Brooks and Kubler inhibitors are important matters that greatly impact clinical care for patients such as those with RA who require effective and long-term pain and symptom relief. The available evidence does not conclusively support a mechanistic effect of COX-2 inhibitors on hemostasis. Of note, recent research has shown that acetaminophen also significantly inhibits prostacyclin and thromboxane synthesis (Schwartz et al 2006), suggesting that there is a general lack of information regarding the mechanistic effects of commonly used analgesic agents. Etoricoxib appears to be associated with a low incidence of renovascular adverse events (hypertension, lower extremity edema, or congestive heart failure) consistent with fluid retention observed with all selective and nonselective NSAIDs (Curtis et al 2004). The EDGE study reported a numerically higher incidence of hypertension-related adverse events and a significantly higher percentage of patients discontinuing therapy with etoricoxib 90 mg QD compared with diclofenac 50 mg TID (11.7% versus 5.9%, respectively, for adverse events; 2.3% versus 0.7%, respectively, for discontinuations, RR 1.60 with 95% CI 1.06, 2.18) (Merck 2005). In addition, a higher rate of new hypertension medication use was reported with etoricoxib compared with diclofenac (27.4 versus 22.3 events per 100 patient-years; RR 1.24, p < 0.001). Serious hypertension- related adverse events were rare (Merck 2005). In a pooled analysis of 12-week data from 4770 patients with OA, RA, or chronic LBP, the risk of renovascular adverse events associated with etoricoxib 60 mg, 90 mg, or 120 mg QD was low and generally similar to that observed with naproxen 500 mg BID or ibuprofen 800 mg TID (Curtis et al 2004). It is therefore important to monitor blood pressure in all patients taking NSAIDs (FDA 2005a). Analysis of pooled data from more than 6700 patients (representing approximately 6500 patient-years of observation) suggested that treatment with etoricoxib ≥ 60 mg QD was not associated with an excess risk of serious thrombotic cardiovascular adverse events (fatal or nonfatal cardiac, cerebrovascular, or peripheral vascular events confirmed by a blinded external committee) compared with placebo (RR 1.11; 95% CI 0.32, 3.81) or non-naproxen NSAIDs (diclofenac 50 mg TID or ibuprofen 800 mg TID; RR 0.83, 95% CI, 0.26, 2.64) (Curtis, Mukhopadhyay, et al 2003). There were fewer such events associated with naproxen 500 mg BID, which was evaluated separately from other traditional NSAIDs because of its potential cardio- protective activity (etoricoxib versus naproxen RR 1.70; 95% CI 0.91, 3.18) (Curtis, Mukhopadhyay, et al 2003). 52 The EDGE study revealed no clear difference between etoricoxib and diclofenac with respect to the overall incidence of confirmed thrombotic cardiovascular events (1.25 versus 1.15 events per 100 patient years, respectively; RR 1.07) (Baraf et al 2005b). There were slight differences in the profile of cardiovascular events with etoricoxib versus diclofenac (eg, 26 versus 19 cardiac events); however, the numbers were too small to draw firm conclusions (Baraf et al 2005b; Merck 2005) and any potential difference appeared to be ameliorated in patients receiving concomitant aspirin therapy (FDA 2005c). The MEDAL Program (Multinational Etoricoxib and Diclofenac Arthritis Long-term) comparing etoricoxib with diclofenac in over 34 000 RA and OA patients from three component clinical studies, EDGE (completed), EDGE 2 and MEDAL (both studies ongoing), over more than 18 months (with some patients receiving treatment for up to 40 months) is underway. This program is the first noninferiority comparison of thrombotic cardiovascular events between a traditional NSAID (diclofenac) and a selective COX-2 inhibitor (etoricoxib), and it will provide further insight into the long-term cardiovascular safety of etoricoxib and diclofenac. Additionally, as part of an ongoing safety surveillance effort, a thrombotic cardio- vascular event procedure was established in 1998 prior to phase IIb etoricoxib studies in order to collect cardiovascular safety data for etoricoxib, NSAID comparators and placebo across etoricoxib’s clinical development program. Analysis of the available cardiovascular data for all COX-2 inhibitors, including etoricoxib, has led both the FDA and the European Medicines Agency (EMEA) to request the addition of warnings about the potential for increased cardiovascular risk in the prescribing information for these agents (EMEA 2005b; FDA 2005b). In the US, this directive has been extended to apply to all NSAIDs (except aspirin), irrespective of their COX-2 selectivity (FDA 2005b). These warnings highlight the need for careful patient selection based on evaluation of the benefits and risks of therapy. Patient support/disease management programs American College of Rheumatologists (ACR) guidelines indicate that pharmacologic therapies such as NSAIDs, DMARDs, and/or glucocorticoids should be used alongside nonpharmacologic strategies (eg, patient education, joint exercise) in the management of RA (ACRRAG 2002). COX-2 inhibitors may be selected for drug treatment in Therapeutics and Clinical Risk Management 2006:2(1)