Editorial Says Avandia ‘Potentially Dangerous’; GSK Says Study ‘Reassuring’
June 5, 2007 – Preliminary data from a heart-safety study of Avandia --
released on the eve of a Congressional hearing into the matter -- do not settle
questions raised about the diabetes drug's possible heart attack risks.
Avandia maker GlaxoSmithKline says the study findings are
"reassuring." But three new editorials from TheNew England
Journal of Medicine suggest that doctors and patients will not be
reassured.
The GSK-funded RECORD study, managed by an independent steering committee,
enrolled some 4,500 type 2 diabetes patients from Europe, Asia, and Australia.
All the patients take the standard diabetes drugs metformin or sulfonylurea.
Half added Avandia to their treatment, and half received a combination of
metformin and sulfonylurea.
The study is supposed to continue until most patients have been treated for
six years. However, a recent NEJM study that combined all available data
suggested that Avandia might raise a person's risk of heart attack by 42%. In
response to the resulting furor, the study authors -- and the
NEJM'seditors -- decided to release data collected after patients had
completed only 3.75 years of the study.
The study's findings, as reported by Newcastle University researcher Philip
D. Home, DPhil, and colleagues:
- There is no evidence that Avandia increases death from all causes of heart
disease or death from all causes. Avandia patients did slightly worse than
other patients, but the difference is not statistically significant, meaning it
could be due to chance.
- Avandia more than doubles a person's risk of heart failure, although that
risk is still low. This result was expected, as the class of drugs to which
Avandia belongs has this effect.
- The study data are "insufficient" to determine whether the drug
increases a person's risk of heart attack. The data "are consistent with as
much as a 19% improvement, and as much as an 86% worsening, in risk," Home
and colleagues report.
In a telephone news conference held to discuss the findings, GSK chief
medical officer Ronald Krall, MD, said the study findings exonerate
Avandia.
"These results are reassuring to doctors and to patients, both those
with diabetes and those taking Avandia," Krall said. "These results add
to the weight of evidence ... showing that Avandia is comparable in safety to
the standard diabetes drugs."
But editorials published alongside the study paint a far different
picture.
The study has several flaws, notes David M. Nathan, MD, director of the
diabetes center at Massachusetts General Hospital and professor of medicine at
Harvard Medical School in Boston.
"The interim results of the RECORD trial do not provide any assurance of
the safety of treatment with [Avandia]," Nathan writes. "Physicians may
find it difficult to explain to patients why they are starting treatment with a
potentially dangerous drug when other choices with longer and better safety
records are available."
The other editorial is by Bruce M. Psaty, MD, PhD, of the University of
Washington in Seattle and Curt D. Furberg, MD, PhD, of Wake Forest University
in Winston-Salem, N.C. Psaty and Furberg's previous editorial on Avandia
questioned the FDA's wisdom in approving the drug.
Now Psaty and Furberg say the very low number of heart disease events in the
RECORD trial is suspicious. Coupled with the study's high dropout rate, they
suggest this leaves the study without enough statistical power to achieve its
goal of proving that Avandia is not inferior in heart safety to standard
diabetes drugs.
Moreover, they suggest that when the study findings are combined with data
from previous studies, Avandia is still associated with significant risk of
heart attack.
"The level of risk, a hazard ratio of 1.33 (a 33% increase in heart
attack risk), is substantial and approximately equivalent in magnitude -- but
in the opposite direction - to the health benefits of lipid-lowering statin
drugs," Psaty and Furberg write.
And an editorial by NEJM Editor Jeffrey M. Drazen, MD, and
colleagues, states "even a small increase in cardiovascular risk in a
fragile population of patients with type 2 diabetes is of considerable
concern.
"There is continued uncertainty about the cardiovascular safety of
[Avandia]," Drazen and colleagues conclude.
Krall and Glaxo Vice President of Clinical Development Murray Stewart, FRCP,
say that these conclusions distort the RECORD findings.
"It would be very unfortunate if doctors tried to make decisions based
on these very small differences between Avandia and standard diabetes
drugs," Krall said. "The best interpretation of these findings would be
that there are no differences between Avandia and sulfonylurea with
metformin."
"I am actually pleased the numbers are small," Stewart said.
"This shows that good diabetes care is making a difference. People in this
study kept their glucose down. This is very reassuring data."
- Does
Avandia increase heart attack risk ? Our expert is not yet convinced. Read
nurse Laurie Anderson’s blog to find out why.
WebMD Health News
By:
Daniel J. DeNoon
Reviewer:
Louise Chang, MD 06/05/2007
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