This Article  • Full text  • PDF  • CME Course for This Article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (99)  • Contact me when this article is cited  Related Content  • Related letters  • Related articles  • Similar articles in JAMA  Topic Collections  • Evidence-Based Medicine  • Review  • Randomized Controlled Trial  • Cardiovascular Disease/ Myocardial Infarction  • Alert me on articles by topic

A Systematic Review of the Observational Studies of Selective and Nonselective Inhibitors of Cyclooxygenase 2

Patricia McGettigan, MD, FRACP; David Henry, MB, ChB, FRCP

JAMA. 2006;296:1633-1644. Published online September 12, 2006 (doi:10.1001/jama.296.13.jrv60011).

Context  Evidence that rofecoxib increases the risk of myocardial infarction has led to scrutiny of other nonsteroidal anti-inflammatory drugs (NSAIDs). Regulatory agencies have provided variable advice regarding the cardiovascular risks with older nonselective NSAIDs.

Objective  To undertake a systematic review and meta-analysis of controlled observational studies to compare the risks of serious cardiovascular events with individual NSAIDs and cyclooxygenase 2 inhibitors.

Data Sources  Searches were conducted of electronic databases (1985-2006), scientific meeting proceedings, epidemiological research Web sites, and bibliographies of eligible studies.

Study Selection  Eligible studies were of case-control or cohort design, reported on cardiovascular events (predominantly myocardial infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with nonuse/remote use of the drugs as the reference exposure. Of 7086 potentially eligible titles, 17 case-control and 6 cohort studies were included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23 on NSAIDs, and 13 on both groups of drugs.

Data Extraction  Two people independently extracted data and assessed study quality with disagreements resolved by consensus.

Data Synthesis  Data were combined using a random-effects model. A dose-related risk was evident with rofecoxib, summary relative risk with 25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19 (95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI, 0.91-1.23). Among older nonselective drugs, diclofenac had the highest risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI, 0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07 (95% CI, 0.97-1.18).

Conclusions  This review confirms the findings from randomized trials regarding the risk of cardiovascular events with rofecoxib and suggests that celecoxib in commonly used doses may not increase the risk, contradicts claims of a protective effect of naproxen, and raises serious questions about the safety of diclofenac, an older drug.

Author Affiliations: Discipline of Clinical Pharmacology, School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia, Dr McGettigan and Dr Henry.

RELATED LETTERS

Cyclooxygenase Inhibitors and Cardiovascular Risk
Frank Andersohn, Samy Suissa, and Edeltraut Garbe
JAMA. 2007;297(6):586-587.
EXTRACT | FULL TEXT  

Cyclooxygenase Inhibitors and Cardiovascular Risk—Reply
David Henry and Patricia McGettigan
JAMA. 2007;297(6):587-588.
EXTRACT | FULL TEXT  

RELATED ARTICLES

COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk: The Seduction of Common Sense
David J. Graham
JAMA. 2006;296(13):1653-1656.
EXTRACT | FULL TEXT  

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials
Jingjing Zhang, Eric L. Ding, and Yiqing Song
JAMA. 2006;296(13):1619-1632.
ABSTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Guidelines for the clinical management of familial adenomatous polyposis (FAP)
Vasen et al.
Gut 2008;57:704-713.
ABSTRACT | FULL TEXT  

Acceleration of Cardiovascular Disease by a Dysfunctional Prostacyclin Receptor Mutation: Potential Implications for Cyclooxygenase-2 Inhibition
Arehart et al.
Circ. Res. 2008;102:986-993.
ABSTRACT | FULL TEXT  

Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis
Solomon et al.
Circulation 2008;117:2104-2113.
ABSTRACT | FULL TEXT  

Cyclooxygenase-2 Inhibitors and Most Traditional Nonsteroidal Anti-inflammatory Drugs Cause Similar Moderately Increased Risks of Cardiovascular Disease
Hennekens and Borzak
J CARDIOVASC PHARMACOL THER 2008;13:41-50.
ABSTRACT  

Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists
Sidiropoulos et al.
Rheumatology (Oxford) 2008;47:355-361.
ABSTRACT | FULL TEXT  

Comparison of two different dosages of celecoxib with diclofenac for the treatment of active ankylosing spondylitis: results of a 12-week randomised, double-blind, controlled study
Sieper et al.
Ann Rheum Dis 2008;67:323-329.
ABSTRACT | FULL TEXT  

2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction
American College of Cardiology/American Heart Asso et al.
J Am Coll Cardiol 2008;51:210-247.
FULL TEXT  

2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in Collaboration With the Canadian Cardiovascular Society Endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee
Antman et al.
Circulation 2008;117:296-329.
FULL TEXT  

Cardiovascular Thromboembolic Adverse Effects Associated with Cyclooxygenase-2 Selective Inhibitors and Nonselective Antiinflammatory Drugs
Joshi et al.
Anesth. Analg. 2007;105:1793-1804.
ABSTRACT | FULL TEXT  

EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases
Hoes et al.
Ann Rheum Dis 2007;66:1560-1567.
ABSTRACT | FULL TEXT  

Emerging Paradigms, Platforms, and Unifying Themes in Biomarker Science
Becker
J Am Coll Cardiol 2007;50:1777-1780.
FULL TEXT  

Non-steroidal anti-inflammatory drugs and myocardial infarctions: comparative systematic review of evidence from observational studies and randomised controlled trials
Scott et al.
Ann Rheum Dis 2007;66:1296-1304.
ABSTRACT | FULL TEXT  

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine
Anderson et al.
J Am Coll Cardiol 2007;50:e1-e157.
FULL TEXT  

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine
Anderson et al.
J Am Coll Cardiol 2007;50:652-726.
FULL TEXT  

Microsomal Prostaglandin E2 Synthase: A Safer Target than Cyclooxygenases?
Timmers et al.
Mol. Interv. 2007;7:195-199.
ABSTRACT | FULL TEXT  

Human Pharmacology of Naproxen Sodium
Capone et al.
J. Pharmacol. Exp. Ther. 2007;322:453-460.
ABSTRACT | FULL TEXT  

Rofecoxib and Cardiovascular Adverse Events in Adjuvant Treatment of Colorectal Cancer
Kerr et al.
NEJM 2007;357:360-369.
ABSTRACT | FULL TEXT  

Nonselective Nonsteroidal Antiinflammatory Drugs and Cardiovascular Risk: Are They Safe?
Waksman et al.
The Annals of Pharmacotherapy 2007;41:1163-1173.
ABSTRACT | FULL TEXT  

Meta-analysis: Acupuncture for Osteoarthritis of the Knee
Manheimer et al.
ANN INTERN MED 2007;146:868-877.
ABSTRACT | FULL TEXT  

Association of Aspirin and Nonaspirin Nonsteroidal Anti-inflammatory Drugs With Cancer Incidence and Mortality
Bardia et al.
JNCI J Natl Cancer Inst 2007;99:881-889.
ABSTRACT | FULL TEXT  

The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame
Salinas et al.
J CARDIOVASC PHARMACOL THER 2007;12:98-111.
ABSTRACT  

Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability?
Brune and Furst
Rheumatology (Oxford) 2007;46:911-919.
ABSTRACT | FULL TEXT  

Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association
Antman et al.
Circulation 2007;115:1634-1642.
FULL TEXT  

Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study
Rahme and Nedjar
Rheumatology (Oxford) 2007;46:435-438.
ABSTRACT | FULL TEXT  

Cardiovascular Effects of the Cyclooxygenase Inhibitors
White
Hypertension 2007;49:408-418.
FULL TEXT  

Cyclooxygenase Inhibitors and Cardiovascular Risk
Andersohn et al.
JAMA 2007;297:586-587.
FULL TEXT  

The Adenoma Prevention with Celecoxib and Prevention of Colorectal Sporadic Adenomatous Polyps Trials: Stepping Stones to Progress
Hawk and Viner
Cancer Epidemiol. Biomarkers Prev. 2007;16:185-187.
FULL TEXT  

ADDITIONAL ARTICLES ABSTRACTED IN ACP JOURNAL CLUB
Evid. Based Med. 2007;12:30-30.
FULL TEXT  

Pain Management in Elderly Patients
Hix
Journal of Pharmacy Practice 2007;20:49-63.
ABSTRACT  

NSAID Trials and the Choice of Comparators -- Questions of Public Health Importance
Psaty and Weiss
NEJM 2007;356:328-330.
FULL TEXT  

COX-2 Inhibitors and NSAIDs: More Data on CV Risk
Journal Watch Cardiology 2006;2006:2-2.
FULL TEXT  

COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk: The Seduction of Common Sense
Graham
JAMA 2006;296:1653-1656.
FULL TEXT