Vioxx risk lingers after stopping drug

TRENTON, N.J.; October 14, 2008

A doubled risk of heart attack, stroke and death persisted at least a year after people stopped taking withdrawn painkiller Vioxx, according to an analysis of long-term data from the study that led drugmaker Merck & Co. to stop selling the drug.

The analysis, published online Tuesday by the British medical journal The Lancet, also appears to show the higher risk started soon after patients began taking Vioxx, though the study notes a small sample size precludes a definitive finding on this issue.

Doctors critical of Merck and its reporting of Vioxx studies have long argued increased cardiovascular risks from the former blockbuster arthritis drug started after just a few months' use and persisted after use ended.

Merck continues to insist cardiac risks didn't increase until people took Vioxx for about 18 months — a cornerstone of its strategy to fight tens of thousands of lawsuits by people claiming harm from Vioxx.

The new findings should be interpreted cautiously because of the small number of patients who suffered heart attacks, strokes and related problems after participating in the three-year study, said Doug Watson, a cardiovascular epidemiologist and senior director at Merck Research Labs.

He said the study had some other limitations and noted the authors stated that "small numbers prohibit detailed conclusions about when the increased risk begins and ends."

"But our data are compatible with an early increase in risk that seems to persist for about 1 year after 3 years of treatment," the authors added.

Known by the acronym APPROVe, the study was intended to prove that Vioxx, heavily promoted as relieving pain with lower gastrointestinal risks than older anti-inflammatory drugs, could prevent recurrence of colon cancer. Merck stopped the study two months early and pulled the drug from the market on Sept. 30, 2004, when data showed roughly double the risk of cardiovascular complications and death in the group getting Vioxx, over those getting placebo.

Merck funded the new analysis, provided the data and commented on an early draft of the report but said it had no other involvement. The analysis was conducted by six scientists who worked on APPROVe, plus two statistics experts at the University of Wisconsin who were not involved then, the company said.

The eight researchers reported in The Lancet that in the year after the 2,587-patient study was halted, 34 people who had taken Vioxx and 18 who had taken placebo suffered a heart attack, for a 94 percent higher risk with Vioxx; strokes occurred in 19 Vioxx users and nine people on placebo, for a risk slightly more than double. Altogether, 76 Vioxx users and 46 placebo takers had a heart attack, stroke, blood clot or died during that follow-up year.

The increase in those complications was roughly the same as what was found during the three-year trial and the first two weeks after the study ended — the period included when Merck first reported results of APPROVe in the New England Journal of Medicine in February 2005.

Merck critics have said it was inappropriate to end patient follow-up 14 days after the study.

"This study is raising an important red flag about that" cutoff, showing the risk persisted for at least a year, although too few patients were followed longer than that to see if the risk subsided, said Dr. Harlan Krumholz, a Yale University cardiologist who has assisted Vioxx plaintiffs suing Merck.

"It adds another important chapter to the Vioxx story, but also is an important warning to us about how we assess the safety of medication" long-term, including after use stops, Krumholz said.

After Merck published its first analysis of APPROVe, numerous experts criticized it. Editors of the New England Journal in 2006 published a correction stating the risk of heart problems was elevated throughout the time people took Vioxx.

Merck posted all the data from APPROVe — the data used in the new study — on its Web site that same month.

In an editorial, doctors from the University of Oxford in England and Catholic University of Rome wrote that differences in the approach of the new analysis make it clear there's no "latent period" before Vioxx increases heart risks, and shows the danger appears to have been worse in people who already had risk factors — something they said is shown in a combined analysis of six studies of Celebrex.

Made by Pfizer Inc., Celebrex is the only drug from the same class as Vioxx still on the market in the United States.

The editorial writers also note that older nonsteroidal anti-inflammatory drugs — such as naproxen and ibuprofen — also can bring cardiovascular risk, plus risks of stomach bleeding and other complications.

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