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

Summary Background The vascular and gastrointestinal eff ects of non-steroidal anti-infl ammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-infl ammatory 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 (124 513 participants, 68 342 personyears) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial in farction, 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, ob struction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefl y due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also signifi cantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). 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 signifi cantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased signifi cantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), nonsignifi cantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional eff ects 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 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation. Introduction Non-steroidal anti-infl ammatory drugs (NSAIDs) are among the most widely used drugs in the world. They are chiefl y used to treat pain, but their long-term use is limited by serious gastrointestinal side-eff ects. NSAIDs inhibit the two recognised forms of prostaglandin G/H synthase (also referred to as cyclo-oxygenase [COX]), namely COX-1 and COX-2. 1 Since the analgesic and antiinfl ammatory eff ects of NSAIDs are mediated by inhibition of COX-2, and their gastrointestinal side eff ects mostly by inhibition of COX-1, NSAIDs which selectively inhibit COX-2 might reduce the risk of gastrointestinal toxicity compared with other NSAIDs. Several such COX-2 selective drugs (collectively known as coxibs) were developed in the 1990s, and early trials comparing coxibs versus traditional NSAIDs (tNSAIDS) seemed to confi rm that coxibs at doses with similar analgesic effi cacy had less gastrointestinal toxicity. 2,3 Unfortunately, however, subsequent placebo-controlled trials also showed unequivocally that coxibs were associated with an increased risk of atherothrombotic vascular events. 4,5 Soon after these placebo-controlled trials were reported, a meta-analysis of randomised trials comparing a coxib versus placebo or a coxib versus tNSAID indicated that some tNSAIDs might also have adverse eff ects on atherothrombotic events, but that these hazards might depend on the degree and duration of suppression of platelet COX-1