Following the recent withdrawal of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib (Vioxx^ÂR) from the market, a new comparative study concluded that the drug has little or no impact on the risk for myocardial infarction (MI), and that celecoxib (Celebrex^ÂR) has a substantial cardioprotective effect.¹

The study, to be published in the Annals of Internal Medicine, surveyed 1718 recent sufferers of MI for their history of analgesic use. A significant difference in MI risk was found in patients using rofecoxib versus other NSAIDs, particularly celecoxib. "This difference was not due to an increased risk for MI among rofecoxib users, but rather an association between celecoxib and lower odds of MI," reported researchers, led by Stephen E. Kimmel, MD, of the University of Pennsylvania School of Medicine, in Philadelphia.

Although three large studies of patient databases have failed to detect this cardioprotective effect,² the suggestion that celecoxib may lower odds of MI was bolstered by the observation that the drug had an even more pronounced effect in patients not using aspirin. The authors explain the discrepancy with previous results by pointing out that the design of the present study allowed for removal of confounding variables, most notably body mass index and physical activity, that could not be accounted for in prior analyses and that have a strong effect on MI risk.

Though several other studies, most notably the APPROVe (Adenomatous Polyp Prevention on Vioxx) and VIGOR (Vioxx Gastrointestinal Outcomes Research) trials, have indicated an increase in MI risk associated with rofecoxib, COX-2 inhibitors are thought to have a number of potentially beneficial cardiovascular effects, including reduction in levels of C-reactive protein, LDL cholesterol, vascular inflammation, and atherogenesis.

The observed difference in MI risk between rofecoxib and celecoxib confirms previous results, however, and is consistent with their inhibitory profiles. Nonselective NSAIDs such as ibuprofen and naproxen inhibit both the COX-1 and COX-2 enzymes. COX-1 inhibition is associated with the cardioprotective effects of reduced thromboxane A₂ levels, while s elective COX-2 inhibition reduces levels of the cardioprotective prostaglandin I₂.

One model suggests that the strong selectivity of rofecoxib for COX-2 causes imbalance in these COX products, thus leading to cardiovascular disease and MI. Celecoxib, however, is somewhat less selective, and has been shown in other studies to provide benefits to vascular endothelial function that rofecoxib does not.³ The authors comment that, "although limitations of these mechanism studies make their applicability to the clinical effects of the drugs unclear, our study results are consistent with the theory that differences within the class of COX-2 inhibitors may exist."

In the current study, odds ratios (ORs) for MI were adjusted for a variety of potentially confounding cardiovascular risk factors. When compared with patients not using NSAIDs, ibuprofen or diclofenac (OR 0.53), naproxen (OR 0.48), and celecoxib (OR 0.43) were seen to reduce risk of MI. In addition, no significant MI risk was found among users of rofecoxib when compared to patients not using NSAIDs (OR 1.16). However, rofecoxib was seen to increase risk for MI when compared with celecoxib (OR 2.72), ibuprofen or diclofenac (OR 2.04), or with naproxen in the absence of aspirin (OR 3.39).

The investigators urge caution, however, in interpretation of these results. Since drug use history was collected by telephone interview, patient recall represents a significant possible source of reporting error. They suggest that this phenomenon is not likely to have an effect on the comparison of rofecoxib and celecoxib, as there is no reason to expect differential recall between these two drugs.

In an accompanying editorial, Axel Finckh, MD, and Mark D. Aronson, MD, of Harvard Medical School in Boston, Massachusetts, discussed the results in light of other recent work that points to a differential risk for cardiovascular disease among this class of drugs.⁴ "Overall, these studies suggest that not all COX-2 inhibitors share the same cardiovascular risk as rofecoxib, but the evidence is currently too limited to exclude the possibility of a COX-2 inhibitor class effect," Drs. Finckh and Aronson wrote. Given this uncertainty, they recommend caution when prescribing selective NSAIDs. "Physicians should avoid COX-2 inhibitors as a first-line agent in patients with cardiovascular risk factors and average risk for gastrointestinal toxicity."

This work was supported by Searle Pharmaceuticals (now Pfizer, Inc) and Merck and Co, Inc.

1. Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med. 2005;142(3).

2. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet. 2002;360:1071-1073.

3. Hermann M, Camici G, Fratton A, et al. Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension. Circulation. 2003;108:2308-2311.

4. Finckh A, Aronson MD. Cardiovascular risks of cyclooxygenase-2 inhibitors: where we stand now . Ann Intern Med. 2005;142(3).