Lancet: Vioxx substantially increases risk of stroke, MI and death

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Long term follow-up data confirms that use of the Cox-2 inhibitor rofecoxib (Vioxx) substantially increases the risk of stroke, heart attack and death compared with placebo, according to conclusions from the APPROVe trial, which were published online ahead of print in the Lancet.

The randomized, placebo-controlled trial, led by John A Baron, MD, from Dartmouth Medical School in Lebanon, N.H., and colleagues, aimed to assess the effects of three-year treatment with rofecoxib on recurrence of cancerous polyps in the bowel. Researchers examined 2,587 patients from 108 centers globally during 2000 and 2001, and patients were initially monitored for adverse events only while on treatment and for 14 days afterwards.

In 2004, Merck voluntarily withdrew Vioxx from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.

The researchers attempted to follow up for one year all patients that stopped treatment due to cardiovascular toxicity. The end-point studied was the combined incidence of non-fatal MI, non-fatal stroke and death from cardiovascular, haemorrhagic, or unknown causes (the Antiplatelet Trialists' Collaboration [APTC] combined endpoint).

Follow-up data were obtained for 84 percent of participants, and the researchers found that the relative risk of reaching APTC was increased by 79 percent in the rofecoxib group compared with placebo. The data was consistent with earlier findings of increased risk while on treatment or 14 days afterwards, in which the relative risk of reaching APTC was more than doubled (a 112 percent increased risk).

In terms of the individual outcomes after one-year follow up, the risk of MI or stroke was roughly doubled for rofecoxib patients compared with placebo, while the relative risk of death increased by 31 percent. There was no substantial change in the increased relative risk of cardiovascular events over time.

“Our data are compatible with an early increase in risk that seems to persist for about one year after three years of treatment. All these drugs are effective analgesic and anti-inflammatory agents, and seem to reduce risks of colorectal neoplasia. However, these benefits will have to be weighed against their proven or possible cardiovascular risks in assessing their suitability in various clinical settings,” the authors concluded.

"The results of randomized trials are consistent with all coxibs having some vascular risk, but also that some traditional NSAIDs carry similar risks. Switching from a coxib to a traditional NSAID will not necessarily avoid these vascular hazards, but will result in a two-to-three-fold increase in the risk of a serious upper gastrointestinal complication — i.e., perforation, obstruction, or bleed,” Colin Baigent, MD from clinical trial service unit and epidemiological studies at University of Oxford in England, and Carlo Patrono, MD, from Catholic University in Rome, wrote in an accompanying commentary.