Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib.
BACKGROUND
In comparing aspirin, nonselective nonsteroidal antiinflammatory agents (NSAIDs), and cyclooxygenase (COX)-2 inhibitors, variation in platelet inhibitory effects exists that may be associated with differential risks of cardiovascular (CV) thrombotic events. Among the randomized, controlled trials with the COX-2 inhibitor rofecoxib, one study demonstrated a significant difference between rofecoxib and its NSAID comparator (naproxen) in the risk of CV thrombotic events. A combined analysis of individual patient data was undertaken to determine whether there was an excess of CV thrombotic events in patients treated with rofecoxib compared with those treated with placebo or nonselective NSAIDs.


RESULTS
CV thrombotic events were assessed across 23 phase IIb to V rofecoxib studies. Comparisons were made between patients taking rofecoxib and those taking either placebo, naproxen (an NSAID with near-complete inhibition of platelet function throughout its dosing interval), or another nonselective NSAIDs used in the development program (diclofenac, ibuprofen, and nabumetone). The major outcome measure was the combined end point used by the Antiplatelet Trialists' Collaboration, which includes CV, hemorrhagic, and unknown deaths; nonfatal myocardial infarctions; and nonfatal strokes. More than 28 000 patients, representing >14 000 patient-years at risk, were analyzed. The relative risk for an end point was 0.84 (95% CI: 0.51, 1.38) when comparing rofecoxib with placebo; 0.79 (95% CI: 0.40, 1.55) when comparing rofecoxib with non-naproxen NSAIDs; and 1.69 (95% CI: 1.07, 2.69) when comparing rofecoxib with naproxen.


CONCLUSIONS
This analysis provides no evidence for an excess of CV events for rofecoxib relative to either placebo or the non-naproxen NSAIDs that were studied. Differences observed between rofecoxib and naproxen are likely the result of the antiplatelet effects of the latter agent.
Konstam
M A
MA
Division of Cardiology, New England Medical Center, Boston, Massachusetts, USA. MKonstam@Lifespan.org
Weir
M R
MR
Reicin
A
A
Shapiro
D
D
Sperling
R S
RS
Barr
E
E
Gertz
B J
BJ
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000517:prevention & control; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002908:Chronic Disease; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D017327:Clinical Trials, Phase IV as Topic / Q000706:statistics & numerical data; D015897:Comorbidity; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D017116:Low Back Pain / Q000188:drug therapy; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy; D016016:Proportional Hazards Models; D011451:Prostaglandin-Endoperoxide Synthases; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012306:Risk; D013450:Sulfones; D013927:Thrombosis / Q000453:epidemiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases