Table 1 Pooled analysis of upper gastrointestinal safety: perforations ulcers and bleeds with etoricoxib versus nonselective nonsteroidal antiinflammatory drugs (NSAIDs)* (Ramey et al 2005) Upper gastrointestinal events† Confirmed events Etoricoxib Nonselective NSAIDs All investigator-reported events Etoricoxib Nonselective NSAIDs Confirmed complicated events Etoricoxib Nonselective NSAIDs All investigator-reported complicated events Etoricoxib Nonselective NSAIDs Number of events/patients (%) Patient-years 40/3226 (1.24) 55/2215 (2.48) 47/3226 (1.46) 64/2215 (2.89) 19/3226 (0.59) 23/2215 (1.04) 22/3226 (0.68) 28/2215 (1.26) 4001.65 2225.46 4001.37 2224.50 4007.24 2229.66 4007.15 2229.41 Rate per 100 patient-years (95% CI) 1.00 (0.71, 1.36) 2.47 (1.86, 3.22) 1.17 (0.86, 1.56) 2.88 (2.22, 3.67) 0.47 (0.29, 0.74) 1.03 (0.65, 1.55) 0.55 (0.34, 0.83) 1.26 (0.83, 1.82) Etoricoxib for arthritis and pain Relative risk‡ (95% CI) p-value‡ 0.48 (0.32, 0.73) < 0.001 0.49 (0.33, 0.72) < 0.001 0.59 (0.32, 1.09) 0.55 (0.31, 0.98) 0.09 0.41 * Data from 10 clinical trials in 5441 patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis treated with etoricoxib 60 mg, 90 mg, or 120 mg QD (average dose, 87.3 mg; n = 3226; median exposure 12.4 patient-months; total exposure 4001.65 patient-years) or nonselective NSAIDs ibuprofen 800 mg TID, diclofenac 50 mg TID, or naproxen 500 mg BID (n = 2215; median exposure 6.3 patient-months; total exposure 2 225.46 patient-years). † Gastrointestinal perforation, symptomatic ulcer, or gastrointestinal bleeding. ‡ Based on the Cox proportional hazards model. Abbreviations: BID, twice daily; CI, confidence interval; NSAIDs, nonsteroidal antiinflammatory drug; QD, every day;TID, three times daily. (Hunt, Harper, Watson, et al 2003) (p < 0.01 for each comparison). In addition, results from several large pooled analyses also support the favorable gastrointestinal tolerability profile of etoricoxib (Hunt, Harper, Watson, et al 2003; Watson et al 2004; Ramey et al 2005). An analysis of 5441 patients with OA, RA, or AS from 10 clinical trials, showed that etoricoxib 60 to 120 mg QD was associated with a lower incidence of PUBs than traditional NSAIDs (ibuprofen 800 mg TID, diclofenac 50 mg TID, naproxen 500 mg BID) (Table 1) (Ramey et al 2005). The superior PUB profile of etoricoxib during the first year of treatment in the pooled population was driven primarily by comparison with naproxen (Merck 2005). In the pooled analysis, as well as the EDGE study, the reduction in PUBs with etoricoxib versus traditional NSAID comparator(s), appeared to be negated in patients receiving concomitant aspirin therapy (Merck 2005). Data from 4782 patients with OA, RA, chronic LBP, or AS, showed that etoricoxib 60 mg to 120 mg QD was associated with less discontinuation due to dyspepsia (p = 0.007) and lower new use of gastroprotective agents (p < 0.001) compared with the NSAIDs diclofenac and naproxen (mean follow-up 80.5 versus 73.1 weeks) (Watson et al 2004). Renovascular and cardiovascular tolerability All selective and traditional NSAIDs inhibit prostanoid biosynthesis (Warner and Mitchell 2004); however, it has Therapeutics and Clinical Risk Management 2006:2(1) been hypothesized that selective suppression of COX-2- dependent synthesis of prostacyclin (a vasodilator and inhibitor of platelet aggregation and vascular smooth muscle cell proliferation) without concomitant inhibition of COX- 1-dependent synthesis of thromboxane A2 (a vasoconstrictor and promoter of platelet aggregation and vascular proliferation), may increase the risk of cardiovascular adverse effects owing to thromboembolism or elevated blood pressure in patients predisposed to such events (FitzGerald 2002, 2004; Clark et al 2004; Warner and Mitchell 2004). Clinical trials have suggested that long term use of celecoxib and rofecoxib may be associated with more cardiovascular events than placebo or nonselective NSAIDs (Bombardier et al 2000; FDA 2001; Bresalier et al 2005; Solomon et al 2005), and this has led to the market withdrawal of rofecoxib worldwide. However, there has been uncertainty over these findings as a result of the small number of events reported and methodological problems with the trials. For example, the trials were statistically underpowered to evaluate thrombotic events, comparisons between trials were limited by the different proportions of patients with RA (an independent risk factor for cardiovascular disease [Solomon et al 2003]), and concomitant aspirin therapy or use of a naproxen comparator group may have had a confounding cardioprotective effect (FitzGerald 2002; Clark et al 2004; Warner and Mitchell 2004). The outstanding questions surrounding the cardio- vascular safety of traditional NSAIDs and selective COX-2 51