REVIEW Cardiovascular Risk and Inhibition of Cyclooxygenase A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2 Patricia McGettigan, MD, FRACP David Henry, MB, ChB, FRCP I N THE LAST 5 YEARS, INTEREST IN THE cardiovascular effects of the rela- tively selective inhibitors of cy- clooxygenase 2 (COX-2) has been intense. In October 2004, rofecoxib was withdrawn from world markets after a randomized placebo-controlled trial found that in doses of 25 mg/d, it in- creased rates of cardiovascular events in patients with colorectal polyps. 1 The results were confirmed by several large pharmacoepidemiological studies. 2-4 Celecoxib continues to be widely used, despite meta-analyses of randomized controlled trials showing an increased risk of myocardial infarction. 5,6 Attention has turned to the cardio- vascular safety of the older nonselec- tive nonsteroidal anti-inflammatory drugs (NSAIDs).These agents are used extensively and some are available in many countries without prescription. NSAIDs reversibly block both isoforms of cyclooxygenase but vary in their de- gree of selectivity. 7 In one trial, it was suggested that the apparent excess car- diovascular risk with rofecoxib may be explained by a “cardioprotective” effect of the comparator drug, naproxen. 8 However, the results of another trial sug- gested that naproxen may increase the risk of myocardial infarction, 9 and a re- cently published meta-analysis of ran- domized trials has implicated high doses of ibuprofen and diclofenac. 6 Regulatory authorities have pro- vided variable advice regarding the safety of NSAIDs. In the United States, the US Food and Drug Administration See related Review and Editorial. Author Affiliations: Discipline of Clinical Pharmacol- ogy, School of Medicine and Public Health, The Uni- versity of Newcastle, New South Wales, Australia, Dr McGettigan and Dr Henry. Corresponding Author: David Henry, MB, ChB, FRCP, Clinical Pharmacology, Level 5 Clinical Sciences Bldg, New- castle Mater Hospital, Waratah, New South Wales 2298, Australia (david.henry@newcastle.edu.au). Context Evidence that rofecoxib increases the risk of myocardial infarction has led to scrutiny of other nonsteroidal anti-inflammatory drugs (NSAIDs). Regulatory agen- cies have provided variable advice regarding the cardiovascular risks with older non- selective NSAIDs. Objective To undertake a systematic review and meta-analysis of controlled obser- vational studies to compare the risks of serious cardiovascular events with individual NSAIDs and cyclooxygenase 2 inhibitors. Data Sources Searches were conducted of electronic databases (1985-2006), sci- entific meeting proceedings, epidemiological research Web sites, and bibliographies of eligible studies. Study Selection Eligible studies were of case-control or cohort design, reported on cardiovascular events (predominantly myocardial infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with nonuse/remote use of the drugs as the reference exposure. Of 7086 potentially eligible titles, 17 case-control and 6 cohort studies were included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23 on NSAIDs, and 13 on both groups of drugs. Data Extraction Two people independently extracted data and assessed study qual- ity with disagreements resolved by consensus. Data Synthesis Data were combined using a random-effects model. A dose- related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment. Cele- coxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxi- cam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18). Conclusions This review confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac, an older drug. JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv60011) www.jama.com ©2006 American Medical Association. All rights reserved. (Reprinted) JAMA, Published online September 12, 2006 E1 at For Medical Sciences, on September 16, 2006 www.jama.com Downloaded from