Etoricoxib 30, 60 and 90 mg demonstrated clinical efficacy in patients with OA in the first 6 weeks of therapy [5
]; this level of efficacy was maintained during the 46-week active comparator controlled period. The magnitude of improvement observed with the etoricoxib 60 and 90 mg groups was similar to that of the diclofenac group; the efficacy demonstrated by the etoricoxib 60 and 90 mg groups was slightly greater than that observed with the etoricoxib 30 mg group. This was most evident in the efficacy evaluation of patients treated with the same dose of etoricoxib from the beginning of the study through the second extension. All treatments were generally well tolerated and no new or unique findings related to safety or tolerability were revealed during long-term dosing of etoricoxib (i.e., over 52 weeks).
Patients who received the same dose of etoricoxib from the beginning of the base study through the second extension demonstrated that, generally, the treatment effect reached a plateau at approximately week 6 of therapy; the treatment effect was maintained at that level through week 52 of the study.
In the placebo-controlled period (part I) of the base study, the treatment responses of etoricoxib 30 mg were significantly greater than that of placebo, but were approximately one-half to two-thirds of that of etoricoxib 60 mg as assessed by the primary endpoints. Etoricoxib 60 and 90 mg provided similar efficacy, indicating that the 60 mg dose was the minimal dose with maximal efficacy [5
]. During the extension studies, however, patients who continued on the 30 mg dose had a treatment response that more closely approximated that of the 60 mg and 90 mg doses; the treatment effect for all treatment groups was maintained for up to 52 weeks. Furthermore, the treatment effect with etoricoxib (30, 60 and 90 mg) was similar to that of diclofenac 150 mg. These results should be interpreted cautiously as the number of patients in each of the treatment groups was relatively small and decreased over time due to discontinuations from the study.
Both etoricoxib and diclofenac appeared to be well-tolerated. However, patients in the etoricoxib group experienced fewer GI nuisance symptoms during the extensions. A larger proportion of patients in the diclofenac group discontinued due to these GI nuisance symptoms. In 8 previous clinical trials, less patients on etoricoxib discontinued due to a GI symptom vs. comparator nonselective NSAIDs [6
]. In one randomized controlled trial, patients receiving etoricoxib had less fecal blood loss versus ibuprofen and in another trial, etoricoxib patients had fewer endoscopically detectable lesions versus naproxen; these data suggest that etoricoxib may be associated with a reduced incidence of GI perforations, ulcers, or bleeds (PUBs) [7
]. Additionally, in a large clinical trial, etoricoxib 90 mg demonstrated a superior GI tolerability profile compared with diclofenac 150 mg; there were significantly fewer patients on etoricoxib that experienced a GI AE versus diclofenac [8
There was only one serious thrombotic cardiovascular (CV) event during the active comparator-controlled period, which occurred in a patient receiving diclofenac. In this study, use of low dose aspirin, which is a factor that is indicative of CV risk, was not allowed since the study was initiated before the GI COX-2 hypothesis was proven. Although aspirin users were excluded from the study, patients with other cardiovascular risk factors (i.e., chest pain, hypertension, history of smoking, hypercholesterolemia, palpitation, mitral valve prolapse, and sinus bradycardia) were allowed in the study.
To assess either GI or CV safety, larger and longer-term trials or pooled analyses are required since the incidence of such events is relatively rare [9
]. In a pooled analysis of the etoricoxib development program, the rate of serious thrombotic CV events in patients treated with etoricoxib was not discernibly different than in patients treated with NSAIDs that are not associated with potent and sustained antiplatelet effects such as diclofenac and ibuprofen [11
]. Although no discernible difference was observed in comparison to placebo either, the placebo-controlled thrombotic CV safety data for etoricoxib are limited in quantity and in duration to 12 weeks. However, results from longer-term, placebo-controlled trials with rofeocoxib and celecoxib suggest that use of COX-2 selective inhibitors are associated with an increased incidence of adverse CV events compared to placeb [12
]. Large, long-term trials to assess the CV safety profile of etoricoxib are ongoing.
Renovascular effects were also examined during the 52-week treatment period since NSAIDs and COX-2 selective inhibitors can affect renal physiology [14
]. In the base study, there was a small number of renovascular AEs; most common with the 90-mg dose, minimal with the 60-mg dose, and not detectable with 30 mg etoricoxib [5
]. Overall, renovascular effects were of limited clinical significance during the active comparator periods. The incidence of congestive heart failure was low (1 event in a patient receiving etoricoxib 60 mg) and the incidence of hypertension with etoricoxib was generally similar to that of diclofenac, although the number of hypertension events was dose-related. The risks for renovascular effects in prior trials of the etoricoxib clinical development program were low with a shallow dose response and were generally similar to those found with naproxen or ibuprofen [16