On the basis of these data, one should recommend that COX-2 selective inhibitors be used in patients with arthropathies, especially OA and RA, who are at increased risk for upper GI complications from nonselective NSAIDs . Established risk factors for the development of PUBs in patients treated with nonselective NSAIDs include age ≥ 65, a history of peptic ulcer disease or of upper GI bleeding, concomitant use of oral corticosteroids or anticoagulants, and, possibly, smoking and alcohol consumption [16–18]. Fendrick stated that the "unrestricted access to COX-2 selective inhibitors could be both clinically and economically advantageous because of the high likelihood of...safety benefits from coxibs" and suggested that "COX-2 selective inhibitors should be offered as first-line therapy to these high-risk patients" .
Unfortunately, the reality of the situation in the autumn of 2002 is not that simple. Two major questions remain unanswered: 1) are COX-2 selective inhibitors associated with an increased risk of cardiovascular thrombotic events? and 2) does concomitant therapy with low-dose aspirin, used for cardioprotection, eliminate the safety benefit of COX-2 selective inhibitors in comparison with nonselective NSAIDs?
The first question is based on the surprising finding in the VIGOR trial that patients who received rofecoxib had higher risk of cardiovascular thrombotic events, particularly nonfatal myocardial infarction, than patients who received naproxen . Fitzgerald and Patrono proposed three hypotheses to explain these results: an antithrombotic effect of naproxen, a prothrombotic effect of rofecoxib, and the 'play of chance' . Five observational epidemiologic studies published in the past 2 years examined the effect of NSAIDs, particularly naproxen, on the risk of cardiovascular thrombotic events including myocardial infarction; these studies were reviewed recently by Strand and Hochberg . The results of a majority of these studies are consistent with a modest protective effect of naproxen on the development of nonfatal myocardial infarction; indeed, Dalen, in his editorial accompanying the three papers published in the Archives of Internal Medicine, concluded that the most likely explanation of the results in the VIGOR trial was "that naproxen decreases the incidence of acute myocardial infarction" . Patrono suggested that a combination of a protective effect of naproxen and the "play of chance" operating in a short-term study [median follow-up of 9 months] with small numbers of events in a low-risk population [event rate below 1% per year] explained the findings in the VIGOR trial (Patrono C, Invited Lecture on 28 October 2002 at annual meeting of American College of Rheumatology, New Orleans, LA). Two meta-analyses have failed to demonstrate an increased risk of cardiovascular thrombotic events in patients receiving rofecoxib at doses ranging from 12.5 to 50 mg per day in comparison with both placebo and nonselective NSAIDs other than naproxen [23, 24]. However, the dose of rofecoxib in the VIGOR trial was double the highest FDA-approved dose for chronic treatment in both OA and RA, and there were small numbers of patients treated who received this dose in the phase II and III OA and RA trials in which naproxen was not used as a comparator. Ray recently published results of a retrospective cohort study using data from the Tennessee Medicaid database and reported that new users of rofecoxib at doses greater than 25 mg per day had almost a twofold increased risk of serious cardiovascular events in comparison with controls not receiving NSAIDs, while users of rofecoxib at doses of 25 mg per day or less had no increased risk of such events . The results of a meta-analysis of data from 15 controlled trials of celecoxib involving over 30,000 patients failed to demonstrate an increased risk of cardiovascular thrombotic events in patients who received celecoxib compared with those who received placebo or nonselective NSAIDs including naproxen . Similarly, the results of an analysis of pooled data from four randomized, controlled trials of valdecoxib in over 3000 patients with RA failed to demonstrate an increased risk of cardiovascular thrombotic events .
Thus, it is unlikely that this increased risk is a class effect of COX-2 selective inhibitors when used in therapeutic doses. It seems prudent, however, not to use doses higher than those recommended for chronic therapy – i.e. rofecoxib 12.5 or 25 mg per day, celecoxib 200 or 400 mg per day, or valdecoxib 10 mg per day. Insufficient data are available at present to make definitive statements about the use of etoricoxib, other than to note that at recommended doses of 60 or 90 mg per day for chronic therapy of OA and RA, respectively, there is no apparent increased risk of cardiovascular thrombotic events in comparison with placebo and, in patients with RA, there is a reduced risk of such events in patients randomized to naproxen, the comparator NSAID in the phase III trials (Arcoxia Product Information, Merck & Co, Inc, Whitehouse Station, NJ, USA).