Tuesday, June 5, 2007

Latest on Avandia (Rosiglitazone)

Mr. B. has previously posted twice on Avandia:

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


“Avandia flagged by FDA as a possible heart risk five years ago”

These posts were stimulated by a paper in the New England Journal of Medicine: “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.” that was published May 21.

Today appeared online several editorials and a paper. These will appear in the July 5 edition of the journal. But since this is such an important topic and of wide interest, an abstract is given below.

BOTTOM LINE: Data to date are inconclusive. This is a good thing because it means that the drug is apparently not absolutely terrible in which case the study might have been stopped. Hopefully the study at its conclusion will provide a firmer basis for making a decision about the use of the drug. If you have personal health concerns about these matters please consult your doctor.

Original Article

Published at www.nejm.org June 5, 2007

Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis

Philip D. Home, D.M., D.Phil., Stuart J. Pocock, Ph.D., Henning Beck-Nielsen, D.M.S.C., Ramón Gomis, M.D., Ph.D., Markolf Hanefeld, M.D., Ph.D., Nigel P. Jones, M.A., Michel Komajda, M.D., John J.V. McMurray, M.D., for the RECORD Study Group


Background A recent meta-analysis raised concern regarding an increased risk of myocardial infarction and death from cardiovascular causes associated with rosiglitazone treatment of type 2 diabetes.

Methods We conducted an unplanned interim analysis of a randomized, multicenter, open-label, noninferiority trial involving 4447 patients with type 2 diabetes who had inadequate glycemic control while receiving metformin or sulfonylurea, in which 2220 patients were assigned to receive add-on rosiglitazone (rosiglitazone group), and 2227 to receive a combination of metformin plus sulfonylurea (control group). The primary end point was hospitalization or death from cardiovascular causes.

Results Because the mean follow-up was only 3.75 years, our interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (hazard ratio, 1.08; 95% confidence interval [CI], 0.89 to 1.31). After the inclusion of end points pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93 to 1.32). There were no statistically significant differences between the rosiglitazone group and the control group regarding myocardial infarction and death from cardiovascular causes or any cause. There were more patients with heart failure in the rosiglitazone group than in the control group (hazard ratio, 2.15; 95% CI, 1.30 to 3.57).

Conclusions Our interim findings from this ongoing study were inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes. Rosiglitazone was associated with an increased risk of heart failure. The data were insufficient to determine whether the drug was associated with an increase in the risk of myocardial infarction.

Published at www.nejm.org June 5, 2007 (10.1056/NEJMe078118)

Rosiglitazone — Continued Uncertainty about Safety
Jeffrey M. Drazen, M.D., Stephen Morrissey, Ph.D., and Gregory D. Curfman, M.D.

On May 21, 2007, the Journal published a meta-analysis by Nissen and Wolski1 that indicated an increased cardiovascular risk associated with rosiglitazone (Avandia), a thiazolidinedione used to treat type 2 diabetes. We published this analysis because it indicated an increase of about 40% in the risk of myocardial infarction among patients receiving rosiglitazone as compared with those receiving either an alternative oral diabetes therapy (metformin or a sulfonylurea) or placebo. Since rosiglitazone is widely used for the treatment of type 2 diabetes and since the analysis considered all publicly available data on the topic, we published the article to make health care professionals and their patients aware of these potential adverse effects. Although we ensured that the article and accompanying editorial spelled out both the strengths and the weaknesses of the analysis, we knew that a patient-level analysis performed by the manufacturer of rosiglitazone confirmed the findings. The article raised substantial uncertainty about the cardiovascular safety of rosiglitazone. Even a small increase in cardiovascular risk in a fragile population of patients with type 2 diabetes is of considerable concern.

As a result of our publication of this article, the steering committee of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes, or RECORD, trial undertook an unplanned interim analysis of some of the cardiovascular end points in that trial. The results of that interim analysis appear in this issue of the Journal.

The clinical impact of these data needs to be clarified. To do so, we asked a diabetologist, a cardiovascular epidemiologist, and a drug-safety expert to give their interpretations, which can be found in the accompanying editorials. Both editorials express uncertainty about the safety of rosiglitazone.

When a drug is approved for marketing, its full safety profile cannot be known, and the data from the two studies we have published represent a clear example of how difficult it can be to determine drug safety. In this age of freely available information, drugs cannot easily be parsed into "safe" and "unsafe" categories. Instead, there will be shades of safety that must be graded against shades of efficacy. As new data about the safety of an approved drug become available, they should not be suppressed. On the contrary, they should be reported to health care professionals, patients, and participants in ongoing clinical trials, even if that means creating uncertainty about the safety of a drug. Although there may be uncertainty about a drug's safety, there should be no uncertainty about the need for open and honest disclosure.