Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials.
Journal: 2006/June - British Medical Journal
ISSN: 1756-1833
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.
METHODS
Meta-analysis of published and unpublished tabular data from randomised trials, with indirect estimation of the effects of traditional NSAIDs.
METHODS
Medline and Embase (January 1966 to April 2005); Food and Drug Administration records; and data on file from Novartis, Pfizer, and Merck.
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.
Relations:
Content
Citations
(282)
References
(14)
Clinical trials
(1)
Diseases
(2)
Drugs
(9)
Chemicals
(2)
Organisms
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
BMJ 332(7553): 1302-1308

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

Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF
Department of Pharmacology, University of Rome “La Sapienza,” Rome, Italy
Correspondence to: C Baigent ku.ca.xo.ustc@tnegiab.niloc
Correspondence to: C Baigent ku.ca.xo.ustc@tnegiab.niloc
Accepted 2006 Apr 19.

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.

Abstract
Click here to view.

Notes

An external file that holds a picture, illustration, etc.
Object name is webplus.f2.gifA table, two extra figures, a statistical appendix, and extra references are on bmj.com

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.

Notes
An external file that holds a picture, illustration, etc.
Object name is webplus.f2.gifA table, two extra figures, a statistical appendix, and extra references are on bmj.com
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.

References

  • 1. FitzGerald GA, Patrono CThe coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345: 433-42. [[PubMed][Google Scholar]
  • 2. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et alComparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: 1520-8. [[PubMed][Google Scholar]
  • 3. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, et alComparison of lumiracoxib with naproxen and ibuprofen in the therapeutic arthritis research and gastrointestinal event trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364: 665-74. [[PubMed][Google Scholar]
  • 4. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et alCardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352: 1092-102. [[PubMed][Google Scholar]
  • 5. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et alCardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352: 1071-80. [[PubMed][Google Scholar]
  • 6. Patrono C, García Rodríguez LA, Landolfi R, Baigent CLow-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005;353: 2373-83. [[PubMed][Google Scholar]
  • 7. Robinson KA, Dickersin KDevelopment of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol 2002;31: 150-3. [[PubMed][Google Scholar]
  • 8. Antiplatelet Trialists' CollaborationCollaborative overview of randomised trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308: 81-106. [Google Scholar]
  • 9. Levin B. Celecoxib in adenoma prevention—the PreSAP trial. Slide presentation at: Meeting of the FDA Advisory Committee on COX-2 Inhibitors and NSAIDS, 16-18 February 2005, Gaithersburg, MD. Available at: (accessed 2 Dec 2005).[PubMed]
  • 10. Early Breast Cancer Trialists' Collaborative Group. Treatment of early breast cancer: worldwide evidence 1985-1990. Oxford: Oxford University Press, 1990.
  • 11. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, et alEfficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;125: 1481-92. [[PubMed][Google Scholar]
  • 12. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et alComplications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352: 1081-91. [[PubMed][Google Scholar]
  • 13. Furberg CD, Psaty BM, FitzGerald GAParecoxib, valdecoxib, and cardiovascular risk. Circulation 2005;111: 249. [[PubMed][Google Scholar]
  • 14. Baigent C, Patrono CSelective cyclooxygenase 2 inhibitors, aspirin, and cardiovascular disease: a reappraisal. Arthritis Rheum 2003;48: 12-20. [[PubMed][Google Scholar]
  • 15. Brochier MLEvaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction: the flurbiprofen French trial. Eur Heart J 1993;14: 951-7. [[PubMed][Google Scholar]
  • 16. Fornaro G, Rossi P, Mantica PG, Caccia ME, Aralda D, Lavezzari M, et alIndobufen in the prevention of thromboembolic complications in patients with heart disease: a randomized, placebo-controlled, double-blind study. Circulation 1993;87: 162-4. [[PubMed][Google Scholar]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.