Cyclooxygenase-2 inhibition and cardiovascular events.

Abstract

Introduction of selective cyclooxygenase (COX)-2 inhibitors held a promise of improved treatment of arthritis without the gastrointestinal effects associated with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), which effect both COX-1 and COX-2 activity. Celecoxib, etodolac, meloxicam, and rofecoxib are classified as selective COX-2 inhibitors. Initial placebo and large scale comparative trials with NSAIDs have shown the effectiveness of selective COX-2 inhibition with a lower incidence of gastrointestinal side effects in patients with arthritis.1,2⇓ These data, along with extensive marketing programs such as direct-to-consumer advertising, led to wide scale use. See p 191 Caution to this enthusiasm was raised by suggestions that prostacyclin (PGI-2) inhibition with relatively unopposed platelet thromboxane (TX)A2 generation may lead to thrombotic risk. Then, the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial1 comparing rofecoxib to the NSAID naproxen in patients with rheumatoid arthritis showed a 5-fold increase in atherothrombotic cardiovascular events associated with rofecoxib. In contrast, the Celecoxib Long-Term Arthritis Safety Study (CLASS)2 showed no increase in cardiovascular events with celecoxib compared with an NSAID in patients with osteoarthritis. One possible explanation for the differences between these studies may relate to findings from a direct, double-blind, randomized comparison where rofecoxib significantly raised blood pressure and increased the development of edema relative to celecoxib.3 A summary of major comparative trials with selective COX-2 inhibitors by Mukherjee et al4 suggested that both rofecoxib and celecoxib may be associated with an increase in cardiovascular events. Although there was no apparent evidence for increased cardiovascular events with celecoxib in CLASS,2 Mukherjee et al4 noted that the comparators in the 2 studies were different with regard to cardiovascular risk. They suggested that naproxen decreased cardiovascular risk, thereby increasing the relative risk of rofecoxib in the VIGOR trial,1 whereas ibuprofen, the comparator in …