Cardiovascular Risk Associated with Cox-2 Inhibitors

The APPROVe trial 1 randomized 2586 patients to receive either 25mg of rofecoxib daily or placebo. The aim of the trial was to investigate the effect of rofecoxib in the prevention of colorectal adenomas in patients with a history of adenomas. All investigator-reported serious adverse events were adjudicated in a blinded fastion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 years of follow-up, as compared with 26 patients in the placebo group (RR 1.92, 95% CI 1.19 to 3.11) (1 extra thrombotic event per 139 patient years). The risk became apparent after 18 months of treatment.

The Adenoma Prevention with Celecoxib (APC) trial 2 randomized a total of 2035 patients with a history of colorectal neoplasia to receive celecoxib 200mg or 400mg twice daily or placebo. All deaths were categorized as cardiovascular or noncardiovascular, and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme. During a follow-up of 2.8 to 3.1 years, a composite cardiovascular end point of death, myocardial infarction, stroke or heart failure was reached in 7 of 679 patients in the placebo group (1.0%), compared with 16 of 685 patients receiving 200mg of celecoxib twice daily (2.3%), and with 23 of 671 patients receiving 400mg of celecoxib twice daily (3.4%, hazard ratio, 3.4, 95% CI 1.4 to 7.8, NNH = 42.

In the CABG surgery study 3 1671 patients were randomized to receive intravenous parecoxib for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by valdecoxib; or placebo for 10 days. The primary endpoint was the frequency of predefined asverse events, including cardiovascular events. As compared with the group given placebo alone, both the active treatment groups had a higher proportion of patients with at least one confirmed adverse event (7.4% in each of the two groups vs 4.0% in the placebo group, RR 1.9, 95% CI 1.1 to 3.2 for each comparison with the placebo group), NNH = 29. The risk of cardiovascular events was 2.0% in the active treatment groups vs 0.5% in the placebo group, RR 3.7, 95% CI 1.0 to 13.5)

In the VIGOR trial 4, patients taking rofecoxib had a greater risk of having a myocardial infarction (MI) than patients taking naproxen (RR 4.03, 95% CI, 2.86 to 5.68).

The following decision support rules contain links to this evidence summary:

• The choice of NSAIDs in people with high cardiovascular risk http://www.ebmeds.org/ebmeds/ebmeds_home.asp?mode=scripts&submode=view&id=scr00588&country=UK

References

• Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005 Mar 17;352(11):1092-102. [PubMed]
• Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M, Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005 Mar 17;352(11):1071-80. [PubMed]
• Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005 Mar 17;352(11):1081-91. [PubMed]
• Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000 Nov 23;343(21):1520-8, 2 p following 1528. [PubMed]