Monday, May 21, 2007

Not a Pretty Sight
Avandia - aka Rosiglitazone - Another Medical Train Wreck?

[Note: NEJM is a subscriber based service. But Mr. B. logged on to the site - as you can, too - and was given access to an important paper. Extracts are posted below in the belief that they are important and that this is permitted under the fair use doctrine. Please consult the whole article if this is a matter of medical importance to you. If the NEJM is too heavy duty for you, here is a link to an article in Time.]

From the New England Journal of Medicine Web Site:

Published at May 21, 2007 (10.1056/NEJMoa072761)

Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes
Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.


Background Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined.

Methods We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarction and death from cardiovascular causes.

Results Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06).

Conclusions 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.

From the Discussion

Our study has important limitations. We pooled the results of a group of trials that were not originally intended to explore cardiovascular outcomes. Most trials did not centrally adjudicate cardiovascular outcomes, and the definitions of myocardial infarction were not available. Many of these trials were small and short-term, resulting in few adverse cardiovascular events or deaths. Accordingly, the confidence intervals for the odds ratios for myocardial infarction and death from cardiovascular causes are wide, resulting in considerable uncertainty about the magnitude of the observed hazard. Furthermore, we did not have access to original source data for any of these trials. Thus, we based the analysis on available data from publicly disclosed summaries of events. The lack of availability of source data did not allow the use of more statistically powerful time-to-event analysis. A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest. Although such a dedicated trial has not been completed for rosiglitazone, the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial may provide useful insights.34

Despite these limitations, our data point to the urgent need for comprehensive evaluations to clarify the cardiovascular risks of rosiglitazone. The manufacturer's public disclosure of summary results for rosiglitazone clinical trials is not sufficient to enable a robust assessment of cardiovascular risks. The manufacturer has all the source data for completed clinical trials and should make these data available to an external academic coordinating center for systematic analysis. The FDA also has access to study reports and other clinical-trial data not within the public domain. Further analyses of data available to the FDA and the manufacturer would enable a more robust assessment of the risks of this drug. Our data suggest a cardiovascular risk associated with the use of rosiglitazone. Until better precision of the estimates of the risks of this treatment on cardiovascular events can be delineated in patients with diabetes, patients and providers should give careful consideration to the risks and benefits of their overall treatment plans.

Dr. Nissen reports receiving research support to perform clinical trials through the Cleveland Clinic Cardiovascular Coordinating Center from Pfizer, AstraZeneca, Daiichi Sankyo, Roche, Takeda, Sanofi-Aventis, and Eli Lilly. Dr. Nissen consults for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. No other potential conflict of interest relevant to this article was reported.

What a novel concept! BigU MedSchool should hire some people like Dr. Nissen. They could then serve as examples to MedSchoolDean and to other like-minded Med School faculty here at BigU.

The general situation does not look good to Mr. Bonzo. Parallels are already being drawn with Vioxx, e.g. the link to Time noted above.