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.
Hankey
Graeme J
GJ
Stroke Unit, Department of Neurology, Royal Perth Hospital, Box X2213 GPO, Perth, WA 6001, Australia. gjhankey@cyllene.uwa.edu.au
Eikelboom
John W
JW
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