Rosiglitazone Again on the Ropes
Published: June 28, 2010
ORLANDO -- Rosiglitazone (Avandia) may cause one excess heart attack for every 37 patients treated over five years, according to an updated meta-analysis that has again thrown a negative spotlight on the embattled diabetes drug.
Even with inclusion of the controversial RECORD trial -- hampered by an unplanned, interim analysis reduced its power to answer safety questions -- the estimated number needed to harm remained low at 58, reported Steven E. Nissen, MD, and Kathy Wolski, MPH, the same Cleveland Clinic team that initially blew the whistle on rosiglitazone in a 2007 meta-analysis.
That study and another trial, also critical of rosiglitazone, were both published online while most diabetes experts were gathered here for the American Diabetes Association meeting and just weeks before the FDA is scheduled to revisit rosiglitazone's safety.
* Explain to interested patients that rosiglitazone has been linked to elevated risk of MI in some, but not all, analyses of clinical trial and observational study data and carries a black box warning on this as well as heart failure.
* Caution patients that observational and meta-analysis studies of the sort reported here can neither prove nor disprove causality of the associations they find.
The Nissen/Wolski paper released online in the Archives of Internal Medicine indicated a consistent MI risk elevated by 28% to 39% across sensitivity analyses that was significant at the P=0.04 level in each case. The meta-analysis included 56 randomized trials involving 35,531 patients.
The Other Shoe
In the second paper, rosiglitazone looked substantially worse than pioglitazone (Actos) in an FDA analysis of Medicare data released online in the Journal of the American Medical Association.
The number needed to harm was 60 for the composite of stroke, heart failure, MI, and death with use of rosiglitazone rather than pioglitazone for one year, wrote David J. Graham, MD, MPH, of the FDA Center for Drug Evaluation and Research, and colleagues in the JAMA.
The publication of these further negative results during the ADA's annual meeting here was purely coincidence, Nissen told MedPage Today.
Timing in advance of the FDA advisory committee meeting to decide whether to pull rosiglitazone from the market, though, was not.
The agency decided in November 2007 to leave the drug on the market with the addition of a black box warning for MI on top of the heart failure warning it shares with pioglitazone.
Release of new data on rosiglitazone from RECORD and other trials prompted the agency to take another look.
The new observational and meta-analysis results supporting the "totality of evidence" against rosiglitazone should weigh heavily in the FDA's deliberations, Nissen said.
However, diabetologists here largely felt the analyses were just beating a dead drug.
More circumstantial evidence with largely the same risk estimates but that can neither prove nor disprove the association isn't likely to change many minds that aren't already made up, said David Nathan, MD, of Massachusetts General Hospital in Boston.
"I don't need another study," agreed John Buse, MD, PhD, of the University of North Carolina in Chapel Hill, who has testified about intimidation by drugmaker GlaxoSmithKline. "It's like the Vietnam War, it's essentially unwinnable."
Dueling meta-analyses have gone back and forth on whether the cardiovascular risk with rosiglitazone is real.
But in the absence of quality prospective trial outcomes data, there's no other way to assess the risk, Nissen noted.
GlaxoSmithKline defended rosiglitazone, saying that analyses failed to include the more favorable studies, such as RECORD.
RECORD was the only prospective trial to look at cardiovascular outcomes with rosiglitazone but the unplanned interim analysis, published in the New England Journal of Medicine in 2007 after concerns arose, drew strong criticism.
The researchers, who could not be reached for comment, had called even the final results inconclusive, with no significant increase in MI or cardiac death but a signal for increased risk of heart failure.
However, at a debate held here at the ADA meeting, Nissen castigated RECORD as a "sloppy mess," pointing out that the analysis was by intent to treat without taking into account the massive problem with crossovers in the open-label and unblinded trial.
Nevertheless, Nissen's updated meta-analysis did include a comparison that incorporated RECORD.
Overall, rosiglitazone significantly increased the risk of MI with an odds ratio of 1.28 (95% confidence interval 1.02 to 1.63, P=0.04) but not cardiovascular death.
Exclusion of the RECORD trial suggested an odds ratio for MI of 1.39 with rosiglitazone (95% CI 1.02 to 1.89, P=0.04).
Handwriting on the Wall
These results add to a "relatively consistent message that rosiglitazone might indeed increase the risk of myocardial ischemic events, albeit with an inconsistent message regarding mortality," said David N. Juurlink, MD, PhD, of the University of Toronto, in an editorial accompanying the new analyses in JAMA.
Graham's observational retrospective cohort study of 227,571 Medicare patients age 65 and older from July 2006 to June 2009 showed no greater acute MI risk for rosiglitazone compared with pioglitazone.
But rosiglitazone was associated with significantly elevated risk of all other endpoints:
* Stroke (HR 1.27, 95% CI 1.12 to 1.45)
* Heart failure (HR 1.25, 95% CI 1.16 to 1.34)
* Death (HR 1.14, 95% CI 1.05 to 1.24)
* A composite of all four endpoints (HR 1.18, 95% CI 1.12 to 1.23)
The attributable risk for this composite endpoint was 1.68 (95% CI 1.27 to 2.08) for excess events per 100 person-years of treatment with rosiglitazone compared with pioglitazone.
The difference in outcomes compared with the Nissen analysis is likely accounted for by age, which averaged 74 compared with 54 to 55 in the meta-analysis, Graham and colleagues suggested.
Most studies that have found an increased MI risk were conducted in younger populations. As Nissen put it, younger people survive to be counted as an MI whereas older patients may be more likely to die without a hospitalization.
But despite a potentially less harmful cardiovascular profile, opinions were mixed on pioglitazone.
As one of the editorialists on RECORD and a reviewer on the new Nissen paper, Nathan called himself no fan of either thiazolidinedione.
The ADA and European Association for the Study of Diabetes joint consensus group that Nathan chairs pulled rosiglitazone from its recommendations for treatment of type 2 diabetes.
"Why would we use a drug that might be harmful even -- though it's not conclusive -- when there are so many other choices?" Nathan said in an interview.
Buse warned of heart failure, fracture, weight gain, and anemia problems seen across the class. "There's plenty of baggage for the class as a whole," he said.
Sales of rosiglitazone have steadily dropped from 13.3 million prescriptions annually in 2006 to 2.6 million in 2009, according to data obtained by ABC News from the pharmaceutical intelligence firm IMS Health.
That still leaves rosiglitazone as a billion-dollar drug with "no redeeming qualities," Nissen argued.
"Even a modest increase in the risk of MI in a diabetic population would have serious consequences," Juurlink agreed in his editorial. "Because no unique benefits of rosiglitazone use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify."
In February, Graham -- who earned a reputation as a safety crusader after having raised early concerns about the now withdrawn anti-inflammatory drug rofecoxib (Vioxx) -- and another FDA reviewer had urged that rosiglitazone be pulled from the market, according to a statement included in a Senate report.
The consumer watchdog group Public Citizen took the new analyses as an opportunity to push for the FDA to halt marketing of rosiglitazone and the cardiovascular safety trial the agency had ordered.
"Every month that the FDA fails to get the drug withdrawn from the market means that an additional 150,000 to 200,000 prescriptions will be filled in this country, needlessly exposing people to the increased risk of stroke, heart failure and heart attacks," Sidney M. Wolfe, MD, director of Public Citizen's health research group, said in an email.
When TIDE Comes In
Waiting for certainty with results of the FDA-ordered cardiovascular safety study -- the TIDE trial -- would make patients the losers, Juurlink agreed.
Nissen suggested that TIDE is just a delaying tactic as only roughly 500 of the planned 16,000 patients have been enrolled over 14 months. At this rate, enrollment would take 37 years, he said.
Joel Zonszein, MD, of Albert Einstein College of Medicine in New York City, said that the rosiglitazone debate has degenerated from medical controversy to a political and media feeding frenzy.
"The FDA may recommend removal of rosiglitazone from the US market and termination of the TIDE trial, or may do nothing for now. I am afraid both options will have a negative impact for patients and the health care community partly because of the political and media orgy taking place over the past 3 years," he wrote in an email.
Neil Brooks, MD, of Vernon, Conn., and a past president of the American Academy of Family Physicians, said that he has already made up his mind. "Because of the previous studies I no longer use [rosiglitazone]. I am really surprised that the company continues to market it," Brooks wrote in an email.
Nissen accused GlaxoSmithKline of not having withdrawn the drug already primarily because of the litigation risk.
"It's not about patient care. It's about legal strategy and that's very unfortunate," he said.
However, GlaxoSmithKline kept the focus on the science in a statement to the media.
The company cited the lack of overall risk of heart attack, stroke, or death in the six randomized, controlled trials reported since 2007. Its own updated meta-analysis of 52 clinical trials still shows no significant elevation in myocardial ischemia with a hazard ratio of 1.1 (95% CI 0.89 to 1.35, P=0.38).
This statement was provided to the press days in advance of release of the JAMA and Archives papers, again raising the spectre of a leak.
A company spokesperson, though, responded that advance knowledge of the papers came from a press release read over the phone by reporters seeking comment.
Graham's study was funded by the Office of the Assistant Secretary for Planning and Evaluation, the Centers for Medicare & Medicaid Services, and the FDA. Graham and colleagues reported no conflicts of interest.
Nissen reported having received research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Resverlogix, Takeda, Daiichi-Sankyo, and sanofi-aventis through the Cleveland Clinic Center for Clinical Research within the last 5 years and having consulted for a number of pharmaceutical companies but with all fees paid directly to charity.
Juurlink and Nathan reported no conflicts of interest.
Buse reported having had relationships with GlaxoSmithKline and Takeda in the past, but all contracted through the University of North Carolina.
This article was developed in collaboration with ABC News.
Primary source: Annals of Internal Medicine
Nissen SE, Wolski K "Rosiglitazone revisited: An updated meta-analysis of risk for myocardial infarction and cardiovascular mortality" Arch Intern Med 2010.
Additional source: Journal of the American Medical Association
Graham DJ, et al "Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone" JAMA 2010; 304.
Additional source: Journal of the American Medical Association
Juurlink DN "Rosiglitazone and the case for safety over certainty" JAMA 2010.