NEW YORK (Reuters Health) - Two reports today in two separate journals -- a meta-analysis and a large retrospective study -- provide more evidence linking the thiazolidinedione rosiglitazone to an increased risk of myocardial infarction (MI).
The retrospective study also ties rosiglitazone therapy to an increased risk of stroke, heart failure, and death from any cause in patients aged 65 and older.
In an e-mail to Reuters Health, Dr. Steven E. Nissen, chair of the Department of Cardiovascular Medicine at The Cleveland Clinic and a long-time vocal critic of rosiglitazone, said the two manuscripts "provide overwhelming evidence of the hazards" of the drug.
"Taken together," he wrote, "the two studies demonstrate that this drug has an adverse benefit risk relationship and should be removed from the market. I would advise physicians who are still using rosiglitazone to stop and begin switching their patients to safer alternatives, including pioglitazone."
Concern over the effects of rosiglitazone on the heart arose in 2007 after Dr. Nissen and colleagues published a meta-analysis that showed a significantly elevated risk of MI and a borderline significant increased risk of cardiovascular death with its use.
Today, in the Archives of Internal Medicine, Dr. Nissen and co-author Kathy Wolski, also of the Cleveland Clinic, report results of an updated meta-analysis of 56 randomized controlled trials published through February 2010. These trials lasted at least 24 weeks and included a total of 35,531 patients; 19,509 received rosiglitazone and 16,022 received comparator drugs or placebo. (The journal has made the full text of the article available for free; the link appears below.)
There was no evidence from the updated meta-analysis that rosiglitazone increases the risk of cardiovascular deaths or all-cause mortality.
However, the authors estimate there is a 28% to 39% increased risk of MI with rosiglitazone, with a number needed to harm of 52 with RECORD trial data included and 37 without this trial. (Low event rates in the open-label, noninferiority RECORD trial of rosiglitazone published in 2009 resulted in insufficient statistical power to confirm or refute evidence of increased risk for MI).
Subgroups classified by study length and comparator drug used also showed elevated risks with rosiglitazone. "These findings are consistent with prior meta-analyses conducted by GSK (GlaxoSmithKline), the FDA, and most independent investigators demonstrating an increased risk of MI in patients treated with rosiglitazone," Dr. Nissen and Ms. Wolski note in their report.
"Because no unique benefits of rosiglitazone use have been identified," they add, "administration of this agent solely to lower blood glucose levels is difficult to justify."
The second paper, published in the Journal of the American Medical Association by Dr. David J. Graham, of the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues, reports the results of a large US cohort study examining the risk of cardiovascular events in 227,571 patients aged 65 and older. These patients initiated treatment with either rosiglitazone or pioglitazone between 2006 and 2009 and were followed for up to three years. (This paper too is available online at no charge from the journal; the link appears below.)
There were 8,667 events during the study period. Compared with pioglitazone, rosiglitazone was associated with an increased risk of adverse cardiovascular events, including heart failure (odds ratio, 1.25), stroke (OR, 1.27), death (OR, 1.14), and the composite of acute MI, stroke, heart failure or death (OR, 1.18).
Notably, the authors say the attributable risk for the composite endpoint was 1.68 and the number needed to harm was 60 treated for 1 year.
"The Graham study is well done and large," Dr. David N. Juurlink, author of an editorial in JAMA, told Reuters Health by e-mail, "and it adds to the evidence that rosiglitazone is less safe than pioglitazone."
"I think that was pretty clear before the Graham paper, but this new study throws another log on the fire at the feet of the FDA," added Dr. Juurlink, of Sunnybrook Health Sciences Center, Toronto, Canada.
The US FDA will hold an advisory committee meeting in July to consider whether to remove rosiglitazone from the market.
Reference
http://archinte.ama-assn.org/cgi/content/full/2010.207 http://jama.ama-assn.org/cgi/content/full/jama.2010.920 http://jama.ama-assn.org/cgi/content/full/jama.2010.954
Arch Intern Med 2010.
JAMA 2010.
The retrospective study also ties rosiglitazone therapy to an increased risk of stroke, heart failure, and death from any cause in patients aged 65 and older.
In an e-mail to Reuters Health, Dr. Steven E. Nissen, chair of the Department of Cardiovascular Medicine at The Cleveland Clinic and a long-time vocal critic of rosiglitazone, said the two manuscripts "provide overwhelming evidence of the hazards" of the drug.
"Taken together," he wrote, "the two studies demonstrate that this drug has an adverse benefit risk relationship and should be removed from the market. I would advise physicians who are still using rosiglitazone to stop and begin switching their patients to safer alternatives, including pioglitazone."
Concern over the effects of rosiglitazone on the heart arose in 2007 after Dr. Nissen and colleagues published a meta-analysis that showed a significantly elevated risk of MI and a borderline significant increased risk of cardiovascular death with its use.
Today, in the Archives of Internal Medicine, Dr. Nissen and co-author Kathy Wolski, also of the Cleveland Clinic, report results of an updated meta-analysis of 56 randomized controlled trials published through February 2010. These trials lasted at least 24 weeks and included a total of 35,531 patients; 19,509 received rosiglitazone and 16,022 received comparator drugs or placebo. (The journal has made the full text of the article available for free; the link appears below.)
There was no evidence from the updated meta-analysis that rosiglitazone increases the risk of cardiovascular deaths or all-cause mortality.
However, the authors estimate there is a 28% to 39% increased risk of MI with rosiglitazone, with a number needed to harm of 52 with RECORD trial data included and 37 without this trial. (Low event rates in the open-label, noninferiority RECORD trial of rosiglitazone published in 2009 resulted in insufficient statistical power to confirm or refute evidence of increased risk for MI).
Subgroups classified by study length and comparator drug used also showed elevated risks with rosiglitazone. "These findings are consistent with prior meta-analyses conducted by GSK (GlaxoSmithKline), the FDA, and most independent investigators demonstrating an increased risk of MI in patients treated with rosiglitazone," Dr. Nissen and Ms. Wolski note in their report.
"Because no unique benefits of rosiglitazone use have been identified," they add, "administration of this agent solely to lower blood glucose levels is difficult to justify."
The second paper, published in the Journal of the American Medical Association by Dr. David J. Graham, of the FDA's Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues, reports the results of a large US cohort study examining the risk of cardiovascular events in 227,571 patients aged 65 and older. These patients initiated treatment with either rosiglitazone or pioglitazone between 2006 and 2009 and were followed for up to three years. (This paper too is available online at no charge from the journal; the link appears below.)
There were 8,667 events during the study period. Compared with pioglitazone, rosiglitazone was associated with an increased risk of adverse cardiovascular events, including heart failure (odds ratio, 1.25), stroke (OR, 1.27), death (OR, 1.14), and the composite of acute MI, stroke, heart failure or death (OR, 1.18).
Notably, the authors say the attributable risk for the composite endpoint was 1.68 and the number needed to harm was 60 treated for 1 year.
"The Graham study is well done and large," Dr. David N. Juurlink, author of an editorial in JAMA, told Reuters Health by e-mail, "and it adds to the evidence that rosiglitazone is less safe than pioglitazone."
"I think that was pretty clear before the Graham paper, but this new study throws another log on the fire at the feet of the FDA," added Dr. Juurlink, of Sunnybrook Health Sciences Center, Toronto, Canada.
The US FDA will hold an advisory committee meeting in July to consider whether to remove rosiglitazone from the market.
Reference
http://archinte.ama-assn.org/cgi/content/full/2010.207 http://jama.ama-assn.org/cgi/content/full/jama.2010.920 http://jama.ama-assn.org/cgi/content/full/jama.2010.954
Arch Intern Med 2010.
JAMA 2010.
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