Follow-up data confirm rofecoxib substantially increases risk of stroke, heart attack and death

October 13, 2008

Long term follow-up data from the APPROVe trial confirms that use of the Cox-2 inhibitor rofecoxib* substantially increases the risk of stroke, heart attack and death compared with placebo. These are the conclusions of an Article published early Online and in an upcoming edition of The Lancet. The paper was written by Professor John A Baron, Dartmouth Medical School, Lebanon, New Hampshire, USA, Dr Robert Bresalier, MD Anderson Cancer Center, University of Texas, USA, and Professor Dion Morton, University of Birmingham, UK and colleagues.

The APPROVe study was a randomised, placebo-controlled trial, which aimed to assess the effects of 3-year treatment with rofecoxib on recurrence of cancerous polyps in the bowel. The study looked at 2587 patients from 108 centres worldwide during 2000 and 2001, and patients were initially monitored for adverse events only while on treatment and for 14 days afterwards. In this paper, the researchers attempted to follow-up for one year all patients that had had to stop treatment because of cardiovascular toxicity. The end-point studied was the combined incidence of non-fatal heart attack, 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% of participants, and the researchers found that the relative risk of reaching APTC was increased by 79% in the rofecoxib group compared with placebo. This 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% increased risk). In terms of the individual outcomes after one-year follow up, the risk of heart attack or stroke was roughly doubled for rofecoxib patients compared with placebo, while the relative risk of death increased by 31%. There was no substantial change in the increased relative risk of cardiovascular events over time.

The authors conclude: "Our data are compatible with an early increase in risk that seems to persist for about 1 year after 3 years of treatment. The cardiovascular toxicity seems to be a class effect; indeed, studies of other selective COX-2 inhibitors have reported similar findings. Conventional non-aspirin NSAIDs** may share the same toxicity to the extent that they are COX-2 selective. 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."

In an accompanying Comment, Dr Colin Baigent, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK, and Dr Carlo Patrono, Catholic University of Rome, Italy, say: "The results of randomised 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 -- ie, perforation, obstruction, or bleed.

A physician choosing between alternative anti-inflammatory regimens for a patient needs to be able to weigh each regimen's hazards, especially cardiovascular and gastrointestinal risks." They add that further research is needed to create a validated method for estimating the risk of a serious gastrointestinal complication.
For Professor John A Baron, Dartmouth Medical School, Lebanon, New Hampshire, USA, please contact communications director Hali Wickner T) +1 603-650-1520 E) /

Dr Robert Bresalier, MD Anderson Cancer Center, University of Texas, USA, T) 1-713-745-4340 E)

Professor Dion Morton, University of Birmingham, UK T) +44(0) 121-627-2282 E)

Dr Colin Baigent, Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK contact by e-mail only E)

Notes to editors: * In 2004, Merck voluntarily withdrew rofecoxib (Vioxx) from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use.
**NSAID = Non-steroidal anti-inflammatory drug

Full Article and Comment:


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