Review uncovers new killer drug  - Common painkiller may
induce heart attacks.nature.com

Published online: 12 September 2006; Updated online: 13 September
2006 | doi:10.1038/news060911-6
Review uncovers new killer drug
Common painkiller may induce heart attacks.
Meredith Wadman

A huge review of studies on pain relievers has found that a
widely-used medicine may confer cardiovascular risks as serious as
those found with Vioxx, an arthritis medicine that was withdrawn
from the market two years ago.

Diclofenac, an older non-steroidal anti-inflammatory drug (NSAID),
has been on the market for decades and is one of the most-widely
prescribed anti-inflammatories in the world — especially in Europe.
At commonly prescribed doses, it was found to increase the risk of
cardiovascular events — primarily heart attack and sudden death — by
40%.

The good news from the study is that there are alternatives.
"European consumers would be better off switching [from diclofenac]
to naproxen," says David Graham, a safety official at the US Food
and Drug Administration, who authored an editorial1 accompanying the
published review. Naproxen was found to neither increase nor
decrease cardiac risk.

The meta-analysis, published online today by the Journal of the
American Medical Association, looked at 23 studies involving some
1.6 million people2. The studies were not gold-standard clinical
trials, but the review's huge scope lends it weight, says Graham.
"It looked at all NSAIDs across the board, at all available evidence
for those NSAIDs. In that regard, it's unprecedented and in my view
becomes authoritative."

Not everyone agrees. "Our view is that this meta-analysis is
incomplete and the findings have not been critically analyzed," says
John Gilardi, a spokesperson for Novartis in Basel, Switzerland.
Novartis markets diclofenac under the trade name Voltaren. "Other
epidemiological data does not indicate an increased cardiovascular
risk of diclofenac versus other non-steroidal anti-inflammatory
drugs, or NSAIDs," he says.

The study authors — Patricia McGettigan of the University of
Newcastle in New South Wales, Australia, and David Henry of
Newcastle Mater Hospital in Waratah, New South Wales — call for a
review of the regulatory status of diclofenac, which is marketed as
a generic drug and also under the trade names Voltaren, Cataflam,
Solaraze and Arthrotec.

Dodgy outlier

The JAMA review looked at both standard NSAIDs and at a newer class
of drugs hoped to cause fewer side-effects.

Standard NSAIDS, such as ibuprofen or naproxen, work to relieve pain
by blocking one form of the cyclooxygenase enzyme — cox-2 — at sites
of tissue injury. But because they also work on another form, cox-1,
which is found in the gut, they also often damage the
gastrointestinal tract. A new generation of drugs, selective for
cox-2 alone, were created with the hope of easing pain without
damaging the gut.

Vioxx (rofecoxib) is one of these drugs. But Vioxx was withdrawn
from the market after studies showed that it substantially increased
the risk of heart attack and other serious cardiovascular events.
The new JAMA study confirms these earlier findings, showing that the
risk is dose-related (more than doubling at high doses), begins
immediately and is elevated in the first month of use.

But Vioxx may be unique in its class in the extent to which it
causes these side-effects. Steve Nissen, a cardiologist at the
Cleveland Clinic who is running a separate trial that includes
Celebrex (a chemical cousin of Vioxx and a common cox-2 inhibitor),
says that the JAMA study hints that Vioxx is an outlier. "It looks
like it's really a problem with one or two drugs but not all of
them," he says. This opens the possibility that other such NSAIDs
will be safe, even if Vioxx is not.

The study suggests that Celebrex (celecoxib) is not harmful to the
heart at the commonly used dose of 200 mg, but seems to be unsafe at
doses of 400 mg or more.

For the future, researchers are aiming to find a class of
anti-inflammatories that will both be kind to the stomach and to the
heart. Research released by the Proceedings of the National Acadamy
of Sciences this week shows promising news of a drug target, found
in a mouse model, that slows the development of atherosclerosis.
This might help a new class of 'super NSAIDs' not only steer clear
of heart disease risk but work to reduce it.

In the meantime, the JAMA study may cause problems for Merck. The
company is currently using diclofenac as a comparison drug in a
trial of Arcoxia, a next-generation cox-2 inhibitor developed to
succeed Vioxx for arthritis patients. Merck spokesperson Christopher
Loder says that the company stands by their choice of diclofenac for
this trial.

* UPDATE 12 September 2006 - This story has been updated with
comments from Novartis and Merck, which were received after the
story went to press.

References
  Graham D. J. Journal of the American Medical Association,
  advance online publication 296 (2006).
  McGettigan P.& Henry D. J., Journal of the American Medical
  Association, advance online publication 296 (2006).

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