Berlin, Germany - Contrary to the findings of the large randomized Celecoxib Long-term Arthritis Safety Study (CLASS) and a number of epidemiological studies, which suggest no increased cardiovascular risk for celecoxib (Celebrex, Pfizer), researchers are warning that all COX-2 inhibitors pose a threat and that this risk may also be an issue for patients without preexisting risk factors [1]. "There is growing evidence to suggest that the increasing risk of myocardial infarction [MI] is a class effect of COX-2-selective [nonsteroidal anti-inflammatory drugs] NSAIDs," lead author Dr Frank Andersohn (Institute of Clinical Pharmacology Charité, Humboldt-University Berlin, Germany) told heartwire. The group's findings appear April 17, 2006 online in Circulation.

Dr Edeltraut Garbe (Source: Arzneimittelkommission der deutschen Ärzteschaft)

Along with senior author Dr Edeltraut Garbe (Humboldt-University Berlin), Andersohn explained that these new findings are in accord with the Adenoma Prevention with Celecoxib (APC) trial, which also detected an increased cardiovascular risk associated with celecoxib [2].

Among the most surprising aspects of the results, the researchers point out that they observed a rather low hazard ratio for acute MI with rofecoxib (Vioxx, Merck). Andersohn told heartwire that this result was unexpected but may be explained by the low daily doses of rofecoxib prescribed to most patients.

"In our nested case-control analysis, only three patients (two cases and one control) were exposed to doses of >25 mg," Andersohn said. He noted that 45% of cases and 54% of controls used 12.5 mg of rofecoxib per day. The researchers note that other epidemiological studies have reported no significantly elevated risk for lower doses. They suggest the cardiovascular risk associated with rofecoxib may lie primarily in high-dose courses of the drug [3].

Our study shows that the use of COX-2-selective NSAIDS in patients without major cardiovascular risk factors may also cause important harmful effects.

In the present analysis, the investigators looked at more than 480 000 patients registered in the UK General Practice Research Database with at least one prescription for a nonsteroidal anti-inflammatory drug. The researchers compared over 3600 patients with acute MI with more than 13 900 controls matched for age, sex, year of cohort entry, and general practice. They calculated hazard ratios for acute MI associated with the use of COX-2-selective and nonselective NSAIDs.

Current use of etoricoxib (Arcoxia, Merck) was associated with a 2.09-fold increased risk of acute MI compared with no NSAID use. Other selective NSAIDs also significantly increased the risk of acute MI. For valdecoxib (Bextra, Pfizer), the hazard ratio was 4.60; however, the confidence interval was wide because of the low number of valdecoxib users.

The researchers report that hazard ratios for acute MI appeared to increase with higher daily doses of COX-2 inhibitors. They add that the US Food and Drug Administration recently requested labeling changes from the pharmaceutical manufacturers of NSAIDs to include a boxed warning alerting of the potential risk for patients with cardiovascular disease or risk factors. "Our study shows that the use of COX-2-selective NSAIDS in patients without major cardiovascular risk factors may also cause important harmful effects."

Andersohn and colleagues point out that the analysis of the duration of use was limited by the low number of cases and controls continuously exposed for more than 12 months. They also note that the number of patients currently exposed to aspirin was too low to permit a valid assessment of a possible interaction between aspirin and current NSAID use. "In addition," Andersohn said, "there may be a substantial number of patients buying aspirin over the counter, which might also bias such an analysis."

Andersohn and Garbe told heartwire that a class effect of coxibs is also supported by biological plausibility. "It is known that COX-2 inhibition suppresses vascular production of prostacyclin without affecting thromboxane A₂ synthesis. This might lead to elevated blood pressure, accelerated atherogenesis, and an exaggerated thrombotic response to the rupture of an atherosclerotic plaque."