Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124\u2008513 participants, 68\u2008342 person-years) and 474 trials of one NSAID versus another NSAID (229\u2008296 participants, 165\u2008456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1\ub737, 95% CI 1\ub714-1\ub766; p=0\ub70009) or diclofenac (1\ub741, 1\ub712-1\ub778; p=0\ub70036), chiefly due to an increase in major coronary events (coxibs 1\ub776, 1\ub731-2\ub737; p=0\ub70001; diclofenac 1\ub770, 1\ub719-2\ub741; p=0\ub70032). Ibuprofen also significantly increased major coronary events (2\ub722, 1\ub710-4\ub748; p=0\ub70253), but not major vascular events (1\ub744, 0\ub789-2\ub733). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0\ub793, 0\ub769-1\ub727). Vascular death was increased significantly by coxibs (1\ub758, 99% CI 1\ub700-2\ub749; p=0\ub70103) and diclofenac (1\ub765, 0\ub795-2\ub785, p=0\ub70187), non-significantly by ibuprofen (1\ub790, 0\ub756-6\ub741; p=0\ub717), but not by naproxen (1\ub708, 0\ub748-2\ub747, p=0\ub780). 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 (coxibs 1\ub781, 1\ub717-2\ub781, p=0\ub70070; diclofenac 1\ub789, 1\ub716-3\ub709, p=0\ub70106; ibuprofen 3\ub797, 2\ub722-7\ub710, p<0\ub70001; and naproxen 4\ub722, 2\ub771-6\ub756, p