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Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis

BMJ 2005; 330 doi: (Published 09 June 2005) Cite this as: BMJ 2005;330:1366
  1. Julia Hippisley-Cox (Julia.hippisley-cox{at}, professor of clinical epidemiology and general practice1,
  2. Carol Coupland, senior lecturer in medical statistics1
  1. 1 Institution 13th floor, Tower Building, University Park, Nottingham NG2 7RD
  1. Correspondence to: J Hippisley-Cox
  • Accepted 13 April 2005


Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.

Design Nested case-control study.

Setting 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.

Subjects 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.

Outcome measures Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.

Results A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.

Conclusion These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.


  • Contributors JHC initiated and designed the study, got ethical approval, did the data extraction and manipulation, did the analysis, and drafted the paper. CC contributed to the study design, supervised and checked the analysis, advised on interpretation, and contributed to drafting the paper. JHC and CC are both guarantors.

  • Funding This study was unfunded. QRESEARCH is a not for profit organisation that has received funding from the Department of Health, Health Protection Agency, National Audit Office, Disability Rights Commission, Medicines Partnership, Royal College of Physicians, and various universities for unrelated analyses and research. QRESARCH is entirely independent of the pharmaceutical industry.

  • Competing interests None declared.

  • Ethical approval Trent Multi-Centre Research Ethics Committee.

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