learned to administer rescue naloxone injections when they observe fellow addicts in apparent overdose situations, and these experiences are now being extended to intranasal naloxone formulations, the author writes, adding: “A tremendous opportunity exists for pharmacists in helping to reduce opioid-related morbidity and mortality. The paradigms discussed above related to therapeutic use of opioids in pain management, emergency medicine, and the abusing population deserve consideration. Pharmacists can take a leading role in developing legislation that is permissive of naloxone rescue. Clearly, pharmacists can assist in the training and dissemination of information regarding the proposed rescue program with their local community emergency medical services staff. Finally, pharmacy organizations should take a leading role in designing opioid harm reduction strategies, research studies, and operational models for pharmacists in their communities.” (D. P. Wermeling, dwermel@uky.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 2, 2010 * Vol. 17, No. 127
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (2010; 33).
Insulin Requirements During Hemodialysis: Basal insulin requirements vary by as much as 25% on the day after maintenance hemodialysis, compared with the previous day, according to a study of 10 patients with type 2 diabetes (pp. 1409–12). Using a 24-hour euglycemic clamp and a standardized 2,200-calorie diet, researchers found these variations in insulin requirements before and after hemodialysis: “Mean capillary glycemia was 5.5 ± 0.3 mmol/l prehemodialysis and 5.3 ± 0.2 mmol/l posthemodialysis (P = 0.39). Pre- and posthemodialysis areas under the glucose curve were comparable. This was achieved by infusing 23.6 ± 7.7 IU/24 h prehemodialysis vs. 19.9 ± 4.9 IU/24 h posthemodialysis, indicating a 15.3% decrease posthemodialysis (P = 0.09). Basal insulin needs decreased from 0.4 ± 0.1/h prehemodialysis to 0.3 ± 0.1/h posthemodialysis (P = 0.01). Total boluses were decreased by 2.2 ± 3.1 IU (P = 0.15). Changes in blood urea did not correlate with changes in insulin needs (r = 0.1, P = 0.79).” (E. Sobngwi, eugene.sobngwi@newcastle.ac.uk)
Vitamin D & Beta-Cell Function: Among 25 young adults newly diagnosed with type 1 diabetes, daily administration of vitamin D had no effect on loss of pancreatic beta-cell function, researchers report (pp. 1443–8). In an open-label study, 25 patients received 1-alpha, 25-dihydroxyvitamin D3 for 9 months in doses of 0.25 mcg daily. An additional 40 patients received the same intervention or placebo and were followed for a total of 18 months. Results showed: “Safety assessment showed values in the normal range in nearly all patients, regardless of whether they received 1,25(OH)2D3 or placebo. No differences in AUC C-peptide, peak C-peptide, and fasting C-peptide after a mixed-meal tolerance test between the treatment and placebo groups were observed at 9 and 18 months after study entry, with [about] 40% loss for each parameter over the 18-month period. A1C and daily insulin requirement were similar between treatment and placebo groups throughout the study follow-up period.” (A. G. Ziegler, anziegler@lrz.uni-muenchen.de)
Quick-Release Bromocriptine in Type 2 Diabetes: Among 3,095 patients with type 2 diabetes, fewer cardiovascular events occurred with quick-release bromocriptine than with placebo, a study shows (pp. 1503–8). Investigators used an all-cause–safety end point of any serious adverse event (SAE). Cardiovascular disease (CVD) events included myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure. The authors report these results: “In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respectively) (HR 0.60 [95% two-sided CI 0.35–0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group.” (J. M. Gaziano, jmgaziano@partners.org)
Infliximab for Refractory Diabetic Macular Edema: A small Phase III trial supports further study of infliximab for treating diabetic macular edema refractory to laser photocoagulation (pp. 1523–8). Infliximab doses at 0, 2, 6, and 14 weeks produced these results: “Early Treatment of Diabetic Retinopathy Study (ETDRS) scores dropped from 31.6 ± 5.1 (mean ± SD) letters read at baseline to 28.8 ± 11.6 letters read at week 16 in six placebo-treated eyes and improved to 35.4 ± 11.2 letters read after infliximab. In contrast, visual acuity improved from 23.5 ± 10.3 at baseline to 30.4 ± 13.4 letters read at week 16 in eight infliximab-treated eyes and was sustained at completion of placebo treatment (31.4 ± 12.1 letters read). The excess visual acuity in infliximab-treated eyes was greater by 24.3% compared with that in placebo-treated eyes (95% CI 4.8–43.7; P = 0.017). Infliximab treatment was well tolerated.” (P. P. Sfikakis, psfikakis@med.uoa.gr)

>>>PNN NewsWatch
* In suburban Washington, DC, four FDA panels assessed ways of reducing medication errors through four types of improvements, pharmacist.com reports: container/label design, evaluating safety of labels, packaging, and testing of proprietary names.
*
PNN will not be published on Mon., July 5, Independence Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 6, 2010 * Vol. 17, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 6 issue of the Annals of Internal Medicine (2010; 153).
STDs with ED Drugs: Counseling about safe-sex practices should be provided when medications for erectile dysfunction are prescribed, conclude researchers who found an increased risk of sexually transmitted diseases, especially HIV, among nearly 34,000 men in the year after they began use of these drugs (pp. 1–7). Explaining that “the observed association between ED drug use and STDs may have more to do with the types of patients using ED drugs rather than a direct effect of ED drug availability on STD rates,” the investigators provide these details about their analysis of claims data among men aged 40 years and older: “Users of ED drugs had higher rates of STDs than nonusers the year before initiating ED drug therapy (214 vs. 106 annually per 100,000 persons; P = 0.003) and the year after (105 vs. 65; P = 0.004). After adjustment for age and other comorbid conditions, users of ED drugs had an odds ratio (OR) for an STD of 2.80 (95% CI, 2.10 to 3.75) in the year before initiating drug therapy; the OR was 2.65 (CI, 1.84 to 3.81) in the year after. These differences were largely due to infections with HIV. The OR for HIV infection was 3.32 (CI, 2.38 to 4.36) in the year before and 3.19 (CI, 2.11 to 4.83) in the year after an ED drug prescription was filled. Significant changes in STD rates from the year before to the year after the first ED drug prescription was filled were not documented (adjusted OR for STD for users before vs. after the first ED drug prescription was filled, 0.96 [CI, 0.87 to 1.06]).” (A. B. Jena, jena.anupam@mgh.harvard.edu)
Extended-Duration VTE Prophylaxis: The benefits of extended-duration low-molecular-weight heparin prophylaxis against venous thromboembolism, already established in high-risk patients, extend to acutely ill medical patients restricted to bed rest, those older than 75 years, and women, researchers report (pp. 8–18). At 370 sites in 20 countries on four continents, these results were identified in a trial of subcutaneous enoxaparin 40 mg/day or placebo in nearly 6,000 patients aged 40 years or older with recently reduced mobility (bed rest or sedentary without [level 1] or with [level 2] bathroom privileges): “Extended-duration enoxaparin reduced VTE incidence compared with placebo (2.5% vs. 4%; absolute risk difference favoring enoxaparin, −1.53% [95.8% CI, −2.54% to −0.52%]). Enoxaparin increased major bleeding events (0.8% vs. 0.3%; absolute risk difference favoring placebo, 0.51% [95% CI, 0.12% to 0.89%]). The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility.” (R. D. Hull, rdhull@ucalgary.ca)

>>>Lancet Highlights
Source:
July 3 issue of Lancet (2010; 376).
Tranexamic Acid in Bleeding Trauma: Among 20,211 patients with bleeding trauma presenting to 274 hospitals in 40 countries, tranexamic acid reduced mortality, compared with placebo (pp. 23–32). Early infusions of tranexamic acid provided these benefits: “All-cause mortality was significantly reduced with tranexamic acid (1,463 [14.5%] tranexamic acid group vs 1,613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85–0.97; p = 0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76–0.96; p = 0.0077).” (CRASH-2 Trial Collaborators)

>>>PNN JournalWatch
* Update in Gastroenterology and Hepatology, in Annals of Internal Medicine, 2010; 153: 34–39. (N. J. Greenberger)
* Nurse Versus Doctor Management of HIV-Infected Patients Receiving Antiretroviral Therapy (CIPRA-SA): A Randomised Non-inferiority Trial, in
Lancet, 2010; 376: 33–40. (C. Orrell, catherine.orrell@hiv-research.org.za)
* Novel Approach to Antibiotic Prophylaxis in Percutaneous Endoscopic Gastrostomy (PEG): Randomised Controlled Trial, in
BMJ, 2010; 341: c3115. (J. Blomberg, john.blomberg@karolinska.se)
* D
2 Receptor Genetic Variation and Clinical Response to Antipsychotic Drug Treatment: A Meta-Analysis, in American Journal of Psychiatry, 2010; 167: 763–72. (J-P Zhang)
* Measurement Issues in Trials of Pediatric Acute Diarrheal Diseases: A Systematic Review, in
Pediatrics, 2010; 126: e222–31. (B. C. Johnston)
* Childhood Cancer Survivors: Transition to Adult-Focused Risk-Based Care, in
Pediatrics, 2010; 126: 129–36. (T. O. Henderson)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 7, 2010 * Vol. 17, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 7 issue of JAMA (2010; 304).
Glucosamine in Lower Back Pain/Lumbar Osteoarthritis: Six months of glucosamine therapy had no significant effect on symptoms of chronic lower back pain (LBP) and degenerative lumbar osteoarthritis, researchers report (pp. 45–52). In 250 patients who received oral glucosamine 1,500 mg or placebo daily, these outcomes were recorded using the Roland Morris Disability Questionnaire (RMDQ) and the quality-of-life EuroQol-5 Dimensions (EQ-5D) instrument at the end of the 6-month treatment period and at a 1-year follow-up visit: “At baseline, mean RMDQ scores were 9.2 (95% confidence interval [CI], 8.4–10.0) for glucosamine and 9.7 (95% CI, 8.9–10.5) for the placebo group (P = .37). At 6 months, the mean RMDQ score was the same for the glucosamine and placebo groups (5.0; 95% CI, 4.2–5.8). At 1 year, the mean RMDQ scores were 4.8 (95% CI, 3.9–5.6) for glucosamine and 5.5 (95% CI, 4.7–6.4) for the placebo group. No statistically significant difference in change between groups was found when assessed after the 6-month intervention period and at 1 year: RMDQ (P = .72), LBP at rest (P = .91), LBP during activity (P = .97), and quality-of-life EQ-5D (P = .20). Mild adverse events were reported in 40 patients in the glucosamine group and 46 in the placebo group (P = .48).” (P. Wilkens, philip.wilkens@medisin.uio.no)
Reflecting on “the ongoing enigma of chronic low back pain,” an editorialist writes (
pp. 93–4): “Some challenges are unique to back pain. Unlike other common chronic illnesses, there is no dominant organization that represents the chronic LBP community, advocating for greater attention and funding for LBP research. It is ironic that in the United States orders of magnitude more resources are spent on treatments for chronic LBP of limited or unknown value than on research to study existing and promising new approaches that could provide more hope for patients. Moreover, the fragmented clinical silos in which chronic LBP treatments are often delivered (eg, primary care, physical therapy, surgery, interventional procedures, behavioral therapy, complementary and alternative medicine practice) rarely align to force an objective appraisal of efficacy and collaborate to identify optimal treatment approaches.” (A. L. Avins, andrew.avins@ucsf.edu)
Tight Blood Pressure Control in Hypertension, Diabetes, & Coronary Artery Disease: In a subgroup analysis of 6,500 patients in the International Verapamil SR-Trandolapril Study (INVEST), all of whom had hypertension, diabetes, and coronary artery disease, tight control of systolic blood pressure was no better than usual control in improving cardiovascular outcomes (pp. 61–8). Patients received either a calcium antagonist or beta-blocker followed by ACE inhibitor, diuretic, or both to achieve systolic BP of less than 130 and diastolic BP of less than 85 mm Hg. Tight control was defined as systolic BPs of less than 130 mm Hg, usual control as 130–139 mm Hg, and uncontrolled as 140 mm Hg or higher. Looking for a primary outcome of first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke, the investigators found: “During 16,893 patient–years of follow-up, 286 patients (12.7%) who maintained tight control, 249 (12.6%) who had usual control, and 431 (19.8%) who had uncontrolled systolic BP experienced a primary outcome event. Patients in the usual-control group had a cardiovascular event rate of 12.6% vs a 19.8% event rate for those in the uncontrolled group (adjusted hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.25–1.71; P < .001). However, little difference existed between those with usual control and those with tight control. Their respective event rates were 12.6% vs 12.7% (adjusted HR, 1.11; 95% CI, 0.93–1.32; P = .24). The all-cause mortality rate was 11.0% in the tight-control group vs 10.2% in the usual-control group (adjusted HR, 1.20; 95% CI, 0.99–1.45; P = .06); however, when extended follow-up was included, risk of all-cause mortality was 22.8% in the tight control vs 21.8% in the usual control group (adjusted HR, 1.15; 95% CI, 1.01–1.32; P = .04).” (R. M. Cooper-DeHoff, dehoff@cop.ufl.edu)

>>>PNN NewsWatch
* A Maryland pharmacy owner, Pamela Arrey, has been sentenced to 57 months in prison for health care fraud, aggravated identity theft, and conspiracy to misbrand pharmaceuticals, reports the Justice Dept.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 8, 2010 * Vol. 17, No. 130
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 8 issue of the New England Journal of Medicine (2010; 363).
Late-Onset Hypogonadism: Decreased serum testosterone levels can be linked to presence of three sexual symptoms in middle-aged and older men, researchers report (pp. 123–5). In a study of 3,369 European men aged 40–79 years, these relationships between testosterone concentrations and symptoms were identified when data were split into training and validation sets: “In the training set, symptoms of poor morning erection, low sexual desire, erectile dysfunction, inability to perform vigorous activity, depression, and fatigue were significantly related to the testosterone level. Increased probabilities of the three sexual symptoms and limited physical vigor were discernible with decreased testosterone levels (ranges, 8.0 to 13.0 nmol per liter [2.3 to 3.7 ng per milliliter] for total testosterone and 160 to 280 pmol per liter [46 to 81 pg per milliliter] for free testosterone). However, only the three sexual symptoms had a syndromic association with decreased testosterone levels. An inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level was observed. These relationships were independently confirmed in the validation set, in which the strengths of the association between symptoms and low testosterone levels determined the minimum criteria necessary to identify late-onset hypogonadism.” (F. C. W. Wu, frederick.wu@manchester.ac.uk)
Commenting on this report and the trial released last week and published in this issue showing adverse effects of testosterone supplementation (see PNN, July 1;
pp. 109–22, S. Bhasin, bhasin@bu.edu), an editorialist makes these observations about the early termination of the latter study (pp. 189–91): “Many readers may disagree with the decision of the data and safety monitoring board to terminate the study early. Results of studies terminated early may differ from those of larger, longer-term studies. Also, readers will speculate that the higher rates of adverse events in the testosterone group may have been due to the fact that the two groups of men had different baseline characteristics, with a higher rate of hyperlipidemia and statin use and of hypertension in the testosterone group before the experimental interventions. To me, the decision of the data and safety monitoring board seems reasonable. For whatever reason, there were higher rates of cardiovascular disease in the group of men who were receiving testosterone in this study than in their counterparts who were receiving placebo.
“Although this result sounds a note of caution in general concerning testosterone administration in older men, it certainly should not deter investigators from proceeding with additional, larger studies of testosterone administration in well-characterized groups of older men to more clearly outline benefits and risks. Similarly, it should not prevent clinicians from prescribing testosterone replacement for well-established late-onset hypogonadism, although it should provide some new caution about the administration of testosterone in older men who have an extensive history of cardiovascular disease and immobility.” (W. J. Bremner)
Genomewide Association Studies: In a review article, an author assesses the clinical utility of genomewide association studies in prediction of human disease (pp. 166–76). Detailing how hundreds of thousands of single-nucleotide polymorphisms (SNPs) can be translated into useful information, the reviewer writes: “Genomewide association studies have proved successful in identifying genetic associations with complex traits. This reasonably unbiased approach to surveying the genome has opened doors to potential treatments by revealing the unexpected involvement of certain functional and mechanistic pathways in a variety of disease processes. Although the approach has proved powerful in identifying robust associations between many SNPs and traits, much additional work is needed to determine the functional basis for the observed associations so that appropriate interventions can be developed. Much more remains to be learned about how variations in intronic and intergenic regions (where the vast majority of SNP–trait associations reside) influence gene expression, protein coding, and disease phenotypes.” (T. A. Manolio, manolio@nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 9, 2010 * Vol. 17, No. 131
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
July 6 issue of the Journal of the American College of Cardiology (2010; 56).
Dyspnea in Patients Receiving Ticagrelor: Dyspnea occurs more frequently with ticagrelor therapy in patients with coronary artery disease than with clopidogrel, according to data from the ONSET/OFFSET study (pp. 185–93). In 123 stable aspirin-treated patients with CAD, ticagrelor (180 mg load, then 90 mg twice daily), clopidogrel (600 mg load, then 75 mg daily), or placebo for 6 weeks produced these results in a double-blind, double-dummy design: “After drug administration, dyspnea was reported by 38.6%, 9.3%, and 8.3% of patients in the ticagrelor, clopidogrel, and placebo groups, respectively (p < 0.001). Most instances were mild and/or lasted <24 h, although 3 patients discontinued ticagrelor because of dyspnea. Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week, respectively, after drug administration. In all treatment groups, and in ticagrelor-treated patients with dyspnea, there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters.” (R. F. Storey, r.f.storey@sheffield.ac.uk)
Dietary Flavanols in Coronary Artery Disease: Endothelial dysfunction in 16 patients with coronary artery disease was improved through 1-month supplementation with flavanol-containing cocoa, researchers report (pp. 218–24). High-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily produced these effects: “Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-[circulating angiogenic cells (CACs)], as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and … migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: –4.2 ± 2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74 ± 32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs.” (C. Heiss, christian.heiss@med.uni-duesseldorf.de)

>>>PNN NewsWatch
* The antimalarial agent Qualaquin should not be used for treatment of nighttime leg cramps, FDA reiterated yesterday. The quinine sulfate product is not approved for this use, the agency said. To further emphasize this point, FDA has approved a risk-management plan that includes patient information to be provided at the time of dispensing of Qualaquin.
*
Que She, an herbal weight loss product marketed as a dietary supplement, contains active pharmaceutical ingredients, including fenfluramine, propranolol, sibutramine, and ephedrine, FDA said yesterday. These ingredients, identified in an FDA analysis of Que She capsule contents, are not listed on the product label and could be harmful to patients, especially those with pre-existing cardiovascular conditions. FDA added that Que She, advertised as “Slimming Factor Capsule” and as “an all-natural blend of Chinese herbs,” has been widely distributed on Internet sites such as the Bouncing Bear Botanicals, and at retail outlets, including Sacred Journey in Lawrence, KS.
*
FDA is calling for public comments on new requirements that caloric and nutritional content of foods be posted by certain chain restaurants and similar retail food operations and vending machines. Such disclosures are required under the Affordable Care Act, the health care reform law.
* In an extension of a Jan. 15 recall, an additional 21 lots of
Benadryl, Motrin IB, and Tylenol products are being recalled by McNeil Consumer Healthcare, the company announced yesterday. These products, all solid oral dosage forms, may have been exposed to 2,4,6-tribromoanisole while stored on pallets, causing a musty or moldy odor, McNeil said. More information about this and other McNeil recalls is available at www.mcneilproductrecall.com.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 12, 2010 * Vol. 17, No. 132
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 10 issue of Lancet (2010; 376).
Prevention of Type 2 Diabetes: In 207 patients with impaired glucose tolerance, combination therapy with low-dose rosiglitazone and metformin reduced by two-thirds the risk of development of type 2 diabetes, researchers report (pp. 103–11). Adverse effects of the drugs were uncommon and the number needed to treat was 4, added investigators with the CANOE (CAnadian Normoglycemia Outcomes Evaluation) trial. Over a median of 3.9 years, these outcomes were noted with rosiglitazone 2 mg and metformin 500 mg twice daily or placebo: “Vital status was obtained in 198 (96%) participants, and medication compliance (taking at least 80% of assigned medication) was 78% (n = 77) in the metformin and rosiglitazone group and 81% (n = 80) in the placebo group. Incident diabetes occurred in significantly fewer individuals in the active treatment group (n = 14 [14%]) than in the placebo group (n = 41 [39%]; p < 0.0001). The relative risk reduction was 66% (95% CI 41–80) and the absolute risk reduction was 26% (14–37), yielding a number needed to treat of 4 (2.70–7.14). 70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p = 0.0002). Insulin sensitivity decreased by study end in the placebo group (median –1.24, IQR –2.38 to –0.08) and remained unchanged with rosiglitazone and metformin treatment (–0.39, –1.30 to 0.84; p = 0.0006 between groups). The change in beta-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo –252.3, –382.2 to –58.0 vs rosiglitazone and metformin –221.8, –330.4 to –87.8; p = 0.28). We recorded an increase in diarrhoea in participants in the active treatment group compared with the placebo group (16 [16%] vs 6 [6%]; p = 0.0253).” (B. Zinman, zinman@lunenfeld.ca)
Identifiable Risk Factors for Stroke: Reporting 10 risk factors that are associated with 90% of ischemic and hemorrhagic stroke, authors advocate interventions targeted at reducing blood pressure and smoking and promoting physical activities and healthy diet (pp. 112–23). Conducted in 22 countries in 2007–10, a case–control study shows these odds ratios (ORs) and population-attributable risks (PARs) among patients with acute first stroke: “In the first 3,000 cases (n = 2337, 78%, with ischaemic stroke; n = 663, 22%, with intracerebral haemorrhagic stroke) and 3,000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26–3.08; PAR 34.6%, 99% CI 30.4–39.1); current smoking (2.09, 1.75–2.51; 18.9%, 15.3–23.1); waist-to-hip ratio (1.65, 1.36–1.99 for highest vs lowest tertile; 26.5%, 18.8–36.0); diet risk score (1.35, 1.11–1.64 for highest vs lowest tertile; 18.8%, 11.2–29.7); regular physical activity (0.69, 0.53–0.90; 28.5%, 14.5–48.5); diabetes mellitus (1.36, 1.10–1.68; 5.0%, 2.6–9.5); alcohol intake (1.51, 1.18–1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9–14.4); psychosocial stress (1.30, 1.06–1.60; 4.6%, 2.1–9.6) and depression (1.35, 1.10–1.66; 5.2%, 2.7–9.8); cardiac causes (2.38, 1.77–3.20; 6.7%, 4.8–9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49–2.40 for highest vs lowest tertile; 24.9%, 15.7–37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3–92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3–93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke.” (M. J O’Donnell, donnm@mcmaster.ca">odonnm@mcmaster.ca)

>>>PNN JournalWatch
* Exercise-Induced Cardiac Troponin Elevation: Evidence, Mechanisms, and Implications, in Journal of the American College of Cardiology, 2010; 56: 169–76. (R. Shave, rshave@uwic.ac.uk)
* Refining the Definition of Hypereosinophilic Syndrome, in
Journal of Allergy and Clinical Immunology, 2010; 126: 45–9. (H-U Simon, hus@pki.unibe.ch)
* Acute Left Ventricular Dysfunction in the Critically Ill, in
Chest, 2010; 138: 198–207. (A. Chockalingam, chockalingama@health.missouri.edu)
* Advances in the Diagnosis, Pathogenesis, and Management of Autoimmune Hepatitis, in
Gastroenterology, 2010; 139: 58–72.e4. (A. J. Czaja, czaja.albert@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 13, 2010 * Vol. 17, No. 133
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 12 issue of the Archives of Internal Medicine (2010; 170).
Vitamin D & Cognitive Decline: Patients with low serum levels of vitamin D had greater rates of cognitive decline in a 6-year study, researchers report (pp. 1135–41). Participants in InCHIANTI, a population-based study conducted in 1998–2006 in Tuscany, used follow-up assessments every 3 years—including administration of the Mini-Mental State Examination (MMSE), with substantial decline was defined as 3 or more points, and the Trail-Making Tests A and B—to make these associations: “The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels <25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (75 nmol/L) was 1.60 (95% CI, 1.19–2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03–1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A.” (D. J. Llewellyn, david.llewellyn@pms.ac.uk)
Discussing whether vitamin D’s “place in the sun” has arrived, editorialists provide this summary of available evidence (
pp. 1099–100): “Randomized controlled trials provide a rigorous evaluation of the hypotheses generated by the results of observational studies. To date, there have only been a few RCTs of vitamin D supplementation that have addressed nonskeletal end points, and none that have been designed to assess important ‘hard’ outcomes such as cancer incidence or vascular events. However, findings from RCTs of vitamin D supplementation that have fracture as an outcome or that have surrogate measures of nonskeletal health as outcomes suggest that observational studies of vitamin D have also produced misleadingly optimistic results. Vitamin D supplementation does not reduce overall fracture risk and may increase the risk of the most serious fragility fracture, that of the proximal femur. When coadministered with calcium supplements, vitamin D produces a marginal reduction in fracture risk that is comparable to that produced by calcium alone. Similarly, recent RCTs of vitamin D supplementation have failed to demonstrate positive effects on body weight, glycemic control in type 2 diabetes mellitus, incidence of type 2 diabetes, and incidence of respiratory infections. Advocates for vitamin D supplementation maintain that the fracture trials failed to adequately characterize the vitamin D status of participants and/or studied inadequate doses. That may be so, but evaluation of ‘adequate’ doses in clinical trials has not yet been undertaken. Put simply, a rigorous evidence base for recommending vitamin D supplementation for improving health outcomes, either skeletal or nonskeletal, in community-dwelling individuals does not currently exist, beyond the avoidance of vitamin D levels that can produce osteomalacia.” (A. Grey, a.grey@auckland.ac.nz)
Screening for Drug Use in Primary Care: Asking patients how many times they have used drugs illegally or without a prescription during the past year accurately identifies users in the primary care setting, according to a study of 286 patients (pp. 1155–60). Researchers approached adult patients in waiting rooms to recruit them into the study, which compared results of the 10-item Drug Abuse Screening Test (DAST-10) and drug testing with responses to this question: “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” Results showed: “The single screening question was 100% sensitive (95% confidence interval [CI], 90.6%–100%) and 73.5% specific (95% CI, 67.7%–78.6%) for the detection of a drug use disorder. It was less sensitive for the detection of self-reported current drug use (92.9%; 95% CI, 86.1%–96.5%) and drug use detected by oral fluid testing or self-report (81.8%; 95% CI, 72.5%–88.5%). Test characteristics were similar to those of the DAST-10 and were affected very little by participant demographic characteristics.” (P. C. Smith, peter.smith@bmc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 14, 2010 * Vol. 17, No. 134
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 14 issue of JAMA (2010; 304).
Telecare for Pain, Depression in Patients with Cancer: Centralized telecare management with automated symptom monitoring lessened pain and depression severity, compared with usual care, in a study of patients with cancer (pp. 163–71). Nurse–physician teams provided centralized telecare, and patients provided information on symptoms using a system of their choice, either interactive voice-recorded telephone calls or Web-based surveys. Medications were managed using antidepressant and analgesic algorithms based on information from large clinical trials. Results showed: “Of the 405 participants enrolled in the study, 131 had depression only, 96 had pain only, and 178 had both depression and pain. Of the 274 patients with pain, 137 patients in the intervention group had greater improvements in [Brief Pain Inventory (BPI)] pain severity over the 12 months of the trial whether measured as a continuous severity score or as a categorical pain responder (30% decrease in BPI) than the 137 patients in the usual-care group (P < .001 for both). Similarly, of the 309 patients with depression, the 154 patients in the intervention group had greater improvements in [(20-item Hopkins Symptom Checklist (HSCL-20)] depression severity over the 12 months of the trial whether measured as a continuous severity score or as a categorical depression responder (≥50% decrease in HSCL) than the 155 patients in the usual care group (P < .001 for both). The standardized effect size for between-group differences at 3 and 12 months was 0.67 (95% confidence interval [CI], 0.33–1.02) and 0.39 (95% CI, 0.01–0.77) for pain, and 0.42 (95% CI, 0.16–0.69) and 0.41 (95% CI, 0.08–0.72) for depression.” (K. Kroenke, kkroenke@regenstrief.org)
Nonprogressive HIV Disease: Clinical management of the unusual patient whose HIV infection does not progress is reviewed in a Clinician’s Corner contribution (pp. 194–201): “As of 2008, more than 33 million adults and children have been estimated to be living with human immunodeficiency virus (HIV). Among them are rare patients (<0.5%) who have remained clinically well without antiretroviral therapy after almost 20 years of infection. They maintain stable CD4 cell counts and suppressed HIV replication to levels comparable with those measured in patients receiving combination antiretroviral therapy. No known epidemiologic or behavioral factors are predictive of untreated, nonprogressive HIV infection; however, host genetics and immune response factors, most specifically HLA antigen class I–restricted HIV-specific CD8 T cells, appear to be primarily responsible for this remarkable phenotype in a majority of these individuals. These patients offer hope that durable control of HIV infection is possible and can provide important insight to inform the development of the next generation of HIV/AIDS vaccines and immune-based therapies. This article reviews clinical features of these unique patients and discusses them in the context of nonprogressors enrolled in other cohorts. Potential mechanisms underlying nonprogressive HIV infection and scientific discoveries, facilitated by the participation of these patients in clinical trials, of relevance to the design of an efficacious HIV/AIDS vaccine are also highlighted.” (M. Connors, mconnors@nih.gov)
Updated Conflict Disclosure Form for Journal Authors: An editorial, one being published simultaneously in all journals whose editors are members of the International Committee of Medical Journal Editors, unveils an updated conflict-of-interest reporting form to “lessen confusion” among authors, readers, and the public (pp. 212–3; C. Mulrow, cmulrow@mail.acponline.org)

>>>PNN NewsWatch
* The possibility of severe liver injury during use of leflunomide (Arava) is the subject of a boxed warning in product labeling announced yesterday by FDA.
*
FDA has taken another step in the Colleague Volumetric Infusion Pump saga, requiring Baxter to provide customers with refunds, replacement pumps, or lease terminations.
* The
White House yesterday announced a new national HIV/AIDS strategy, one that seeks to make the U.S. a place “where new HIV infections are rare” and all people with HIV infection have “unfettered access to high-quality, life-extending care, free from stigma and discrimination.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 15, 2010 * Vol. 17, No. 135
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 15 issue of the New England Journal of Medicine (2010; 363).
Rituximab in Antibody-Associated Vasculitis: Two articles and an editorial explore the usefulness of rituximab in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis.
In 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement, rituximab-based therapy was not superior to standard intravenous cyclophosphamide, the RITUXVAS study shows (
pp. 211–20). Added to a standard glucocorticoid regimen over a 4-week period, rituximab 375 mg/sq m/wk with cyclophosphamide pulses (n = 33) provided these results in comparison with a control group receiving intravenous cyclophosphamide followed by azathioprine (n= 11): “The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 sq m of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P= 0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P = 0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P = 1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P = 0.14).” (R. B. Jones, rbjones@doctors.org.uk)
Rituximab performed better than cyclophosphamide in the RAVE study, which included 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis (
pp. 221–32). Based on analysis of a primary end point of remission of disease without the use of prednisone at 6 months, rituximab 375 mg/sq m/wk for 4 weeks and cyclophosphamide 2 mg/kg/day provided these results: “Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P < 0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.” (U. Specks, specks.ulrich@mayo.edu)
Editorialists discuss the “substantial” practical implications of these studies (
pp. 285–6): “Rituximab might be considered as an option for first-line therapy for induction of remission of ANCA-associated disease. It remains unclear whether rituximab should be used with glucocorticoids alone or in combination with intravenous cyclophosphamide.…
“Another critical and practical consideration is the need for maintenance immunosuppressive therapy. During the 12-month follow-up in the RITUXIVAS trial, patients received azathioprine as standard therapy to maintain remission. Although many patients require long-term immunosuppressive therapy to prevent relapsing disease, some practitioners discontinue or substantially reduce therapy to maintain remission in patients with a reduced propensity for relapse. The important unanswered question is whether anti–B-cell therapy will alter the immunopathogenetic process, permitting the discontinuation or reduction of therapy to maintain remission. Here again, understanding the basic pathogenetic mechanisms of ANCA-associated disease should inform the development of reliable biomarkers of remission and relapse so that physicians will know when to initiate, discontinue, or reduce the use of immunomodulating drugs. For now, RITUXIVAS and RAVE lend hope for our patients that targeted therapy may quell this B-cell–driven autoimmune disease.” (R. J. Falk)

>>>PNN NewsWatch
* The fate of rosiglitazone (Avandia, GlaxoSmithKline) now rests with FDA staff, following yesterday’s recommendation by an advisory panel that the drug carry stronger warnings and have restrictions that would eliminate 95% of current use, the Washington Post reports.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 16, 2010 * Vol. 17, No. 136
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Jul/Aug issue of the Journal of the American Pharmacists Assoc. (2010; 50).
Diabetes Care of Community Pharmacy Patients: Lack of adequate diabetes care among patients of community pharmacies provides opportunities for the profession, write researchers who analyzed data from the 2005 Medical Expenditure Panel Survey (pp. 478–84). Assessing the proportions of patients whose care met American Diabetes Association standards, the investigators determined: “In 2005, 1,455 patients with diabetes who were diagnosed before 2005 filled prescriptions through community pharmacies. Gaps occurred between the diabetes care of these patients and ADA standards. Examples include the following: ADA recommends at least two glycosylated hemoglobin (A1C) tests annually, but 19.52% of the study population reported less than two A1C tests in 2005; ADA recommends annual influenza vaccinations, but 42.46% of the study population reported not receiving an influenza vaccination in 2005; and ADA recommends weight control, but 83.74% of the study population was overweight or obese.” (J. Wang, jwang26@uthsc.edu)
Patient Knowledge of Acetaminophen: Education is needed for patients regarding acetaminophen recognition, dosing, and potential for toxicity, researchers report (pp. 485–9). Among 284 patients at four Alabama outpatient facilities, these deficiencies in knowledge were revealed using a 12-item investigator-administered questionnaire: “Two-thirds of the 284 patients completing the survey reported current or recent use of pain, cold, or allergy medication. Of these, 25% reported knowing the active ingredient. Of patients, 46% and 13% knew that ‘acetaminophen’ and ‘APAP,’ respectively, were synonymous with ‘Tylenol.’ Several patients (12%) believed that ingesting a harmful amount of acetaminophen was difficult or impossible. One-third of patients correctly identified the maximum daily dose, 10% reported a dose greater than 4 g, 25% were unsure of the dose, and 7% were unsure whether a maximum dose existed. One-half recognized liver damage as the primary toxicity. Results were similar between acetaminophen users and nonusers.” (L. B. Hornsby, hornslb@auburn.edu)
Medication Reconciliation in Ambulatory Settings: Accuracy of nurse-conducted medication reconciliation in ambulatory settings is poor, even after pharmacist-provided educational interventions, a study from Memphis shows (pp. 490–5). Researchers report an inadequate level of accuracy both before (Phase 1) and after (Phase 2) education of medical and nursing staff. Analysis of 90 medication reconciliation forms in each phase of the study showed these results: “In Phase 1, 14.4% of medication reconciliation forms were correct. The remaining forms contained 190 potentially significant errors. After the education interventions, 18.9% of medication reconciliation forms were correct and the others contained 139 potentially significant errors.” (L. Peyton, lpeyton@uu.edu)
Chronic Care in California: Nonadherence to both clinical practice guidelines by prescribers and medication therapy by patients is common in California Medicaid beneficiaries, according to a retrospective cohort study (pp. 496–507). The 2002–04 analysis included 1.1 million beneficiaries. Eligibility and claims data showed the following among patients with dyslipidemia, hypertension, coronary artery disease (CAD), heart failure, or diabetes: “The proportion of patients without a prescription fill for recommended medications varied by disease (43% hypertension, 40% dyslipidemia and CAD, and 25% diabetes and heart failure). For Medicaid-only beneficiaries with diabetes, 78% lacked glycosylated hemoglobin tests, 62% lacked low-density lipoprotein cholesterol tests, and 50% lacked eye exams. Medication nonadherence was high (69% hypertension, 64% CAD, 57% heart failure, 48% dyslipidemia, 41% diabetes). Overall, younger age, Medicaid-only status, and black/other race were associated with poorer rates.” (M. B. Nichol, mnichol@usc.edu)

>>>PNN NewsWatch
* John J. Castellani takes the reins at the Pharmaceutical Research and Manufacturers of America on Sept. 1, assuming the role of president and chief executive officer formerly held by Billy Tauzin. Castellani has been president and CEO of Business Roundtable for the past 9 years.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 19, 2010 * Vol. 17, No. 137
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 17 issue of Lancet (2010; 376).
COX-2 Inhibitor v. NSAID/PPI for Arthritis: Compared with diclofenac plus omeprazole, celecoxib produced fewer upper and lower gastrointestinal events during a 6-month study of patients with osteoarthritis or rheumatoid arthritis, report CONDOR investigators (pp. 173–9). Patients were negative for Helicobacter pylori, and they were at least 60 years of age or, if they had a history of gastrointestinal ulceration, 18 years or older. A primary endpoint of a composite of clinically significant gastrointestinal events showed these outcomes: “4,484 patients were randomly allocated to treatment (2,238 celecoxib; 2,246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4.3, 95% CI 2.6–7.0; p < 0.0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p = 0.0006).” (F. K. L. Chan, fklchan@cuhk.edu.hk)
Genetics & Vitamin D: People with variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport are at increased risk of vitamin D insufficiency, a study shows (pp. 180–8). Genome-wide association studies of 25-hydroxyvitamin D concentrations in 34,000 patients of European descent provided five epidemiological cohorts. Results showed: “Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p = 1.9 × 10–109 for rs2282679, in GC); 11q12 (p = 2.1×10–27 for rs12785878, near DHCR7); and 11p15 (p = 3.3 × 10–20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p = 6.0 × 10–10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20–2.78, p = 2.3 × 10–48) or lower than 50 nmol/L (1.92, 1.70–2.16, p = 1.0 × 10–26) compared with those in the lowest quartile.” (T. D. Spector, tim.spector@kcl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Effect of Small Studies on Meta-analyses: Inclusion of studies with fewer than 100 patients can distort results of meta-analyses, report researchers who looked at the literature on pain of osteoarthritis of the knee and hip (c3515). In a meta-epidemiological study, the results of 13 meta-analyses that included 153 randomized trials and 41,605 patients were analyzed for the relative effects of small studies: “On average, treatment effects were more beneficial in small than in large trials (difference in effect sizes –0.21, 95% confidence interval –0.34 to –0.08, P = 0.001). Depending on criteria used, six to eight funnel plots indicated small study effects. In six of 13 meta-analyses, the overall pooled estimate suggested a clinically relevant, significant benefit of treatment, whereas analyses restricted to large trials and predicted effects in large trials yielded smaller non-significant estimates.” (P. Jüni, juni@ispm.unibe.ch)

>>>PNN NewsWatch
* Recent warnings from FDA focus on a recall of Coumadin 1 mg tablet blister packs (may not meet specification for isopropanol, which is needed for maintaining warfarin in the crystalline state); the need to not use lots of Advair Diskus Inhalers that were stolen from a distribution warehouse in 2009 (product has been found in pharmacies); and a possible small increase in cancer risk associated with use of angiotensin II receptor blockers.

>>>PNN JournalWatch
* Investigation and Management of Congestive Heart Failure, in BMJ, 2010; 341: doi:10.1136/bmj.c3657. (B. Arroll, b.arroll@auckland.ac.nz)
* Rapidly Growing Mycobacteria Infection in Patients with Cancer, in
Clinical Infectious Diseases, 2010; 51: 422–34. (G. Redelman–Sidi, redelmansidi@hotmail.com)
* American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer, in
Journal of Clinical Oncology, 2010; 28: 10.1200/JCO.2009.26.3756. (American Society of Clinical Oncology, guidelines@asco.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 20, 2010 * Vol. 17, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and July 20 issue of the Annals of Internal Medicine (2010; 153).
Contextual Errors in Medical Care: Overlooking patients’ environmental or behavioral factors is common in medical care, according to a study of physicians’ attention to contextual information such as transportation, economic, and caretaker situations (pp. 69–75). Four scenarios, each with one biomedical and one contextual red flag, were presented to physicians in 14 practices, with these results: “Physicians probed fewer contextual red flags (51%) than biomedical red flags (63%). Probing for contextual or biomedical information in response to red flags was usually necessary but not sufficient for an error-free plan of care. Physicians provided error-free care in 73% of the uncomplicated encounters, 38% of the biomedically complicated encounters, 22% of the contextually complicated encounters, and 9% of the combined biomedically and contextually complicated encounters.” (S. J. Weiner, sweiner@uic.edu)
Ribavirin for Chronic Hepatitis E: Results of ribavirin therapy in two patients with chronic hepatitis E infection support further study, researchers report (pp. 85–9). Doses of 12 mg/kg/day for 12 weeks produced these results: “Both patients had normalized liver function test results after 2 weeks of treatment and cleared HEV after 4 weeks of treatment. Hepatitis E virus RNA remained undetectable in the serum and stools throughout follow-up (3 months and 2 months for the first and second patient, respectively). Side effects were considered mild.” (V. Mallet, vincent.mallet@cch.aphp.fr)
Guidelines for Osteoporosis Screening: In an update to 2002 guidelines for osteoporosis screening from the U.S. Preventive Services Task Force, panelists find that treatments are effect and well studied in women, but that evidence is lacking for men and for screenings in general (pp. 99–111): “Risk-assessment instruments are modest predictors of low bone density (area under the curve, 0.13 to 0.87; 14 instruments) and fractures (area under the curve, 0.48 to 0.89; 11 instruments); simple and complex instruments perform similarly. Dual-energy x-ray absorptiometry predicts fractures similarly for men and women; calcaneal quantitative ultrasonography also predicts fractures, but correlation with dual-energy x-ray absorptiometry is low. For postmenopausal women, bisphosphonates, parathyroid hormone, raloxifene, and estrogen reduce primary vertebral fractures. Trials are lacking for men. Bisphosphonates are not consistently associated with serious adverse events; raloxifene and estrogen increase thromboembolic events; and estrogen causes additional adverse events.” (H. D. Nelson, nelsonh@ohsu.edu)
Haitian Relief Effort: The response of a Miami medical school to the Jan. 12 earthquake in Haiti is detailed (early release): “The Miller School of Medicine of the University of Miami and Project Medishare, an affiliated not-for-profit organization, provided a large-scale relief effort in Haiti after the earthquake of 12 January 2010. Their experience demonstrates that academic medical centers in close geographic proximity to natural disasters can help deliver effective medical care through a coordinated process involving mobilization of their own resources, establishment of focused management teams at home and on the ground with formal organizational oversight, and partnership with governmental and nongovernmental relief agencies. Geographic proximity to the disaster area allows for prompt arrival of medical personnel and equipment. The recruitment and organized deployment of large numbers of local and national volunteers are indispensable parts of this effort. Multidisciplinary teams on short rotations can form the core of the medical response.” (W. W. O’Neill, WONeill@med.miami.edu)
Plagiarism in Resident Assays: One in 20 resident-applications essays contained plagiarism in a 2005–07 study (pp. 112–20). “The essays of non–U.S. citizens were more likely to demonstrate evidence of plagiarism,” write the authors. “Other characteristics associated with the prevalence of plagiarism included medical school location outside the United States and Canada; previous residency or fellowship; lack of research experience, volunteer experience, or publications; a low United States Medical Licensing Examination Step 1 score; and nonmembership in the Alpha Omega Alpha Honor Medical Society.” (S. Segal, bsegal@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 21, 2010 * Vol. 17, No. 139
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 21 issue of JAMA (2010; 304).
HIV Vaccine Testing: Induction of antibody production appears to occur commonly in noninfected patients in HIV vaccine trials, a study shows (pp. 275–83). Results vary depending on the vaccine type and the kind of enzyme immunoassay (EIA) HIV antibody kits used, with researchers reporting these rates of vaccine-induced seropositivity/reactivity (VISP): “Among 2,176 participants free of HIV infection who received a vaccine product, 908 (41.7%; 95% confidence interval [CI], 39.6%–43.8%) had VISP, but the occurrence of VISP varied substantially across different HIV vaccine product types: 399 of 460 (86.7%; 95% CI, 83.3%–89.7%) adenovirus 5 product recipients, 295 of 552 (53.4%; 95% CI, 49.2%–57.7%) recipients of poxvirus alone or as a boost, and 35 of 555 (6.3%; 95% CI, 4.4%–8.7%) of DNA-alone product recipients developed VISP. Overall, the highest proportion of VISP (891/2176 tested [40.9%]) occurred with the HIV 1/2 (rDNA) EIA kit compared with the rLAV EIA (150/700 tested [21.4%]), HIV-1 Plus O Microelisa System (193/1309 tested [14.7%]), and HIV 1/2 Peptide and HIV 1/2 Plus O (189/2150 tested [8.8%]) kits. Only 17 of the 908 participants (1.9%) with VISP tested nonreactive using the HIV 1/2 (rDNA) kit. All recipients of a glycoprotein 140 vaccine (n = 70) had VISP, with 94.3% testing reactive with all 3 EIA kits tested. Among 901 participants with VISP and a Western blot result, 92 (10.2%) had a positive Western blot result (displaying an atypical pattern consistent with vaccine product), and 592 (65.7%) had an indeterminate result. Only 8 participants with VISP received a vaccine not containing an envelope insert.” (L. R. Baden, lbaden@partners.org)
Cost Savings with Generic Antiretroviral Agents: Increased procurement and reduced costs have resulted from use of generic antiretroviral agents (ARVs) in 16 countries served by the US President’s Emergency Plan for AIDS Relief (PEPFAR), researchers report (pp. 313–20). Annual surveys in 2005 to 2008 showed these patterns: “ARV expenditures increased from $116.8 million (2005) to $202.2 million (2008); and procurement increased from 6.2 million to 22.1 million monthly packs. The proportion spent on generic ARVs increased from 9.17% (95% confidence interval [CI], 9.17%–9.18%) in 2005 to 76.41% (95% CI, 76.41%–76.42%) in 2008 (P < .001), and the proportion of generic packs procured increased from 14.8% (95% CI, 14.79%–14.84%) in 2005 to 89.33% (95% CI, 89.32%–89.34%) in 2008 (P < .001). In 2008, there were 8 PEPFAR programs that procured at least 90.0% of ARV packs in generic form; South Africa had the lowest generic procurement (24.7%; 95% CI, 24.6%–24.8%). Procurement of generic fixed-dose combinations increased from 33.3% (95% CI, 33.24%–33.43%) in 2005 to 42.73% (95% CI, 42.71%–42.75%) in 2008. Estimated yearly savings generated through generic ARV use were $8,108,444 in 2005, $24,940,014 in 2006, $75,645,816 in 2007, and $214,648,982 in 2008, a total estimated savings of $323,343,256.” (C. B. Holmes, holmescb@state.gov)
2010 AIDS Recommendations: Updated guidelines for management of patients with HIV infection are presented by the International AIDS Society–USA Panel (pp. 321–33): “Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count ≤500/µL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count >500/µL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.” (M. A. Thompson, drmt@mindspring.com)

>>>PNN NewsWatch
* Good Health announced yesterday that it is recalling certain lots of its dietary supplement product Vialipro. FDA analysis found that the product contained sulfoaildenafil, a sildenafil analogue.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 22, 2010 * Vol. 17, No. 140
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 22 issue of the New England Journal of Medicine (2010; 363).
Sensor-Augmented Insulin-Pump Therapy: Compared with injections, insulin given with a sensor-augmented pump led to better clinical outcomes in a study of 485 adults and children with type 1 diabetes (pp. 311–20). The Sensor-Augmented Pump Therapy for A1C Reduction (STAR) 3 trial compared pumps found: “At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P < 0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person–years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person–years, P = 0.58). There was no significant weight gain in either group.” (R. M. Bergenstal, richard.bergenstal@parknicollet.com)
Writing that the “focus now has to move on to translating this evidence into effective practice so that the broader population of patients with type 1 diabetes can realize these benefits,” an editorialist says insulin pump therapy has “come of age” (
pp. 383–4): “What can be done to overcome these barriers to the adoption of this technology? The use of continuous glucose monitoring by patients will almost certainly grow as the next generation of smaller, simpler devices with increased reliability and accuracy becomes available. The development of an infrastructure to support training and follow-up care will also be essential. Such supports could include Web-based training programs so that patients who do not have access to specialized diabetes centers can develop the advanced self-management skills that the use of continuous glucose monitoring requires. The use of data-analysis software to identify glucose patterns could simplify therapeutic decision making and follow-up care.” (H. A. Wolpert)
Gene Therapy for X-Linked SCID: In nine patients with X-linked severe combined immunodeficiency (SCID-X1), gene therapy corrected the immunodeficiency for a decade after treatment of bone marrow cells, researchers report (pp. 355–64): “Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy.” (S. H. Hacein-Bey-Abina, salima.hacein-bey@nck.ap-hop-paris.fr)
Path to Personalized Medicine: The heads of FDA and NIH describe steps their agencies are taking to facilitate implementation of personalized medicine (pp. 301–4): “In February, the NIH and the FDA announced a new collaboration on regulatory and translational science to accelerate the translation of research into medical products and therapies; this effort includes a joint funding opportunity for regulatory science. Working with academic experts, companies, doctors, patients, and the public, we intend to help make personalized medicine a reality. A recent example of this collaboration is an effort to identify new investigational agents to which certain tumors, identified by their genetic signatures, are responsive.…
“When the federal government created the national highway system, it did not tell people where to drive—it built the roads and set the standards for safety. Those investments supported a revolution in transportation, commerce, and personal mobility. We are now building a national highway system for personalized medicine, with substantial investments in infrastructure and standards. We look forward to doctors’ and patients’ navigating these roads to better outcomes and better health.” (M. A. Hamburg)

>>>PNN NewsWatch
* Acting on last week’s hearings on rosiglitazone (Avandia, GlaxoSmithKline), FDA yesterday stopped enrollment of new patients into the TIDE (Thiazolidinedione Intervention With Vitamin D Evaluation) trial. Participants already enrolled can continue under the partial clinical hold directed by FDA.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 23, 2010 * Vol. 17, No. 141
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
July issue of the Journal of the American Geriatrics Society (2010; 58).
Estrogens & Cognitive Function: In women aged 65 to 80 years, any cognitive benefits produced by conjugated equine estrogen (CEE) therapies are small, not detectable, or not clinically relevant, researchers report (pp. 1263–71). In the Women’s Health Initiative, 2,304 women without dementia at enrollment had these outcomes while taking placebo or CEE 0.625 mg/day with or without medroxyprogesterone acetate 10 mg/day: “Assignment to CEE-based therapies was associated with small mean relative decrements in global cognitive function and several domain-specific cognitive functions during the trial, which largely persisted through up to 4 years after the trial. The strongest statistical evidence was for global cognitive function (0.07–standard deviation decrements during [P = .007] and after [P = .01] the trial). For domain-specific scores, the mean decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.” (M. A. Espeland, mespelan@wfubmc.edu)
Vitamin D & Falls: Analyzing data from 10 randomized controlled trials, investigators confirm the efficacy of vitamin D supplements in preventing falls in older adults (pp. 1299–310): “In pooled analysis, vitamin D therapy (200–1,000 IU) resulted in 14% (relative risk (RR) = 0.86, 95% confidence interval (CI) = 0.79–0.93; I2 = 7%) fewer falls than calcium or placebo (number needed to treat = 15). The following subgroups had significantly fewer falls: community-dwelling (aged <80), adjunctive calcium supplementation, no history of fractures or falls, duration longer than 6 months, cholecalciferol, and dose of 800 IU or greater. Meta-regression demonstrated no linear association between vitamin D dose or duration and treatment effect. Post hoc analysis including seven additional studies (17 total) without explicit fall definitions yielded smaller benefit (RR = 0.92, 95% CI = 0.87–0.98) and more heterogeneity (I2 = 36%) but found significant intergroup differences favoring adjunctive calcium over none (P = .001).” (R. Rastogi Kalyani, rrastogi@jhmi.edu)

>>>Rheumatology Report
Source:
July issue of Arthritis & Rheumatism (2010; 62).
Statins in Autoimmune Disorders: Through their inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, statins might be useful in controlling production of type I interferons in autoimmune conditions such as systemic lupus erythematosus, according to an ex vivo study of human plasmacytoid dendritic cells (PDCs) (pp. 2073–85): “Statins inhibited IFN-alpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFN-alpha production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFN-alpha production by PDCs from SLE patients and SLE serum-induced IFN-alpha production.” (T. Ito, itot@takii.kmu.ac.jp)
Genetics & RA: Responses of patients with rheumatoid arthritis to anti-tumor necrosis factor alpha therapy can be predicted based on presence of an RA risk allele at the PTPRC (CD45) gene locus, a 1,283-patient study shows (pp. 1849–61). Better responses to etanercept, infliximab, or adalimumab were associated with a single-nucleotide polymorphism in this gene locus. The association was stronger in patients who were positive for autoantibodies than in negative individuals. (R. M. Plenge, rplenge@partners.org)

>>>PNN NewsWatch
* Federal marshals yesterday seized cyanide antidote kits at Keystone Pharmaceuticals, FDA said. The kits, containing sodium thiosulfate and sodium nitrite injections, were manufactured by PrimaPharma of San Diego, a company that FDA said had operated in violation of current Good Manufacturing Practices. FDA said the kits were unapproved, misbranded, and adulterated.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 26, 2010 * Vol. 17, No. 142
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 24 issue of Lancet (2010; 376).
Olaparib in Breast, Ovarian Cancer: In two studies, the orally active poly(ADP-ribose) polymerase (PARP) inhibitor olaparib showed efficacy in women with advanced breast and ovarian cancer.
In a Phase II trial, women with confirmed
BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer received continuous oral olaparib at the maximum tolerated dose (400 mg twice daily) or a lower dose (100 mg twice daily), with these results as measured by objective response rates (ORRs) (pp. 235–44): “Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).” (A. Tutt, andrew.tutt@icr.ac.uk)
In a Phase II trial, women with confirmed genetic BRCA1 or BRCA2 mutations, and advanced ovarian cancer had these responses to olaparib (
pp. 245–51): “Patients had been given a median of three (range 1–16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20–51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4–31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4).” (M. W. Audeh, william.audeh@cshs.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Efficacy of HPV Vaccine: Sustained protection and substantial reduction of burden were demonstrated in a study of a quadrivalent human papillomavirus vaccine (c3493). Among 17,622 women aged 16–26 years, three doses of a quadrivalent HPV vaccine (serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6 produced these results: “In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma.” (J. Dillner, joakim.dillner@med.lu.se)

>>>PNN JournalWatch
* Outcomes Associated with Opioid Use in the Treatment of Chronic Noncancer Pain in Older Adults: A Systematic Review and Meta-Analysis, in Journal of the American Geriatrics Society, 2010; 58: 1353–69. (C. Reid, mcr2004@med.cornell.edu)
* Does Pregnancy Provide Vaccine-like Protection Against Rheumatoid Arthritis, in
Arthritis & Rheumatism, 2010; 62: 1842–8. (K. A. Guthrie, kguthrie@fhcrc.org)
* Cardiovascular Risk-Estimation Systems in Primary Prevention: Do They Differ? Do They Make a Difference? Can We See the Future?, in
Circulation, 2010; 122: 300–10. (I. Graham, ian.graham@amnch.ie)
* Assessing Health Reform’s Impact on Four Key Groups of Americans, in
Health Affairs, 2010: 10.1377/hlthaff.2010.0595. (J. P. Newhouse, newhouse@hcp.med.harvard.edu)
* Disease Management 360o: A Scorecard Approach to Evaluating TRICARE’s Programs for Asthma, Congestive Heart Failure, and Diabetes, in
Medical Care, 2010; 48: 683–93. (W. Yang)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 27, 2010 * Vol. 17, No. 143
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and July 26 issue of the Archives of Internal Medicine (2010; 170).
Intervention in HIV-Discordant Couples: Couple-focused risk reduction was significantly more effective in increasing safe-sex practices among 535 HIV-discordant heterosexual couples than individual-focused health promotions, a study shows (10.1001/archinternmed.2010.261). Participants, with a mean age of 43 and 40% of men HIV positive, received couple-focused Eban HIV/STD risk-reduction intervention or attention-matched individual-focused health promotion comparison, with these results: “Generalized estimating equation analyses revealed that the proportion of condom-protected intercourse acts was larger among couples in the intervention group (0.77) than in the comparison group (0.47; risk ratio, 1.24; 95% confidence interval [CI], 1.09 to 1.41; P = .006) when adjusted for the baseline criterion measure. The adjusted percentage of couples using condoms consistently was higher in the intervention group (63%) than in the comparison group (48%; risk ratio, 1.45; 95% CI, 1.24 to 1.70; P < .001). The adjusted mean number of (log)unprotected intercourse acts was lower in the intervention group than in the comparison group (mean difference, –1.52; 95% CI, –2.07 to –0.98; P < .001).… The overall HIV seroconversion at the 12-month follow-up was 5 (2 in the intervention group, 3 in the comparison group) of 535 individuals, which translates to 935 per 100,000 population.” (W. Pequegnat, wpequegn@mail.nih.gov)
MI Risk with Protease Inhibitors: In a case–control study, researchers determined that the risk of myocardial infarction is increased with all protease inhibitors except saquinavir (pp. 1228–38). But several nuances were found in the study, which relied on data from the French Hospital Database on HIV. Cases were 289 patients with first MIs in 2000–06. They were compared with 884 matched controls, with these results: “Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample (odds ratios [ORs], 2.01; 95% confidence interval [CI], 1.11–3.64) but not in the subset of matched cases and controls (81%) who did not use cocaine or intravenous drugs (1.27; 0.64–2.49). Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir (OR, 1.53; 95% CI, 1.21–1.94 per year) and lopinavir with ritonavir (1.33; 1.09–1.61 per year). Exposure to all non-[nucleoside reverse transcriptase inhibitors] was not associated with risk of MI.” (D. Costagliola, dcostagliola@ccde.chups.jussieu.fr)
Optimizing Acid-Suppressing Drug Prescribing in Primary Care: A multifaceted intervention by an insurance company failed to change patterns of prescribing of acid-suppressing drugs by primary care practitioners, researchers report (pp. 1264–8). Provision of an optimization protocol, lists of patients on long-term therapy, and financial compensation for additional consultations had these effects of prescribers’ patterns: “At baseline, 2.4% of the patients (n = 967 506) of the participating practices used ASDs frequently on a long-term basis (>180 daily defined doses [DDDs] annually). During the 6-month intervention, 14.1% of the patients in the intervention group reduced ASD consumption compared with 13.7% in the control group (adjusted relative risk, 1.04; 95% confidence interval [CI], 0.97–1.11). Changes in intervention and control group in mean volume of ASD prescription per patient were similar (beta = 0.33 for DDD; 95% CI –3.00 to 3.60).” (H. M. Smeets, h.m.smeets@umcutrecht.nl)

>>>PNN NewsWatch
* FDA on Friday approved the first generic enoxaparin sodium injection (Sandoz Inc.).
* More hearings on
FDA’s Risk Evaluation and Mitigation Strategy approach to drug safety are set for today and tomorrow in suburban Washington, DC. Public comments will be heard on the program in general. The sessions follow last week’s rejection of FDA’s proposed REMS for long-acting and extended-release opioid products by two advisory panels. In a 25–10 vote, panel members told the agency that stronger measures are needed to address the epidemic of prescription drug abuse that has made CDC-reported deaths from prescription opioid drugs more common than those from heroin and cocaine combined.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 28, 2010 * Vol. 17, No. 144
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Aug. issue of Medical Care (2010; 48).
Assessing Local Prescribing Patterns: The “driving area of clinical care” (DACC) technique proved useful in identifying treatment variation in a local area, researchers report (pp. 710–7). Using Iowa Medicaid data on thiazide diuretic prescribing for hypertension as a test case, the investigators measured geographic prescribing patterns at the ZIP Code level, finding these results: “Each measure described a significant portion of the variation in the use of thiazide diuretics, and measured patient characteristics were well balanced across patient groups based on each measure. In multivariate analysis, the DACC-based measure had a stronger relationship with thiazide choice for individual patients than either primary care service areas–based or individual physician-based measures.” (G. Fang, gang-fang@uiowa.edu)

>>>Pharmacotherapy Report
Source:
Aug. issue of Pharmacotherapy (2010; 30).
Reducing Cardiovascular Risk in Primary Care: Nonspecialist pharmacists improved statin use but did not achieve reductions in cardiovascular risks among 176 adult patients in a study of protocol-driven care in a primary care clinic (pp. 766–75). After meeting with a pharmacist and receiving general counseling about cardiovascular disease, study participants were randomized to follow-up by the pharmacist or usual care for at least 6 months. The “simple pharmacist protocol, consisting of patient screening and cardiovascular risk stratification, identification and reminders about uncontrolled risk factors, and drug adherence support,” produced these results: “Neither the mean reduction in 10-year risk (–2.68 for the follow-up group and −1.25 for the single-contact group, one-tailed p = 0.098) nor individual risk factors were significantly different between groups. The proportion of patients exhibiting statin adherence of 80% or greater did not significantly differ between groups at study end (73.1% [57/78] and 80.0% [52/65], respectively, p = 0.333). However, 85.2% (75/88) in the follow-up group continued with statin therapy at the end of the study compared with 67.0% (59/88) in the single-contact group (p = 0.005). Statin initiations were more frequent in the follow-up group than in the single-contact group (75.0% [30/40) vs 48.9% [22/45], p = 0.013).” (D. Blackburn, d.blackburn@usask.ca)
Standardization of Renal Drug Dosing: A number of problems with renal drug dosing are uncovered in an analysis of prescribing information on new molecular entities from 1998 through 2007 and a Web-based survey of 204 nephrology and critical care pharmacy practitioners (pp. 776–86). Information from Micromedex, Lexi-Comp, Epocrates Rx, and American Hospital Formulary Service (AHFS) Drug Information and the survey showed the following trends for 44 NMEs: “The most common index of renal function was creatinine clearance; the Cockcroft–Gault equation was specified in the prescribing information of 11 NMEs. Standardization for body weight was inconsistent, with prescribing information for four NMEs reporting renal function in ml/minute/1.73 sq m. The prescribing information or tertiary sources did not mention use of estimated glomerular filtration rate (eGFR) or the Modification of Diet in Renal Disease Study (MDRD) equation. Epocrates Rx provided the most abbreviated renal dosing information, whereas AHFS Drug Information was the most comprehensive, and Lexi-Comp includes a renal function calculator. Nearly all (86%) clinical pharmacists indicated that automated eGFR is reported at their institutions, although they do not use these predictions for dosing in patients with impaired renal function, and their approaches to renal function estimation varied widely.” (T. C. Dowling, tdowling@rx.umaryland.edu)
PPIs & Clopidogrel: In the Clopidogrel Medco Outcomes Study, 16,690 patients had these outcomes following percutaneous coronary interventions with stent placement (pp. 787–96): “In the 9,862 patients receiving clopidogrel alone, 1,766 (17.9%) experienced a major adverse cardiovascular event compared with 1,710 patients (25.0%) who received concomitant clopidogrel-PPI therapy (adjusted hazard ratio 1.51, 95% confidence interval 1.39–1.64, p < 0.0001). Similar associations of increased risk were observed for each PPI studied (omeprazole, esomeprazole, pantoprazole, and lansoprazole).” (J. R. Teagarden)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 29, 2010 * Vol. 17, No. 145
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 29 issue of the New England Journal of Medicine (2010; 363).
Sipuleucel-T for Castration-Resistant Prostate Cancer: A therapeutic cancer vaccine prolonged overall survival in a Phase III trial of 512 men with metastatic castration-resistant prostate cancer but did not affect time to disease progression (pp. 411–22). Sipuleucel-T, an autologous active cellular immunotherapy, or placebo administered intravenously every 2 weeks produced these outcomes: “In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P = 0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P = 0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache.” (P. W. Kantoff, philip_kantoff@dfci.harvard.edu)
An editorialist, noting that “the findings in this study raise a few questions” while pointing to other agents in development, writes that “the prospects for improved therapy for prostate cancer have never been so encouraging” (
pp. 479–81): “Abiraterone blocks the synthesis of androgens; 51% of men who were treated with 1 g of the drug per day had a reduction in PSA levels of at least 50%, and 27% of patients had a partial tumor response. Experimental drug MDV3100 blocks nuclear translocation of the androgen receptor. In a phase 1 and 2 study, antitumor effects were noted at every dose of the agent, including a reduction in PSA levels of at least 50% in 56% of patients, responses in soft-tissue lesions in 22% and in stabilized bone lesions in 56%, and a reduction in circulating tumor-cell counts in 49%.” (D. L. Longo)
Geographic Variations in Medicare Costs: Large variations in Medicare medical costs in various parts of the U.S. are not offset by reduced pharmaceutical spending, authors write in a Perspectives article (pp. 405–9). In fact, the group notes, drug costs also need to be evaluated geographically: “Areas with high medical spending do not have offsetting lower pharmaceutical spending; in fact, if the coding practices in different regions are not too dissimilar, the substantial variation in pharmaceutical spending does not seem to be strongly associated with variations in medical spending at all. Spending on pharmaceuticals itself is variable and thus warrants scrutiny similar to that given to medical spending, in order to glean lessons about optimal prescribing, insurance characteristics, and resource allocation. Our findings reinforce the importance of understanding the drivers of geographic variation, since increases in medical spending or pharmaceutical spending do not appear to be associated with offsetting savings in the other realm. Using this more complete measure of spending reveals that area-level variation in total spending is not driven primarily by patient characteristics. These data may offer us an opportunity to gain insight into the underlying causes of the intensity of use of health care resources and the potential for public policy actions to improve the value of the health care delivered in the United States.” (Y. Zhang)

>>>PNN NewsWatch
* FDA yesterday approved an additional indication for glycopyrrolate: Treatment of chronic severe drooling caused by neurologic disorders in children ages 3–16 years. A decades-old drug formerly approved for treatment of peptic ulcers and reduction of salivation in patients under anesthesia. An oral solution of the drug will be marketed by Shionogi Pharma under the trade name Cuvposa.
* Requirements for FDA’s
Risk Evaluation and Mitigation Strategies “are burdensome for doctors and pharmacists, cost too much to carry out, and keep patients from accessing needed drugs,” writes a Wall Street Journal blogger.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
July 30, 2010 * Vol. 17, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2010; 33).
Rosiglitazone & Cognitive Impairment: In 97 older individuals with mild cognitive impairment (MCI) and type 2 diabetes, rosiglitazone protected against cognitive decline during a 36-week trial, researchers report (pp. 1706–11). Mental function was assessed using the Mini-Mental State Examination (MMSE), Rey Verbal Auditory Learning Test (RAVLT) total recall, and Trail Making Tests (TMT-A and TMT-B). Results showed the following with metformin, metformin plus rosiglitazone, and dietary interventions in patients recently started on antidiabetic regimens: “Mean ± SD values in the entire population were as follows: A1C 7.5 ± 0.5%, fasting plasma glucose (FPG) 8.6 ± 1.3 mmol/l, fasting plasma insulin (FPI) 148 ± 74 pmol/l, MMSE 24.9 ± 2.4, TMT-A 61.6 ± 42.0, TMT-B 162.8 ± 78.7, the difference between TMT-B and TMT-A [DIFFBA] 101.2 ± 58.1, and RAVLT 24.3 ± 2.1. At follow-up, ANOVA models tested changes in metabolic control parameters (FPI, FPG, and A1C). Such parameters improved in the metformin and metformin/rosiglitazone groups (Ptrend < 0.05 in both groups). ANCOVA repeated models showed that results for the metformin/rosiglitazone group remained stable for all neuropsychological tests, and results for the diet group remained stable for the MMSE and TMT-A and declined for the TMT-B (Ptrend = 0.024), executive efficiency (DIFFBA) (Ptrend = 0.026), and RAVLT memory test (Ptrend = 0.011). Results for the metformin group remained stable for the MMSE and TMTs but declined for the RAVLT (Ptrend = 0.011). With use of linear mixed-effects models, the interaction term, FPI × time, correlated with cognitive stability on the RAVLT in the metformin/rosiglitazone group (beta = −1.899; P = 0.009).” (G. Paolisso, giuseppe.paolisso@unina2.it)
Effects of Oral Antidiabetic Agents: Oral antidiabetic (OAD) agents work quickly to lower serum glucose levels, a meta-analysis shows, but those effects are modest, with A1C levels unlikely to fall by more 1.5 percentage points (pp. 1859–64): “A total of 61 trials reporting 103 comparisons met the selection criteria, which included 26,367 study participants, 15,760 randomized to an intervention drug(s), and 10,607 randomized to placebo. Most OAD agents lowered A1C levels by 0.5−1.25%, whereas thiazolidinediones and sulfonylureas lowered A1C levels by ~1.0–1.25%. By meta-regression, a 1% higher baseline A1C level predicted a 0.5 (95% CI 0.1–0.9) greater reduction in A1C levels after 6 months of OAD agent therapy. No clear effect of diabetes duration on the change in A1C with therapy was noted.” (D. Sherifali, dsherif@mcmaster.ca)
Patient Survival During Renal Replacement Therapy: Patients with type 1 diabetes and end-stage renal disease are living longer now than three decades ago, and the increase comes despite a marked jump in the age of patients at the start of therapy, a study shows (pp. 1718–23). A Finnish cohort of 1,604 patients was compared with 1,556 patients with glomerulonephritis who started RRT. Results showed: “Median survival time of patients with type 1 diabetes increased progressively from 3.60 years during 1980–1984 to >8 years in 2000–2005. In 2000–2005, the unadjusted relative risk of death was 0.55 compared with 1980–1984. After adjustment for the most important variables, the corresponding relative risk of death was only 0.23. For patients with glomerulonephritis, the adjusted relative risk decreased to a lesser extent to 0.30 (P = 0.007).” (M. Haapio, mikko.haapio@hus.fi)

>>>PNN NewsWatch
* Eosinophilic pneumonia during daptomycin (Cubicin) therapy is the subject of an FDA drug safety alert issued yesterday. Health professionals should closely monitor patients being treated with daptomycin for this condition, FDA said. Patients on the drug should immediately contact their health professional if they develop a new or worsening fever, cough, shortness of breath, or difficulty breathing.
* Women using
Evamist, a transdermal spray formulation of estradiol, should avoid contact of the area of application (usually the inside of the forearm) with children and pets, FDA is warning. Premature puberty can be induced in exposed children, with breast enlargement in those of either gender and nipple development in girls. Pets can have similar symptoms plus vulvar swelling.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 2, 2010 * Vol. 17, No. 147
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 31 issue of Lancet (2010; 376).
HDL Utility in High-Dose Statin Therapy: While HDL cholesterol levels are useful during initial cardiovascular assessments, they become less so after patients have been treated with high-dose statin therapy, JUPITER researchers report (pp. 333–9). Based on a primary endpoint of first nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularisation, or cardiovascular death, rosuvastatin or placebo produced these results in adults without diabetes or cardiovascular disease: “For 17,802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p < 0.0001). In 8,901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43–3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35–0.83, p = 0.0039) and on-treatment (0.55, 0.35–0.87, p = 0.0047). By contrast, among the 8,900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14–1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62–2.03, p = 0.82) or on-treatment (1.03, 0.57–1.87, p = 0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group.” (P. M. Ridker, pridker@partners.org)
Mortality Risk in HIV Infection: Higher-than-normal mortality rates were detected in a study of people living with HIV who had never received antiretroviral therapy (ART) but still maintained high CD4 levels (pp. 340–5). However, because men who had sex with men had only modest increases in mortality, investigators in the Study Group on Death Rates at High CD4 Count in Antiretroviral Naive Patients surmised that increased mortality risks might be the result of non-HIV risk factors. Nevertheless, early ART should be assessed as a way of reducing mortality risk, the group concluded.

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Calcium Supplements & MI: Administered without vitamin D, calcium supplements increase patients’ risk of myocardial infarction and other serious cardiovascular events, according to a meta-analysis of 15 trials (c3691): “In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02 to 1.67, P = 0.035). Non-significant increases occurred in the incidence of stroke (1.20, 0.96 to 1.50, P = 0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, P = 0.057), and death (1.09, 0.96 to 1.23, P = 0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01 to 1.59, P = 0.038).” (I. R. Reid, i.reid@auckland.ac.nz)
After noting that evidence is lacking that calcium/vitamin D supplements are effective for treating osteoporosis, an editorialist reaches this conclusion (
c3856): “On the basis of the limited evidence available, patients with osteoporosis should generally not be treated with calcium supplements, either alone or combined with vitamin D, unless they are also receiving an effective treatment for osteoporosis for a recognised indication. Research on whether such supplements are needed as an adjunct to effective agents is urgently required.” (J. G. F. Cleland, j.g.cleland@hull.ac.uk)

>>>PNN JournalWatch
* Treatment and Care for Injecting Drug Users with HIV Infection: A Review of Barriers and Ways Forward, in Lancet, 2010; 376: 355–66. (D. Wolfe, dwolfe@sorosny.org)
* Cost-Effectiveness of Interventions to Prevent and Control Diabetes Mellitus: A Systematic Review, in
Diabetes Care, 2010; 33: 1872–94. (R. Li, eok8@cdc.gov)
* 2010 Consensus Statement on the Worldwide Standardization of the Hemoglobin A1C Measurement, in
Diabetes Care, 2010; 33: 1903–4. (R. Hanas, ragnar.hanas@vgregion.se)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 3, 2010 * Vol. 17, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Aug. 3 issue of the Annals of Internal Medicine (2010; 153).
Low-Carb v. Low-Fat Diets: Weight loss can be achieved with either low-carbohydrate or low-fat diets, but cardiovascular benefits accrue only with the low-carbohydrate option, a study shows (pp. 147–57). At three academic medical centers, 307 adults with a mean age of 45.5 years and a mean body mass index of 36.1 kg/sq m had these outcomes when assigned to low-carbohydrate (20 g/day for 3 months, then increases of 5 g/day per week until stable, desirable weight was achieved) or low-fat (1200–1800 kcal/day; ≤30% calories from fat) diet: “Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years.” (G. D. Foster, gfoster@temple.edu)
Clinical Drug Trial Outcomes: Drug trials funded by industry take longer to get published and report more favorable outcomes than other clinical drug trials, researchers report (pp. 158–66). Using data on the website ClinicalTrials.gov, investigators analyzed trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006. Results showed: “Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization–funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization–funded trials without industry contributions (P = 0.005 across groups).” (F. T. Bourgeois, florence.bourgeois@childrens.harvard.edu)
CER Progress Report: Investment of $1.1. billion in stimulus-bill money into comparative effectiveness research has yielded these results, an author writes (early release): “President Obama sees ever-rising health care costs as a principal threat to the nation’s fiscal solvency and believes that research can help to solve the problem. Because he has taken the first steps to test this hypothesis, the immediate future of CER looks bright. In the past 16 months, federal legislation has launched CER, and federal agencies have spent a large bolus of CER funding expeditiously and wisely. However, compared with what lies ahead, these remarkable accomplishments will seem relatively trivial. In the next decade, the United States must absorb 32 million currently uninsured people into the health care system while simultaneously improving the quality of care and slowing cost increases. These accomplishments will require a transformation of U.S. health care. Comparative effectiveness research is a necessary part of this change, but it is hardly sufficient to achieve it. Even if it succeeds in providing clearer guidance on what works best and in whom, CER could still become the scapegoat for failure to achieve the larger goals of health care reform.” (H. C. Sox, hsox@comcast.net)

>>>PNN NewsWatch
* FDA has approved influenza vaccine for the 2010–11 season, and CDC has issued guidelines for their use.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 4, 2010 * Vol. 17, No. 149
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (2010; 126).
I.V. Antibiotics & Urinary Tract Infections: Based on findings that length of antibiotic therapy is not associated with treatment failure, a study of infants hospitalized with urinary tract infections shows that shorter antibiotic courses might be feasible (pp. 196–203). Retrospective cohort analysis of infants younger than 6 months of age whose 1999–2004 hospitalizations were recorded in the Pediatric Health Information System showed the following: “Of the 12,333 infants who met the inclusion criteria, 240 (1.9%) experienced treatment failure. The treatment failure rates were 1.6% for children who received short-course intravenous antibiotic treatment and 2.2% for children who received long-course treatment. Treatment courses varied substantially across hospitals and with patient-level characteristics. After multivariate adjustment, including propensity scores, there was no significant association between treatment group and outcomes, with an odds ratio for long versus short treatment of 1.02 (95% confidence interval: 0.77–1.35). Known presence of genitourinary abnormalities, but not age, predicted treatment failure.” (P. W. Brady)
Vitamin A Supplements in NICUs: Marked variation in use of vitamin A supplementation remains among neonatal intensive care units, a study shows, despite increasing overall use of these products (e367–73). An analysis of extremely low birth weight infants who were admitted within 7 days of birth to NICUs participating in the Pediatric Health Information System database in 2005–08 and a survey of NICU medical directors provided these insights: “Among 4,184 eligible infants cared for in 30 NICUs, 1,005 infants (24%) received vitamin A. Eighteen centers (60%) used vitamin A for some patients. Infants discharged in 2007 (odds ratio: 2.7 [95% confidence interval: 1.4–5.3]) and 2008 (odds ratio: 2.8 [95% confidence interval: 1.4–5.8]), compared with 2005, were more likely to receive vitamin A. NICU medical directors from centers using vitamin A, compared with centers that did not adopt vitamin A supplementation, reported stronger beliefs in the efficacy of vitamin A to reduce the incidence of bronchopulmonary dysplasia (83% vs 33%; P = .03) and in the ease with which vitamin A could be implemented (75% vs 22%; P = .02).” (H. C. Kaplan)
Management of Phenylketonuria: In a state-of-the-art review of phenylketonuria, authors provide these assessment of “important [unanswered] questions on the management of this disorder” (pp. 333–41): “The mainstay of treatment is a phenylalanine-restricted diet, but its application varies between and within countries. Beyond diet treatment, there is a lack of consensus on the use of newer treatments such as tetrahydrobiopterin. Although neonatal screening and early treatment has meant that most well-treated children grow up with near-normal IQ scores, the effect of relaxing metabolic control on cognitive and executive function later in life is still not fully understood. Although it is clear from the available literature that the active control of blood phenylalanine levels is of vital importance, there are other treatment-related factors that affect outcome. A uniform and firmly evidence-based approach to the management of phenylketonuria is required.” (F. Feillet)

>>>PNN NewsWatch
* FDA is warning consumers about ingestion of an industrial bleach product and use of two dietary supplements. Miracle Mineral Supplement, or MMS, is distributed on Internet sites and through online auctions, FDA said. The product, 28% sodium chlorite solution, is used for stripping textiles and in industrial water treatment. But, FDA said, the distributors instruct consumer to mix the solution with citrus or other acidic juices. High doses of the bleach can cause nausea, vomiting, diarrhea, and symptoms of severe dehydration, the agency advised. FDA also warned that the dietary supplements ejaculoid XXTREME and stimuloid II contain sulfoaildenafil, an analogue of sildenafil.
* Two lots of
NeoProfen, Lundbeck’s brand of ibuprofen lysine, are being recalled because of visible particulate matter, FDA said. Separately, the agency warned of serious medication errors when nimodipine oral capsules are given intravenously. The drug can produce death, cardiac arrest, severe hypotension, and other complications when administered intravenously.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 5, 2010 * Vol. 17, No. 150
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 5 issue of the New England Journal of Medicine (2010; 363).
Suicidality & Antiepileptic Drugs: While previous findings of a link between suicide-related events and use of antiepileptic drugs are confirmed in a study of 5 million patients, the association was significant only for those with depression and among subsets who did not have epilepsy, depression, or bipolar disorder (pp. 542–51). Among patients in the U.K., these associations between use and suicidality were noted: “In a cohort of 5,130,795 patients, the incidence of suicide-related events per 100,000 person–years was 15.0 (95% confidence interval [CI], 14.6 to 15.5) among patients without epilepsy, depression, bipolar disorder, or antiepileptic-drug treatment, 38.2 (95% CI, 26.3 to 53.7) among patients with epilepsy who did not receive antiepileptic drugs, and 48.2 (95% CI, 39.4 to 58.5) among patients with epilepsy who received antiepileptic drugs. In adjusted analyses, the use of antiepileptic drugs was not associated with an increased risk of suicide-related events among patients with epilepsy (odds ratio, 0.59; 95% CI, 0.35 to 0.98) or bipolar disorder (1.13; 95% CI, 0.35 to 3.61) but was significantly associated with an increased risk among patients with depression (1.65; 95% CI, 1.24 to 2.19) and those who did not have epilepsy, depression, or bipolar disorder (2.57; 95% CI, 1.78 to 3.71).” (A. Arana, arana.riskmr@gmail.com)
New Agents for Hereditary Angioedema: Three articles detail the utility of investigational agents in prophylaxis and treatment of patients with hereditary angioedema.
Nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks by more than 2 hours and, used prophylactically, halved the frequency of acute attacks in studies of patients with hereditary angioedema (
pp. 513–22). The treatment study included 68 patients, while 22 patients participated in the prophylaxis study. Those receiving the C1 inhibitor concentrate prophylactically “also had significant reductions in both the severity and the duration of attacks, in the need for open-label rescue therapy, and in the total number of days with swelling,” researchers report. (B. L. Zuraw, bzuraw@ucsd.edu)
Significant improvements in 71 patients with hereditary angioedema followed administration of ecallantide, a recombinant plasma kallikrein inhibitor (
pp. 523–31). Treatment outcome scores, which used a scale of –100 (significant worsening) to +100 (significant improvement), were 50.0 in the ecallantide group and 0 in the placebo group, the investigators note. “The estimated time to significant improvement was 165 minutes with ecallantide versus more than 240 minutes with placebo (P = 0.14),” the article states. “There were no deaths, treatment-related serious adverse events, or withdrawals owing to adverse events.” (M. Cicardi, marco.cicardi@unimi.it)
In patients with hereditary angioedema presenting with cutaneous or abdominal attacks, a selective bradykinin B2 receptor antagonist, icatibant, provided significant benefits in a comparison with tranexamic acid in one study but was no better than placebo in a second trial (
pp. 532–41). In the For Angioedema Subcutaneous Treatment (FAST) 1 and 2 trials, 56 and 74 patients were randomized. The median times to clinically relevant relief of symptoms were 2.5 and 4.6 hours with icatibant and placebo in FAST-1, respectively, a nonsignificant difference. In FAST-2, those values were 2.0 and 12.0 hours with icatibant and tranexamic acid, respectively. “The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial,” the researchers add. (A. Banerji, abanerji@partners.com)
An editorialist writes of “therapies old and new” for hereditary angioedema (
pp. 581–3): “Only nanofiltered C1 inhibitor concentrate was tested (and proved effective) for prophylaxis—an important but neglected area. To save lives, acute attacks must be treated promptly. Plasma-derived C1 inhibitor has proved to be safe and effective during decades of use. Newer agents eliminate the perceived risk of infection; some provide additional target specificity.… Practical matters, particularly the stability of the drug and the route of administration, are likely to be critical, because optimal therapy requires prompt self-administration at the first hint of an attack.” (B. P. Morgan)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 6, 2010 * Vol. 17, No. 151
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2010; 58).
Warfarin Prescribing in VA Nursing Home Patients: Patients receiving warfarin in Veterans Affairs nursing homes are generally on appropriate doses with effective monitoring, a retrospective cohort study shows (pp. 1475–80). During the first half of 2008 in five VA homes, these results were noted for veterans on warfarin: “Over 6 months, 160 patients received 10,380 person–days of warfarin. INRs were in the therapeutic range for 55% of the person–days, and 99% of the INR tests were repeated within 4 weeks of the previous result. On an individual level, 49% of patients had INRs in the target range for 50% or more of their person–days. Achieving this outcome was more likely in patients with prevalent warfarin use than with new use (adjusted odds ratio (AOR) = 2.86, 95% confidence interval (CI) = 1.06–7.72). Conversely, patients with a history of a stroke (AOR = 0.38, 95% CI = 0.18–0.80) were less likely to have therapeutic INRs for 50% or more of their days.” (S. L. Aspinall, sherrie.aspinall@va.gov)
Encouraging Seniors to Become Active: Among community-dwelling seniors with chronic diseases in two centers in Los Angeles, an activation intervention—in the form of money for watching motivational videos—showed promise and should be investigated further, researchers report (pp. 1496–503). Participants in one center received a $50 gift card if they attended at least three group screenings of videos that informed and motivated viewers about self-management of chronic conditions. Those in the other center received no incentive for attendance. Results showed: “Participants attending the encouraged senior center were more likely to attend three or more group screenings (77.8% vs 47.2%, P = .001). At 6-month follow-up, participants from either center who attended three or more group screenings (n = 74, 64%) reported significantly greater activation (P < .001), more minutes walking (P < .001) and engaging in vigorous physical activity (P = .006), and better health-related quality of life (Medical Outcomes Study 12-item Short-Form Survey (SF-12) mental component summary, P < .001; SF-12 physical component summary, P = .002).” (D. L. Frosch, froschd@pamfri.org)
Changing Medication Use with Increased Death Probability: In a methodological study of older Medicare beneficiaries, researchers show that analysis of medication intensity can be measured by mean number of prescription fills per month and that this can be associated with generally appropriate changes in prescribing patterns that reflect predicted probabilities of death (pp. 1549–55). Specifically, the investigators note, intensity of use of symptom-relief medications rises with increased probability of death, and use of maintenance medications such as statins and agents for osteoporosis declines: “For symptom relief medications, there is relatively constant use with increasing probability of death, along with greater intensity of use. For the two chronic medications, there was a monotonic decrease in use but at a relatively constant intensity. Decline in statin use ranged from 34.4% in the lowest mortality stratum to 17.6% for those in the highest (P < .001). Use of osteoporosis drugs fell from 10.4% to 6.6% over the same range (P < .001).” (T. Shaffer, tshaffer@rx.umaryland.edu)

>>>PNN NewsWatch
* As A/H3N2 influenza infections begin emerging in several states, the CDC’s Advisory Committee on Immunization Practices has restricted use of one brand of influenza vaccine in young children, pharmacist.com reports. An outbreak of H3N2 has occurred in two nonbordering counties in eastern Iowa, CDC reports, and isolated infections are occurring in several states. Clinicians need to be aware that influenza can occur in summer months when patients present with flulike symptoms, CDC said. ACIP, during a conference call on Thursday, voted to recommend that Merck’s Afluria not be used in children 6 months to 8 years of age unless no other product is available and benefits exceed risks for the patient. The recommendation is based on identification of a higher rate of fever with convulsions in a small number of children who had received this product in Australia, where it is marketed by CSL as Fluvax.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 9, 2010 * Vol. 17, No. 152
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 7 issue of Lancet (2010; 376).
Intensive Glycemic Control in Diabetes: Higher mortality in an intensive glycemic therapy arm led to early termination of the ACCORD trial, researchers report, with the implication that the “microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease–related mortality, increased weight gain, and high risk for severe hypoglycaemia” (pp. 419–30). Targeting of A1C levels to 6% or less or 7.0–7.9% led to these changes in first (dialysis or renal transplantation, high serum creatinine, or retinal photocoagulation or vitrectomy) and second (peripheral neuropathy plus the first composite outcome) composite outcomes: “10,251 patients were randomly assigned, 5,128 to the intensive glycaemia control group and 5,123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5,107 patients in the intensive group versus 444 of 5,108 in the standard group (HR 1.00, 95% CI 0.88–1.14; p = 1.00), and the second composite outcome was noted in 1,591 of 5,107 versus 1,659 of 5,108 (0.96, 0.89–1.02; p = 0.19). Results were similar at study end (first composite outcome 556 of 5,119 vs 586 of 5,115 [HR 0.95, 95% CI 0.85–1.07, p = 0.42]; and second 1,956 of 5,119 vs 2,046 of 5,115, respectively [0.95, 0.89–1.01, p = 0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p < 0.05).” (F. Ismail–Beigi, faramarz.ismail-beigi@case.edu)
Once-Weekly Exenatide: Compared with either sitagliptin or pioglitazone in 491 patients with type 2 diabetes, once-weekly exenatide significantly improved glucose control while allowing weight loss and producing few hypoglycemic episodes, the DURATION-2 trial shows (pp. 431–9). Subcutaneous exenatide 2 mg once weekly, oral sitagliptin 100 mg once daily, or oral pioglitazone 45 mg once daily produced these outcomes: “Treatment with exenatide reduced HbA1c (least square mean –1.5%, 95% CI –1.7 to –1.4) significantly more than did sitagliptin (–0.9%, –1.1 to –0.7) or pioglitazone (–1.2%, –1.4 to –1.0). Treatment differences were −0.6% (95% CI –0.9 to –0.4, p < 0.0001) for exenatide versus sitagliptin, and −0.3% (–0.6 to –0.1, p = 0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (–2.3 kg, 95% CI–2.9 to −1.7) was significantly greater than with sitagliptin (difference –1.5 kg, 95% CI –2.4 to –0.7, p = 0.0002) or pioglitazone (difference –5.1 kg, –5.9 to –4.3, p < 0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n = 38, 24%, and n = 16, 10%, respectively) and diarrhoea (n = 29, 18%, and n = 16, 10%, respectively); upper-respiratory-tract infection (n = 17, 10%) and peripheral oedema (n = 13, 8%) were the most frequent events with pioglitazone.” (R. M. Bergenstal)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Preventing Dementia: Eating fruits and vegetables and reducing diabetes and depression are collectively more or just as important in the prevention of dementia than addressing genetic causes, a prospective cohort study shows (c3885). Among 1,433 people older than 65 in France, a Cox model showed these contributors to dementia: crystallized intelligence, 18.11%; depression, 10.31%, fruit and vegetable consumption, 6.46%; diabetes, 4.88%; and apolipoprotein E epsilon-4 allele, 7.11%. (K. Ritchie, karen.ritchie@inserm.fr)

>>>PNN JournalWatch
* Psychopathology in Children and Adolescents with Migraine in Clinical Studies: A Systematic Review, in Pediatrics, 2010; 126: 323–32. (J. Bruijn)
* Cannabis Use and the Course of Schizophrenia: 10-Year Follow-Up After First Hospitalization, in
American Journal of Psychiatry, 2010; 167: 987–93. (D. J. Foti)
* Sleep and Hypertension, in
Chest, 2010; 138: 434–43. (D. A. Calhoun, dcalhoun@uab.edu)
* Systematic Review and Meta-analysis: Renal Safety of Tenofovir Disoproxil Fumarate in HIV-Infected Patients, in
Clinical Infectious Diseases, 2010; 51: 496–505. (M. Tonelli)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 10, 2010 * Vol. 17, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 9/23 issue of the Archives of Internal Medicine (2010; 170).
Medication Information in Community Pharmacies: Community pharmacies do a good job of distributing consumer medication information (CMI) with prescription medications, a study shows, but the quality of that information is suspect (pp. 1317–24). The researchers conclude that “private sector initiatives to provide useful CMI have failed,” adding these details from 365 pharmacies that filled lisinopril and metformin prescriptions for professional shoppers: “Six percent of pharmacies did not provide any written CMI. A mean (SD) of 60.2% (20.7%) and 57.7% (20.1%) of the criteria for useful CMI were met for lisinopril and metformin prescriptions, respectively. Shortcomings concerned especially ‘directions about use’ with means of 53.4% (95% confidence interval [CI], 51.4%–56.5%) and 45.6% (43.7%–47.6%), and ‘comprehensibility/legibility,’ with means of 43.8% (42.6%–44.9%) and 42.6% (41.1%–43.7%) for lisinopril and metformin, respectively. The CMI leaflets ranged from 33 to 2,482 words, with more than 1,000-word differences among those meeting higher than 80% of the content criteria, suggesting large variations in conciseness. Chain pharmacies had better adherence to content criteria than did independent stores, with mean differences of 22.1% (95% CI, 15.8%–28.4%) for lisinopril and 21.1% (95% CI, 14.9%–27.3%) for metformin.” (A. G. Winterstein, almut@cop.ufl.edu)
Medicare Part D & Out-of-Pocket Expenses: Medicare beneficiaries who previously lacked prescription drug coverage are benefitting financially from Part D but at a relatively large cost to the federal government, researchers report (pp. 1325–30). A longitudinal study of out-of-pocket expenditures for medications by 1,504 beneficiaries shows these results in 2005 and 2006: “Mean annual out-of-pocket expenditures on medications decreased by 32% ($320; 95% confidence interval [CI], $250–$391), from $1,011 to $691, in the year after Part D was implemented for all Medicare beneficiaries in the Medical Expenditure Panel Survey. Mean annual out-of-pocket expenditures on medications decreased by 49% ($748; 95% CI, $600–$897), from $1,533 to $784, in beneficiaries without previous drug coverage who enrolled in a Part D plan. Beneficiaries who did not enroll experienced a mean reduction of 32% ($353; 95% CI, $188–$518), from $1,116 to $763. Mean annual out-of-pocket expenditures on medications remained similar in dual Medicare and Medicaid beneficiaries.” (C. Millett, c.millett@imperial.ac.uk)
Optimizing Medication Use with CPOE: Alerts generated by a computerized provider order entry (CPOE) drug warning system can reduce the number of potentially inappropriate medications (PIMs) ordered for patients 65 years or older, researchers report (pp. 1331–6). Comparing pre-CPOE 2004 orders with those generated in 2005–08, researchers determined: “The mean (SE) rate of ordering medications that were not recommended dropped from 11.56 (0.36) to 9.94 (0.12) orders per day after the implementation of a CPOE warning system (difference, 1.62 [0.33]; P < .001), with no evidence that the effect waned over time. There were no appreciable changes in the rate of ordering medications for which only dose reduction was recommended or that were not targeted after CPOE implementation. These effects persisted in autoregressive models that accounted for secular trends and season (P < .001).” (M. L. P. Mattison, mmattiso@bidmc.harvard.edu)
Allopurinol Treatment of Gout in Patients with HF: A case–control analysis confirms beneficial effects of allopurinol in patients with gout and heart failure (pp. 1358–64). Analysis of health care databases in Quebec showed that 25,090 patients with gout and HF had a 64% higher risk of HF readmission and death, but these outcomes occurred 31% less often among those on continuous allopurinol. (L. Pilote, louise.pilote@mcgill.ca)

>>>PNN NewsWatch
* FDA yesterday announced recalls of two more dietary supplements that it says are adulterated with prescription medications. Affected are all lots of Revivexxx Extra Strength (containing undeclared tadalafil, FDA says) and Solo Slim/Solo Slim Extra Strength (didesmethyl sibutramine) with expiration dates of Aug. 2013 or earlier.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 11, 2010 * Vol. 17, No. 154
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 11 issue of JAMA (2010; 304).
Trends in MRSA Infections: Methicillin-resistant Staphylococcus aureus (MRSA) infections have declined in hospital settings, but iatrogenic community cases increased during 2005 through 2008, researchers report (pp. 641–7). In nine metropolitan areas with 15 million people, laboratory-identified episodes of invasive MRSA, including bloodstream infections (BSIs), were evaluated and classified. Results showed: “From 2005 through 2008, there were 21,503 episodes of invasive MRSA infection; 17,508 were health care associated. Of these, 15,458 were MRSA BSIs. The incidence rate of hospital-onset invasive MRSA infections was 1.02 per 10,000 population in 2005 and decreased 9.4% per year (95% confidence interval [CI], 14.7% to 3.8%; P = .005), and the incidence of health care–associated community-onset infections was 2.20 per 10,000 population in 2005 and decreased 5.7% per year (95% CI, 9.7% to 1.6%; P = .01). The decrease was most prominent for the subset of infections with BSIs (hospital-onset: –11.2%; 95% CI –15.9% to –6.3%; health care–associated community-onset: –6.6%; 95% CI –9.5% to –3.7%).” (A. J. Kallen, AKallen@cdc.gov)
Looking at MRSA alone “will always provide an incomplete epidemiological picture,” editorialists warn (
pp. 687–9): “Although the present decrease in MRSA may be used to argue for or against MRSA-specific vs general infection prevention interventions, these arguments would be missing the point. The decreases are occurring for a reason, and only by improving existing surveillance and prevention research programs can clinicians and infection control researchers begin to explain why. Such research will be essential for guiding future approaches to all S aureus prevention. Although MRSA may be in decline, it is unlikely that S aureus will follow suit.” (D. J. Diekema, daniel-diekema@uiowa.edu)
Oral Bisphosphonates & Esophageal Cancer: Esophagitis caused by oral administration of bisphosphonates is not linked to increased risk of esophageal cancer, a cohort analysis shows (pp. 657–63). In the U.K. General Practice Research Database, researchers found these patterns for 1996–2006: “Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. Excluding patients with less than 6 months’ follow-up, there were 41,826 members in each cohort (81% women; mean age, 70.0 (SD, 11.4) years). One hundred sixteen esophageal or gastric cancers (79 esophageal) occurred in the bisphosphonate cohort and 115 (72 esophageal) in the control cohort. The incidence of esophageal and gastric cancer combined was 0.7 per 1,000 person–years of risk in both the bisphosphonate and control cohorts; the incidence of esophageal cancer alone in the bisphosphonate and control cohorts was 0.48 and 0.44 per 1,000 person–years of risk, respectively. There was no difference in risk of esophageal and gastric cancer combined between the cohorts for any bisphosphonate use (adjusted hazard ratio, 0.96 [95% confidence interval, 0.74–1.25]) or risk of esophageal cancer only (adjusted hazard ratio, 1.07 [95% confidence interval, 0.77–1.49]). There also was no difference in risk of esophageal or gastric cancer by duration of bisphosphonate intake.” (C. R. Cardwell, c.cardwell@qub.ac.uk)
Trends in Emergent Care: A twofold greater-than-expected increase in the number of emergency department (ED) visits from 1997 through 2007 is cited as evidence that this care setting increasingly serves as a safety net for medically underserved patients (pp. 664–70). “Between 1997 and 2007, ED visit rates increased from 352.8 to 390.5 per 1,000 persons (rate difference, 37.7; 95% confidence interval [CI], –51.1 to 126.5; P = .001 for trend)…,” researchers found in the National Hospital Ambulatory Medical Care Survey. “Adults with Medicaid accounted for most of the increase in ED visits; the visit rate increased from 693.9 to 947.2 visits per 1,000 enrollees between 1999 and 2007 (rate difference, 253.3; 95% CI, 41.1 to 465.5; P = .001 for trend). Although ED visit rates for adults with ambulatory care–sensitive conditions remained stable, ED visit rates among adults with Medicaid increased from 66.4 in 1999 to 83.9 in 2007 (rate difference, 17.5; 95% CI, –5.8 to 40.8; P = .007 for trend). The number of facilities qualifying as safety-net EDs increased from 1,770 in 2000 to 2,489 in 2007.” (N. Tang, ntang@medicine.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 12, 2010 * Vol. 17, No. 155
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 12 issue of the New England Journal of Medicine (2010; 363).
Sildenafil in Advanced Idiopathic Pulmonary Fibrosis: In 180 patients with advanced idiopathic pulmonary fibrosis, oral sildenafil produced significant improvements in several secondary outcomes, but the drug failed to affect the study’s primary measure of increases in the 6-minute walk distance of 20% or more patients (pp. 620–8). Using doses of 20 mg three times daily, the investigators found these results during a 12-week placebo-controlled period and a 12-week follow-up period with all patients on open-label sildenafil: “The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P = 0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups.” (D. A. Zisman, dzisman@sansumclinic.org)
Treatment Intensity in Early-Stage Hodgkin’s Lymphoma: Reduction of intensity of therapy for early-stage Hodgkin’s lymphoma may be possible, according to a study that varied chemotherapy and radiation doses (pp. 640–52). In 1,370 patients with newly diagnosed disease, two or four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were followed by 20 or 30 Gy of radiation therapy. Results showed: “The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P = 0.39) or overall survival (P = 0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P = 1.00) or overall survival (P = 0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy.” (A. Engert, a.engert@uni-koeln.de)
In a review article on early-stage Hodgkin’s lymphoma, an author explains that treatments are now so effective that the current focus of research is on avoidance of late but serious adverse effects (
pp. 653–62): “The treatment of patients with early-stage Hodgkin’s lymphoma is one of the success stories of modern oncology. Today, more than 90% of such patients will survive for at least 5 years after diagnosis, regardless of their presenting characteristics, and treatment results have been so good that clinical trials are now focusing on minimizing the intensity of treatment to avoid late, potentially fatal toxic effects. It appears that the use of a standard chemotherapy regimen alone and use of fewer cycles of chemotherapy plus involved-field radiotherapy yield equivalent rates of survival among patients with low-risk, early-stage Hodgkin’s lymphoma, and this may also be the case for patients with high-risk, early-stage disease. Given the trend toward less intensive treatment, it will be important to watch for a point at which treatment becomes inadequate and the number of deaths from Hodgkin’s lymphoma will begin to increase.” (J. O. Armitage, joarmita@unmc.edu)
Improving Quality by Measuring Accountability: Measures of accountability must meet four process-related criteria if quality is to improve in health care, authors argue (pp. 683–8). First, evidence must be strong that the care process in question actually leads to improved outcomes. The measure must accurately capture whether the process has been provided, the authors continue, and the measure must address a process with “few intervening care processes that must occur before the improved outcome is realized.” Finally, the measure should be one whose implementation is not likely to lead to unintended adverse consequences. (M. R. Chassin)

>>>PNN NewsWatch
* Novacare LLC is recalling a number of dietary supplements because FDA says they contain undeclared sulfoaildenafil, an analogue of sildenafil. The products have been sold on the Internet and through retailers under a number of names, including Stiff Nights, Aziffa, and Size Matters.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 13, 2010 * Vol. 17, No. 156
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 17 issue of the Journal of the American College of Cardiology (2010; 56).
Reassessing “Normal” in LDL Concentrations: With new Adult Treatment Panel guidelines coming in 2011, authors of three articles discuss what should be considered the normal serum content of LDL cholesterol and at what age people should be considered for statin therapy.
“What are we waiting for?” asks the author of the first viewpoint/commentary piece (
pp. 627–9). Take the case of a 30-year-old man with hypercholesterolemia and a Framingham risk of 6%, the writer begins. He does not qualify for drug treatment. But if all of his risk factors remained the same over the next 30 years, his age would advance the Framingham risk to 20%, and he would then qualify for treatment. “In the intervening 30 years, the extent of his coronary atherosclerosis has been relentlessly increasing, and the probability that 1 of those maturing lesions will rupture has been increasing along with it,” the writer explains. “We have lost 30 years during which it might have been possible to significantly slow progression and improve the chances that this man could avoid a myocardial infarction.” (D. Steinberg, dsteinberg@ucsd.edu)
Pharmacogenetics could be the answer in preventing an inordinate expansion of statin use if LDL cholesterol normality were redefined, argues the author of the second article (
pp. 630–6). After noting that ATP III LDL-C levels “seem far too high,” he notes: “An inevitable outcome of change in the LDL-C initiation and target would be a significant increase in the use of statin drugs. The emergence of pharmacogenetic testing offers a possible solution to overuse. Although one reason for the failure of potent lipid-lowering therapy to markedly reduce cardiac events is the ‘too little/too late’ hypothesis; a second seldom considered reason is that the drugs are ineffective in as yet unrecognized subsets. Pharmacogenetics suggests that this is highly likely. For instance, one common polymorphism colloquially called KIF-6 (the kinesin-like protein 6 Trg 719 Arg polymorphism) is thought to influence both intracellular transport and endothelial function. In carriers of KIF-6, intensive statin therapy was associated with a 6.8-fold greater reduction in cardiac events than in noncarriers in the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial, despite the same level of on-treatment LDL-C and CRP. Conversely, noncarriers of the KIF-6 variant, approximately 40% of the U.S. population, experienced virtually no difference in adverse outcomes despite the major differences in on-treatment LDL-C levels between the atorvastatin 80-mg and pravastatin 40-mg treatment groups. Thus, the dose and/or use of statins coincident with altered initiation and target criteria could be tempered by better selection of therapeutic candidates if pharmacogenetic testing can provide insight into those most likely to benefit from therapy.” (J. S. Forrester, barbmd@gmail.com)
While noting that more research is needed regardless of whether the ATP IV panel aggressively alters the LDL recommendations, the authors of the final article envision a path forward (
pp. 637–40): “The approach advocated by Steinberg and Forrester is a reasonable next step: to consider statins for younger persons, perhaps starting at age 30, in those with risk factors that convey high lifetime (as opposed to 10-year) risk for CHD. Treating high-risk persons with more to gain in the long run increases the likelihood that treatment will eventually result in net benefit for patients. This approach will have a limited population-level impact because many events actually occur in the more numerous lower-risk people and thus would fall short of the impact envisioned by Forrester (‘unseating coronary disease as the nation’s leading killer&rsquoWinking. A dramatic expansion of treatment guidelines (including treatment of young adults with lower lifetime risk), along with excellent adherence, would be required to achieve this goal. Such a dramatic expansion in statin prescribing would expose many more people to the uncertain benefits, harms, and costs of lifelong statin therapy and is best approached incrementally by future guidelines.” (M. J. Pletcher, mpletcher@epi.ucsf.edu)

>>>PNN NewsWatch
* Increased risk of aseptic meningitis is associated with use of lamotrigine, FDA said yesterday. In patients with the condition and in whom no other cause is identifiable, drug discontinuation should be considered.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 16, 2010 * Vol. 17, No. 157
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 14 issue of Lancet (2010; 376).
Rimonabant for Prevention of Cardiovascular Events: Blockade of the endocannabinoid receptor with rimonabant increased suicides and produced other serious neuropsychiatric events, causing early termination of both a study of cardiovascular-event prevention and development of the drug, researchers report (pp. 517–23). At 974 hospitals in 42 countries, 18,695 patients at increased risk of vascular disease or with previous events indicating presence of such disease, investigators administered rimonabant 20 mg or placebo, with these results: “At a mean follow-up of 13.8 months (95% CI 13.6–14.0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3.9%) patients assigned to rimonabant and 375 (4.0%) assigned to placebo (hazard ratio 0.97, 95% CI 0.84–1.12, p = 0.68). With rimonabant, gastrointestinal (3,038 [33%] vs 2,084 [22%]), neuropsychiatric (3,028 [32%] vs 1,989 [21%]), and serious psychiatric side-effects (232 [2.5%] vs 120 [1.3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide.” (E. J. Topol, etopol@scripps.edu)
Writing an “obituary for a wonder drug,” editorialists note (
pp. 489–90): “Although the investigators stressed that rimonabant should not be seen as a miracle drug for weight loss, the public would probably see it as such. Medical supervision of rimonabant use, including periodic screening for neuropsychiatric side-effects, is unlikely to be strict in daily practice. Also, if used for cosmetic weight-reduction, the drug might be used episodically rather than long term, as in CRESCENDO. On the basis of these arguments, the European Medicines Agency’s decision seems appropriate. Similar arguments were made in the Agency’s decision to suspend sibutramine, another weight-loss drug with a slightly increased risk of cardiovascular side-effects.
“The story of rimonabant might be tarnished by low public and regulatory acceptance for a drug designed to counteract the consequences of our abundant lifestyle. Focus should now return to motivating patients to control their caloric intake and increase physical activity. Although cumbersome, this approach is causal and safe. New strategies to more effectively achieve these lifestyle changes are needed.” (S. M. Boekholdt)

>>>PNN NewsWatch
* An emergency contraceptive approved for use up to 5 days after unprotected intercourse or contraceptive failure was approved on Friday by FDA. Ella contains 30 mg of the progesterone agonist/antagonist ulipristal acetate. It requires a single dose. The dose may need to be repeated if vomiting occurs with 3 hours of administration. The safety and efficacy of ulipristal were demonstrated in two Phase III clinical trials. Adverse effects most frequently observed with the drug in clinical trials were headache, nausea, abdominal pain, dysmenorrhea, and fatigue.

>>>PNN JournalWatch
* Cardiovascular Effects of Marine Omega-3 Fatty Acids, in Lancet, 2010; 376: 540–50. (P. Saravanan, drplsuk@yahoo.co.uk)
* Disparities in Breast Cancer Mortality Trends Between 30 European Countries: Retrospective Trend Analysis of WHO Mortality Database, in
BMJ, 2010; 341: c3620. (P. Autier, philippe.autier@i-pri.org)
* Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment, in
Gastroenterology, 2010; 139: 393–408.e2. (A. Pietrangelo, antonello.pietrangelo@unimore.it)
* Cardiovascular Disease and CKD: Core Curriculum 2010, in
American Journal of Kidney Diseases, 2010; 56: 399–417. (M. J. Samak, msarnak@tuftsmedicalcenter.org)
* Epidemiology, Surveillance, and Prevention of Hepatitis C Virus Infections in Hemodialysis Patients, in
American Journal of Kidney Diseases, 2010; 56: 371–8. (P. R. Patel, ppatel@cdc.gov)
* Neoadjuvant Treatment of Unresectable Medullary Thyroid Cancer With Sunitinib, in
Journal of Clinical Oncology, 2010; 28: e390–2. (J. M. Cleary)
* Comparative Effectiveness Research, Evidence-Based Medicine, and the AAN, in
Neurology, 2010; 75: 562–7. (J. A. French, jacqueline.french@nyumc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 17, 2010 * Vol. 17, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 17 issue of the Annals of Internal Medicine (2010; 153).
Liability Outcomes with Medical-Error Disclosure: Claims and liability costs have not increased at the University of Michigan as a result of full disclosure and compensation offers for medical errors, an analysis shows (pp. 213–21). The policy was implemented in 2001. From 1995 to 2007, these patterns were noted for number of new claims for compensation, number of claims compensated, time to claim resolution, and claims-related costs: “After full implementation of a disclosure-with-offer program, the average monthly rate of new claims decreased from 7.03 to 4.52 per 100,000 patient encounters (rate ratio [RR], 0.64 [95% CI, 0.44 to 0.95]). The average monthly rate of lawsuits decreased from 2.13 to 0.75 per 100,000 patient encounters (RR, 0.35 [CI, 0.22 to 0.58]). Median time from claim reporting to resolution decreased from 1.36 to 0.95 years. Average monthly cost rates decreased for total liability (RR, 0.41 [CI, 0.26 to 0.66]), patient compensation (RR, 0.41 [CI, 0.26 to 0.67]), and non–compensation-related legal costs (RR, 0.39 [CI, 0.22 to 0.67]).” (A. Kachalia, akachalia@partners.org)
Steroid Pretreatment in Deceased Organ Donors: Posttransplantation acute renal failure was unaffected by administration of corticosteroids to organ donors after they had died, researchers report (pp. 222–30). At three renal transplantation centers in Austria and Hungary, methylprednisolone 1,000 mg or placebo was administered intravenously to 269 deceased, heart-beating organ donors at least 3 hours before organ harvesting. In 455 patients receiving kidneys from these donors, these results occurred: “52 of 238 recipients (22%) of kidneys from steroid-treated donors and 54 of 217 recipients (25%) of kidneys from placebo-treated donors had ARF (difference, 3 percentage points [95% CI, −11 to 5 percentage points]). One graft was lost on day 1 in each group, and 1 recipient in the placebo group died of cardiac arrest on day 2. The median duration of ARF was 5 days (interquartile range, 2 days) in the steroid group and 4 days (interquartile range, 2 days) in the placebo group (P = 0.31). The groups had similar trajectories of serum creatinine level in the first week (P = 0.72). Genomic analysis showed suppressed inflammation and immune response in kidney biopsies from deceased donors who received corticosteroids.” (R. Oberbauer, rainer.oberbauer@meduniwien.ac.at)
Quality of Hepatitis C Care: In the U.S., quality of care for chronic hepatitis C virus (HCV) infection is suboptimal, a national study indicates (pp. 231–9). Using data from a health insurance company research database, investigators conducted a retrospective cohort study, with these results: “Proportions of patients meeting quality indicators varied, ranging from 21.5% for vaccination to 79% for the HCV genotype testing indicator. Overall, 18.5% of patients (95% CI, 18% to 19%) received all recommended care. Older age and presence of comorbid conditions were associated with lower quality, whereas elevated liver enzyme levels, cirrhosis, and HIV infection were associated with higher quality. Patients who saw both generalists and specialists received the best care (odds ratio of receiving care for which a patient is eligible: specialists alone, 0.79 [CI, 0.66 to 0.95]; primary care physician alone, 0.44 [CI, 0.40 to 0.48]).” (F. Kanwal, fasiha.kanwal@va.gov)

>>>PNN NewsWatch
* Midodrine hydrochloride could soon be off the U.S. market, if a unique move made yesterday by FDA fails to produce postapproval evidence of benefits of the drug in patients with hypotension. Marketed as ProAmatine by Shire Development and generic companies, midodrine was approved in 1996 on an accelerated basis. FDA required a postapproval study to confirm that the drug provided clinical benefits through improvements in activities of daily living or other measures. In its first-ever “proposal to withdraw marketing approval,” FDA said that no such evidence has been provided, and the agency gave Shire 15 days to request a hearing on the matter. If no hearing is requested, marketers of generic versions of the drug would have 30 days to submit written comments. FDA will then consider the submissions and make a decision on whether to withdraw midodrine from the U.S. market.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 18, 2010 * Vol. 17, No. 159
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 18 issue of JAMA (2010; 304).
Gentamicin–Collagen Sponge Use in Cardiac Surgery: A gentamicin–collagen sponge, approved for use in cardiac surgery in 54 countries but not the U.S., failed to provide a significant advantage over no intervention among 1,502 American patients at high risk for sternal wound infections (pp. 755–62). In a Phase III trial that provided all patients with prophylactic systemic antibiotics and rigid sternal fixation, insertion of two sponges with a total gentamicin content of 260 mg between sternal halves at surgical closure provided with these outcomes when compared with no intervention: “Of 1,502 patients, 1,006 had diabetes (67%) and 1,137 were obese (body mass index >30) (76%). In the primary analysis, there was no significant difference in sternal wound infection in 63 of 753 patients randomized to the gentamicin–collagen sponge group (8.4%) compared with 65 of 749 patients randomized to the control group (8.7%) (P = .83). No significant differences were observed between the gentamicin–collagen sponge group and the control group, respectively, in superficial sternal wound infection (49/753 [6.5%] vs 46/749 [6.1%]; P = .77), deep sternal wound infection (14/753 [1.9%] vs 19/749 [2.5%]; P = .37), ASEPSIS score (mean [SD], 1.9 [6.4] vs 2.0 [7.2]; P = .67), or rehospitalization for sternal wound infection (23/753 [3.1%] vs 24/749 [3.2%]; P = .87).” (E. Bennett-Guerrero, Elliott.BennettGuerrero@Duke.edu)
Identifying Delirium at the Bedside: The Confusion Assessment Method (CAM) is the best method for detecting delirium at the bedside, a systematic review reports (pp. 779–86). The Mini-Mental State Examination (MMSE), widely used in research, was least useful, the authors concluded, adding these details for 25 studies of 11 instruments in 3,027 patients: “Positive results that suggested delirium with likelihood ratios (LRs) greater than 5.0 were present for the Global Attentiveness Rating (GAR), Memorial Delirium Assessment Scale (MDAS), [CAM], Delirium Rating Scale Revised-98 (DRS-R-98), Clinical Assessment of Confusion (CAC), and Delirium Observation Screening Scale (DOSS). Normal results that decreased the likelihood of delirium with LRs less than 0.2 were calculated for the GAR, MDAS, CAM, DRS-R-98, Delirium Rating Scale (DRS), DOSS, Nursing Delirium Screening Scale (Nu-DESC), and [MMSE]. The Digit Span test and Vigilance ‘A’ test in isolation have limited utility in diagnosing delirium. Considering the instrument’s ease of use, test performance, and clinical importance of the heterogeneity in the confidence intervals (CIs) of the LRs, the CAM has the best available supportive data as a bedside delirium instrument (summary-positive LR, 9.6; 95% CI, 5.8-16.0; summary-negative LR, 0.16; 95% CI, 0.09–0.29). Of all scales, the MMSE (score <24) was the least useful for identifying a patient with delirium (LR, 1.6; 95% CI, 1.2–2.0).” (C. L. Wong, camilla.wong@utoronto.ca)

>>>Rheumatology Highlights
Source:
Aug. issue of Arthritis & Rheumatism (2010; 62).
Effects of Rituximab on Gene Expression in Sjogren’s Syndrome: Anti-CD20 treatment modifies expression of genes in patients with Sjogren’s syndrome, researchers report, and this highlights “the importance of studying the differential expression of B cell and IFN pathway signaling molecules” (pp. 2262–71). In an open-label study of 15 patients, these results were noted: “With gene expression data obtained before treatment, patients could be correctly classified in terms of whether they would be responders or nonresponders to rituximab. Gene pathway analysis demonstrated that the B cell signaling pathway was the most profoundly differentially expressed before treatment in the responders compared with nonresponders. Subclassification of patients based on the level of infiltration also demonstrated differential expression of genes belonging to the interferon (IFN) pathway between responders and nonresponders. Furthermore, unsupervised analysis based on gene expression modification before and after treatment allowed identification of 8 genes that were differentially expressed between responders and nonresponders, with the difference remaining significant after Bonferroni correction.” (V. Devauchelle-Pensec, valerie.devauchelle-pensec@chu-brest.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 19, 2010 * Vol. 17, No. 160
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 19 issue of the New England Journal of Medicine (2010; 363).
Ipilimumab in Metastatic Melanoma: Overall survival was improved among patients with metastatic melanoma when ipilimumab was administered, either alone or in combination with glycoprotein 100 (gp100) peptide vaccine, researchers report (pp. 711–23). The fully human monoclonal antibody blocks cytotoxic T-lymphocyte–associated antigen 4, thereby potentiating an antitumor T-cell response. Included in the study were 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma whose disease had progressed while on therapy. In four induction courses given every 3 weeks, patients received ipilimumab 3 mg/kg plus gp100, ipilimumab alone, or gp100 alone, with these results: “The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P < 0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.” (F. S. Hodi, stephen_hodi@dfci.harvard.edu)
Cancer can be treated by “targeting the immune system,” an editorialist writes, but obstacles remain (
pp. 779–81): “Despite dramatic effects in a subgroup of patients receiving the anti–CTLA-4 drug, the majority of patients with metastatic melanoma do not respond to this agent, and further work is vital to improve these results. Future efforts should include the rational combination of anti–CTLA-4 agents or alternative checkpoint inhibitors with targeted therapies or other immune agents. Instead of attempting to marginally increase the median survival, the primary goal of these new combination therapies should be to enhance the percentage of long-term survivors, thereby elevating the ‘tail’ of the survival curve. It should be possible to realize this goal if there is adequate synergy and cooperation among academia, regulatory agencies, and the pharmaceutical industry.” (P. Hwu)
Early Palliative Care in Metastatic Non–Small-Cell Lung Cancer: Introduction of palliative care soon after diagnosis of metastatic non–small-cell lung cancer decreased the need for aggressive care at the end of life yet also improved survival, a study reports (pp. 733–42). Patients received either early palliative care with standard oncologic care or standard oncologic care alone. Quality of life and mood, measured using the Functional Assessment of Cancer Therapy–Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale, showed these results over 12 weeks: “Of the 151 patients who underwent randomization, 27 died by 12 weeks and 107 (86% of the remaining patients) completed assessments. Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (mean score on the FACT-L scale [in which scores range from 0 to 136, with higher scores indicating better quality of life], 98.0 vs. 91.5; P = 0.03). In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms (16% vs. 38%, P = 0.01). Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02).” (J. S. Temel, jtemel@partners.org)
Tai Chi for Fibromyalgia: Compared with wellness education and stretching, Yang-style tai chi improved symptoms of fibromyalgia and health-related quality of life, according to an NIH-funded study (pp. 743–54). Among 66 patients with fibromyalgia, those in the tai chi group had significantly improved scores on two instruments, compared with control patients. Scores on the Fibromyalgia Impact Questionnaire and both the physical and mental components of the 36-item Short-Form Health Survey were improved, and benefits were sustained over 24 weeks. (C. Wang, cwang2@tuftsmedicalcenter.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 20, 2010 * Vol. 17, No. 161
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (2010; 126).
Vitamin D & Food Allergy: Could correction of vitamin D deficiencies (VDDs) in young children stem the epidemic of food allergies (FAs)? Perhaps, authors write in a Rostrum article (pp. 217–22): “FA is the consequence of maladaptive immune responses to common and otherwise innocuous food antigens. Concurrent with the increase in FA is an epidemic of vitamin D deficiency (VDD) caused by several factors, especially decreased sunlight/UVB exposure. There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity. We propose a ‘multiple-hit’ model in which VDD in a developmentally critical period increases susceptibility to colonization with abnormal intestinal microbial flora and gastrointestinal infections, contributing to abnormal intestinal barrier permeability and excess and inappropriate exposure of the immune system to dietary allergens. A compounding effect (and additional ‘hit&rsquoWinking of VDD is the promotion of a pro-sensitization immune imbalance that might compromise immunologic tolerance and contribute to FA. We propose that early correction of VDD might promote mucosal immunity, healthy microbial ecology, and allergen tolerance and thereby blunt the FA epidemic in children.” (C. A. Camargo, ccamargo@partners.org)
Providing Adherence Information to Prescribers: Provided with adherence information through electronic prescription systems, interested clinicians can help patients with asthma adhere to inhaled corticosteroids, researchers report (pp. 225–31). In a southeast Michigan health system, adherence was estimated for nearly 2,700 patients using prescription and fill data. This information could be viewed by 88 intervention prescribers. Compared with 105 control providers, intervention prescribers changed outcomes when they took time to access the information: “At the study end for the intention-to-treat analysis, ICS adherence was not different among patients in the intervention arm compared with those in the control arm (21.3% vs 23.3%, respectively; P = .553). However, adherence was significantly higher among patients whose clinician elected to view their detailed adherence information (35.7%) compared with both control arm patients (P = .026) and intervention arm patients whose provider did not view adherence data (P = .002).” (L. K. Williams, kwillia5@hfhs.org)
Influenza Vaccination & Egg Allergy: No cases of anaphylaxis occurred in 830 patients with confirmed egg allergy who received an adjuvanted monovalent pandemic H1N1 influenza vaccine, a study reports (pp. 317–23). Concluding that reactions are theoretically possible but that administration appears safe, the investigators report these results when patients received vaccine either as a single dose or, if they had previous respiratory or cardiovascular reactions after egg ingestion, in two doses, the first with 10% of the total dose and the balance 30 minutes later: “Among the 830 patients with confirmed egg allergy, only 9% required the vaccine to be administered in divided doses. No patient had an anaphylactic reaction. Nine patients had minor allergic symptoms treated with an antihistamine (1 in the 60 minutes after vaccination and 8 in the following 23 hours), and 3 others received salbutamol (1 in the first 60 minutes after vaccination). Further vaccination of more than 3,600 other children with reported egg allergy caused no anaphylaxis based on the criteria of the Brighton Collaboration, although 2 patients received epinephrine for symptoms compatible with allergy.” (G. De Serres, gaston.deserres@ssss.gouv.qc.ca)

>>>PNN NewsWatch
* Medication therapy management has been in the news over the past week, reports pharmacist.com. In the New York Times, MTM services at an Augusta, GA, pharmacy were featured, and the article also explained how the family-owned Barney’s Pharmacy provides counseling, education, and even exercise classes to patients with diabetes. The chair of the American Medical Association Board of Trustees, Aradis Dee Hoven, MD, writes in the Aug. 23 American Medical News that collaborative drug therapy management agreements provide an effective way for pharmacists to increase contributions to the health care team.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 23, 2010 * Vol. 17, No. 162
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 21 issue of Lancet (2010; 376).
Naltrexone–Bupropion for Obesity: Patients with overweight or obesity benefit from a course of naltrexone plus bupropion, a study shows (pp. 595–605). In the Contrave Obesity Research I (COR-I) trial, 1,742 patients with high body mass index (BMI) values and dyslipidemia or hypertension received placebo or sustained-release naltrexone 16 or 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets, with these results: “Mean change in bodyweight was −1.3% (SE 0.3) in the placebo group, −6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p < 0.0001 vs placebo) and −5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p < 0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p < 0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p < 0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo.” (F. L. Greenway, frank.greenway@pbrc.edu)
Pentavalent Rotavirus Vaccine: Administered orally to young infants, a pentavalent rotavirus vaccine proved effective, leading authors to express support for WHO recommendations for expanded administration programs. Two studies are reported, one of 5,468 infants in sub-Saharan Africa (pp. 606–14; K. M. Neuzil, kneuzil@path.org) and another of 2,036 infants in Asia (pp. 615–23; J. C. Victor, cvictor@path.org). During a median of 527 days of monitoring, vaccine efficacy against severe rotavirus gastroenteritis in the first study was 39.3%. In the Asian trial, vaccine efficacy was 48.3% against severe disease during nearly 2 years of follow-up. In both trials, serious adverse events occurred in similar proportions of those receiving vaccine and placebo.

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Management of Remitted First-Episode Psychosis: Compared with placebo, maintenance therapy with quetiapine reduced relapses among 178 patients with first-episode psychosis, researchers report (c4024). Patients had received at least 1 year of antipsychotic drug therapy in 2003–06 when they were either continued on quetiapine 400 mg/day or switched to placebo. Results showed: “The Kaplan–Meier estimate of the risk of relapse at 12 months was 41% (95% confidence interval 29% to 53%) for the quetiapine group and 79% (68% to 90%) for the placebo group (P < 0.001). Although quetiapine was generally well tolerated, the rate of discontinuation due to adverse or serious adverse events was greater in the quetiapine group (18%; 16/89) than in the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; chi square = 3.20, df = 1; P = 0.07).” (E. Y. H. Chen, eyhchen@hku.hk)

>>>PNN JournalWatch
* Stroke Prevention and Treatment, in Journal of the American College of Cardiology, 2010; 56: 683–91. (J. D. Marsh, jdmarsh@uams.edu)
* Cardiac Index Is Associated with Brain Aging: The Framingham Heart Study, in
Circulation, 2010; 122: 690–7. (A. L. Jefferson, angelaj@bu.edu)
* Outcomes and Costs of Community Health Worker Interventions: A Systematic Review, in
Medical Care, 2010; 48: 792–808. (M. Viswanathan)
* Ashamed To Admit It: Owning Up to Medical Error, in
Health Affairs, 2010; 29: 1549–51. (D. Ofri, dofri@blreview.org)
* Why the Affordable Care Act Needs a Better Name: ‘Americare,’ in
Health Affairs, 2010; 29: 1496–7. (W. M. Sage, wsage@law.utexas.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 24, 2010 * Vol. 17, No. 163
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from the Annals of Internal Medicine (2010; 153).
Impact of Health Care Reform on Clinical Medicine: To “realize the full benefits of the Affordable Care Act, physicians will need to embrace rather than resist change,” according to an article with two White House coauthors (early release). After listing 10 changes that “will reshape the practice of medicine,” the authors write that either hospitals or physicians will be central in a reformed health care system: “These reforms will unleash forces that favor integration across the continuum of care. Some organizing function will need to be developed to track quality measures, account for and manage shared financial incentives, and oversee care coordination. Consequently, the health care system will evolve into 1 of 2 forms: organized around hospitals or organized around physician groups. These coordinating functions, to the extent that they currently exist, traditionally have been managed by hospitals or health plans. Only hospitals or health plans can afford to make the necessary investments in information technology and management skills. This is not inevitable. As physicians organize themselves into increasing larger groups—patient-centered medical home practices and accountable care organizations—they are, out of necessity, investing in information technology tools that are becoming both cheaper and more capable and investing in the acquisition or development of management skills that could provide these organizing functions efficiently for physicians groups.” (E. J. Emanuel)

>>>Health Affairs Highlights
Source:
Aug. issue of Health Affairs (2010; 29).
Quality of Care of Unsupervised Nurse Anesthetists: In 14 states that allow certified nurse anesthetists to practice without physician supervision, Medicare patient outcomes were not significantly different after procedures in which anesthesia was managed by anesthesiologists or teams versus nurse anesthetist solo groups, researchers report (pp. 1469–75). In 2001, CMS began allowing states to opt out of reimbursement requirements for surgeons or anesthesiologists to oversee provision of anesthesia by certified registered nurse anesthetists. Examination of Medicare data from 1999 through 2005 shows that nurse solo groups provided anesthesia for 21% of surgeries in 14 opt-out states, compared with 10% of procedures in non–opt-out states. Procedures handled by nurses alone or by teams of physicians and nurses were less complex than those handled by anesthesiologists working alone. Mortality rates fell generally over the 7-year period. For nurse anesthetists in opt-out states, mortality rates increased in the years before the CMS change and fell thereafter. Complications occurred less often over the study period, with improvements in care seen in all groups. Based on the findings, the authors write, “We recommend that CMS return to its original intention of allowing nurse anesthetists to work independently of surgeon or anesthesiologist supervision without requiring state governments to formally petition for an exemption. This would free surgeons from the legal responsibility for anesthesia services provided by other professionals. It would also lead to more-cost-effective care as the solo practice of certified registered nurse anesthetists increases.” (J. Cromwell, jcromwell@rti.org)
Educating Health Professionals for Team-Based Care: Fundamental changes are needed in the education of health professionals if the promises of team-based primary care are to be realized, authors write (pp. 1476–80). Working toward a goal of “collaborative education,” university administrators and faculty should consider the need for “a revolution in how we train our providers”: “Team-based primary care offers the potential to dramatically improve the quality and efficiency of care, but its broader adoption is hindered by an education system that trains health professions in silos. Collaborative models that educate multiple practitioners together are needed to create a new generation of health professionals able to work in efficiently functioning teams. Changes in professional cultures, organizational structures, clinical partnerships, admissions, accreditation, and funding models will be required to support the expansion of collaborative education effectively.” (B. Schuetz, bschuetz@nehi.net)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 25, 2010 * Vol. 17, No. 164
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 25 issue of JAMA (2010; 304).
Birth Defects with Antiviral Agents: Among babies born to women who used antiviral agents for herpes infections during the first trimester of pregnancy, no increase was noted in the risk of major birth defects (pp. 859–66). The following patterns were noted for 837,795 infants born alive in Denmark in 1996–2008: “Among 1,804 pregnancies exposed to acyclovir, valacyclovir, or famciclovir in the first trimester, 40 infants (2.2%) were diagnosed with a major birth defect compared with 19,920 (2.4%) among the unexposed (adjusted POR, 0.89; 95% confidence interval [CI], 0.65–1.22). For individual antivirals, a major birth defect was diagnosed in 32 of 1,561 infants (2.0%) with first-trimester exposure to acyclovir (adjusted POR, 0.82; 95% CI, 0.57–1.17) and in 7 of 229 infants (3.1%) with first-trimester exposure to valacyclovir (adjusted POR, 1.21; 95% CI, 0.56–2.62). Famciclovir exposure was uncommon (n = 26), with 1 infant (3.8%) diagnosed with a birth defect. Exploratory analyses revealed no associations between antiviral drug exposure and 13 different subgroups of birth defects, but the number of exposed cases in each subgroup was small.” (B. Pasternak, bjp@ssi.dk)
Editorialists write that this study is “an important advance” in knowledge of the teratogenic risks of these antiviral agents but that more research is needed (
pp. 905–6). Specifically, they cite the need for data from the U.S., along with the pharmacy-related challenges of obtaining such figures: “Why has such a study not been performed in the United States? The Nordic countries have an integrated health care system in which data from multiple sources can readily be merged to answer medical questions. In contrast, the United States has a fragmented system that makes it extremely difficult to address these questions. Yet the situation is not hopeless. Pharmacy records and birth defects registry data in the United States are computerized. The Health Information Technology for Economic and Clinical Health Act (2009) was enacted to stimulate universal use of electronic medical records in the United States and the formation of a nationally linked network that will provide access to data in these records. Ideally, these efforts will increase the amount of information that could be used to determine, for instance, whether or not acyclovir is a teratogen, and to answer a great many other important medical questions.
“However, important issues need to be addressed before the potential of such a system can be realized. Privacy must be protected whenever identifiers are used to link data from multiple sources. The quality of the data must be reviewed critically for each application. For example, vaccines may be obtained from sources such as grocery or discount stores that do not keep detailed records. Ignoring these sources of exposure would lead investigators to misclassify some individuals as unvaccinated. Data on prescriptions filled have inherent limitations in that it is not clear when, or even if, the medication was actually used, leading to possible exposure misclassification. These and other similar issues must be and are being addressed to make it feasible to use electronic health information to monitor drug safety and assess drug benefits.” (J. L. Mills,
jamesmills@nih.gov)

>>>PNN NewsWatch
* Inclusion of entacapone in the combination-product Stalevo (Novartis) appears to increase patients’ risk of cardiovascular events—including myocardial infarction, stroke, and cardiovascular death—FDA said recently. In the Stalevo Reduction In Dyskinesia Evaluation—Parkinson’s Disease (STRIDE-PD) trial, 7 MIs and 1 cardiovascular death occurred among patients taking entacapone/carbidopa/levodopa, compared with none among those on carbidopa/levodopa. In a meta-analysis of trials that included 4,800 patients, 27 cardiovascular events occurred in those on all 3 drugs, compared with 10 in two-drug group. Entacapone is also available in a single-ingredient Novartis product, Comtan.
* A nitric oxide delivery device,
Inomax DS (Ikaria), is being recalled nationally. In Class I recall notices, FDA and Ikaria said that a pressure switch could fail and thereby cause interruption of drug flow when the cylinder empties earlier than anticipated.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 26, 2010 * Vol. 17, No. 165
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 26 issue of the New England Journal of Medicine (2010; 363).
PLX4032 Treatment of Metastatic Melanoma: PLX4032, an inhibitor of mutated serine–threonine protein kinase B-RAF (BRAF), produced complete and partial tumor regressions in most patients with metastatic melanomas with the V600E BRAF mutation, a study shows (pp. 809–19). Phase I study of oncogene-targeted therapy produced these results with two oral doses per day until disease progression: “A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.” (K. T. Flaherty, kflaherty@partners.org)
Melanoma is “an unlikely poster child for personalized cancer therapy,” write editorialists (
pp. 876–8): “Nonetheless, the data provided by Flaherty and colleagues represent a major advance in the treatment of metastatic melanoma. But what’s next? How much can we improve on these results—especially in terms of extending the duration of disease control—through combination therapy or even by manipulating the dose and schedule of single-agent therapy? When should this therapy be moved to the adjuvant setting? How can we achieve similar success in treating patients with wild-type BRAF? The prospects for patients with metastatic melanoma have never been brighter, but the need for further progress through laboratory research and well-conducted clinical trials is as great as—or greater than—ever.” (K. S. M. Smalley)
Treatment of Polycystic Kidney Disease: Two studies assess treatments for autosomal dominant polycystic kidney disease (ADPKD).
In adults with ADPKD, sirolimus therapy for 18 months failed to halt kidney growth, researchers report (
pp. 820–9). In an open-label study, 100 patients aged 18–40 years received target doses of sirolimus 2 mg daily or standard care, with these results: “At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1,330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1,422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P = 0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group.” (R. P. Wüthrich, rudolf.wuethrich@usz.ch)
Everolimus worked better, slowing kidney growth in patients with ADPKD but failing to halt progression of renal impairment (
pp. 830–40). Over a 2-year period, double-blind therapy with the inhibitor of mammalian target of rapamycin was compared with placebo: “Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P = 0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P = 0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P = 0.27) and by 181 ml and 215 ml, respectively, after 2 years (P = 0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P = 0.003) and by 56 ml and 93 ml, respectively, after 2 years (P = 0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P = 0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups.” (G. Walz, gerd.walz@uniklinik-freiburg.de)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 27, 2010 * Vol. 17, No. 166
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Early-release articles from Circulation and Circulation: Cardiovascular Quality and Outcomes (2010; 122).
Safety of Thiazolidinediones: The antidiabetic drugs pioglitazone and rosiglitazone have similar cardiovascular adverse effects and risks, according to an analysis of 2001–05 data from a managed-care population (doi: 10.1161/CIRCOUTCOMES.109.911461). Pharmacy records were used to identify the first claim for the drugs, and the National Death Index provided information on causes of death. Using a primary outcome measure of time to composite event of acute myocardial infarction, acute heart failure, or death, researchers found these differences among 36,628 pioglitazone- and rosiglitazone-treated patients in a propensity score–matched population: “Of the rosiglitazone-treated patients, 602 (4.16%) had an AMI, AHF, or death compared with 599 (4.14%) propensity score–matched pioglitazone-treated patients. No significant difference was observed between matched groups for risk of composite event (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15; P = 0.666) when patients were followed from index date until end of study period, termination of enrollment status, or diagnosis of AMI/AHF/death.” (D. Wertz, dwertz@healthcore.com)
The challenges of translating retrospective, observational data like those above notwithstanding, assessment of medication safety will increasingly rely on such studies, an editorialist writes (
doi: 10.1161/CIRCOUTCOMES.110.958413): “Ultimately, our understanding of drug safety will necessarily depend predominantly upon observational data. Approaches relying on voluntary reports of possible safety events are simply inadequate. In such cases, the numerators of patients with events are biased, and the denominators of all patients who receive therapy are not available. Fortunately, large data sets with longitudinal follow-up such as those used by Wertz and colleagues are increasingly available. Sources of robust data to assess drug safety include national registries or large integrated health plans. For example, the Center for Drug Evaluation and Research, which is sponsored by the FDA through the HMO Research Network, has created the capacity to perform observational pharmacosurveillance in extraordinarily large populations. Such efforts have great potential for providing more timely information on the outcomes of drug use in the populations who receive treatment in clinical practice.” (F. A. Masoudi, fred.masoudi@ucdenver.edu)
Cardiovascular Health of Asian Americans: Health disparities in Asian Americans should be the focus of increased attention, according to a call-to-action science advisory from the American Heart Association (doi: 10.1161/CIR.0b013e3181f22af4). Of the six major subgroups of Asian Americans, two are underserved (those of Korean and Vietnamese descent) and two are at very high risk of cardiovascular disease (Asian Indians and Filipinos). AHA recommends changes in the way data are collected on Asian Americans, with oversampling of the six groups (Chinese and Japanese are the other two) and differentiation of results by those groups; development of standard measurement tools that take into account the culture, foods, and variances in adiposity in these groups; and research into treatment patterns and outcomes for subgroups, risk prediction based on factors important for these groups; ways of detecting differences in body fat that are not picked up by body mass index; genetic mutations and differences in allelic frequency; culturally specific lifestyle and medication interventions; and biologic and social factors relevant to Asian Americans. (L. P. Palaniappan)
Antiplatelets After Drug-Eluting Stent Implantation: During the first year after implantation of drug-eluting stents, the decision to stop antiplatelet therapy is often made on individual or prescriber preferences, a Spanish study shows (doi: 10.1161/CIRCULATIONAHA.110.938290). The study quantifies the decisions to stop therapy among 1,622 patients, 234 of whom interrupted treatment with at least one antiplatelet agent. (I. Ferreira-González, nacho@ferreiragonzalez.com)

>>>PNN NewsWatch
* TimeOut is the latest dietary supplement marketed for sexual enhancement that FDA is warning consumers to avoid because it contains a sildenafil derivative. The agency reports that the product is marketed primarily online.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 30, 2010 * Vol. 17, No. 167
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 28 issue of Lancet (2010; 376).
Trastuzumab for Upper GI Cancers: Results of the ToGA (Trastuzumab for Gastric Cancer) trial support use of trastuzumab as “a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer,” study investigators write (pp. 687–97). In 24 countries, patients were included if their tumors overexpressed HER2 protein. They received either capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or that chemotherapy regimen in combination with intravenous trastuzumab. Results of the open-label, Phase III trial showed the following: “Median follow-up was 18.6 months (IQR 11–25) in the trastuzumab plus chemotherapy group and 17.1 months (9–25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12–16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10–13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60–0.91; p = 0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups.” (Y-J Bang, bangyj@snu.ac.kr)
Boceprevir for Hepatitis C Infection: In patients with untreated genotype 1 hepatitis C infection, twice as many patients had sustained responses when the direct-acting agent boceprevir was added to peginterferon/ribavirin therapy, according to results of the SPRINT-1 trial (pp. 705–16). In this article, two parts of the study are reported. Part 1 included 520 treatment-naive patients who received peginterferon alfa-2b plus ribavirin for 48 weeks (PR48); those two drugs for 28 or 48 weeks, with boceprevir added after a 4-week run-in phase (PR4/PRB24); or peginterferon alfa-2b, ribavirin, and boceprevir for 28 or 48 weeks (PRB28/48). In Part 2 of the study, 75 patients received either PRB48 or low-dose ribavirin plus peginterferon alfa-2b and boceprevir three times a day for 48 weeks (low-dose PRB48). Using a primary endpoint of sustained virologic response (SVR) at 24 weeks, study results showed the following: “Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44–64], p = 0.013 for PRB28; 58/103 [56%, 44–66], p=0.005 for PR4/PRB24; 69/103 [67%, 57–76], p < 0.0001 for PRB48; and 77/103 [75%, 65–83], p < 0.0001 for PR4/PRB44; vs 39/104 [38%, 28–48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.” (P. Y. Kwo, pkwo@iupui.edu)
Treatment of Endometriosis & Infertility: Authors of a review article provide these insights into management of endometriosis and infertility (pp. 730–8): “Medical and surgical treatments for endometriosis have different effects on a woman’s chances of conception, either spontaneously or via assisted reproductive technologies (ART). Medical treatments for endometriosis are contraceptive.… Medical treatment—eg, 3–6 months of gonadotropin-releasing hormone analogues—improves the outcome of ART. When age, ovarian reserve, and male and tubal status permit, surgery should be considered immediately so that time is dedicated to attempts to conceive naturally. In other cases, the preference is for administration of gonadotropin-releasing hormone analogues before ART, and no surgery beforehand. The strategy of early surgery, however, seems counterintuitive because of beliefs that milder non-surgical options should be offered first and surgery last (only if initial treatment attempts fail).” (D. de Ziegler, ddeziegler@orange.fr)

>>>PNN JournalWatch
* Dronedarone: A New Antiarrhythmic Agent, in Pharmacotherapy, 2010; 30: 904–15. (O. Oyetayo)
* Treatment Options for Multiple Sclerosis: Current and Emerging Therapies, in
Pharmacotherapy, 2010; 30: 916–27. (F. M. Gengo, fgengo@dentinstitute.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Aug. 31, 2010 * Vol. 17, No. 168
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (2010; 33).
Statin Effects on C-Reactive Protein: In 26 patients with type 2 diabetes, atorvastatin significantly reduced and stabilized concentrations of high-sensitivity C-reactive protein, compared with simvastatin (pp. 1948–50). Three-month trials of the statins, conducted in crossover fashion, produced these results when lipids and hsCRP were measured 10 times over 5 weeks after each 3-month period: “LDL was comparable on either treatment: atorvastatin 2.2 ± 0.2 vs. 2.1 ± 0.3 mmol/l (mean ± SD; P = 0.19). CRP of individuals taking atorvastatin was significantly lower than when they were taking simvastatin (median 1.08 vs. 1.47 mg/l, P = 0.0002) and was less variable (median SD of logCRP 0.0036 vs. 0.178, P = 0.0001).” (T. Sathyapalan)
Combining Ezetimibe with Simvastatin : Patients with type 2 diabetes who did not reach lipid targets with statin therapy alone benefitted from addition of ezetimibe to their regimens, researchers report (pp. 1954–6). The study included 108 patients who had been treated with simvastatin 40 mg/day but whose total cholesterol concentrations remained above 135 mg/dL. After 2 months of added ezetimibe 10 mg/day or placebo, these results were obtained: “Unlike placebo, ezetimibe decreased LDL cholesterol from 99 ± 31 to 66 ± 22 mg/dl, total cholesterol from 162 ± 36 to 124 ± 30 mg/dl, and apolipoprotein B from 83 ± 22 to 64 ± 18 mg/dl (P < 0.0001 for all changes versus placebo). A total of 72 and 17% of patients on ezetimibe or placebo achieved LDL levels <70 mg/dl, respectively (P < 0.0001). Treatment was well tolerated.” (P. Ruggenenti)
Glutamine & Glycemic Control in Adolescents: Postexercise overnight hypoglycemia occurred more frequently following glutamine treatment than with placebo in 10 adolescents with pump-treated type 1 diabetes, a study shows (pp. 1951–3). Patients randomly received a glutamine or placebo drink before exercise (3:00 pm exercise session consisting of four 15-min treadmill/5-min rest cycles) and at bedtime, with these results for the crossover study: “Blood glucose levels dropped comparably (52%) during exercise on both days. However, the overnight number of hypoglycemic events was higher on glutamine than placebo (≤70 mg/dl, P = 0.03 and ≤60, P = 0.05). The cumulative probability of nighttime hypoglycemia was increased on glutamine days (80%) versus placebo days (50%) (P = 0.02).” (N. Mauras)
Cancer & Insulin Glargine: A significant association between higher doses of insulin glargine and incident cancer was identified in nested case–control study (pp. 1997–2003). A dataset of 1,340 insulin-treated ambulatory patients with type 2 diabetes was compared with control patients, with these results: “During a median follow-up of 75.9 months (interquartile range 27.4–133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10–0.39] versus 0.16 IU/kg/day [0.12–0.24], P = 0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18–13.53], P < 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues.” (E. Mannucci)
Vitamin D & Diabetes: New cases of type 2 diabetes occur significantly less often in women with higher plasma levels of 25-hydroxyvitamin D, the Nurses’ Health Study reports (pp. 2021–3). Comparing 608 women with incident type 2 diabetes with 559 control patients, the investigators found: “After adjusting for matching factors and diabetes risk factors, including [body mass index (BMI)], higher levels of plasma 25-OHD were associated with a lower risk for type 2 diabetes. The odds ratio for incident type 2 diabetes in the top (median 25-OHD, 33.4 ng/ml) versus the bottom (median 25-OHD, 14.4 ng/ml) quartile was 0.52 (95% CI 0.33–0.83). The associations were consistent across subgroups of baseline BMI, age, and calcium intake.” (A. G. Pittas)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 1, 2010 * Vol. 17, No. 169
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Sept. 1 issue of JAMA (2010; 304).
Heparin Doses in Patients with Fondaparinux-Treated ACS When Undergoing PCI: Bleeding complications during and immediately after percutaneous coronary interventions were not changed when doses of heparin were lowered in 2,026 patients with non–ST-segment elevation acute coronary syndromes initially treated with fondaparinux (doi: 10.1001/jama.2010.1320). In the Fondaparinux Trial With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes (FUTURA)/OASIS-8 trial, patients received low-dose unfractionated heparin 50 U/kg or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT). A composite primary outcome of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI showed: “The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54–1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16–0.97; P = .04). For the key secondary outcome [composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30], the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00–2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98–2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15).” (S. S. Jolly, jollyss@mcmaster.ca)
Determinants of Cardiovascular Risk: A number of clinical descriptors can be used to identify elevated risk of cardiovascular events in patients with and without atherosclerosis, researchers report (doi: 10.1001/jama.2010.1322). Analysis of those in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry showed: “A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5,481 patients experienced at least 1 event, including 2,315 with cardiovascular death, 1,228 with myocardial infarction, 1,898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%–19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15 264) had a lower risk (12.2%; 95% CI, 11.4%–12.9%); and patients without established atherothrombosis but with risk factors only (n = 8,073) had the lowest risk (9.1%; 95% CI, 8.3%–9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36–1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57–1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78–2.24; P < .001) each were associated with a significantly higher risk of the primary end point.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
Genetic Testing & Risk-Reducing Surgery: In women who were carriers of the BRCA1 or BRCA2 mutations, risk-reducing surgery lowered the risk of breast and ovarian cancer, compared with similar patients who did not have the surgeries (pp. 967–75). The authors conclude, “The use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.” (T. R. Rebbeck, rebbeck@mail.med.upenn.edu)

>>>PNN NewsWatch
* FDA-TRACK is a new system being implemented to “advance the President’s commitment to transparency, public participation, and collaboration in the work of government.” Key performance indicators on more than 100 FDA program offices will be gathered monthly and made available to senior leadership and the public.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 2, 2010 * Vol. 17, No. 170
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 2 New England Journal of Medicine (2010; 363).
Sibutramine & Cardiovascular Outcomes: Long-term sibutramine therapy in overweight and obese patients is associated with increased risk of nonfatal myocardial infarction and nonfatal stroke, but not with cardiovascular death or all-cause mortality, results of an Abbott-funded study show (pp. 905–17). The Sibutramine Cardiovascular Outcomes (SCOUT) trial included 10,744 overweight or obese participants, all aged 55 years or older. After a 6-week lead-in phase in which everyone received sibutramine, patients were randomly assigned to sibutramine or placebo. Effects on primary outcome events (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death) were as follows: “The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P = 0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P = 0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P = 0.03). The rates of cardiovascular death and death from any cause were not increased.” (W. P. T. James, jeanhjames@aol.com)
Describing sibutramine as “another flawed diet pill” and noting that its marketing has been suspended in the European Union, editorialists write (
pp. 972–4): “The SCOUT trial was designed as an efficacy trial to determine whether weight loss with sibutramine would improve cardiovascular outcomes. No improvement was observed. Among subjects with preexisting cardiovascular disease, cardiovascular outcomes were worse. Among patients who had diabetes with at least one other cardiovascular risk factor but without preexisting cardiovascular disease, outcomes were unimproved. Thus, the modest weight loss with sibutramine did not translate into clinical benefit.” (G. D. Curfman)
Antiplatelet Dosing in ACS: Higher doses of clopidogrel and aspirin do not provide significant benefits in patients with acute coronary syndromes, researchers report (pp. 930–42). In the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT–OASIS 7) trial, 25,086 patients with an acute coronary syndrome referred for an invasive strategy received either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300–325 mg daily) or lower-dose aspirin (75–100 mg daily). Using a primary outcome of cardiovascular death, myocardial infarction, or stroke at 30 days, the investigators determined: “The primary outcome occurred in 4.2% of patients assigned to double-dose clopidogrel as compared with 4.4% assigned to standard-dose clopidogrel (hazard ratio, 0.94; 95% confidence interval [CI], 0.83 to 1.06; P = 0.30). Major bleeding occurred in 2.5% of patients in the double-dose group and in 2.0% in the standard-dose group (hazard ratio, 1.24; 95% CI, 1.05 to 1.46; P = 0.01). Double-dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis among the 17,263 patients who underwent PCI (1.6% vs. 2.3%; hazard ratio, 0.68; 95% CI, 0.55 to 0.85; P = 0.001). There was no significant difference between higher-dose and lower-dose aspirin with respect to the primary outcome (4.2% vs. 4.4%; hazard ratio, 0.97; 95% CI, 0.86 to 1.09; P = 0.61) or major bleeding (2.3% vs. 2.3%; hazard ratio, 0.99; 95% CI, 0.84 to 1.17; P = 0.90).” (S. R. Mehta, smehta@mcmaster.ca)
An editorialist points out that these findings are counter to those from this trial presented a European meeting last year (
pp. 976–7). That presentation led many prescribers to adopt double-dose clopidogrel dosing, he adds. (V. Fuster)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 3, 2010 * Vol. 17, No. 171
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Sept. issue of Pharmacotherapy (2010; 30).
Atenolol & Metabolic Changes: High plasma levels of atenolol may be a factor in hyperglycemic effects of the drug, according to a small study (pp. 872–8). In 15 patients with hypertension who participated in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study, open-label treatment of patients with atenolol produced these 24-hour plasma atenolol concentrations during a pharmacokinetics visit: “A significant association was noted between atenolol area under the concentration-time curve (AUC) and change in fasting glucose level when adjusted for covariates (p = 0.0025); the effect was strongest in women. No significant relationship was noted between plasma atenolol concentration and glucose AUC during oral glucose tolerance testing (r = 0.08, p = 0.78), nor between atenolol AUC and change in triglyceride levels (r = 0.13, p = 0.63).” (J. A. Johnson, johnson@cop.ufl.edu)
Synergistic Antifracture Effects of Statins, Hormones: In women aged 50 years and older, statins and hormone therapy appear to act synergistically to protect against skeletal fractures, according to a case–control study (pp. 879–87). Data from a New Mexico health plan were used to identify 1,001 women with incident fractures of hip, wrist, forearm, or spine in 2000–05 and 2,607 matched controls. “Current” use was used to mean 12 months before the index date and “continuous” use indicated an 80% or greater medication possession ratio during those 12 months. Results showed: “Nineteen percent of the study participants were current hormone therapy users; 9.5% were current and 4.8% were continuous statin users. No association between continuous statin use and fractures was observed among never or past hormone therapy users (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.53–1.22). In contrast, a strong protective effect (OR 0.19, 95% CI 0.04–0.87) was observed among women who concurrently used statins and hormone therapy for 1 year, independent of age; corticosteroid, bisphosphonate, thiazide diuretic, calcitonin, methotrexate, or antiepileptic drug use; chronic kidney disease; and Charlson comorbidity index.” (L. Bakhireva)
Charcoal Cookies: In eight healthy volunteers, a new charcoal cookie formulation was as effective as aqueous charcoal suspension for reducing absorption of cimetidine, researchers report (pp. 888–94). After participants ingested cimetidine 800 mg and either water, cookies, or suspension, the researchers found these patterns: “Both charcoal products effectively adsorbed cimetidine, resulting in decreased absorption of most of the cimetidine dose. No significant difference was noted in the median percent decrease in cimetidine AUC between the charcoal suspension and charcoal cookie (91.8% vs 82.1%, p = 0.505).” (W. Klein-Schwartz)
Concerns About Dronedarone: Commenting on a review article of dronedarone use in patients with atrial fibrillation (pp. 916–27; F. M. Gengo, fgengo@dentinstitute.com), editorialists express these concerns (pp. 867–71): “Given the evidence with dronedarone, we believe that its use should be limited to those patients with symptomatic atrial fibrillation requiring rhythm control strategies who have failed other antiarrhythmic therapy primarily due to intolerable adverse effects or adverse electrocardiographic effects (bradycardia, atrioventricular block, or QT-interval prolongation). Until results from additional studies demonstrating a favorable risk:benefit ratio with dronedarone compared with other antiarrhythmic agents become available, dronedarone’s place in the management of symptomatic atrial fibrillation will remain largely undefined.” (D. E. Hilleman, hilleman@creighton.edu)

>>>PNN NewsWatch
* An increased mortality risk is being observed in patients treated with tigecycline (Tygacil, Wyeth), compared with other agents used in treating serious infections, FDA announced this week. The increased risk was seen most clearly in patients treated off-label for hospital-acquired pneumonia, especially ventilator-associated pneumonia. Patients being treated for the approved indications of complicated skin and skin structure infections and complicated intra-abdominal infections also had increased risk, as did those treated off-label for diabetic foot infections, FDA said.
*
PNN will not be published on Mon., Sept. 6, Labor Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 7, 2010 * Vol. 17, No. 172
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Oral Bisphosphonates & Risk of Esophageal Cancer: Among 6 million people whose health records are stored in the U.K. General Practice Research Database, those who used oral bisphosphonates had higher rates of esophageal cancer, compared with nonusers, with a doubling of risk associated with 5 years’ use of the drugs, researchers report (c4444). Participants included in the study were aged 40 years or older. Between 1995 and 2005, esophageal cancer was diagnosed in 2,954 patients; 2,018 had gastric cancer; and 10,641 had colorectal cancer. Compared with five matched controls per case, these patterns were noted: “The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to1.66; P = 0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity = 0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.” (J. Green, jane.green@ceu.ox.ac.uk)

>>>Internal Medicine Report
Source:
Sept. 7 issue of the Annals of Internal Medicine (2010; 153).
Diets & Mortality: Among patients using low-carbohydrate diets, those who consumed animal sources of fat and protein had higher rates of all-cause mortality, compared with men and women whose diets emphasized vegetable sources of fats and protein, a study shows (pp. 289–98). Using data from the Nurses’ Health Study and Health Professionals’ Follow-up Study, investigators found these associations of diet with mortality during 26 years of follow-up in 85,168 women and 20 years of monitoring in 44,548 men: “The overall low-carbohydrate score was associated with a modest increase in overall mortality in a pooled analysis (hazard ratio [HR] comparing extreme deciles, 1.12 [95% CI, 1.01 to 1.24]; P for trend = 0.136). The animal low-carbohydrate score was associated with higher all-cause mortality (pooled HR comparing extreme deciles, 1.23 [CI, 1.11 to 1.37]; P for trend = 0.051), cardiovascular mortality (corresponding HR, 1.14 [CI, 1.01 to 1.29]; P for trend = 0.029), and cancer mortality (corresponding HR, 1.28 [CI, 1.02 to 1.60]; P for trend = 0.089). In contrast, a higher vegetable low-carbohydrate score was associated with lower all-cause mortality (HR, 0.80 [CI, 0.75 to 0.85]; P for trend ≤ 0.001) and cardiovascular mortality (HR, 0.77 [CI, 0.68 to 0.87]; P for trend < 0.001).” (T. T. Fung, teresa.fung@simmons.edu)
Financial Incentives & Disproportionate Share Hospitals: Financial incentives improved care in U.S. hospitals serving large numbers of poor patients, compared with hospitals without such incentives, according to retrospective study (pp. 299–306; A. K. Jha, ajha@hsph.harvard.edu)

>>>PNN JournalWatch
* Asthma in Older Adults, in Lancet, 2010; 376: 803–13. (P. G. Gibson, peter.gibson@newcastle.edu.au)
* Management of Severe Asthma in Children, in
Lancet, 2010; 376: 814–25. (A. Bush, a.bush@rbh.nthames.nhs.uk)
* Role of Viral Respiratory Infections in Asthma and Asthma Exacerbations, in
Lancet, 2010; 376: 826–34. (W. W. Busse, wwb@medicine.wisc.edu)
* Changes in Drug Use and Out-of-Pocket Costs Associated with Medicare Part D Implementation: A Systematic Review, in
Journal of the American Geriatrics Society, 2010; 58: 1764–79. (J. M. Polinski, jpolinski@partners.org)
* Intranasal Medication Delivery for Children: A Brief Review and Update, in
Pediatrics, 2010; 126: 532–7. (T. R. Wolfe)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 8, 2010 * Vol. 17, No. 173
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 8 issue of JAMA (2010; 304).
Adjuvant Chemotherapy After Pancreatic Cancer Resection: Gemcitabine provided no survival advantage over fluorouracil plus folinic acid following resection of pancreatic cancer, according to findings from the European Study Group for Pancreatic Cancer (ESPAC)-3 trial (pp. 1073–81). A total of 1,088 patients whose pancreatic duct adenocarcinoma had been resected were randomized to open-label fluorouracil plus folinic acid followed by fluorouracil or gemcitabine. Results from the Phase III trial of 6 months’ duration showed the following: “Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1–43.4) months’ follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1–25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4–26.4) months for those treated with gemcitabine (21 = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81–1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.” (J. P. Neoptolemos, j.p.neoptolemos@liverpool.ac.uk)
Despite these findings, “adjuvant therapy for resected pancreatic adenocarcinoma is now firmly established as offering a modest but real improvement in overall survival at 5 years with about double the number of patients alive compared with no treatment,” an editorialist writes (
pp. 1124–5). “Much attention has been paid to improving adjuvant clinical trial design, in particular excluding patients who have undergone palliative resections from adjuvant studies and streamlining other eligibility criteria. The ESPAC investigators have significantly contributed to the establishment of standard adjuvant therapy. Results from the ongoing European and US studies will further refine practice over the next decade; however, there is much to be done including identification of new and active drugs for treating pancreatic cancer that may be translated into the adjuvant setting. Other directions deserving further evaluation include the role of neoadjuvant or preoperative therapy for patients with resectable pancreatic adenocarcinoma, an approach that offers several theoretical advantages over an adjuvant approach. Even though pancreatic cancer remains one of the most challenging malignancies, the next decade looks incrementally brighter.” (E. M. O’Reilly, reillye@mskcc.org">oreillye@mskcc.org)
Retrying Nevirapine Therapy in Children with HIV Infection: Children who acquire HIV following unsuccessful perinatal prophylaxis with nevirapine can later benefit from reintroduction of the drug after viral suppression has been achieved with protease inhibitors, researchers report (pp. 1082–90). At a South African hospital, 195 children who had viral suppression during protease inhibitor therapy were randomized to stavudine and lamivudine plus either ritonavir-boosted lopinavir or nevirapine, with these results: “Plasma viremia greater than 50 copies/mL occurred less frequently in the switch group (Kaplan–Meier probability, 0.438; 95% CI, 0.334–0.537) than in the control group (0.576; 95% CI, 0.470–0.668) (P = .02). Confirmed viremia greater than 1,000 copies/mL occurred more frequently in the switch group (0.201; 95% CI, 0.125–0.289) than in the control group (0.022; 95% CI, 0.004–0.069) (P < .001). CD4 cell response was better in the switch group (median CD4 percentage at 52 weeks, 34.7) vs the control group (CD4 percentage, 31.3) (P = .004). Older age (relative hazard [RH], 1.71; 95% CI, 1.08–2.72) was associated with viremia greater than 50 copies/mL in the control group. Inadequate adherence (RH, 4.14; 95% CI, 1.18–14.57) and drug resistance (RH, 4.04; 95% CI, 1.40-–1.65) before treatment were associated with confirmed viremia greater than 1,000 copies/mL in the switch group.” (L. Kuhn, lk24@columbia.edu)
IRBs: Effective or Not?: A commentary, authored by an NIH bioethicist, calls for research on whether institutional review boards are effective “at achieving their goals and whether they are worth the substantial investment of time and resources” (pp. 1122–3; C. Grady, cgrady@nih.gov).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 9, 2010 * Vol. 17, No. 174
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 9 New England Journal of Medicine (2010; 363).
Detecting TB & Rifampin Resistance: An automated molecular test reliably detected Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF) in untreated sputum samples in less than 2 hours, researchers report (pp. 1005–15). Xpert MTB/RIF was used to process samples from 1,730 patients. Compared with microscopy and solid/liquid cultures, the molecular test produced these results: “Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive tuberculosis (98.2%) and 124 of 171 with smear-negative tuberculosis (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). Among patients with smear-negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2%. As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria. Sequencing resolved all but two cases in favor of the MTB/RIF assay.” (C. C. Boehme, catharina.boehme@finddiagnostics.org)
Calling for a “game change” in tubercular diagnosis, editorialists envision elimination of this disease (
pp. 1070–1): “It is clear that improvements in diagnostics are driving a virtuous cycle in care: the promise of improved tests drives their uptake, their uptake results in better health outcomes, improved outcomes attract more funding for health care systems, and better-funded systems are an incentive to the development of even better technologies. We are particularly optimistic about the potential role of governments, product developers, and companies in emerging economies with high tuberculosis burdens, such as China, India, Brazil, and South Africa. These countries now have the capacity to develop low-cost generic or novel assays adapted to local contexts and incorporate their scale-up in both national tuberculosis-control programs and private laboratories, supported by successful public–private partnerships. Emerging economies have the potential to become global leaders in innovative product development and delivery. If these countries successfully tackle their own tuberculosis problems, the elimination of tuberculosis by 2050 might become a reality.” (P. M. Small)
Controlling Multidrug-Resistant TB: Authors of a review article outline “critical steps for prevention and control” of multidrug-resistant tuberculosis (pp. 1050–8): “Every one of the recommendations in this article for improving the treatment and control of MDR tuberculosis requires action beyond national tuberculosis control programs, sometimes in the political environment outside the health care system. This is a highly ambitious but necessary agenda for health authorities in the affected countries and for the global health community. The steps involved in controlling MDR tuberculosis are also important steps toward strengthening health care systems, including progress in achieving universal health care coverage. If this policy agenda is not pursued with urgency, the human and financial costs to societies will be profound.” (E. Jaramillo, jaramilloe@who.int)
Gentamicin–Collagen Sponges in Colorectal Surgery: An increased rate of surgical-site infections followed use of gentamicin–collagen sponges in colorectal surgery, a study shows (pp. 1038–49). The paradoxical results were produced in a Phase III trial of 602 patients undergoing open or laparoscopically assisted colorectal surgery at 39 U.S. sites. Insertion of two sponges above the fascia at the time of surgical closure was compared with no intervention, with this impact: “The incidence of [60-day] surgical-site infection was higher in the sponge group (90 of 300 patients [30.0%]) than in the control group (63 of 302 patients [20.9%], P = 0.01). Superficial surgical-site infection occurred in 20.3% of patients in the sponge group and 13.6% of patients in the control group (P = 0.03), and deep surgical-site infection in 8.3% and 6.0% (P = 0.26), respectively. Patients in the sponge group were more likely to visit an emergency room or surgeon’s office owing to a wound-related sign or symptom (19.7%, vs. 11.0% in the control group; P = 0.004) and to be rehospitalized for surgical-site infection (7.0% vs. 4.3%, P = 0.15).” (E. Bennett-Guerrero, elliott.bennettguerrero@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 10, 2010 * Vol. 17, No. 175
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Sept. 14 issue of the Journal of the American College of Cardiology (2010; 56).
Clinical Utility of High On-Treatment Platelet Reactivity to ADP: Large-scale studies of platelet function measurement during clopidogrel–aspirin therapy using high on-treatment reactivity to adenosine diphosphate should be conducted, authors of a JACC White Paper recommend (pp. 919–33). “Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence,” the authors write. “However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines.” The group concludes: “The absolute level of platelet reactivity during treatment (i.e., on-treatment platelet reactivity) is proposed by the consensus of all the authors to be a better measure of thrombotic risk than responsiveness to clopidogrel. Currently available evidence supports the concept of a threshold for on-treatment platelet reactivity that may be used to stratify patient risk for ischemic/ thrombotic events following [percutaneous coronary intervention (PCI)], including stent thrombosis. At the present time, high on-treatment platelet reactivity in the setting of PCI has been defined by [receiver-operator characteristic] analyses.… However, there are no large-scale clinical studies to date demonstrating that the adjustment of antiplatelet therapy based on any of [several] cut points improves clinical outcomes. Finally, PCI patients with diabetes and patients with [acute coronary syndromes] treated medically as compared to those treated with PCI may have different high on-treatment platelet reactivity cut points.” (P. A. Gurbel, pgurbel@lifebridgehealth.org)
Identifying Ranolazine’s Mechanism of Action: Ranolazine likely produces its beneficial effects in ischemic heart disease by increasing regional coronary blood flow in ischemic areas, a study shows (pp. 934–42). Among 191 patients, these results were found during exercise treadmill tests: “Compared with placebo, ranolazine produced a dose-dependent reduction in ST-segment depression that became more marked as exercise-induced ischemia became more pronounced, associated with clinically minor decreases in heart rate and blood pressure.” (P. H. Stone, pstone@partners.org)

>>>PNN NewsWatch
* FDA yesterday launched a campaign to regulate electronic cigarettes as drugs, devices, and combination products with a drug as the primary mode of action. The action means that, if FDA has its way, companies seeking to market such products will have to seek approval by filing investigational new drug applications (IND) and then, after conducting clinical studies of efficacy and safety, new drug applications (NDAs). After that, if companies want to sell the products without a prescription, they would need to meet the label-comprehension and actual-use studies needed for OTC marketing. Electronic cigarettes are products designed to deliver nicotine or other substances to a user in the form of a vapor, FDA said. They usually comprise a rechargeable, battery-operated heating element, a replaceable cartridge that may contain nicotine or other chemicals, and an atomizer that, when heated, converts the contents of the cartridge into a vapor. This vapor can then be inhaled by the user.
* Pediatric use of
pralidoxime chloride (Protopam Chloride, Baxter) for treatment of poisoning by organophosphates was approved yesterday by FDA. The product was approved for adults in 1964 and has been used off-label for many years, the agency acknowledged in its announcement. “Improving the drug’s label with new dosing information for children will give health care professionals better guidance on how to use this drug safely and effectively,” said Russell Katz, MD, director of the Division of Neurology Products in FDA’s Center for Drug Evaluation and Research.
*
Gadolinium-based contrast agents (GBCAs) can cause nephrogenic systemic fibrosis (NSF), FDA said in requiring new warnings for the products. Three GBCAs—Magnevist (Bayer), Omniscan (GE Healthcare), and Optimark (Covidien)—will be described as inappropriate for use among patients with acute kidney injury or chronic severe kidney disease. All GBCA labels will emphasize the need to screen patients to detect these types of kidney dysfunction before administration.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 13, 2010 * Vol. 17, No. 176
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 11 issue of Lancet (2010; 376).
Ivabradine in Chronic Heart Failure: Heart-rate reduction with ivabradine proved important in management of patients with chronic heart failure, according to results of the SHIFT trial (pp. 875–85). In this report, one of two from SHIFT published in this issue (pp. 886–94; M. Böhm, boehm@uks.eu), patients with symptomatic heart failure and left-ventricular ejection fractions of 35% or lower were randomly assigned to ivabradine titration up to 7.5 mg daily or placebo, with these results: “Data were available for analysis for 3,241 patients in the ivabradine group and 3,264 patients allocated placebo. Median follow-up was 22.9 (IQR 18–28) months. 793 (24%) patients in the ivabradine group and 937 (29%) of those taking placebo had a primary endpoint event (HR 0.82, 95% CI 0.75–0.90, p < 0.0001). The effects were driven mainly by hospital admissions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; HR 0.74, 0.66–0.83; p < 0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; HR 0.74, 0.58–0.94, p = 0.014). Fewer serious adverse events occurred in the ivabradine group (3,388 events) than in the placebo group (3,847; p = 0.025). 150 (5%) of ivabradine patients had symptomatic bradycardia compared with 32 (1%) of the placebo group (p < 0.0001). Visual side-effects (phosphenes) were reported by 89 (3%) of patients on ivabradine and 17 (1%) on placebo (p < 0.0001).” (K. Swedberg, karl.swedberg@gu.se)
Recombinant Hepatitis E Vaccine: Three doses of a recombinant hepatitis E vaccine was well tolerated and effective among healthy adults in a Chinese trial (pp. 895–902). Patients included in the Phase III trial were aged 16 to 65 years when the first dose of HEV 239 or placebo (hepatitis B vaccine) was administered. Over the following 19 months, these results were recorded: “11,165 of the trial participants were tested for hepatitis E virus IgG, of which 5,285 (47%) were seropositive for hepatitis E virus. Participants were randomly assigned to vaccine (n = 56,302) or placebo (n = 56,302). 48,693 (86%) participants in the vaccine group and 48,663 participants (86%) in the placebo group received three vaccine doses and were included in the primary efficacy analysis. During the 12 months after 30 days from receipt of the third dose 15 per-protocol participants in the placebo group developed hepatitis E compared with none in the vaccine group. Vaccine efficacy after three doses was 100.0% (95% CI 72.1–100.0). Adverse effects attributable to the vaccine were few and mild. No vaccination-related serious adverse event was noted.” (N-S Xia, nsxia@xmu.edu.cn)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Isoniazid Resistance in Tuberculous Meningitis: Randomized clinical trials are needed to identify the optimal treatment of patients with isoniazid-resistant tuberculous meningitis, according to authors who report higher mortality in this group of individuals (c4451). Using data from the CDC’s National Tuberculosis Surveillance System, the investigators found these patterns: “Between 1993 and 2005, 1,896 patients had a clinical diagnosis of tuberculous meningitis and positive cultures from any site. In 123 (6%) of these patients, isoniazid resistance was present on initial susceptibility testing. The unadjusted association between initial isoniazid resistance and subsequent death among these 1,896 patients did not reach statistical significance (odds ratio 1.38, 95% confidence interval 0.94 to 2.02). However, among 1,614 patients with positive cerebrospinal fluid cultures, a significant unadjusted association was found between initial isoniazid resistance and subsequent death (odds ratio 1.61, 1.08 to 2.40). This association increased after adjustment for age, race, sex, and HIV status (odds ratio 2.07, 1.30 to 3.29).” (C. Vinnard, christopher.vinnard@uphs.upenn.edu)

>>>PNN JournalWatch
* Diagnosis and Management of Barrett’s Oesophagus, in BMJ, 2010; 341: c4551. (J. Jankowski, j.a.jankowski@qmul.ac.uk)
* Personality Disorders in DSM-5, in
American Journal of Psychiatry, 2010; 167: 1026–8. (J. Shedler)
* Role of Somatostatins in Gastroenteropancreatic Neuroendocrine Tumor Development and Therapy, in
Gastroenterology, 2010; 139: 742–53.e1. (K. E. Öberg, kjell.oberg@medsci.uu.se)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 14, 2010 * Vol. 17, No. 177
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Sept. 13 issue of the Archives of Internal Medicine (2010; 170).
Reducing MRSA Infections After Cardiac Surgery: Intranasal mupirocin for all patients and prophylactic vancomycin for colonized individuals has significantly reduced methicillin-resistant Staphylococcus aureus wound infections after cardiac surgery, researchers report (doi:10.1001/archinternmed.2010.326). Postoperative wound infection rates in the 3 years before and after this comprehensive MRSA intervention program showed these patterns: “Postoperative MRSA wound infections decreased by 93% (32 infections per 2,767 cases in the baseline period vs 2 infections per 2,496 cases in the intervention period; relative risk, 0.069; P < .001). Overall wound infection rates decreased from 2.1% to 0.8% (59 infections per 2,769 cases vs 20 infections per 2,496 cases; P < .001). During the intervention period, there was no change in the number of MRSA infections after noncardiac surgery.” (E. E. Walsh, Edward.walsh@rochestergeneral.org)
Senior Care Provided by Primary Care Clinicians: Practicing clinicians “struggle with the uncertainties of applying disease-specific guidelines to their older patients with multiple conditions,” authors write (doi:10.1001/archinternmed.2010.318). Better decision making could result from “more data, alternative guidelines, approaches to reconciling their own and their patients’ priorities, the support of their subspecialist colleagues, and an altered reimbursement system,” the group notes, adding details from focus groups of 40 physicians, nurse practitioners, and physician assistants: “The participants were concerned about their patients’ ability to adhere to complex regimens derived from guideline-directed care. There was variability in beliefs regarding, and approaches to balancing, the benefits and harms of guideline-directed care. There was also variability regarding how the participants involved patients in the process of decision making, with clinicians describing conflicts between their own and their patients’ goals. The participants listed a number of barriers to making good treatment decisions, including the lack of outcome data, the role of specialists, patient and family expectations, and insufficient time and reimbursement.” (T. R. Fried, terri.fried@yale.edu)
ED Visits by Those on Chronic Opioid Therapy: Emergency department visits (EDVs) and adverse drug events (ADEs) occur more often among patients on chronic Schedule II opioid therapy, an analysis of Arkansas Medicaid and HealthCore claims shows (pp. 1425–32). Patients had at least 90 continuous days of opioid therapy within 6-month periods in 2000–05 with no cancer diagnoses. Regression analysis showed the following for EDVs and ADEs within 12 months of the opioid use: “Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non–Schedule II opioids alone (relative risk range, 1.09–1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64–4.00).” (M. D. Sullivan, sullimar@u.washington.edu)
An editorialist writes that he has “come to question whether the long-term treatment of nonmalignant pain is causing more harm than good” (
pp. 1422–4): “Four things can be said with certainty. First, the use of opioid treatment for nonmalignant conditions has grown during the last 2 decades. Second, with the increase in the use of opioid treatment for nonmalignant pain, there has also been an increase in the number of deaths due to opioid overdose. Third, long-term opioid use is associated with a number of adverse consequences in addition to overdose, including decreased cognitive function, constipation, hyperesthesias (increased pain due to the use of opioids), immune suppression, hormonal changes, addiction, and diversion of medication (sale to others). Fourth, although it is clear that opioids relieve short-term pain, there is no evidence from randomized controlled studies indicating that they are effective in the long-term treatment of chronic pain.” (M. H. Katz, mhkatz59@yahoo.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 15, 2010 * Vol. 17, No. 178
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Early-release articles from and Sept. issue of Pediatrics (2010; 126).
Thimerosal & Autism: No relationship between exposure to thimerosal-containing vaccines and development of autism spectrum disorder (ASD) was found in a case–control study conducted in three managed-care organizations (doi:10.1542/peds.2010-0309). Compared in the study were 256 children with ASD and 752 matched controls. Interviews of parents and medical records showed the following relationships between exposure to ethylmercury and ASD and two ASD subcategories, autistic disorder and ASD with regression: “There were no findings of increased risk for any of the 3 ASD outcomes. The adjusted odds ratios (95% confidence intervals) for ASD associated with a 2-SD increase in ethylmercury exposure were 1.12 (0.83–1.51) for prenatal exposure, 0.88 (0.62–1.26) for exposure from birth to 1 month, 0.60 (0.36–0.99) for exposure from birth to 7 months, and 0.60 (0.32–0.97) for exposure from birth to 20 months.” (C. S. Price)
Physician Adoption of Papillomavirus Vaccination: While most pediatricians and family physicians are offering human papillomavirus vaccinations to patients, many do not recommend it strongly to younger adolescent girls, a survey of 850 physicians shows (pp. 425–33). Respondents also indicated that financial barriers are common with the vaccine. The survey, completed by about 80% of those contacted, showed these additional results: “Ninety-eight percent of pediatricians and 88% of family physicians were administering HPV vaccine in their offices (P < .001). Among those physicians, fewer strongly recommended HPV vaccination for 11- to 12-year-old female patients than for older female patients (pediatricians: 57% for 11- to 12-year-old patients and 90% for 13- to 15-year-old patients; P < .001; family physicians: 50% and 86%, respectively; P < .001). The most-frequently reported barriers to HPV vaccination were financial, including vaccine costs and insurance coverage. Factors associated with not strongly recommending HPV vaccine to 11- to 12-year-old female patients included considering it necessary to discuss sexuality before recommending HPV vaccine (risk ratio: 1.27 [95% confidence interval: 1.07–1.51]) and reporting more vaccine refusals among parents of younger versus older adolescents (risk ratio: 2.09 [95% confidence interval: 1.66–2.81]).” (M. F. Daley)

>>>PNN NewsWatch
* Pegloticase (Krystexxa, Savient Pharmaceuticals) has been approved as a second-line therapy for gout, FDA announced yesterday. The agent, a pegylated enzyme that is specific for uric acid, is administered by intravenous infusion in doses of 8 mg given every 2 weeks. In 6-month clinical trials, 212 patients had significantly lower serum uric acid levels during treatment with pegloticase. However, one in every four patients on the drug had severe allergic reactions during infusion, necessitating dispensing of corticosteroids and antihistamines with the drug. Other reactions during clinical trials included gout flare, nausea, injection-site bruising, irritation of the nasal passages, constipation, chest pain, and vomiting. FDA also noted that physicians should be cautious about administering pegloticase to patients with congestive heart failure because the drug was not studied in this patient population. Krystexxa is being approved with a Risk Evaluation and Mitigation Strategy that includes a medication guide for patients and materials for health providers to communicate the risk of severe infusion and allergic reactions.
*
Long-term use of bisphosphonates is associated with atypical femur fractures, the American Society of Bone and Mineral Research warns in a task force report published in the Journal of Bone and Mineral Research. “Most of the patients who experienced these atypical femur fractures had been taking bisphosphonates for more than 5 years,” task force chair Elizabeth Shane, MD, said in a news release. “However, we are concerned that there may be a relationship between these fractures and long-term bisphosphonate use and, although the risk is low, we want to make sure that people know about the warning signs.”
* An FDA advisory panel yesterday voted 15–9 against making
dextromethorphan a scheduled substance, bringing praise from the Consumer Healthcare Products Association, a trade group.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 16, 2010 * Vol. 17, No. 179
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 16 issue of the New England Journal of Medicine (2010; 363).
Neuromuscular Blockers in Early ARDS: A multicenter study supports use of neuromuscular blocking agents during mechanical ventilation in patients with early, severe adult acute respiratory distress syndrome (pp. 1107–16). Benefits of the intervention included better adjusted 90-day survival rates and more time off the ventilator without any increase in muscle weakness, the investigators conclude. Among 340 patients in intensive-care units with onset of severe ARDS within the past 48 hours, cisatracurium besylate or placebo for 48 hours produced these outcomes: “The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P = 0.04), after adjustment for both the baseline Pao2:FIo2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P= 0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P = 0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups.” (L. Papazian, laurent.papazian@ap-hm.fr)
An editorialist, noting that this study provides “a step back from a developing paradigm in critical care” of less interventions, writes that “this study raises many unanswered questions in addition to those concerning putative mechanisms of action” (
pp. 1176–80): “What is the optimal duration of use of neuromuscular blocking agents? Is the observed benefit specific to cisatracurium or shared within the drug class? Would very heavy sedation produce results similar to those reported? Why does the beneficial effect appear to be present only in patients with more severe hypoxemia? The answers to these and other questions will ultimately determine whether, how, and when neuromuscular blocking agents are used to improve the outcomes of patients with ARDS.” (A. S. Slutsky)
INCB018424 in Myelofibrosis: INCB018424, a potent and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, was useful for reversing symptoms of myelofibrosis in 153 patients over a median treatment period of 14.7 months, researchers report (pp. 1117–27). “The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia,” the authors wrote of this Phase I/II trial. “A dose-dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (≥50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis.” (S. Verstovsek, sverstov@mdanderson.org)

>>>PNN NewsWatch
* New dosing recommendations for valganciclovir in children and adolescents undergoing kidney or heart transplants were released yesterday by FDA. This change is being made to prevent potential valganciclovir overdosing in children with low body weight, low body surface area, and below normal serum creatinine. The revised dosing recommendations are being updated to include an upper limit on the calculated creatinine clearance using the modified Schwartz formula.
*
Forest Pharmaceuticals has agreed to pay $164 million for criminal actions, FDA announced yesterday. Charges against the company included marketing its Levothroid brand of levothyroxine sodium tablets without FDA approval, increasing its distribution of the product at a point when FDA had directed a phase-out, and ignoring subsequent warning letters.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 17, 2010 * Vol. 17, No. 180
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Sept. Journal of Allergy and Clinical Immunology (2010; 126).
MicroRNAs in Atopic Dermatitis: A recently discovered class of small noncoding molecules, microRNAs may be involved in the skin inflammation processes that lead to atopic dermatitis, a study of expression in tissues and cells suggests (pp. 581–9.e20). Regulation of cytotoxic T lymphocyte–associated antigen (CTLA-4) by miR-155, assessed with luciferase reporter assays and flow cytometry, showed: “miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in TH cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.” (E. Sonkoly, eniko.sonkoly@ki.se)
Adherence with Inhalers: In patients with asthma, adherence is affected little by provision of a corticosteroid and long-acting beta-agonist in a single inhaler, a study shows (pp. 505–10). Over a 24-week period, 111 patients had these adherence patterns as measured by covert electronic monitors when they received the drugs separately or in combination: “Complete adherence data from the final 6-week period were available for 49 and 54 subjects in the separate and combination groups, respectively. The mean (SD) adherence was 73.7% (36.0) for [fluticasone dipropionate (FP)], 76.7% (30.5) for salmeterol, and 82.4% (24.5) for FP/salmeterol. There were no significant differences in adherence between FP/salmeterol and FP (–8.7%; 95% CI, –10.6 to 3.3) and salmeterol (–5.6%; 95% CI, –16.4 to 5.1). There was no significant difference in overuse among the FP, salmeterol, or FP/salmeterol groups. In 2 (4%) of 49 subjects, salmeterol was effectively taken as monotherapy during a 6-week period.” (R. Beasley, Richard.Beasley@mrinz.ac.nz)

>>>Rheumatology Highlights
Source:
Sept. issue of Arthritis & Rheumatism (2010; 62).
Revised RA Classification Scheme Focuses on Early Disease: Revisions to the American College of Rheumatology classification criteria for rheumatoid arthritis are intended to “refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘rheumatoid arthritis,’” a task force writes (pp. 2569–81). ACR members working jointly with representatives of the European League Against Rheumatism, revised the 1987 ACR criteria, concluding to emphasize the “features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features”: “In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1).” (A. J. Silman, a.silman@arthritisresearchuk.org)
Editorialists call the new criteria “a game changer” but note these challenges in implementation (
pp. 2592–4): “Change can be difficult for a generation of rheumatologists used to classifying RA with the old criteria. Concerns over the absence of erosion in the scoring system, as well as the absence of the necessity of symmetric joint involvement, will be raised. The working group does acknowledge that the presence of erosions typical for RA would justify classification of a patient as having RA, but also raises the question of what is meant by significant erosive disease and what evidence of erosions should be considered acceptable as signifying ‘typical for RA…’ Additional concerns exist regarding the utility of these classification criteria for the primary care physician who must determine synovitis by examination and then exclude other possible diagnoses that might explain the synovitis.” (S.Cohen, arthdoc@aol.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 20, 2010 * Vol. 17, No. 181
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 18 issue of Lancet (2010; 376).
Dabigatran for Stroke Prevention in Atrial Fibrillation: Local quality of INR control can affect the relative benefits of new therapies in anticoagulation, reports a study that showed better vascular outcomes with dabigatran in centers with poor INR control than in those with better baseline numbers (pp. 975–83). In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 18,113 patients at 951 sites received dabigatran 110 or 150 mg twice daily or warfarin dose adjusted to INR of 2.0—3.0. Over a median of 2 years, these changes were recorded in center’s mean time in therapeutic range (cTTR): “The quartiles of cTTR for patients in the warfarin group were: less than 57.1%, 57.1–65.5%, 65.5–72.6%, and greater than 72.6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p = 0.89) or 150 mg dabigatran (interaction p = 0.20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p = 0.71) or 150 mg dabigatran (interaction p = 0.89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p = 0.03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p = 0.036 and p = 0.0006, respectively) and total mortality (interaction p = 0.066 and p = 0.052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR.” (L. Wallentin, lars.wallentin@ucr.uu.se)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 341).
Glucosamine, Chondroitin in Osteoarthritis: In patients with osteoarthritis of the knee or hip, glucosamine and chondroitin, given separately or in combination, are no more effective than placebo for reducing joint pain or changing the rate of narrowing of joint spaces, a network meta-analysis concludes (c4675). Investigators combined direct evidence from clinical trials of more than 200 patients with knee or hip osteoarthritis “with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points.” Results showed: “10 trials in 3,803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was −0.4 cm (95% credible interval −0.7 to −0.1 cm) for glucosamine, −0.3 cm (−0.7 to 0.0 cm) for chondroitin, and −0.5 cm (−0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P = 0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero.” (P Jüni, juni@ispm.unibe.ch)

>>>PNN NewsWatch
* A possible association between use of pioglitazone (Actos, Takeda) with bladder cancer is being investigated, FDA said on Friday. In a 5-year analysis of study data, overall results showed no association, but subanalyses showed that those with the longest exposures to the drug and those taking the highest doses had increased risks of bladder cancer.

>>>PNN JournalWatch
* Application of Genetic/Genomic Approaches to Allergic Disorders, in Journal of Allergy and Clinical Immunology, 2010; 126: 425–36. (G. K. Khurana Hershey, Gurjit.Khurana.Hershey@cchmc.org)
* Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines: 2010 Revision, in
Journal of Allergy and Clinical Immunology, 2010; 126: 466–76. (H. J. Schünemann, schuneh@mcmaster.ca)
* Anisakidosis: Perils of the Deep, in
Clinical Infectious Diseases, 2010; 51: 806–12. (N. S. Hochberg, nhoch@bu.edu)
* Determining the Optimal Pneumococcal Vaccination Strategy for Adults: Is There a Role for the Pneumococcal Conjugate Vaccine?, in
Chest, 2010; 138: 486–90. (M. L. Metersky, Metersky@nso.uchc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 21, 2010 * Vol. 17, No. 182
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 21 issue of the Annals of Internal Medicine (2010; 153).
Gender & Darunavir–Ritonavir Therapy: After finding nonsignificant sex-based differences in a study of antiretroviral therapy that might have resulted from greater discontinuation rates among women, researchers conclude that greater efforts are needed to keep HIV-positive women in clinical trials (pp. 349–57). An open-label Phase IIIb study conducted at 65 sites enrolled 287 women and 142 men. Participants received darunavir–ritonavir, 600/100 mg twice daily, along with an investigator-selected optimized background regimen, with these results: “A higher proportion of women discontinued treatment than men (32.8% vs. 23.2%; P = 0.042); more women than men discontinued treatment for reasons other than virologic failure. Response rates in women and men at week 48 were 50.9% and 58.5%, respectively (intention-to-treat [time-to-loss of virologic response (TLOVR)]), and 73.0% and 73.5%, respectively (TLOVR censored for patients who withdrew for reasons other than virologic failure). The absolute difference in response, based on logistic regression and adjusted for baseline log10 viral load and CD4+ cell count, was −9.6 percentage points (95% CI, −19.9 to 0.7 percentage points; P = 0.067) for intention-to-treat TLOVR and −3.9 percentage points (CI, −13.9 to 6.0 percentage points; P = 0.438) for TLOVR population that censored patients who withdrew for reasons other than virologic failure. Adverse events were similar between the sexes. The most common grade 2 to 4 adverse events that were considered at least possibly treatment related in women and men were nausea (5.2% and 2.8%, respectively), diarrhea (4.5% and 4.9%, respectively), and rash (2.1% and 2.8%, respectively).” (J. Currier, jscurrier@mednet.ucla.edu)
Palifermin Prevention of Severe Oral Mucositis: Administered before each cycle of chemotherapy, a single dose of palifermin can reduce the occurrence and severity of oral mucositis, a study shows (pp. 358–67). In 48 patients with sarcoma who were treated with doxorubicin-based chemotherapy, intravenous palifermin 180 mcg/kg or placebo provided these outcomes when given 3 days before chemotherapy for up to six cycles: “A median of 6 blinded cycles (range, 1 to 6) were completed by the palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, −44 percentage points [95% CI, −71 to −16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, −38 percentage points [CI, −67 to −9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the palifermin group vs. 31% in the placebo group; P = 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label palifermin.” (S. Vadhan–Raj, svadhanr@mdanderson.org)
PPIs & Cardiovascular Outcomes: Patients taking proton-pump inhibitors after discharge from hospitalizations for myocardial infarction had worse outcomes regardless of concomitant clopidogrel use, researchers report (pp. 378–86). The clopidogrel interaction with PPIs has been controversial, leading Danish investigators to conduct a national cohort study using linked administrative registry data. Among those discharged in 2000–06, these trends were noted: “Of 56,406 included patients, 9,137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24,702 patients (43.8%) who received clopidogrel, 6,753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).” (M. Charlot, mc@heart.dk)

>>>PNN NewsWatch
* FDA has taken action against five companies it says are marketing dietary supplements containing aromatase inhibitors.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 22, 2010 * Vol. 17, No. 183
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 22/29 issue of JAMA (2010; 304).
Self-Management Counseling in Heart Failure: Compared with education about heart failure, a self-management intervention failed to improve outcomes among 902 participants in the Heart Failure Adherence and Retention Trial (HART) (pp. 1331–8). Using a partially blinded design, investigators provided either educational tip sheets by mail along with telephone check-in calls or the tip sheets in person to groups of patients along with multiple meetings on self-management skills. Results after 2–3 years showed: “Patients were representative of typical clinical populations (mean age, 63.6 years; 47% women, 40% racial/ethnic minority, 52% with annual family income less than $30,000, and 23% with preserved systolic function). The rate of the primary end point [death or heart failure hospitalization] in the self-management group was no different from that in the education group (163 [40.1%)] vs 171 [41.2%], respectively; odds ratio, 0.95 [95% confidence interval, 0.72–1.26]). There were no significant differences on any secondary end points, including death, heart failure hospitalization, all-cause hospitalization, or quality of life.” (L. H. Powell, lpowell@rush.edu)
Asking how the “help of the largest health care workforce”—patients—can be effectively “enlisted,” editorialists make these comments (
pp. 1383–4): “In the study by Powell et al, eighteen 2-hour group meetings were spread out over the course of 1 year at considerable cost and inconvenience to the patients. Ultimately, electronic media, rather than in-person meetings with nurses and physicians, may become the predominant method of delivering health information, ensuring implementation of advice and treatment and sending motivational messages efficiently and effectively. This will need the support of health professionals for the foreseeable future to introduce patients to the programs and to identify patients who are outside the expected patterns of disease or behavior. The repertoire of such electronic strategies most likely will increase with experience. Home telemonitoring is a natural extension of this strategy, allowing patients to send information to clinicians about symptoms, weight, heart rate and rhythm, and blood pressure from their homes on a daily or weekly basis. Telemonitoring increases the uptake of therapy and reduces mortality. These systems can provide information and motivational messages—for example, by using video messaging and interactive television—supported by but not primarily delivered by a health professional.” (J. G. F. Cleland, j.g.cleland@hull.ac.uk)
Identifying High-Risk Patients with Atherothrombosis: Among patients with atherothrombosis, several clinical characteristics can be used to identify those at highest risk of future ischemic events, researchers report (pp. 1350–7). “Polyvascular disease is the strongest predictor of future ischemic events; a history of previous ischemic events, particularly if such events occurred in the prior 12 months, and a diagnosis of diabetes each are strongly associated with further risk elevation,” they write, adding these details from their analysis of 4-year follow-up of those in the Reduction of Atherothrombosis for Continued Health (REACH) Registry: “A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5,481 patients experienced at least 1 event, including 2,315 with cardiovascular death, 1,228 with myocardial infarction, 1,898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%–19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%–12.9%); and patients without established atherothrombosis but with risk factors only (n = 8,073) had the lowest risk (9.1%; 95% CI, 8.3%–9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-–1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57–1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-–2.24; P < .001) each were associated with a significantly higher risk of the primary end point.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 23, 2010 * Vol. 17, No. 184
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 23 issue of the New England Journal of Medicine (2010; 363).
Fondaparinux for Superficial-Vein Thrombosis: For treatment of acute, symptomatic superficial-vein thrombosis in 3,002 patients, fondaparinux 2.5 mg daily for 45 days improved outcomes and symptoms, and it did so without inducing serious adverse effects, a study shows (pp. 1222–32). A primary efficacy outcome included a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. In follow-up through day 77, the researchers found: “The primary efficacy outcome occurred in 13 of 1,502 patients (0.9%) in the fondaparinux group and 88 of 1,500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P < 0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P < 0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo.” (H. Decousus, herve.decousus@chu-st-etienne.fr)
After pointing out that the number needed to treat in the above study was 88 and that the cost of 45 days of fondaparinux therapy in 1,500 patients would be at least $3.13 million, editorialists have this to say about postmarketing studies (
pp. 1278–80): “We recommend that the Food and Drug Administration give serious thought to mandating phase 3.5 trials to document the costs, the effects on quality of life, and the cost-effectiveness of new interventions so as to reach a consensus regarding their worthiness. Until such data are available and consensus is reached, it would seem premature to recommend that fondaparinux be used routinely in the treatment of superficial-vein thrombosis.” (L. Goldman)
Genetics & Asthma: While finding “a few common alleles” in patients of all ages with asthma, investigators conducting a genomewide association study mostly confirmed that the heterogeneous nature of the disease extends to its genetic basis (pp. 1211–21): “Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma.” (W. O. C. M. Cookson, w.cookson@imperial.ac.uk)

>>>PNN NewsWatch
* Fingolimod (Gilenya, Novartis) has been approved by FDA for treatment of relapsing forms of multiple sclerosis. The drug boasts a number of “firsts”: the first approved sphingosine 1-phosphate receptor (S1PR) modulator, first oral treatment for relapsing MS, and a first-line treatment for this condition. S1PR modulators are believed to prevent lymphocytes from leaving lymph nodes and migrating to CNS tissues, where they produce MS symptoms through actions on the protective myelin sheath of neurons. In clinical trials, fingolimod 0.5 mg significantly reduced relapses by 52% at 1 year, compared with intramuscular interferon beta-1a. The new drug also significantly reduced disease activity, compared with interferon beta-1a, as measured by the number of new and newly enlarged T2 lesions on MRI scans (1.6 vs 2.6, respectively, at 1 year). Data from a 2-year placebo-controlled study showed a significant 54% reduction in relapse rate with fingolimod, and risk of disability progression among patients on the drug was reduced by 30% at 3 months, compared with those on placebo. Serious adverse effects of fingolimod include bradycardia or bradyarrhythmias, infections, macular edema, shortness of breath, and hepatic damage. More common but less serious ADEs include headache, influenza, diarrhea, back pain, elevation of liver enzymes, and cough.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 24, 2010 * Vol. 17, No. 185
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Sept./Oct. issue of the Journal of the American Pharmacists Association (2010; 50).
Promoting Tobacco Cessation in Community Pharmacies: Two research articles focus on tobacco cessation in community pharmacies.
Professional and respectful ways of enacting ask, advise, and refer (AAR) tobacco-cessation programs in community pharmacies should be well received by patients, a study indicates (
pp. 568–74). Semistructured telephone interviews of 24 tobacco users who had recently been counseled about cessation at a community pharmacy produced these themes: “Eight distinct themes were identified. Display of information and resources at pharmacies for use by tobacco users as needed was identified as the most predominant theme and was found to be most helpful by many respondents. Other themes identified in decreasing order of prevalence were: tobacco users’ perceptions of the role of pharmacists in health care, tobacco users’ belief that smoking could interact with a current medication or health condition, tobacco users’ sensitivity toward their tobacco use behavior or being told what to do, nonconfrontational and friendly approach of pharmacists, tobacco users’ readiness to quit at the time of AAR counseling, tobacco user initiation of tobacco use discussion, and tobacco users’ belief that tobacco use is bad.” (P. D. Patwardhan, ppatwardhan@legacyforhealth.org)
Workload, reimbursement, and training are barriers to implementation of more tobacco-cessation activities by pharmacists, according to a study conducted at a Montana continuing education program (
pp. 575–9). At 11 meeting sites, 192 pharmacists completed surveys about their use of the 5 A’s as defined in the U.S. Clinical Practice Guidelines (ask, advise, assess, assist, arrange): “The percent of pharmacists who treated one or more patients using the 5 A’s in the preceding 30 days were as follows: asked about tobacco use, 39%; advised to quit smoking, 54%; assessed for readiness to quit smoking, 36%; assisted with quitting (i.e., cessation counseling), 46%; assisted with advice to use nonprescription cessation medication, 62%; assisted with advice to use prescription cessation medication, 54%; arranged for a follow-up appointment for additional counseling, 6%; and referred to a tobacco quit line, 23%. Most respondents (58%) reported that providing cessation services within routine practice was moderately or highly feasible. The most frequently cited barriers to providing cessation services included lack of time (52%), reimbursement (26%), and training (19%).” (L. A. Dent, larry.dent@umontana.edu)
Take-Back Program Conducted by Student Pharmacists: With a DEA-sponsored National Take-Back Initiative set for tomorrow, authors describe a similar effort in Knoxville, TN, conducted by student pharmacists (pp. 613–8). During 1-year period beginning in Nov. 2008, students worked with community partners to collect medications and mercury-containing thermometers so that they could be disposed of appropriately: “The events increased community awareness of appropriate medication disposal and pharmacists’ roles in safe use of medications. From November 2008 to November 2009, more than 1,100 pounds of unwanted medications were collected through events and the drop box. Additionally, more than 470 pounds of recyclable packaging material was collected and 535 mercury thermometers exchanged.” (A. S. Franks, afranks@uthsc.edu)

>>>PNN NewsWatch
* Citing elevated risks of cardiovascular events such as myocardial infarction and stroke in patients taking rosiglitazone, FDA yesterday announced severe restrictions on use of the drug, marketed by GlaxoSmithKline as Avandia. The agency directed GSK to implement a Risk Evaluation and Mitigation Strategy (REMS) that would ensure provision of complete risk information to patients receiving the drug and document in the medical record that the patient has received and understood the warnings. The REMS program would also require documentation by health care providers that each patient receiving rosiglitazone was either already on the drug or unable to achieve glycemic control while on other antidiabetic medications and not willing to take pioglitazone. GSK must also “commission a re-adjudication of the RECORD study” using a stepwise assessment of mortality results.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 27, 2010 * Vol. 17, No. 186
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 341).
Antipsychotic Drugs & Thromboembolism: Use of antipsychotic agents is associated with increased risk of venous thromboembolism, a study shows, with higher risks among new users and those on second-generation agents (c4245). Investigators conducted a population-based, nested case–control study using the U.K. QResearch primary care database, with cases being patients with first-ever venous thromboembolism in 1996–2007. Results showed: “There were 25,532 eligible cases (15,975 with deep vein thrombosis and 9,557 with pulmonary embolism) and 89,491 matched controls from a study population of 7,267,673. Individuals prescribed antipsychotic drugs in the previous 24 months had a 32% greater risk of venous thromboembolism than non-users, despite adjustment for potential risk factors (odds ratio 1.32, 95% confidence interval 1.23 to 1.42). Patients who had started a new drug in the previous three months had about twice the risk (1.97, 1.66 to 2.33). The risk was greater for individuals prescribed atypical rather than conventional drugs (adjusted odds ratio 1.73, 1.37 to 2.17, for atypical drugs; 1.28, 1.18 to 1.38, for conventional drugs). It also tended to be greater for patients prescribed low rather than high potency drugs (1.99, 1.52 to 2.62, for low potency; 1.28, 1.18 to 1.38, for high potency). The estimated number of extra cases of venous thromboembolism per 10,000 patients treated over one year was 4 (3 to 5) in patients of all ages and 10 (7 to 13) for patients aged 65 and over.” (J. Hippisley–Cox, juliahippisleycox@gmail.com)
Norwegians’ Views on Orphan Drugs: While a survey of 1,547 Norwegians shows strong general support of provision of orphan drugs to patients with rare diseases, respondents also believed limited resources should be used where greater societal good could be accomplished (c4715). The random-sample, Web-based survey, conducted of people aged 40 to 67 years, showed these views on how to choose between funding for a rare versus common disease: “For the equal cost scenario, 11.2% (9.6% to 12.8%) of respondents favoured treating the rare disease, 24.9% (21.7% to 26.0%) the common disease, and 64.9% (62.6% to 67.3%) were indifferent. When the rare disease was four times more costly to treat, the results were, respectively, 7.4% (6.1% to 8.7%), 45.3% (42.8% to 47.8%), and 47.3% (44.8% to 49.8%). Rankings for attitude on a Likert scale indicated strong support for the statements ‘rare disease patients should have the right to treatment even if more expensive’ (mean score 4.5, SD 0.86) and ‘resources should be used to provide the greatest possible health benefits’ (3.9, 1.23).” (A. S. Desser, a.s.desser@medisin.uio.no)

>>>PNN NewsWatch
* An oral contraceptive product that contains folate was approved on Friday by FDA. Bayer’s Beyaz contains the same contraceptive ingredients as Yaz (drospirenone 3 mg/ethinyl estradiol 0.02 mg) and carries three of the same indications as that product (prevention of pregnancy, treatment of symptoms of premenstrual dysphoric disorder in women who choose to use an oral contraceptive for contraception and treatment of moderate acne vulgaris in women at least 14 years of age, only if the patient desires an oral contraceptive for birth control). It also contains levomefolate calcium 0.451 mg, which allows a secondary indication of raising “folate levels for the purpose of reducing the risk of a neural tube defect in a pregnancy conceived while taking the product or shortly after discontinuing the product.”
* Information on the
recalled brands of infant formula, including Isomil and Similac, is available on the FDA website.

>>>PNN JournalWatch
* Rheumatoid Arthritis, in Lancet, 2010; 376: 1094–108. (D. L. Scott, d.scott@nhs.net)
* Assessment of the Human Coronary Collateral Circulation, in
Circulation, 2010; 122: 1210–20. (C. Seiler, christian.seiler@insel.ch)
* Vitamin D Insufficiency and Prognosis in Non-Hodgkin’s Lymphoma, in
Journal of Clinical Oncology, 2010; 28: 4191–8. (J. R. Cerhan, cerhan.james@mayo.edu)
* Preventing Unintended Pregnancy: Pharmacists’ Roles in Practice and Policy via Partnerships, in
Journal of the American Pharmacists Association, 2010; 50: 604–12. (K. B. Farris, karen-farris@uiowa.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 28, 2010 * Vol. 17, No. 187
Providing news and information about medications and their proper use

>>>Kidney Diseases Highlights
Source:
Oct. issue of the American Journal of Kidney Diseases (2010; 56).
Acetylcysteine & Renal Function: N-acetylcysteine (NAC) had no short-term effect on creatinine level and did not decrease protein excretion during 48 hours of treatment, a randomized trial of 60 patients shows (pp. 643–50). Using a primary outcome of change in serum creatinine level between baseline and 4 hours after the last treatment dose, investigators found these effects of four doses of oral NAC 1,200 mg or placebo: “60 patients, mean age of 70 years, 75% men, 50% had diabetes, with mean creatinine clearance of 43.7 ± 18.8 (SD) mL/min were enrolled. Between baseline and 4 hours posttreatment, serum creatinine level decreased by 0.044 ± 0.15 mg/dL in the NAC group and 0.040 ± 0.18 mg/dL in the placebo group (95% CI for difference, −0.09 to 0.08; P = 0.9). No significant differences between groups were observed for change in serum creatinine, cystatin C, urine protein, urine creatinine, or creatinine clearance values at any time.” (L. Moist, louise.moist@lhsc.on.ca)
Hepatitis Immunization in Patients on Hemodialysis: Combined vaccination of patients on hemodialysis with hepatitis A and hepatitis B gave better seroprotection against hepatitis B than did administration of the monovalent hepatitis B product, researchers report (pp. 713–9). Twinrix (inactivated hepatitis A virus [720 ELISA units] and purified hepatitis B virus surface antigen [20 mcg]; Glaxo SmithKline) and Engerix-B (purified hepatitis B virus surface antigen [20 mcg]) were administered intramuscularly at 0, 1, and 6 months with Engerix-B, 40 mcg, at month 2 (intervention arm) or Engerix-B, 40 mcg, at 0, 1, 2, and 6 months (control arm). Results showed: “96 patients were enrolled, and 73 completed the investigation. At 3 months, there was no difference in the groups’ seroprotection rates (25% vs 27%; P = 0.4). At the completion of the vaccination series, using per-protocol analysis, 27 of 40 (68%) and 16 of 33 (49%) had antibody titers >10 mIU/mL in the treatment and control groups, respectively (P = 0.05; RR, 1.4; absolute abatement, 19%). Intention-to-treat analysis showed 58% and 38% seroprotection rates in the treatment and control groups, respectively (P = 0.02; RR, 1.5; absolute abatement, 20%). There was no difference in adverse events.” (C. H. Lee, clee@mcmaster.ca)

>>>Oncology Report
Source:
Sept. 20 issue of the Journal of Clinical Oncology (2010; 28).
Nonadherence with Adjuvant Hormonal Therapy in Breast Cancer: About one-half of women with early-stage breast cancer fail to complete the recommended periods of adjuvant hormonal therapy, a study shows, and high-risk younger women have the highest rates of nonadherence (pp. 4120–8). Analysis of pharmacy records from the northern California Kaiser Permanente system show these patterns in 1996–2007: “We identified 8,769 patients with BC who met our eligibility criteria and who filled at least one prescription for tamoxifen (43%), aromatase inhibitors (26%), or both (30%) within 1 year of diagnosis. Younger or older age, lumpectomy (v mastectomy), and comorbidities were associated with earlier discontinuation, while Asian race, being married, earlier year at diagnosis, receipt of chemotherapy or radiotherapy, and longer prescription refill interval were associated with completion of 4.5 years of therapy. Of those who continued therapy, similar factors were associated with full adherence. Women age younger than 40 years had the highest risk of discontinuation (hazard ratio, 1.51; 95% CI, 1.23 to 1.85). By 4.5 years, 32% discontinued therapy, and of those who continued, 72% were fully adherent.” (D. L. Hershman, dlh23@columbia.edu)

>>>PNN NewsWatch
* Octapharma is withdrawing Octagam, the company’s 5% immune globulin intravenous (human) product, from the U.S. market, FDA announced. Nine thromboembolic events have been associated with the 6 lots of the product that are being withdrawn. While the FDA announcements termed this a “market withdrawal,” the company told PNN that this is a suspension and the product will return to the market.
*
Amgen is recalling certain lots of Epogen and Procrit (epoetin alfa) vials because of possible lamellae (extremely thin glass flakes) in vials.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 29, 2010 * Vol. 17, No. 188
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2010; 33).
Computerized Insulin Order Template: Internal medicine residents had better outcomes when they used a computerized insulin order template to care for 128 patients with type 2 diabetes, a study shows (pp. 2181–3). Compared with usual insulin ordering, patients whose orders were generated using the template had significantly lower mean blood glucose levels (195 ± 66 versus 224 ± 57 mg/dL) without any increase in episodes of hypoglycemia (blood glucose less than 60 mg/dL). (D. J. Wexler, dwexler@partners.org)
Dapagliflozin Monotherapy in Type 2 Diabetes: A new drug that acts independently of insulin produced significant drops in blood glucose without serious hypoglycemia episodes, shows a trial of 558 patients with newly diagnosed type 2 diabetes (pp. 2217–24). Dapagliflozin is a highly selective inhibitor of the renal sodium-glucose cotransporter-2 that is thought to act by increasing urinary excretion of glucose and lowering plasma glucose levels, the authors write. In a 24-week, Phase III trial, dapagliflozin at any of several doses given once daily in the morning (main cohort) or evening (exploratory cohort) produced these outcomes in comparison with placebo: “In the main cohort, mean A1C changes from baseline at week 24 were −0.23% with placebo and −0.58, −0.77 (P = 0.0005 vs. placebo), and −0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results.” (E. Ferrannini, ferranni@ifc.cnr.it)
Vitamin D & Mortality: Patients with type 2 diabetes have higher rates of all-cause and cardiovascular mortality when severely deficient in vitamin D, a longitudinal study shows (pp. 2238–43). Patients with normoalbuminuria (n = 172), microalbuminuria (n = 73), and macroalbuminuria (n = 44) at baseline were followed for a median of 15.0 years, with these associations with plasma 25-hydroxyvitamin D3: “Median (range) vitamin D level was 35.7 (5–136.7) nmol/l. Vitamin D levels were not associated with age, sex, estimated glomerular filtration rate, urinary albumin excretion rate (UAER), or A1C at baseline, but low levels were weakly associated with elevated systolic blood pressure (R = 0.13, P = 0.03). During follow-up, 196 (68%) patients died. All-cause mortality was increased in patients with severe vitamin D deficiency (hazard ratio 1.96 [95% CI 1.29–2.98]). The association persisted after adjustment for UAER, A1C, diabetes duration, and conventional cardiovascular risk factors (2.03 [1.31–3.13]). Severe vitamin D deficiency was associated with increased cardiovascular mortality (1.95 [1.11–3.44]), and the association persisted after adjustment (1.90 [1.15–3.10]). Severe vitamin D deficiency at baseline did not predict progression to micro- or macroalbuminuria.” (C. Joergensen, cijq@steno.dk)
Obesity, Diabetes, and Gut Microbiota: Lifestyle changes that promote healthy gut microbiota could “positively affect prevention and treatment of metabolic disorders,” authors of a review article conclude (pp. 2277–84): “Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being [confirmed] in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle—including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake—may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.” (G. Musso, giovanni_musso@yahoo.it)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.

PNN Pharmacotherapy Line
Sept. 30, 2010 * Vol. 17, No. 189
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 30 issue of the New England Journal of Medicine (2010; 363).
Spleen Tyrosine Kinase Inhibitor & RA: In a Phase II trial of 457 patients, an oral spleen tyrosine kinase (Syk) inhibitor, R788, was effective for reducing rheumatoid arthritis activity but while producing adverse effects such as diarrhea, hypertension, and neutropenia (pp. 1303–12). Using a primary outcome of American College of Rheumatology (ACR) 20 response over a 6-month period, the investigators found: “R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P < 0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P < 0.001 for the comparison of the 100-mg dose with placebo, P = 0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P < 0.001 for the comparison of the 100-mg dose with placebo, P = 0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy.” (M. E. Weinblatt, mweinblatt@partners.org)
Editorialists note the success of tyrosine kinase inhibitors in treatment of cancers and make these observations of use of such agents in rheumatoid arthritis (
pp. 1362–4): “R788 is known to be a relatively potent inhibitor of the receptor tyrosine kinase Ret, a receptor for the glial cell line–derived neurotrophic factor family of extracellular signaling ligands. Ret is involved in development and organogenesis and is expressed in macrophages, which are key contributors to inflammation in rheumatoid arthritis. Thus, the beneficial effects of R788 in patients with rheumatoid arthritis may not be due entirely to its ability to inhibit [the tyrosine kinase] Syk. Another issue that must be considered is that, unlike many other tyrosine kinases, Syk has tumor-suppressing properties. Increased expression of Syk in neoplastic cells from breast-cancer tumors suppresses tumor growth. Moreover, reduced expression of Syk has been found in patients with breast cancer. This suggests that the long-term use of Syk inhibitors should be closely monitored and that its use might be inappropriate for people with a family history of breast cancer.” (J. Rivera)
Reduced-Dose Chemotherapy for Intermediate-Risk Neuroblastoma: Compared with earlier trials, the 3-year survival rates in children with intermediate-risk neuroblastoma were similar with use of reduced-dose chemotherapy in a nonrandomized, Phase III trial (pp. 1313–23). Using four cycles of chemotherapy in patients with favorable histopathological features and hyperdiploidy and eight cycles in other patients, all of whom had stage 3 or 4 disease, the investigators determined: “Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96 ± 1%, with an overall survival rate of 98 ± 1% among patients who had tumors with favorable biologic features and 93 ± 2% among patients who had tumors with unfavorable biologic features.” (K. K. Matthay, matthayk@peds.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, 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.