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Cardiology Groups Stand by Embattled Diabetes Drug Rosiglitazone
By Crystal Phend, Senior Staff Writer, MedPage Today Published: February 24, 2010
American Hearr Association Statement attached


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There's not good enough reason to pick pioglitazone (Actos) over rosiglitazone (Avandia) despite controversy on cardiac safety, according to the American Heart Association and American College of Cardiology.
The evidence on ischemic heart disease and other cardiovascular risks is inconclusive for both drugs, they wrote in a joint advisory published online in Circulation: Journal of the American Heart Association and the Journal of the American College of Cardiology.
Patients who have achieved successful glycemic control on either drug might be continued on it with close monitoring, according to the advisory, which was pushed forward for publication in the wake of a U.S. Senate Finance Committee report that concluded rosiglitazone was responsible for a "substantial excess number" of heart attacks and heart failure compared with pioglitazone.
As part of the report, based on two years of congressional inquiry into the safety of rosiglitazone, two FDA reviewers called for the drug to be pulled from the market.
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* Note that the AHA and ACC do not support choosing pioglitazone over rosiglitazone, citing insufficient evidence on cardiovascular safety concerns.
That's still a possibility, said advisory co-author Robert Eckel, MD, of the University of Colorado at Denver and a past president of the AHA.
The FDA decided in 2007 to beef up warnings in prescribing information with a black box on the potential for MI rather than withdraw rosiglitazone from the market.
Earlier that year, the agency had issued a safety alert on the drug after a large meta-analysis indicated a 43% increase in risk of MI and a possible increase in risk of cardiovascular death with use of rosiglitazone in treating type 2 diabetes.
Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, has indicated that the agency will revisit the rosiglitazone issue in July 2010 based on new data that has emerged in the interim, particularly the RECORD and ACCORD trials.
The only randomized trial to prospectively assess rosiglitazone's cardiovascular effects was the RECORD trial, a more than 4,400-patient open-label comparison between rosiglitazone and add-on metformin and sulfonylurea drugs.
After an inconclusive interim analysis, final results suggested no overall increase in cardiovascular risk but a doubling of heart failure risk with rosiglitazone.
The 14% elevated risk of MI with the drug wasn't significant overall.
However, the trial was underpowered even for the primary endpoint and was hampered by poor medication adherence, a high crossover rate, and an imbalance in other medications like statins favoring the rosiglitazone group.
The majority of evidence against rosiglitazone has come from meta-analyses of randomized trials evaluating its effect on glycemic control from observational studies and analyses of clinical trials targeting glycemic goals with nonrandomized drug selection by physicians, the AHA/ACC advisory noted.
Meta-analyses have had inconsistent results, although a patient-level analysis of 42 randomized trials by drugmaker GlaxoSmithKline and another by the FDA both found increased risk of any ischemic heart disease event but not for the composite of cardiovascular death, MI, or stroke.
A consensus statement from the American Diabetes Association subsequently dropped rosiglitazone from guidelines for treatment of diabetes, calling pioglitazone the more appropriate choice for second-line therapy after lifestyle changes and metformin.
Pioglitazone tended to reduce cardiovascular risk and significantly reduced a secondary composite endpoint of all-cause mortality, nonfatal MI, and stroke in the large PROactive clinical trial designed to look at macrovascular events.
Meta-analysis and observational findings have also suggested reductions in risk or at least no increased risk.
However, there have been only conflicting observational studies comparing the two thiazolidinediones, the AHA/ACC advisory noted, concluding "there remains an inadequate foundation of randomized clinical trials to properly judge the safety or efficacy of either agent with respect to ischemic heart disease events."
What is clear is that both drugs increase risk of heart failure and should not be initiated in patients with class III/IV heart failure, according to the advisory.
Until better data become available, the advisory stated, "clinicians will need to weigh the accepted benefits of improved glycemic control on risk for microvascular disease from glucose-lowering agents against the worrisome, inconclusive, or completely absent information about the effects of these agents on macrovascular disease."
Eckel noted that while the evidence incriminating rosiglitazone cannot be seen as final, physicians who find the lack of black box warning and no signal for cardiovascular harm with pioglitizone persuasive are not alone.
"That's a very reasonable position to be in," he said in an interview. "The clinician has a choice, and that choice would seem to favor pioglitazone with what we currently know."
Ekel reported conflicts of interest with sanofi-aventis, CCMD, and Health Science Media. Co-authors reported conflicts of interest with AstraZeneca, Novartis, GlaxoSmithKline, and Merck Research Labs.
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