NEWCASTLE UPON TYNE , England, June 5 -- On the eve of a congressional hearing on the cardiovascular safety of rosiglitazone (Avandia), the battle lines were drawn.An unplanned interim analysis of a 4,400-patient open-label, cardiovascular safety trial of rosiglitazone found no significant increase in myocardial infarction or cardiac death, but suggested an increased risk of heart failure.
There were 49 MIs in the rosiglitazone arm versus 40 in a control arm (P=0.34) less than four years into a planned six-year trial. The findings from RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) were released online today by the New England Journal of Medicine.
The interim results were in stark contrast with a Cleveland Clinic meta-analysis published online two weeks ago by the NEJM that revealed a 43% increase in the relative risk of an MI for patients with diabetes taking rosiglitazone/
On Wednesday, Rep. Henry Waxman (D-Calif.) was scheduled to convene a hearing into the FDA's handling of rosiglitazone -- from its approval in 1999 through emerging concerns about its cardiovascular safety.
In the interim results of RECORD, according to Philip D. Home, D.M., D.Phil., of Newcastle Diabetes Center and Newcastle University here, and colleagues, there were 217 cardiovascular events in the patients taking rosiglitazone who were hospitalized or died during a mean follow-up of 3.7 years. That compared with 202 events in the control arm. The hazard ratio was 1.08 (95% CI 0.89-1.31, P=0.43). After the inclusion of endpoints pending adjudication, the hazard ratio was 1.11 (95% CI, 0.93 to 1.32).
By contrast, the risk of heart failure in the rosiglitazone arm was double that of the control arm and that was statistically significant. There were 47 cases of heart failure in the rosiglitazone arm versus 22 in the control arm (P=0.003).
The trial randomized 2,220 patients to rosiglitazone plus metformin and 2,227 to metformin plus sulfonylurea. At baseline all patients were well-controlled with either metformin or sulfonylurea. The primary endpoint was hospitalization or death from cardiovascular causes.
The authors concluded that the interim analysis was inconclusive. Although there was not solid evidence of increased risk, there was also too little evidence to prove non-inferiority of rosiglitazone.
"In conclusion," they wrote, "our interim findings from a large, prospective trial are inconclusive with respect to the primary end point of hospitalization or death from cardiovascular causes and are as yet insufficient to claim noninferiority.
"There is no evidence of any increased mortality, either from any cause or from cardiovascular causes. There is a significant increase in the risk of heart failure. The data do not allow a conclusion as to whether treatment with rosiglitazone results in a higher rate of myocardial infarction than does therapy with metformin or a sulfonylurea.
"The study's data and safety monitoring board, which is charged with safeguarding the study patients, has recommended continuation of the trial. Study completion will enable a clearer determination of the long-term cardiovascular effects of treatment with rosiglitazone and thus help determine the most appropriate combination therapies for patients with type 2 diabetes."
The NEJM published three editorials along with the interim analysis -- one of them from the same editorialists -- Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D. -- whose editorial accompanied the Cleveland Clinic meta-analysis in the NEJM that set off the current furor.
The original editorial asserted that "regulatory action by the Food and Drug Administration is now warranted."
Yet Dr. Psaty, of the University of Washington in Seattle, and Dr. Furberg, of Wake Forest University in Winston-Salem, N.C., had pointed out that the study had a number of serious limitations and "the possibility that the findings were due to chance cannot be excluded."
Rosiglitazone has become a cause celebre in the two weeks since the NEJM published online the results of a meta-analysis of published data that reported a 43% increase in risk of myocardial infarction among patients using rosiglitazone.
In that meta-analysis by Steven E. Nissen, M.D., and Kathy Wolski, of the Cleveland Clinic, the odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03).
This time around, Dr. Psatye and Dr. Furberg wrote that it seems unlikely that rosiglitazone will ever demonstrate a cardiovascular benefit and they reiterate their earlier criticism that the drug was approved on the basis of a surrogate endpoint-reduction in laboratory evidence of glycemic control rather than a reduction in clinical complications of diabetes.
David Nathan, M.D., of Massachusetts General Hospital and Harvard Medical School, was also not reassured by the British interim analysis. The findings, he wrote in a second editorial, "were not exculpatory" for a number of reasons that had to do with study design.
Among the flaws of RECORD, Dr. Nathan wrote, was an unexpectedly low event rate -- only 2.5% per year when the trial sample was calculated on an expected rate of 11% per year -- coupled with an unusually high loss to follow-up rate of 3% per year. These problems are compounded by the difficulty of examining data only 3.7 years into a planned six-year trial.
And while an 8% increase in risk of cardiovascular event was not statistically significant, Dr. Nathan mused that it might be problematic for physicians to prescribe a drug that carries that type of risk to diabetics who are already at increased risk of cardiovascular events.
The third editorial -- from the journal's editors -- provided some background on the controversy following the May 21 release of the meta-analysis and concluded that there was no such thing as too much data when it comes to drug safety.
In the 15 days since the release of that paper the FDA has issued a safety alert on rosiglitazone and has announced that it will convene a safety panel to review the drug. At the same time new prescriptions for rosiglitazone have plummeted and the drug's maker, GlaxoSmithKline, has been waging an uphill battle to convince physicians and patients that the drug is safe.
Dr. Nissen, meanwhile, has solidified his role as both a media darling and a lightning rod for controversy on countless blogs, editorials, and television news shows -- including two consecutive Nightline shows on the ABC network.
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