Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors

Abstract

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.

Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions

“…In contrast, there are many drugs associated with a low, but clinically significant, increased risk of adverse events that also occur commonly in the patient population without drug exposure. One example is withdrawn pain medication rofecoxib 34 (Vioxx, Merck, Whitehouse Station, NJ, USA). Although treatment with the drug was shown to significantly increase the incidence of cardiovascular events (relative risk E2), the relatively high background incidence of these adverse events in the patient population and the extended time from start of treatment make it impossible to differentiate drug-induced cases from spontaneous cases.…”

C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases

“…Tumour necrosis factor (TNF) antagonists, chemokine and IL-6 antagonism, nonsteroidal anti-inflammatory agents and statin drugs are among the potential therapies. Selective Cox-2 inhibitors were of particular interest with promising initial results but adverse cardiovascular risks have limited their usage (Mukherjee et al, 2001;Thun et al, 2002;Yau et al, 2003).…”

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

“…Data obtained from several reports clearly indicate an agerelated increase in the expression of COX-2 and PGE2 (Baek et al 2001;Hayek et al 1997;Kim et al 2000), which is consistent with our results in the present study. Over-production of PGE2 eventually gives rise to the age-associated diseases, such as atherosclerosis, Alzheimer's disease, and arthritis (FitzGerald 2003;Mukherjee et al 2001;Pasinetti and Aisen 1998). Therefore, there might exist disordered regulation of COX-2 expression in the aging body.…”