Results:

A total of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years) were included in this meta-analysis. In trials providing individual participant data, the mean age at randomization was 61 years, about two-thirds were female, and 79% were white. Few patients had a history of atherosclerosis (9%), of diabetes (9%), or of upper gastrointestinal peptic ulcer (7%). Major vascular events were increased by approximately one third by COX-2 inhibitors (rate ratio [RR], 1.37; 95% confidence interval [CI], 1.14-1.66; p = 0.0009) or diclofenac (RR, 1.41; 1.12-1.78; p = 0.0036), chiefly due to an increase in major coronary events (COX-2 inhibitors: RR, 1.76; 1.31-2.37; p = 0.0001; diclofenac: RR, 1.70; 1.19-2.41; p = 0.0032). Ibuprofen also significantly increased major coronary events (RR, 2.22; 1.10-4.48; p = 0.0253), but not major vascular events (RR, 1.44; 0.89-2.33). Compared with placebo, of 1,000 patients allocated to COX-2 inhibitors or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (RR, 0.93; 95% CI, 0.69-1.27). Vascular death was increased significantly by COX-2 inhibitors (RR, 1.58; 1.00-2.49; p = 0.0103) and diclofenac (RR, 1.65; 0.95-2.85; p = 0.0187), nonsignificantly by ibuprofen (RR, 1.90; 0.56-6.41; p = 0.17), but not by naproxen (RR, 1.08; 0.48-2.47; p = 0.80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (COX-2 inhibitors: RR, 1.81; 1.17-2.81; p = 0.0070; diclofenac: RR, 1.89; 95% CI, 1.16-3.09; p = 0.0106; ibuprofen: RR, 3.97; 2.22-7.10; p < 0.0001; and naproxen: RR, 4.22; 2.71-6.56; p < 0.0001).