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Last Updated: 2001-08-21 17:14:35 EDT (Reuters Health)

By M. Mary Pennell

WESTPORT, CT (Reuters Health) – A post hoc analysis of separate postmarketing studies of the COX-2 inhibitors celecoxib (Celebrex) and rofecoxib (Vioxx) suggests that treatment with these popular arthritis drugs may increase the risk of myocardial infarction.

A team of Cleveland Clinic Foundation investigators analyzed the cardiovascular event rates in two randomized multicenter trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) and the Celecoxib Long-term Arthritis Safety Study (CLASS), as well as in the 23,407-patient placebo group in a meta-analysis of four large aspirin studies.

The annualized MI rate in that placebo group was 0.52% compared with 0.74% for rofecoxib in VIGOR (p = 0.04) and 0.80% for celecoxib in CLASS (p = 0.02), the investigators report in the August 22nd/29th issue of The Journal of the American Medical Association.

In an interview with Reuters Health, Dr. Steven E. Nissen, vice chair of cardiology at the Cleveland Clinic, said it is possible that the COX-2 inhibitors have "a prothrombotic effect." But Dr. Nissen cautioned that the overall risk for heart attack is very low. He said, too, that the study is limited by its retrospective, observational design.

In the VIGOR study 8076 patients were randomized to rofecoxib 50 mg/d or naproxen 1000 mg/d. Aspirin use was not permitted. There were 111 cardiovascular events in the rofecoxib arm and 50 events in the naproxen arm.

In the CLASS study 8059 patients were randomized to 400 mg of celecoxib b.i.d., 800 mg of ibuprofen t.i.d. or 75 mg of diclofenac b.i.d. Aspirin use was permitted. "The CLASS trial with celecoxib demonstrated no significant difference in cardiovascular events compared with the NSAIDs," the authors write.

Dr. Valentin Fuster, director of the Cardiovascular Institute Mt. Sinai Medical Center, New York, said the JAMA paper requires cautious interpretation because it is not a randomized study. Still, "these drugs are so widely used that we had better pay attention to this observation," he told Reuters Health. He suggested that patients taking the drugs should be listed in a registry so that cardiovascular events could be tracked.

Dr. Steve Geis, group vice president for clinical research at Pharmacia, maker of Celebrex, said the JAMA study is flawed because it "compared all the patients in CLASS to a group of patients who were not taking aspirin." He noted that "22% of the patients in CLASS were taking low-dose aspirin."

A more accurate analysis would compare the patients in CLASS not taking aspirin to the placebo group from the aspirin trials, Dr. Geis said. Using that method, the rate of heart attacks among Celebrex users would be 0.33%. "That's 60% lower than the incidence rate reported for all patients by the authors," he said.

Merck & Co., maker of Vioxx, released a statement saying that based on both the published analysis and Merck's own large-scale-placebo controlled trials, "Merck does not believe the authors' conclusions in the article are scientifically supported by the totality of the data available."

Dr. Laura Demopoulos, senior director of cardiovascular clinical research at Merck, said that the authors made some fundamental mistakes and also overlooked several studies that demonstrated no increased cardiovascular risk for Vioxx. She said that Merck "was aware that the Cleveland Clinic was looking at some data" and that she was aware of meetings between the Clinic investigators and some company representatives, so she was doubly surprised "that they excluded studies that were favorable to Vioxx."

Dr. Demopoulos said Merck has cardiovascular data from 19 controlled clinical studies of rofecoxib that involved more than 28,000 patients. She said the results of those studies demonstrated that the relative risk of cardiovascular events was similar for Vioxx versus placebo as well as for ibuprofen, diclofenac and nabumetone. She said those data were presented to a US Food and Drug Administration advisory panel in February and that Dr. Nissen was a member of that panel.

In their JAMA report, Dr. Nissen and his colleagues also present data from two unpublished trials of rofecoxib, submitted to the US Food and Drug Administration, that allowed the use of low-dose aspirin.

These studies "did not demonstrate the significant increase in cardiovascular event rate noted in VIGOR," they say. However, they note that the trials "had smaller sample sizes [approximately 1000 patients each], used only 25% of the dose of rofecoxib used in VIGOR, and had few events for meaningful comparison. Thus the prothrombotic effect seen with rofecoxib may potentially be dose dependent."

The authors also searched the FDA Adverse Event Reporting System in 2001 and found that 99 thrombotic or embolic events had been attributed to rofecoxib and 102 to celecoxib in the US.

JAMA 2001;286:954-959.

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