Cardiovascular risks almost doubled with Vioxx, researchers confirm

Funded by its manufacturer, Merck Research Laboratories, the largest prospective trial ever to examine the anti-inflammatory drug Vioxx as a chemoprevention agent found that the risk of developing a cardiovascular “event” – heart attacks and/or strokes – was almost double in those patients who received the drug, compared to those who took the placebo, according to a study in The New England Journal of Medicine.

The risk had first been discovered and reported last year by the study’s safety monitoring board, and the trial (known as APPROVe – Adenomatous Polyp Prevention on Vioxx) stopped on September 30, approximately two months prior to scheduled completion. Subsequently, the drug was withdrawn from the US market.

Designed to determine whether the drug could prevent the re-growth of precancerous colon polyps in people who had already had polyps removed, the prospective chemoprevention study randomized 2,586 participants from 108 centers in 29 countries to receive either 25 mgs. of Vioxx daily or a placebo drug for three years, 2001-04.

According to Robert S. Bresalier, MD, of the University of Texas Anderson Cancer Center and the study’s lead author, 46 of the 1,287 patients randomized to take Vioxx daily had confirmed cardiovascular events over the three year period, mostly heart attacks or strokes. In the 1,299 patients given a placebo, there were 26 events. However, each group had the same number of deaths and not all were related to heart attacks or strokes.

“The overall number of cardiovascular events is small, but, nevertheless, the difference between the groups is significant,” said Bresalier, professor and chair of the Department of Gastrointestinal Medicine and Nutrition at Anderson.

According to Bresalier, the most notable trend was that patients did not begin to experience cardiovascular problems such as heart attacks or strokes until after 18 months of treatment. “In the first 18 months, the risks for the two treatments were similar,” he said.

Other cardiac problems, such as hypertension-related events, pulmonary edema and congestive heart failure-related events were much more prevalent in the Vioxx-treated group compared to the placebo group and presented earlier. Yet, data on these cases is less firm, Bresalier noted, because, unlike heart attacks or strokes, these problems were not “adjudicated,” or validated by a separate committee. Since this was not a cardiovascular trial, while investigators reported all events, only the most serious were fully examined.

“Because patient benefit is the most important criteria for any study, it was appropriate to stop the trial,” said Bresalier, who reported receiving a consulting fee as a member of the APPROVe trial steering committee.

“What we don’t know is, if the cardiovascular results seen in Vioxx represents a class effect of COX-2 inhibitors or if this is an individual effect to this drug. I don’t think we can tell this from this one trial or from the trials that are out there at the moment. That’s going to be the real question.”

LATE NOTE:

As reported in the Associated Press and all wire services, on Friday, Feb. 18, a Food & Drug Administration advisory panel narrowly (17-15) recommended that Merck & Co. be

permitted to resume Vioxx sales. The news quickly moved Merck's New York Stock Exchange shares significantly higher (up 13%, or $3.76 to $32.61 per share). Prior to

Merck's decision to withdraw it, Vioxx had been a $2.5 billion-a-year seller.

One of the presentations to the panel was given by David Graham, a whistle-blowing FDA  physician who had provided testimony to the Senate Finance Committee in October 2004 that the agency was biased when it came to removing dangerous drugs from the market.

Committee Chair Sen. Charles Grassley (R-Iowa) – who has maintained the FDA fails to provide adequate resources for drug safety monitoring of products already being sold, and repeatedly condemned its attempts at silencing its in-house critics – has become even more vocal in his criticism of the agency since the conclusion of those hearings.

Commenting in response to the latest panel decision in favor of Vioxx, he stated: “The Joint Advisory Committee meetings this week were valuable for their transparency and respect for the scientific process." But he went on to say, “I remain troubled by the FDA's reluctance to be fully transparent and prioritize issues of drug safety. Specifically, the FDA should value the science of its own employees at least as much as the science presented by drug companies.”

Surprising to many analysts, the panel also voted to allow sales of Pfizer Inc.'s COX-2 inibitors, the painkillers Celebrex and Bextra, with the proviso that Celebrex carry a stronger warning label. While the panel acknowledged cardiovascular risks for all three drugs, it nevertheless voted 31-1 in favor of keeping Celebrex on the market, and 17-13 (with two abstentions) for Bextra.

SOURCE: “Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial.” Bresalier, Robert S. MD; Sandler, Robert S., MD; Quan, Hui, PhD; Bolognese, James A., MStat; Oxenius, Bettina, MD; Horgan, Kevin, MD; Lines, Christopher, PhD; Robert Riddell, Robert, MD; Morton, Dion, MD; Lanas, Angel, MD; Konstam, Marvin A., MD; Baron, John A., MD. Published at www.nejm.org, Feb.15, 2005 (10.1056/NEJMoa050493); print version scheduled for the NEJM, March 17, 2005 issue.