Avandia, Risk of Congestive Heart Failure Significant Safety Risk
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GlaxoSmithKline's rosiglitazone (Avandia) will receive a black box warning by the FDA because of concerns over heart failure associated with use of the drug. Pioglitazone (Actos) will also be subject to a black box warning for the same reason. The drugs, used for treatment of type 2 diabetes, have been scrutinized because of a recent meta-analysis that suggested that rosiglitazone was associated with a significant- increase risk of myocardial infarction and a borderline significant-increase risk of death from cardiovascular causes. (published www.NEJM.org on June 21, 2007 [10.1056/NEJMoa 072761]). Soon on the heels of the publication of this study, Glaxo rushed an interim analysis of its own trial to press. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial was published online in the New England Journal of Medicine on June 5, 2007. In the RECORD study, 4,447 patients with type 2 diabetes who had inadequate control with metformin or a sulfonylurea were randomized to receive add-on rosiglitazone or a combination of metformin and a sulfonylurea. The primary endpoint was hospitalization or death from cardiovascular causes. After mean follow-up of 3.75 years, 217 patients in the rosiglitazone group and 202 patients in the control group had the primary endpoint (hazard ratio 1.08), and after adding in pending primary end points the hazard ratio was 1.11 (95% CI, 0.93 to 1.32). There was no statistically significant difference between either group with regard to myocardial infarction or death from cardiovascular causes or any cause. There was a significantly higher rate of heart failure in rosiglitazone group (HR 2.15; 95% CI, 1.30 to 3.57). The authors conclude that the study was inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes, as there was no evidence of an increased death rate of cardiovascular causes or all causes associated with the drug, but there was a significantly higher rate of heart failure. There was insufficient data to determine if there was an increase risk of myocardial infarction (published at www.NEJM.org June 5, 2007 [10.1056/NEJMoa 073394]). The study was accompanied by 3 editorials that recommended caution in use of rosiglitazone and similar drugs especially in patients at risk for congestive heart failure. And while GlaxoSmithKline sees the study as vindication of the safety the drug, others, including the FDA, see the risk of congestive heart failure as a significant safety risk. Soon after publication of the RECORD study, a congressional hearing was held to discuss the safety of rosiglitazone and within days the FDA issued the black box requirement for rosiglitazone and pioglitazone. During the hearing, it came to light that at least one official at the FDA had suggested stronger warnings on rosiglitazone nearly a year ago, but her recommendation was ignored; she was reassigned and subsequently left the agency. Within several days of the rosiglitazone hearing, legislation was introduced to bolster the FDA's ability to monitor prescription drug side effects, a bill which also includes many of the Institute of Medicines recent recommendations on drug safety, and also included limiting direct-to-consumer advertising for newly approved medications.
Aspirin, Higher Doses No More Effective, Risky
What is the best dose of aspirin for prevention of cardiovascular disease? More than 50 million people take aspirin regularly in doses that range from 50 mg to over 1000 mg per day. The most commonly used doses are 81 mg and 325 mg per day. A recent systematic review of the English-language literature revealed that doses as low as 30 mg/day are effective at fully inhibiting platelet thromboxane production and preventing platelet aggregation. Despite this, higher doses are frequently used. The available evidence, primarily from secondary prevention trials, suggest that doses greater than 81 mg do not enhance efficacy, but do increase risk of GI bleeding and other toxicities. The authors conclude that aspirin doses of 75 mg to 81 mg/day are optimal for the indication of cardiovascular disease prevention, and higher doses are no more effective but are associated with higher risk (JAMA 2007; 297:2018-2024).
Subclinical Hypothyroidism Treatment Benefits
Subclinical hypothyroidism is defined as raised TSH levels with circulating thyroid hormones within the normal range. A new study suggests that treatment of subclinical hypothyroidism improves cardiovascular risk factors and quality of life. One hundred patients with a mean TSH of 6.6 mIU/l who had never received thyroid treatment and did not have cardiovascular disease were enrolled in a randomized, double-blinded crossover study of 100 µg of l-thyroxine or placebo daily for 12 weeks. Treatment with L-thyroxine reduced total cholesterol from an average of 231.6 to 220 mg/dl (P <0.001), LDL cholesterol from 142.9 to 131.3 mg/dl (P < 0.05), and waist to hip ratio from 0.83 to 0.81 (P < 0.006). Treatment also significantly improved endothelial function based on brachial artery flow mediated dilation, an early marker of atherosclerosis. Patients also reported decreased tiredness in the active treatment group, and there was a trend towards improvement in the perceived negative impact of hypothyroidism on sexual function. The authors conclude that treating subclinical hypothyroidism with l-thyroxine lead to significant improvements of cardiovascular risk factors and symptoms of tiredness (J Clin Endocrinol Metab 2007; 92:1715-1723).
FDA approvals
The FDA has approved a new transdermal patch for the treatment of early stage idiopathic Parkinson's disease. Rotigotine transdermal is a once-daily patch that is available in 2, 4 and 6 mg strengths. The drug is a dopamine agonist that affects D3/D2/D1 receptors and is thought to exert its effect via stimulation of dopamine D2 receptors. In clinical trials the patch was shown to improve scores on standardized rating scales for daily living and motor components in Parkinson's disease. The most common side effects are site reactions, dizziness, nausea, vomiting, somnolence and insomnia. Rotigotine transdermal will be available by the end of 2007 and will be marketed by Schwartz Pharma under the trade name Neupro.
The FDA has approved a new continuous contraceptive for women that is designed to eliminate menstruation. Wyeth pharmaceuticals Lybrel is a 28-day pill pack of levonorgestrel and ethinyl estradiol (90 µg/20 µg) that does not contain a placebo or pill-free interval. In clinical trials 59% of women achieved amenorrhea without bleeding or spotting, while 20% experienced spotting but did not require sanitary protection, and 21% required sanitary protection due to breakthrough bleeding. There was also no delay to return of menses after discontinuing the product nor any significant delay in fertility. Lybrel is scheduled to be available by July 2007.
Risedronate (Actonel) has received approval for a new once-a-month dosing schedule for the treatment of osteoporosis. The dose regimen requires patients to take 75 mg tablets on 2 consecutive days each month. The approval was based on a study that compared the monthly regimen with a daily regimen of 5 mg per day and showed no significant difference in efficacy for increasing bone mineral density at the lumbar spine, total hip, and hip trochanter. Risedronate is marketed by Procter & Gamble pharmaceuticals.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5431. E-mail: [email protected].
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