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

BMJ 2006; 332 doi: (Published 01 June 2006) Cite this as: BMJ 2006;332:1302
  1. Patricia M Kearney, clinical research fellow1,
  2. Colin Baigent (colin.baigent{at}, reader in clinical epidemiology1,
  3. Jon Godwin, research fellow1,
  4. Heather Halls, research assistant1,
  5. Jonathan R Emberson, senior statistician1,
  6. Carlo Patrono, professor of pharmacology2
  1. 1 Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF,
  2. 2 Department of Pharmacology, University of Rome “La Sapienza,” Rome, Italy
  1. Correspondence to: C Baigent
  • Accepted 19 April 2006


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Design Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.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


  • Embedded Image A table, two extra figures, a statistical appendix, and extra references are on

  • We acknowledge the help of Novartis (Patrice Matchaba, Xavier Gitton, Elena Ehrsam, Melvin Olson, Bernd Mellein, and Godehard Hoexter), Merck (Sean P Curtis and Judith Boice), and Pfizer (Simon Lowry, George Sands, Rebecca Rosenstein, and Sharon Pan). We thank P S Aisen (Georgetown University), T Higuchi and K Sugihara (Tokyo Medical and Dental University), S Razzi (University of Siena), F K L Chan (Chinese University of Hong Kong), R K S Dionne (National Institutes of Health), G L Bakris (Rush Medical Centre), R S Philipson (GlaxoSmithKline), R K Phillips (St Mark's Hospital) and the APC investigators for providing data from their trials.

  • Contributors: PMK, CB, and CP contributed to the idea for and design of the study, analysis and interpretation of data, and drafting and critical revision of the report. HH contributed to the assembly of the data and drafting and critical revision of the report. JG and JRE contributed to the analysis of the data. CB is the guarantor.

  • Funding The Clinical Trial Service Unit is supported by a core grant from the UK Medical Research Council, by the British Heart Foundation, and by Cancer Research UK. CB is supported by the UK MRC. CP is supported by grants from the Italian Ministry of University and Research to the Center of Excellence on Aging of the “G d'Annunzio” University Foundation and from the Commission of the European Communities (EICOSANOX Project 005033). The authors retained full editorial control of the content of this paper.

  • Competing interests The Clinical Trial Service Unit has a staff policy of not accepting honorariums or other payments from the drug industry, except for the reimbursement of costs to participate in scientific or advisory committee meetings. CB has had such costs reimbursed for attending meetings arranged by Bayer, Merck, Novartis, GlaxoSmithKline, and Astra-Zeneca. He is the lead investigator of the study of heart and renal protection, a study of cholesterol lowering in chronic kidney disease, which is sponsored by the University of Oxford and supported by an unrestricted grant from Merck. CP has received grant support from Bayer, Merck, and Pfizer. In addition, he has received honorariums for lecturing and consulting from Bayer and NiCox. PMK, JG, HH, and JRE have no competing interests. No funding was provided by any drug company for this project. None of the authors has any stockholdings in pharmaceutical companies, and none is involved in advising any organisation or individual on issues related to litigation.

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