BMJ  2006;332:1302-1308 (3 June), doi:10.1136/bmj.332.7553.1302

Research

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

¹ Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF, ² Department of Pharmacology, University of Rome "La Sapienza," Rome, Italy

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Design Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.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

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• Karsh, J. (2006). Les anti-inflammatoires peuvent-ils etre sans risque?. CMAJ 175: 451-451 [Full text]  
• (2006). Hit parade. BMJ 333: 308-308 [Full text]  
• (2006). Update on NSAIDs, COX-2 Inhibitors, and Cardiovascular Risk. JWatch General 2006: 3-3 [Full text]  
• Sanchez-Delgado, E. J (2006). Life without COX 2 inhibitors: Risks and benefits are determined by dose and potency.. BMJ 332: 1451-1452 [Full text]  
• Shaughnessy, A. F, Gordon, A. E (2006). Life without COX 2 inhibitors.. BMJ 332: 1287-1288 [Full text]  

Rapid Responses:

Read all Rapid Responses

'Risk-swapping' to manage therapeutic risk?

John Urquhart
bmj.com, 2 Jun 2006 [Full text]

Cyclooxygenase-2 (COX-2) inhibitors and timing of cardiovascular risks

Prasanta Padhan
bmj.com, 3 Jun 2006 [Full text]

NSAIDs and Cox-2. Dose and Potency

Enrique J. Sánchez-Delgado, MD, Professor
bmj.com, 5 Jun 2006 [Full text]

Reviews on Celecoxib

Iosief Abraha, et al.
bmj.com, 7 Jun 2006 [Full text]

Misleading conclusion on ibuprofen

Johannes C van der Wouden
bmj.com, 24 Aug 2006 [Full text]

Selective and non-selective NSAIDs: Balancing cardiovascular and gastrointestinal risks

Gurkirpal Singh, et al.
bmj.com, 17 Jan 2007 [Full text]

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