Author Affiliations: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.
Atherosclerosis is a process with inflammatory features and selective
cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects
by virtue of inhibiting inflammation. However, by decreasing vasodilatory
and antiaggregatory prostacyclin production, COX-2 antagonists may lead to
increased prothrombotic activity. To define the cardiovascular effects of
COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients
without coronary artery disease, we performed a MEDLINE search to identify
all English-language articles on use of COX-2 inhibitors published between
1998 and February 2001. We also reviewed relevant submissions to the US Food
and Drug Administration by pharmaceutical companies.
Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal
Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term
Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials
with approximately 1000 patients each. The results from VIGOR showed that
the relative risk of developing a confirmed adjudicated thrombotic cardiovascular
event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated
cardiac arrest, sudden or unexplained death, ischemic stroke, and transient
ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38
(95% confidence interval, 1.39-4.00; P = .002). There
was no significant difference in cardiovascular event (myocardial infarction,
stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory
agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors
in both VIGOR and CLASS were significantly higher than that in the placebo
group of a recent meta-analysis of 23 407 patients in primary prevention
trials (0.52%): 0.74% with rofecoxib (P = .04 compared
with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).
The available data raise a cautionary flag about the risk of cardiovascular
events with COX-2 inhibitors. Further prospective trial evaluation may characterize
and determine the magnitude of the risk.
Mukherjee D, Nissen SE, Topol EJ. Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors. JAMA. 2001;286(8):954-959. doi:10.1001/jama.286.8.954