FDA Issues Safety Alert on Avandia
May 21, 2007 was Avandia day in the media. Avandia, whose other name is rosiglitazone, is one of two currently-available drugs in a class of diabetes medications called "TZDs" (thiazolidinediones) or "glitazones". The other is pioglitazone (Actos).
Yesterday saw a flurry of news reports after the New England Journal of Medicine released on-line an scientific article about Avandia and its effects on the heart, titled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes." The full article is available for viewing on-line, as is an accompanying editorial, "Rosiglitazone and Cardiovascular Risk". David Mendosa also discusses the media reaction at his SharePost, Avandia Anxiety.
The authors of the article examined data from 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, and concluded that "Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes."
Apparently the NEJM article was released a few hours earlier than had been originally planned, and the stock market picked it up, and the share price of the manufacturer (GlaxoSmithKline) fell – leading to a media frenzy breathlessly exaggerating the results of the study on the evening news. The FDA promptly issued a Safety Alert with their take on the safety of Avandia. (I’ve reproduced it at the end of this SharePost.) And, of course, GSK issued a rebuttal press release. But as the media buzz increased, inevitably patients taking Avandia became more worried.
Today, I’ve seen several questions from patients concerned about this issue, and I thought I’d use this forum to answer those questions.
Q) I'm currently using Actos [the other TZD], should I discuss with my doctor about stopping it?
A) Avandia and Actos are both in the same class of medications, and thus there is a possibility that any side effect seen with one might occur with the other. That said, the NEJM article was specifically about Avandia, and the authors stated that Actos was different: "The question as to whether the observed risks of rosiglitazone represent a "class effect" of thiazolidinediones must also be considered. Pioglitazone is a related agent also widely used to treat type 2 diabetes mellitus. However, unlike rosiglitazone, pioglitazone has been studied in a prospective, randomized trial of cardiovascular outcomes, called Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE). The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglitazone (hazard ratio, 0.90; P=0.095). A secondary end point consisting of myocardial infarction, stroke, and death from any cause showed a significant effect favoring pioglitazone (hazard ratio, 0.84; P=0.027). Notably, pioglitazone appears to have more favorable effects on lipids, particularly triglycerides, than does rosiglitazone."
Q) Does Avandia increase the risk of a heart attack only when taking the drug or does the increased risk remain after you stop taking the drug (examples of other drugs would include: Vioxx – increased risk of heart attack stopped when you quit taking the drug, versus Phenfen – apparently resulted in permanent heart valve damage, thus increase in risk continued)?
A) First of all, the increased risk is not proven; it’s only the conclusion of a meta-analysis that was published today. As the FDA said: "FDA has not confirmed the clinical significance of the reported increased risk in the context of other studies." By the nature of the data source (mostly clinical trials that study the drug, not what happens after the drug is stopped), there’s no available information about whether the risk persists after discontinuing Avandia.
Q) The FDA bulletin reported that the pooled analysis indicated that "short-term" treatment (defined as 6 months) suggested an increase of 30-40 percent for risk of a heart attack. What if you have taken Avandia for a longer period of time (in the past or still currently using)?
A) The authors of the NEJM article mention that "Time-to-event data for cardiovascular events were not available in any of these trials" – hence the effect of duration of treatment (if any) is unclear from the present meta-analysis. Most studies in the meta-analysis were 6 months’ duration – in fact the authors deliberately excluded studies of short duration: "Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks…".
Q) Has there been any preliminary identification of testing that may be able to indicate potential damage or increased risk conditions?
A) FDA answered this one best: "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."
Q) I've been on Avandamet [Avandia and metformin in a combination tablet] for over 2 years. I'm also concerned about the identified risk factors of Avandia. Is there any change to the risks if you take it with metformin?
A) The meta-analysis did look at studies of patients taking both Avandia and metformin, but there’s no discussion whether the risk changed in patients taking both compared to patients taking only Avandia.
And the most important question of all for patients taking Avandia:
Q) Should I stop taking my Avandia?
A) No! As mentioned above, 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.
And when you go to your physician, bring along the reprint of the FDA Safety Alert, which I reproduce below:
FOR IMMEDIATE RELEASE
May 21, 2007
Susan Cruzan, 301-827-6242
FDA Issues Safety Alert on Avandia
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) [presumably the NEJM 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.
Avandia is manufactured by GlaxoSmithKline, which is based in Research Triangle Park, N.C.