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New Vioxx Data Confirm Concerns About Risk, Doctors Say

Study shows heart dangers began at four months, not 18 as Merck has stated

THURSDAY, May 18, 2006 (HealthDay News) -- News that the cardiovascular risks of Vioxx start to surface earlier than the drug's maker has claimed came as no surprise to experts, who said the latest development only confirms their fears about the safety of the now-withdrawn painkiller.

"I had previously pointed out in publications that the risk is manifested quite early," said Dr. Eric Topol, professor of medicine and genetics at Case Western Reserve University in Cleveland. "So, these new data simply reinforce that concern."

The Wall Street Journal reported Thursday that data submitted by Merck & Co. to the U.S. Food and Drug Administration last week shows Vioxx begins to adversely affect the cardiovascular system after only four months of use -- not the 18 months the company has asserted in the past.

Topol has been at the forefront of the movement to investigate the Vioxx debacle, authoring 16 articles on the topic over the past five years and testifying before the U.S. Food and Drug Administration. "There has never been anything to substantiate an 18- month incubation phase" for Vioxx-related cardiovascular risk, he said.

He also pointed to another study, published last month in the online edition of the Canadian Medical Journal.

In that study, researchers at McGill University, in Montreal, reviewed three years of data on Vioxx and found that 25 percent of users who suffered a heart attack did so within 14 days of taking their first dose of the drug. Topol said the Canadian study "further substantiated" the notion that the dangerous cardiovascular effects begin sooner rather than later.

Another cox-2 expert said the Vioxx saga holds lessons for users of the sole remaining cox-2 on the market -- Celebrex. A second cox-2 drug, Bextra, was pulled in early 2005 due to similar heart concerns.

"This is [medically] newsworthy only in that it may bring attention to clinicians and patients using the currently available cox-2 drug and, potentially, other cox-2 inhibitors in the future," said Dr. Mark Fendrick, a professor of internal medicine at the University of Michigan School of Medicine.

Fendrick has long advised that a combination of an NSAID painkiller, such as naproxen, plus a stomach-protecting drug such as Prilosec or Nexium, can provide similar levels of pain relief as any cox-2 medication -- without the cardiovascular risks.

"I would strongly recommend this older combination over celecoxib [Celebrex] in patients at risk for cardiac events," he said.

When Merck pulled the blockbuster Vioxx from the market in September 2004, it cited data from a major randomized controlled trial, the APPROVE trial. That data was published in March 2005 in the New England Journal of Medicine.

But a newly released 107-page summary of data -- based on a one-year follow-up of APPROVE participants -- includes a key graph tracking the number of "confirmed thrombotic [clotting] cardiovascular events," the WSJ reported. That graph shows that the number of dangerous events among Vioxx users began to outnumber those of people taking a placebo by four months of use.

While the number of cardiovascular events included in the new analysis is not large enough to show statistical significance, it does suggest a trend beginning at four months, experts said.

In contrast, a similar graph appearing in the study as it was published in the New England Journal of Medicine showed no such divergence between the two groups until the 18-month point.

The new data is at odds with Merck's statements on the level of risk faced by former Vioxx users -- the company has long reiterated that risks occur only among long-term users.

Since the drug's withdrawal, thousands of lawsuits from patients who claim Vioxx caused strokes or other cardiovascular events have been filed against Merck, and verdicts have gone both for and against the company. Last month, a Texas jury awarded $32 million to the family of a 71-year-old man; they said Vioxx caused his death after he had taken it for less than a month.

In a statement released to the WSJ, Merck said the new data "do not establish that the risk for Vioxx starts earlier than has previously been reported," noting that for the first 18 months of the trial, "the relative risk for confirmed thrombotic cardiovascular events in the new analysis for Vioxx compared to placebo was similar" to that seen in the old study. Merck officials did not offer a specific explanation for the data included in the key graph.

Controversies linked to Vioxx-related data aren't new.

This past December, editors at the New England Journal of Medicine published a rare "Expression of Concern" letter aimed at Merck. That letter charged that a major study called VIGOR -- published in the journal in 2000 and subsequently used as strong argument for the safety of Vioxx -- was submitted to the journal after data on cardiovascular events among Vioxx trial participants was deleted by Merck, which funded the study.

In a statement released at the time, Merck said it had "promptly and appropriately disclosed the results of the VIGOR study."

More information

For more on cox-2 inhibitors, head to the U.S. Food and Drug Administration.

SOURCES: Eric Topol, M.D., professor, Medicine and Genetics, Case Western Reserve University, Cleveland; Mark Fendrick, M.D., professor, internal medicine, University of Michigan School of Medicine, Ann Arbor; May 18, 2006, Wall Street Journal
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