Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials

Abstract

Objective: To assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events.

Design: Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.

Data sources: Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.

Review methods: Eligible studies were randomised trials that included a comparison of a selective COX 2 inhibitor versus placebo or a selective COX 2 inhibitor versus a traditional NSAID, of at least four weeks' duration, with information on serious vascular events (defined as myocardial infarction, stroke, or vascular death). Individual investigators and manufacturers provided information on the number of patients randomised, numbers of vascular events, and the person time of follow-up for each randomised group.

Results: In placebo comparisons, allocation to a selective COX 2 inhibitor was associated with a 42% relative increase in the incidence of serious vascular events (1.2%/year v 0.9%/year; rate ratio 1.42, 95% confidence interval 1.13 to 1.78; P = 0.003), with no significant heterogeneity among the different selective COX 2 inhibitors. This was chiefly attributable to an increased risk of myocardial infarction (0.6%/year v 0.3%/year; 1.86, 1.33 to 2.59; P = 0.0003), with little apparent difference in other vascular outcomes. Among trials of at least one year's duration (mean 2.7 years), the rate ratio for vascular events was 1.45 (1.12 to 1.89; P = 0.005). Overall, the incidence of serious vascular events was similar between a selective COX 2 inhibitor and any traditional NSAID (1.0%/year v 0.9%/year; 1.16, 0.97 to 1.38; P = 0.1). However, statistical heterogeneity (P = 0.001) was found between trials of a selective COX 2 inhibitor versus naproxen (1.57, 1.21 to 2.03) and of a selective COX 2 inhibitor versus non-naproxen NSAIDs (0.88, 0.69 to 1.12). The summary rate ratio for vascular events, compared with placebo, was 0.92 (0.67 to 1.26) for naproxen, 1.51 (0.96 to 2.37) for ibuprofen, and 1.63 (1.12 to 2.37) for diclofenac.

Conclusions: Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess.

Fig 1

Comparison of effects of different selective COX 2 inhibitors versus placebo on vascular events, myocardial infarction, stroke, and vascular death. Event numbers and person years of exposure, with corresponding mean annual event rates in parenthesis, are presented for patients allocated to selective COX 2 inhibitor and placebo. Event rate ratios for subtotals, with 95% confidence intervals, are indicated by a diamond; rate ratios for individual selective COX 2 inhibitors, with 99% confidence intervals, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX 2 inhibitor compared with placebo, but this is conventionally significant only if the diamond does not overlap the solid line

Fig 2

Comparison of effects of selective COX 2 inhibitors versus placebo among trials with scheduled duration of at least one year. Symbols and conventions are as in fig 1

Fig 3

Comparison of effects of selective COX 2 inhibitors versus traditional NSAIDs on vascular events, myocardial infarction, stroke, and vascular death. Symbols and conventions are as in fig 1. Some trials involved more than one NSAID comparator, so numbers of trials in subtotals are not a strict sum of numbers for each NSAID