By Steven Reinberg
WEDNESDAY, Aug. 8 (HealthDay News) -- The debate over the heart-attack risks posed by the type 2 diabetes drug Avandia has taken another twist, with a new study questioning the results of the research that kick-started the controversy.
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In a study published June 14 in the New England Journal of Medicine, heart expert Dr. Steven E. Nissen, chairman of the Cleveland Clinic's department of cardiovascular medicine, reported a 43 percent increased risk of heart attack among patients taking Avandia (generic name rosiglitazone). Nissen said he uncovered that risk among 42 studies of the drug that he had analyzed.
However, a new analysis of that same data finds no proof of a significant risk of heart attack.
"We don't have sufficient data to adjudicate the association of rosiglitazone with increased cardiovascular risk," said lead researcher Dr. Sanjay Kaul, a cardiologist and professor of medicine at the University of California, Los Angeles. "The data that was analyzed does not allow us to conclude definitively whether the risk of heart attack with rosiglitazone is increased or decreased."
Kaul, who published his findings online Aug. 7 in Annals of Internal Medicine, and his colleagues reexamined the same trials that Nissen had used in his study. Kaul said he found that Nissen's analysis excluded trials that should have been included -- trials that would have lowered the risk of heart attack because none occurred.
In addition, Kaul said, those trials weren't designed to assess the safety of Avandia, and they were too short to establish whether there was a long-term risk for heart attack. "The number of events was very small," Kaul said. "One can legitimately raise the question whether you can predict long-term outcomes looking at short-term clinical trials."
To really answer the question about the potential heart risks associated with Avandia, there needs to be long-term trials specifically designed to see if the drug increases the chances of heart attack, Kaul said.
In response to Nissen's study, the U.S. Food and Drug Administration convened an expert panel in July to consider the heart-attack risk associated with Avandia. The panel recommended that the drug be kept on the market, but that a warning be attached that there may be an increased risk of heart attack. Avandia has already been linked to an increased risk of heart failure. The FDA has requested that Avandia's maker, GlaxoSmithKline, strengthen its warning about heart-failure risk.
Kaul said he agreed with the advisory panel's decision. "Because of the uncertainty, you can't pull a drug off the market. You have to be absolutely certain that there is substantial risk associated with it," he said.
GlaxoSmithKline said it stands behind the drug. "Across the extensive dataset for Avandia, GlaxoSmithKline believes there is no consistent or systematic evidence that Avandia increases the risk of heart attack or cardiovascular death in comparison to other anti-diabetic medicines," the company said in a prepared statement.
Nissen, for his part, said that a more detailed analysis by the FDA that was used by the advisory panel during its deliberations has confirmed the risk of heart attack with Avandia. This more thorough FDA research has left his original study "no longer relevant," he said.
"The FDA presented a more statistically powerful patient-level analysis at the advisory board meeting on rosiglitazone (Avandia)," he said. "This is a far more accurate approach when you have access to patient data, which we did not. The FDA confirmed a 40 percent increase in risk, virtually identical to our findings reported in the New England Journal of Medicine. Further study-level analysis will not yield any important insights," he added.
Kaul, however, disagreed with Nissen that the FDA's analysis confirmed a risk of heart attack from Avandia. According to Kaul, the FDA study looked at both serious and non-serious heart-related events.
"There was not a statistically significant difference between serious and non-serious events, which is exactly what we found," Kaul said. "There was substantial uncertainty associated with those risk estimates. You couldn't say one way or the other whether the risk was increased or decreased. When they looked at myocardial infarction [heart attack], they did not find a statistically significant increased risk," he added.
Kaul agreed that there is a heart-attack risk with Avandia, but the size of the risk is uncertain. "It's no longer statistically significant when you look at myocardial infarction," he said. "But, if tomorrow there is evidence to suggest increased risk, we will be the first ones to acknowledge it."
The Avandia saga has a "lesson" for the FDA, according to an article released online Wednesday by the New England Journal of Medicine and scheduled for publication in the journal's Aug. 30 print edition.
The article was written by Dr. Clifford Rosen, of the Maine Center for Osteoporosis, who headed the recent FDA advisory committee panel that recommended Avandia stay on the market, albeit with stronger warnings.
Rosen said the Avandia story "quickly became obvious to the advisory committee: a new 'wonder drug,' approved prematurely and for the wrong reasons by a weakened and underfunded government agency subjected to pressure from industry, had caused undue harm to patients."
He wrote that, all too often, so-called "surrogate" endpoints are used in studies aimed at estimating a drug's safety and effectiveness, with an eye toward approval. In the case of Avandia, researchers focused on the durability of the patients' blood sugar control ("glycemic durability"), even though blood sugar control is "a relatively poor surrogate for cardiovascular outcomes in type 2 diabetes," Rosen said. In other words, such trials would probably miss the real heart dangers posed by these types of drugs, he wrote.
For example, in one major Avandia trial, patients did achieve much better blood sugar control -- compared to other drugs -- even though their risk for heart failure and heart attack rose, he pointed out.
"These data suggest that we urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary endpoints," he wrote.
And while many experts have pointed to "phase 4" post-marketing surveillance trials of new drugs as a possible means of preventing bad drugs from staying on drug store shelves, Rosen said these trials are observational only. That means their data fall short of the gold standard -- a randomized clinical trial -- so they "will neither solve the overriding problems of drug safety nor ultimately help a chronically underfunded federal agency," he said.
SOURCES: Sanjay Kaul, M.D., cardiologist, professor of medicine, University of California, Los Angeles; Steven E. Nissen, M.D., chairman, department of cardiovascular medicine, Cleveland Clinic; Aug. 7, 2007, Annals of Internal Medicine, online; Aug. 9, 2007, New England Journal of Medicine, online
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