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

Abstract

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 (124,513 participants, 68,342 person-years) 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 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] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly 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 significantly 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 significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly 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 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 1·81, 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.

Figure 1

Effects of coxib therapy on major vascular events, heart failure, cause-specific mortality, and upper gastrointestinal complications Actual numbers for participants are presented, together with the corresponding mean yearly event rate (in parentheses). Participants can contribute only once to the total of major vascular events. Rate ratios (RRs) for all outcomes are indicated by squares and their 99% CIs by horizontal lines. Subtotals and their 95% CIs are represented by diamonds. Squares or diamonds to the left of the solid line indicate benefit. MI=myocardial infarction. CHD=coronary heart disease. Major vascular event=myocardial infarction, stroke, or vascular death. *Includes a further 25 vs 21 major vascular events in patients randomised into trials for which only tabular information was available.

Figure 2

Effects of diclofenac on major vascular events, heart failure, cause-specific mortality, and upper gastrointestinal complications (indirect comparisons) Rate ratios (RRs) are for comparisons of a tNSAID versus placebo, calculated indirectly from ratio of RRs for a coxib versus placebo and RRs for a coxib versus tNSAID, each of which is shown in the vertical columns (see statistical methods). MI=myocardial infarction. CHD=coronary heart disease.

Figure 3

Effects of ibuprofen on major vascular events, heart failure, cause-specific mortality, and upper gastrointestinal complications (indirect comparisons) MI=myocardial infarction. CHD=coronary heart disease. NE=not estimated.

Figure 4

Effects of naproxen on major vascular events, heart failure, cause-specific mortality, and upper gastrointestinal complications (indirect comparisons) MI=myocardial infarction. CHD=coronary heart disease.

Figure 5

Annual absolute effects per 1000 of coxibs and tNSAIDs at different baseline risks of major vascular events and upper gastrointestinal complications For each category of drug (coxib, diclofenac, ibuprofen, and naproxen), the predicted annual absolute risks of major vascular events (±1 SE) are shown (left) for patients with predicted risk of 2·0% or 0·5% per annum of a major vascular event. For comparison, predicted annual absolute risks of upper gastrointestinal complications (±1 SE) are shown for patients with predicted risks of 0·5% or 0·2% per annum (right). Absolute annual risks for placebo-allocated patients are assumed to be those of a hypothetical patient after all appropriate forms of prophylactic treatment (eg, antihypertensive therapy, statin therapy, proton-pump inhibitors) have been instituted.