Dallas Accident Lawyer & Attorney : Fears Nachawati Law Firm : Personal Injury, Wrongful Death : Ft. Worth, San Antonio, Austin, Houston, Texas

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The New England Journal of Medicine reports about the recent drug Trasylol.

September 30 is becoming a day of infamy for drug safety. On that date in 2004, Merck announced that rofecoxib (Vioxx) doubled the risk of myocardial infarction and stroke, and the company withdrew the drug from the market after 5 years of use in more than 20 million patients. On September 30, 2006, a front-page article in the New York Times reported that the Food and Drug Administration (FDA) had issued a warning that the antifibrinolytic drug aprotinin, widely used to reduce perioperative bleeding in patients undergoing cardiac surgery, could cause renal failure, congestive heart failure, stroke, and death.

Some experts had been concerned about aprotinin (Trasylol) ever since its approval in 1993.1 As Hiatt explains in his Perspective article in this issue of the Journal (pages 2171–2173), one of two epidemiologic studies reported early this year provided support for this concern. In an observational study involving 4374 patients who underwent coronary revascularization,2 Mangano et al. found that patients who were given aprotinin had an incidence of postoperative renal failure requiring dialysis that was more than twice that among patients who received different agents. Among patients undergoing uncomplicated coronary-artery surgery, those given aprotinin had a 55% increase in the incidence of myocardial infarction or heart failure and a 181% increase in the incidence of stroke or encephalopathy. The authors advised against further use of the drug, since safer, cheaper alternatives are available.

After the study was published, the FDA moved to convene an advisory committee to reassess the drug's safety and assembled the relevant data. The committee met on September 21, reviewed the available evidence, and concluded that there was no need for additional warnings on the drug's official labeling.

What put aprotinin on the front page on September 30, however, was the revelation that its manufacturer, Bayer, had hired a private contract research organization to perform its own large observational study of postoperative complications in patients given the drug. The analysis, completed in time for the FDA meeting, reached conclusions similar to those of Mangano et al. It, too, adjusted for a wide variety of clinical characteristics and showed that patients who received aprotinin had higher mortality rates and substantially more renal damage than those given other treatments. But neither Bayer nor its contractor had provided the report to the FDA or even acknowledged its existence before the meeting.

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The U.S. Food and Drug Administration (FDA) is aware of a potential safety issue related to Avandia (rosiglitazone), a drug approved to treat type 2 diabetes. Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia. However, other published and unpublished data from long-term clinical trials of Avandia, including an interim analysis of data from the RECORD trial (a large, ongoing, randomized open label trial) and unpublished reanalyses of data from DREAM (a previously conducted placebo-controlled, randomized trial) provide contradictory evidence about the risks in patients treated with Avandia.

Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack should talk to their doctor about this new information as they evaluate the available treatment options for their type 2 diabetes.

FDA's analyses of all available data are ongoing. FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies. Pending questions include whether the other approved treatment from the same class of drugs, pioglitazone, has less, the same or greater risks. Furthermore, there is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions.

"FDA remains committed to assuring that doctors and patients have the latest information available to make treatment and medication use decisions. In this case, FDA is carefully weighing several complex sources of data, some of which show conflicting results, related to the risk of heart attack and heart-related deaths in patients treated with Avandia," said Steven Galson, M.D., M.P.H., director of FDA's Center for Drug Evaluation and Research. "We will complete our analyses and make the results available as soon as possible. FDA will take the issue of cardiovascular risk associated with Avandia and other drugs in this class to an Advisory Committee as soon as one can be convened."

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation. Since the drug was approved, FDA has been monitoring several heart-related adverse events (e.g., fluid retention, edema and congestive heart failure) based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports. FDA has updated the product's labeling on several occasions to reflect these new data, most recently in 2006. The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

Recently, the manufacturer of Avandia provided FDA with a pooled analysis (meta analysis) of 42 randomized, controlled clinical trials in which Avandia was compared to either placebo or other anti-diabetic therapies in patients with type 2 diabetes. The pooled analysis suggested that patients receiving short-term (most studies were 6-months duration) treatment with Avandia may have a 30-40 percent greater risk of heart attack and other heart-related adverse events than patients treated with placebo or other anti-diabetic therapy. These data, if confirmed, would be of significant concern since patients with diabetes are already at an increased risk of heart disease.