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OP0133 Cardiovascular safety profile of rofecoxib: a meta-analysis
  1. DR Shapiro1,
  2. E Barr2,
  3. AS Reicin2
  1. 1Biostatistics
  2. 2Clinical Research, Merck & Co., Inc., Rahway, USA


Background COX-1 inhibition compromises GI homeostasis; however, by inhibiting platelet aggregation, COX-1 blockade is cardioprotective. COX-2 inhibitor therapy results in marked reductions in GI events relative to non-selective NSAID (COX-1/COX-2 inhibitor) therapy. Because COX-2 inhibitors do not have antiplatelet properties, chronic use of COX-2 inhibitors or non-selective NSAIDs may result in differential risks of platelet-mediated vascular events. Evaluation of the impact of these agents on vascular events is complicated by the variable effects of NSAIDs on platelet aggregation. NSAIDs that mediate near complete inhibition of platelet function throughout their entire dosing cycle may be similar to aspirin and reduce the risk of vascular events; other compounds with less substantial platelet inhibition may have no impact on vascular events.

Objectives To evaluate the cardiovascular (CV) safety profile of rofecoxib, a selective COX-2 inhibitor.

Methods A meta-analysis of all Phase IIb-V clinical trials was conducted using individual patient data and focusing on the relative risk of CV thrombotic serious adverse experiences in patients taking rofecoxib as compared to placebo, naproxen (an NSAID with near complete inhibition of platelet function throughout its dosing interval), and non-selective NSAIDs that lack potent sustained inhibition of platelet function (diclofenac, ibuprofen, and nabumetone). The primary metric utilised was the Antiplatelet Trialists’ Collaboration (APTC) combined endpoint of cardiovascular or unknown death, stroke, or myocardial infarction.

Results Over 28,000 patients in 19 studies (Osteoarthritis, Rheumatoid Arthritis, Alzheimer’s, and Chronic Low Back Pain trials) representing over 14,000 patient-years at risk were included in the meta-analysis. The relative risk (95% CI) for an APTC combined endpoint was: 0.59 (0.37, 0.94) when comparing naproxen (n = 7870) vs. rofecoxib (n = 9083); 1.27 (0.64, 2.50) when comparing non-naproxen NSAIDs (n = 2755) vs. rofecoxib (n = 4549); 1.19 (0.73, 1.96) when comparing placebo (n = 3482) vs. rofecoxib (n = 6290); and, 1.31 (0.86, 2.01) when comparing non-naproxen NSAIDs or placebo (n = 6017) vs. rofecoxib (n = 7675).

Conclusion (1) The risk of sustaining a thrombotic cardiovascular event was similar in patients treated with rofecoxib, placebo, or non-selective NSAIDs without sustained effects on platelet function and, (2) the risk of sustaining a thrombotic cardiovascular event was reduced in patients treated with naproxen compared to rofecoxib. This reduction in events on naproxen is likely due to its ability to maintain near complete inhibition of platelet function throughout its dosing interval.

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