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.