Cyclooxygenase-2 inhibitors: are they really atherothrombotic, and if not, why not?
BACKGROUND AND SUMMARY: Selective cyclooxygenase (COX)-2 inhibitors are increasingly being used in place of "conventional" nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving arthritic pain and yet less gastrotoxic. However, the cardiovascular safety of selective COX-2 inhibitors has been questioned because they selectively reduce prostacyclin production, thus disrupting the normal homeostatic balance and promoting a prothrombotic state. These theoretical concerns appear to be supported by the results of clinical trials demonstrating an increased risk of myocardial infarction with COX-2 inhibitors compared with a conventional NSAID, and indirect comparisons of the rates of myocardial infarction among patients treated with a selective COX-2 inhibitor compared with aspirin in different trials. However, emerging data from animal, experimental and clinical studies suggest that COX-2 is atherogenic and thrombogenic, and that selective COX-2 inhibitors may be cardioprotective. Meta-analyses of randomized trials of selective COX-2 inhibitors compared with placebo have demonstrated no excess of cardiovascular events among patients allocated COX-2 inhibitors, and preliminary data from a randomized controlled trial of the selective COX-2 inhibitor meloxicam, in patients with acute coronary syndrome who were treated with aspirin, demonstrated a reduction in cardiovascular events among patients allocated the COX-2 inhibitor.


CONCLUSIONS
Continuing uncertainty regarding the direction and magnitude of any cardiovascular effects of selective COX-2 inhibitors, coupled with their widespread and increasing use, mandates prospective randomized evaluation of their efficacy and safety in patients at increased risk of future cardiovascular events.
Stroke Unit, Department of Neurology, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6001, Australia. gjhankey@cyllene.uwa.edu.au
Graeme J
GJ
Hankey
John W
JW
Eikelboom
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D001168:Arthritis / Q000188:drug therapy; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D018570:Risk Assessment; D013927:Thrombosis / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol