This Article  • Full text  • PDF  • 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 (789)  • Contact me when this article is cited  Related Content  • Related letter  • Related article  • Similar articles in JAMA  Topic Collections  • Quality of Care  • Evidence-Based Medicine  • Drug Therapy  • Adverse Effects  • Alert me on articles by topic  Social Bookmarking   What's this?

Debabrata Mukherjee, MD; Steven E. Nissen, MD; Eric J. Topol, MD

JAMA. 2001;286:954-959.

Atherosclerosis is a process with inflammatory features and selective cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects by virtue of inhibiting inflammation. However, by decreasing vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists may lead to increased prothrombotic activity. To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, we performed a MEDLINE search to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. We also reviewed relevant submissions to the US Food and Drug Administration by pharmaceutical companies.

Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials with approximately 1000 patients each. The results from VIGOR showed that the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23 407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (P = .04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).

The available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. Further prospective trial evaluation may characterize and determine the magnitude of the risk.

Author Affiliations: Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

RELATED LETTER

Cardiovascular Events and COX-2 Inhibitors
Thomas G. Burnakis, Michael Fleming, Marvin A. Konstam, Laura A. Demopoulos, Kenneth D. Grant, E. Joseph Haldey, Marco Pappagallo, Milos Minic, Patrick L. McGeer, Edith G. McGeer, Koji Yasojima, Gurkirpal Singh, William B. White, Andrew Whelton, Debabrata Mukherjee, Steven E. Nissen, Eric J. Topol, Kenneth Sperber, and Louis M. Sherwood
JAMA. 2001;286(22):2808-2813.
EXTRACT | FULL TEXT  

RELATED ARTICLE

August 22/29, 2001
JAMA. 2001;286(8):977-978.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism
Ohashi et al.
Mol. Cell. Biol. 2009;29:3487-3499.
ABSTRACT | FULL TEXT  

Selective cyclooxygenase-2 (COX-2) inhibition reduces proteinuria in renal patients
Vogt et al.
Nephrol Dial Transplant 2009;24:1182-1189.
ABSTRACT | FULL TEXT  

Novel Dithiolethione-Modified Nonsteroidal Anti-Inflammatory Drugs in Human Hepatoma HepG2 and Colon LS180 Cells
Bass et al.
Clin. Cancer Res. 2009;15:1964-1972.
ABSTRACT | FULL TEXT  

The Role of Aspirin in Cardiovascular Disease Prevention in Women
Hopkins and Limacher
AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2009;3:123-134.
ABSTRACT  

Osteoarthritis: An Update on Data Currently Reshaping Practice
Epstein and Taylor
Journal of Pharmacy Practice 2009;22:75-85.
ABSTRACT  

Endothelial Dysfunction in Mice with Streptozotocin-induced Type 1 Diabetes Is Opposed by Compensatory Overexpression of Cyclooxygenase-2 in the Vasculature
Nacci et al.
Endocrinology 2009;150:849-861.
ABSTRACT | FULL TEXT  

The Use and Abuse of Painkillers in International Soccer: Data From 6 FIFA Tournaments for Female and Youth Players
Tscholl et al.
Am J Sports Med 2009;37:260-265.
ABSTRACT | FULL TEXT  

Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes
Kellogg et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;296:H453-H461.
ABSTRACT | FULL TEXT  

Increased Mortality and Cardiovascular Morbidity Associated With Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure
Gislason et al.
Arch Intern Med 2009;169:141-149.
ABSTRACT | FULL TEXT  

The Cardiovascular Research Network: A New Paradigm for Cardiovascular Quality and Outcomes Research
Go et al.
Circ Cardiovasc Qual Outcomes 2008;1:138-147.
ABSTRACT | FULL TEXT  

Nonsteroidal Anti-Inflammatory Drugs Induced Endothelial Apoptosis by Perturbing Peroxisome Proliferator-Activated Receptor-{delta} Transcriptional Pathway
Liou et al.
Mol. Pharmacol. 2008;74:1399-1406.
ABSTRACT | FULL TEXT  

Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk
Eikelboom et al.
Circulation 2008;118:1705-1712.
ABSTRACT | FULL TEXT  

Cyclooxygenase 2-Selective and Nonselective Nonsteroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Up-Regulating Vascular NADPH Oxidases
Li et al.
J. Pharmacol. Exp. Ther. 2008;326:745-753.
ABSTRACT | FULL TEXT  

Recent developments in the perioperative management of adult patients with chronic kidney disease
Craig and Hunter
Br J Anaesth 2008;101:296-310.
ABSTRACT | FULL TEXT  

Hypertension in rheumatoid arthritis
Panoulas et al.
Rheumatology (Oxford) 2008;47:1286-1298.
ABSTRACT | FULL TEXT  

Cyclooxygenase-2 Inhibitors in Colorectal Cancer Prevention: Counterpoint
Jankowski and Hunt
Cancer Epidemiol. Biomarkers Prev. 2008;17:1858-1861.
ABSTRACT | FULL TEXT  

Cyclooxygenase Selectivity of Nonsteroidal Anti-inflammatory Drugs and Risk of Stroke
Haag et al.
Arch Intern Med 2008;168:1219-1224.
ABSTRACT | FULL TEXT  

Clinical Prevention of Recurrence of Colorectal Adenomas by the Combination of Difluoromethylornithine and Sulindac: An Important Milestone
Sporn and Hong
Cancer Prevention Research 2008;1:9-11.
FULL TEXT  

Prevention of Heart Failure: A Scientific Statement From the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group
Schocken et al.
Circulation 2008;117:2544-2565.
ABSTRACT | FULL TEXT  

The FDA Process for the Evaluation and Approval of Orthopaedic Devices
Kirkpatrick and Stevens
J Am Acad Orthop Surg 2008;16:260-267.
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  

Reporting Mortality Findings in Trials of Rofecoxib for Alzheimer Disease or Cognitive Impairment: A Case Study Based on Documents From Rofecoxib Litigation
Psaty and Kronmal
JAMA 2008;299:1813-1817.
ABSTRACT | FULL TEXT  

Newly Approved Does Not Always Mean New and Improved
Anderson et al.
JAMA 2008;299:1598-1600.
FULL TEXT  

Microsomal Prostaglandin E2 Synthase-1 Deletion Leads to Adverse Left Ventricular Remodeling After Myocardial Infarction
Degousee et al.
Circulation 2008;117:1701-1710.
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  

Defining and utilizing surrogates in the evaluation of coronary stents: what do we really want and need to know?
Harrington et al.
J Am Coll Cardiol 2008;51:33-36.
FULL TEXT  

Stretch Induction of Cyclooxygenase-2 Expression in Human Urothelial Cells Is Calcium- and Protein Kinase C {zeta}-Dependent
Jerde et al.
Mol. Pharmacol. 2008;73:18-26.
ABSTRACT | FULL TEXT  

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis
Hong et al.
Am. J. Physiol. Heart Circ. Physiol. 2008;294:H145-H155.
ABSTRACT | 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  

Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes
Kellogg et al.
Diabetes 2007;56:2997-3005.
ABSTRACT | FULL TEXT  

Effect of (S)-4-(1-(5-Chloro-2-(4-fluorophenyoxy)benzamido)ethyl) Benzoic Acid (CJ-42794), a Selective Antagonist of Prostaglandin E Receptor Subtype 4, on Ulcerogenic and Healing Responses in Rat Gastrointestinal Mucosa
Takeuchi et al.
J. Pharmacol. Exp. Ther. 2007;322:903-912.
ABSTRACT | FULL TEXT  

Importance and Challenges of Studying Marketed Drugs: What Is a Phase IV Study? Common Clinical Research Designs, Registries, and Self-Reporting Systems
Glasser et al.
J Clin Pharmacol 2007;47:1074-1086.
ABSTRACT | FULL TEXT  

Celecoxib dilates guinea-pig coronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5 inhibition
Klein et al.
Cardiovasc Res 2007;75:390-397.
ABSTRACT | FULL TEXT  

Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage
Davis et al.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007;292:R2168-R2173.
ABSTRACT | FULL TEXT  

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores
Julius et al.
Proc. Natl. Acad. Sci. USA 2007;104:4808-4813.
ABSTRACT | FULL TEXT  

Angiotensin-(1-7) Inhibits Growth of Human Lung Adenocarcinoma Xenografts in Nude Mice through a Reduction in Cyclooxygenase-2
Menon et al.
Cancer Res. 2007;67:2809-2815.
ABSTRACT | FULL TEXT  

Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force
Rostom et al.
ANN INTERN MED 2007;146:376-389.
ABSTRACT | FULL TEXT  

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

Early termination of drug trials
Jensen and Hampton
BMJ 2007;334:326-326.
FULL TEXT  

Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation
Levick et al.
J. Immunol. 2007;178:641-646.
ABSTRACT | FULL TEXT  

Coxibs and Heart Disease: What We Have Learned and What Else We Need to Know
Zarraga and Schwarz
J Am Coll Cardiol 2007;49:1-14.
ABSTRACT | FULL TEXT  

Licofelone, a Balanced Inhibitor of Cyclooxygenase and 5-Lipoxygenase, Reduces Inflammation in a Rabbit Model of Atherosclerosis
Vidal et al.
J. Pharmacol. Exp. Ther. 2007;320:108-116.
ABSTRACT | FULL TEXT  

Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors
Anning et al.
Blood 2006;108:4059-4062.
ABSTRACT | FULL TEXT  

Role of cyclooxygenase-2 induction by transcription factor Sp1 and Sp3 in neuronal oxidative and DNA damage response
Lee et al.
FASEB J. 2006;20:2375-2377.
ABSTRACT | FULL TEXT  

Did Targeted Therapy Fail Cyclooxygenase Too?
Csiki and Johnson
JCO 2006;24:4798-4800.
FULL TEXT  

The FDA and drug safety: a proposal for sweeping changes.
Furberg et al.
Arch Intern Med 2006;166:1938-1942.
ABSTRACT | FULL TEXT  

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

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials
Zhang et al.
JAMA 2006;296:1619-1632.
ABSTRACT | FULL TEXT  

Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs.
Chaiamnuay et al.
Am J Health Syst Pharm 2006;63:1837-1851.
ABSTRACT | FULL TEXT  

How Direct-To-Consumer Television Advertising For Osteoarthritis Drugs Affects Physicians' Prescribing Behavior
Bradford et al.
Health Aff (Millwood) 2006;25:1371-1377.
ABSTRACT | FULL TEXT  

Lapses at the new England journal of medicine.
Smith
JRSM 2006;99:380-382.
FULL TEXT  

Effect of Enteric Coating on Antiplatelet Activity of Low-Dose Aspirin in Healthy Volunteers
Cox et al.
Stroke 2006;37:2153-2158.
ABSTRACT | FULL TEXT  

Differentiation of Cyclooxygenase 1- and 2-Derived Prostanoids in Mouse Kidney and Aorta
Qi et al.
Hypertension 2006;48:323-328.
ABSTRACT | FULL TEXT  

NSAIDS and the risk of myocardial infarction: do they help or harm?
Bhatt
Eur Heart J 2006;27:1635-1636.
FULL TEXT  

Risk of Death or Reinfarction Associated With the Use of Selective Cyclooxygenase-2 Inhibitors and Nonselective Nonsteroidal Antiinflammatory Drugs After Acute Myocardial Infarction
Gislason et al.
Circulation 2006;113:2906-2913.
ABSTRACT | FULL TEXT  

Evaluation of Urothelial Stretch-Induced Cyclooxygenase-2 Expression in Novel Human Cell Culture and Porcine in Vivo Ureteral Obstruction Models
Jerde et al.
J. Pharmacol. Exp. Ther. 2006;317:965-972.
ABSTRACT | FULL TEXT  

Coxibs Versus Combination NSAID and PPI Therapy for Chronic Pain: An Exploration of the Risks, Benefits, and Costs
Hur et al.
The Annals of Pharmacotherapy 2006;40:1052-1063.
ABSTRACT | FULL TEXT  

Adventures in vascular biology: a tale of two mediators
Moncada
Phil Trans R Soc B 2006;361:735-759.
ABSTRACT | FULL TEXT  

Balancing the cyclooxygenase portfolio.
Armstrong
CMAJ 2006;174:1581-1582.
FULL TEXT  

Clinical Trials in the Wake of Vioxx: Requiring Statistically Extreme Evidence of Benefit to Ensure the Safety of New Drugs
Roth-Cline
Circulation 2006;113:2253-2259.
FULL TEXT  

Understanding the NSAID related risk of vascular events.
Vonkeman et al.
BMJ 2006;332:895-898.
FULL TEXT  

The use of COX-2 inhibitors for acute dental pain: A second look
Huber and Terezhalmy
Journal of the American Dental Association 2006;137:480-487.
ABSTRACT | FULL TEXT  

Aspirin and Clopidogrel Resistance
Michos et al.
Mayo Clin Proc. 2006;81:518-526.
ABSTRACT | FULL TEXT  

Bias in Clinical Intervention Research
Gluud
Am J Epidemiol 2006;163:493-501.
ABSTRACT | FULL TEXT  

A Novel Prostaglandin E Receptor 4-Associated Protein Participates in Antiinflammatory Signaling
Takayama et al.
Circ. Res. 2006;98:499-504.
ABSTRACT | FULL TEXT  

Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis.
Caldwell et al.
JRSM 2006;99:132-140.
ABSTRACT | FULL TEXT  

Can Natriuretic Peptide Levels Predict the Cardiovascular Complications of COX-2 Inhibitors and Nonsteroidal Anti-inflammatory Drugs?
Blankfield
J Am Board Fam Med 2006;19:178-182.
ABSTRACT | FULL TEXT  

Update on Cyclooxygenase-2 Inhibitors
Harris and Breyer
CJASN 2006;1:236-245.
ABSTRACT | FULL TEXT  

Targeting Prostaglandin E2 Receptors as an Alternative Strategy to Block Cyclooxygenase-2-dependent Extracellular Matrix-induced Matrix Metalloproteinase-9 Expression by Macrophages
Pavlovic et al.
J. Biol. Chem. 2006;281:3321-3328.
ABSTRACT | FULL TEXT  

PROSTAGLANDINS AND CANCER
Wang and DuBois
Gut 2006;55:115-122.
FULL TEXT  

Cyclooxygenase-2 induction by bradykinin in aortic vascular smooth muscle cells
Rodriguez et al.
Am. J. Physiol. Heart Circ. Physiol. 2006;290:H30-H36.
ABSTRACT | FULL TEXT  

Cutting Edge: Yin-Yang: Balancing Act of Prostaglandins with Opposing Functions to Regulate Inflammation
Mandal et al.
J. Immunol. 2005;175:6271-6273.
ABSTRACT | FULL TEXT  

Stabilization of Hypoxia-inducible Factor-1{alpha} by Prostacyclin under Prolonged Hypoxia via Reducing Reactive Oxygen Species Level in Endothelial Cells
Chang et al.
J. Biol. Chem. 2005;280:36567-36574.
ABSTRACT | FULL TEXT  

Antipsychotic Drugs in Dementia: What Should Be Made of the Risks?
Rabins and Lyketsos
JAMA 2005;294:1963-1965.
FULL TEXT  

Index Case of Familial Adenomatous Polyposis Revealed by Congenital Hypertrophy of the Retinal Pigment Epithelium
Holmes et al.
ANN INTERN MED 2005;143:618-619.
FULL TEXT  

A Blocking Antibody to Nerve Growth Factor Attenuates Skeletal Pain Induced by Prostate Tumor Cells Growing in Bone
Halvorson et al.
Cancer Res. 2005;65:9426-9435.
ABSTRACT | FULL TEXT  

Coxibs and cardiovascular risk
Zaidi
CMAJ 2005;173:852-853.
FULL TEXT  

Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs
Fosslien
Annals of Clinical & Laboratory Science 2005;35:347-385.
ABSTRACT | FULL TEXT  

Clinical implications of cyclo-oxygenase-2 inhibitors for acute dental pain management: Benefits and risks
SPINK et al.
Journal of the American Dental Association 2005;136:1439-1448.
ABSTRACT | FULL TEXT  

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine
Pratico and Dogne
Circulation 2005;112:1073-1079.
FULL TEXT  

Cyclooxygenase Inhibition and Cardiovascular Risk
Antman et al.
Circulation 2005;112:759-770.
FULL TEXT  

Chemical-Induced Atrial Thrombosis in NTP Rodent Studies
Yoshizawa et al.
Toxicol Pathol 2005;33:517-532.
ABSTRACT | FULL TEXT  

Relative Thromboembolic Risks Associated with COX-2 Inhibitors
Jones
The Annals of Pharmacotherapy 2005;39:1249-1259.
ABSTRACT | FULL TEXT  

Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study
Hudson et al.
BMJ 2005;330:1370.
ABSTRACT | FULL TEXT  

CD40 Ligand: Not Bad to the Bone (Marrow), After All
Ajijola et al.
Arterioscler. Thromb. Vasc. Bio. 2005;25:1088-1090.
FULL TEXT  

Celecoxib-induced deep-vein thrombosis
Chan
The Annals of Pharmacotherapy 2005;39:1138-1138.
FULL TEXT  

Cyclooxygenase-2 Inhibitors Attenuate Angiotensin II-Induced Oxidative Stress, Hypertension, and Cardiac Hypertrophy in Rats
Wu et al.
Hypertension 2005;45:1139-1144.
ABSTRACT | FULL TEXT  

Risk of Hospitalization for Myocardial Infarction Among Users of Rofecoxib, Celecoxib, and Other NSAIDs: A Population-Based Case-Control Study
Johnsen et al.
Arch Intern Med 2005;165:978-984.
ABSTRACT | FULL TEXT  

A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non-Small Cell Lung Cancer
Liao et al.
Clin. Cancer Res. 2005;11:3342-3348.
ABSTRACT | FULL TEXT  

Blood Pressure in Native Americans Switched from Celecoxib to Rofecoxib
Fredy et al.
The Annals of Pharmacotherapy 2005;39:797-802.
ABSTRACT | FULL TEXT  

Inflammatory markers and cardiovascular health in older adults
Kritchevsky et al.
Cardiovasc Res 2005;66:265-275.
ABSTRACT | FULL TEXT  

COX-2: A Molecular Target for Colorectal Cancer Prevention
Brown and DuBois
JCO 2005;23:2840-2855.
ABSTRACT | FULL TEXT  

Acetaminophen and Myocardial Stunning after Transient Ischemia in Rabbit Hearts
Hale and Kloner
J CARDIOVASC PHARMACOL THER 2005;10:121-129.
ABSTRACT