Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2

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Cardiovascular Risk and Inhibition of Cyclooxygenase: A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2
Patricia McGettigan and David Henry
(JAMA, 296:1633-1644, 2006)
Discipline of Clinical Pharmacology, School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
Because evidence indicates that rofecoxib and celecoxib increase the risk of myocardial infarction, examination of other, older, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has ensued. Evidence and advice from regulatory authorities have been variable concerning the safety of NSAIDs. This systematic review and meta-analysis of controlled observational studies compared the risks of serious cardiovascular (CV) events with individual NSAIDs and cyclooxygenase 2 (COX-2) inhibitors.
Searches of electronic databases were conducted for the years 1985 to 2006. In addition, scientific meeting proceedings, epidemiologic research Web sites, and bibliographies of eligible studies were scrutinized. Studies examined were case-control or cohort designed, reported on CV events with COX-2 inhibitors or NSAIDs or both.
Of 7086 possible eligible titles, 17 case-control and 6 cohort studies were included; 13 reported on COX-2 inhibitors, 23 on NSAIDs, and 13 on both types of drugs. The case control analyses included 86,193 cases with CV events (mostly myocardial infarction or sudden cardiac death). All reported risks with nonselective NSAIDs and 9 also with selective COX-2 inhibitors. The 6 cohort studies included 75,520 users of COX-2 inhibitors, 375,619 users of nonselective NSAIDs, and 594,720 unexposed participants. Acute myocardial infarction and sudden CV death were the reported outcomes. Rofecoxib was included in 9 case-control and 2 cohort studies; the summary relative risks (RRs) for CV events were 1.31 and 1.53, respectively. A dose effect was apparent, with a summary RR of 2.19 with doses > 25 mg/d compared with 1.33 for doses of 25 mg/d or less. Celecoxib was studied in 8 case-control and 3 cohort studies. Exposure to the drug did not lead to an increased risk of CV events (RR 1.01 for case-control studies and 1.22 for cohort studies). In studies reporting on ibuprofen, naproxen, diclofenac, indomethacin, and piroxicam, the summary RR with naproxen was 0.97. No significant elevation in risk was reported with ibuprofen or piroxicam, although diclofenac and indomethacin were associated with increased risks of CV events. The summary RR for diclofenac from 9 studies was 1.40. The summary RRs for piroxicam and ibuprofen were 1.06 and 1.07, respectively. Direct comparisons between drugs showed that the summary RR for rofecoxib compared with any nonselective NSAID was 1.21 and that for celecoxib was 0.95. When rofecoxib was compared directly with celecoxib, the summary RR was 1.34. An early risk (within the first 30 days) was also evident with rofecoxib (summary RR of 1.66) but not with celecoxib (RR 1.32). Data were insufficient in determining whether aspirin protects against the CV risk with rofecoxib or other risk-inducing drugs.
Controlled data from these studies confirmed a dose-related risk of CV events with selective COX-2 inhibitors, with risk increasing early in treatment. Celecoxib in the more frequently used doses does not seem to increase the risk. Diclofenac, an older NSAID, also seems to carry therisk of adverse cardiac events and seems to be harmful at the commonly used doses. Reviewing its regulatory status may be in order.

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