Risk For Heart Attack And Death From Cardiovascular Disease For Diabetic Patients Using Avandia: "Uncertain"

(Posted by Tom Lamb at DrugInjuryWatch.com)

On August 6, 2007 the medical journal Annals of Internal Medicine published online an early-release version of a new Avandia article, "Uncertain Effects of Rosiglitazone on the Risk for Myocardial Infarction and Cardiovascular Death", that analyzes the recently reported Nissen and Wolski meta-analysis.  This latest analysis of Avandia (rosiglitazone) study data, done by George A. Diamond, M.D., Leon Bax, M.Sc., and Sanjay Kaul, M.D., will be published in the October 16, 2007 (Volume 147 Issue 8) edition of the Annals of Internal Medicine.

The bottom-line conclusion of this latest Avandia article:

We conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain: Neither increased nor decreased risk is established.

Before we delve further into this Annals of Internal Medicine Avandia article, let’s set the stage.

First, in their article "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes" Steven Nissen, M.D. and Kathi Wolski, M.P.H. reported a meta-analysis of 42 clinical trials involving 27,847 patients which essentially started the ongoing controversy about the safety of Avandia.  They concluded that treatment with Avandia was associated with an approximately 43% greater risk for myocardial infarction and an approximately 64% greater risk for cardiovascular death than placebo or other antidiabetic regimens.

Next, Dr. Nissen and Professor Philip Home, among others, discussed the Avandia drug safety issue in June 2007 at a well-attended session during the annual meeting of the American Diabetes Association.

Thereafter, the controversy started by Nissen and Wolski’s Avandia studies analysis caused the investigators of the large, ongoing trial called, in full, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes, and, in short, RECORD, to perform an unplanned interim analysis.  Their findings were presented in an article by Professor Home and other members of the RECORD Study Group called "Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis".

Now back to this early-release online Avandia data analysis article by Diamond, Bax, and Kaul, according to its Abstract, here is how they reached the bottom-line conclusion set forth above:

A recent, widely publicized meta-analysis of 42 clinical trials concluded that rosiglitazone was associated with an approximately 43% increased risk for myocardial infarction and an approximately 64% increased risk for cardiovascular death. The sensitivity of these conclusions to several methodological choices was not assessed. The meta-analysis was not based on a comprehensive search for all studies that might yield evidence about rosiglitazone’s cardiovascular effects. Studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in study design and outcome assessment. The meta-analytic approach that was used required the exclusion of studies with zero events in the treatment and control groups. Alternative meta-analytic approaches that use continuity corrections show lower odds ratios that are not statistically significant.  We conclude that the risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain: Neither increased nor decreased risk is established.

In the Summary part of the full-text version of this Avandia article, Diamond, Bax, and Kaul go on to offer this opinion:

In the end, we believe that only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. In our opinion, available evidence does not justify what the authors of the original meta-analysis (as well as the media, the U.S. Congress, and worried patient groups) decried as an "urgent need for comprehensive evaluations" [quote from Nissen and Wolski meta-analysis article].

Of course, we have skipped over the recent fall-out from the July 30, 2007 meeting of the FDA’s advisory panels.  But given this mixed set of conclusions reached to date as regards the analysis of Avandia study data currently available, the FDA certainly has a lot to think about concerning this high-profile Avandia drug safety issue.

P.S.  "Avandia Committee Chairman [Clifford J. Rosen] Speaks": Posted by Jacob Goldstein at The Wall Street Journal Online Health Blog.  (8/8/07)

P.S.  Read the New England Journal of Medicine Perspective piece by Clifford J. Rosen, M.D.: "The Rosiglitazone Story — Lessons from an FDA Advisory Committee Meeting", published at www.nejm.org August 8, 2007, and made available for free.  (8/9/07)