Merck Trial Confirms Vioxx's CV Toxicity


Extended follow-up of patients in the Adenomatous Polyp Prevention on Vioxx trial confirms the initial finding that rofecoxib raises the risks of myocardial infarction and stroke.

“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,” reported Dr. John A. Baron of Dartmouth Medical School, Lebanon, N.H., and associates (Lancet 2008 Oct. 14 [doi: 10.1016/S0140–6736(08) 61490–7]).

The APPROVE trial, designed to assess whether rofecoxib (Vioxx) reduced the risk of recurrent colorectal neoplasia, was halted early (in 2004) because the drug appeared to double the risk of cardiovascular toxicity. Rofecoxib was soon withdrawn from the market. The trial, funded by Merck Research Laboratories, was criticized for flaws in its statistical analyses.

Dr. Baron and his associates extended the follow-up to at least 1 year after the drug was discontinued, to further assess rofecoxib's CV toxicity. Follow-up was completed for 1,092 subjects who had taken placebo and 1,074 who had taken rofecoxib.

Thrombotic events occurred in 76 rofecoxib patients and 46 on placebo (overall unadjusted hazard ratio, 1.7). After adjustment for age, sex, aspirin use, and CV risk profile at baseline, the hazard ratio was 1.72 for MI and 2.17 for stroke. Subgroup analyses suggested that rofecoxib particularly affected people already at risk for CV disease, but the data were not conclusive because the number of events was small.

Rofecoxib's cardiovascular toxicity “seems to be a class effect,” since other studies have found similar results with different cyclooxygenase-2 inhibitors. Conventional non-aspirin NSAIDs “may share the same toxicity, to the extent that they are COX-2 selective,” the investigators added.

“All these drugs are effective analgesic and anti-inflammatory agents, and seem to reduce risks of colorectal neoplasia. But these benefits will have to be weighed against their proven or possible cardiovascular risks in assessing their suitability in various clinical settings,” they said.

Dr. Baron received consulting fees from Merck as a member of the trial's steering committee and is a consultant to, and has received research funding, from Bayer.

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