COX-2 selective inhibitors: Adverse cardiovascular effects
- Daniel H Solomon, MD, MPH
Daniel H Solomon, MD, MPH
- Matthew H. Liang Distinguished Chair in Arthritis and Population Health
- Professor of Medicine
- Harvard Medical School
- Section Editors
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Clinical professor, University of Washington, Seattle
- Clinical professor, University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific Arthritis Associates
- Christopher P Cannon, MD
Christopher P Cannon, MD
- Section Editor — Coronary Heart Disease
- Professor of Medicine
- Harvard Medical School
- Deputy Editors
- Paul L Romain, MD
Paul L Romain, MD
- Deputy Editor — Rheumatology
- Assistant Professor of Medicine, Part-time
- Harvard Medical School
- Gordon M Saperia, MD, FACC
Gordon M Saperia, MD, FACC
- Senior Deputy Editor — UpToDate
- Deputy Editor — Cardiovascular Medicine
- Assistant Professor of Medicine
- Tufts University School of Medicine
The use of all nonsteroidal antiinflammatory drugs (NSAIDs), selective and nonselective, is associated with a range of potential adverse effects, including an increased risk of adverse cardiovascular effects. The risk of different events varies depending upon the clinical context, medication, and dose. Both cyclooxygenase (COX)-2 selective NSAIDs (coxibs) and nonselective NSAIDs may increase such risk.
The cardiovascular effects of coxibs and their implications for clinical use will be reviewed here. The cardiovascular effects of nonselective NSAIDs and overviews of the adverse effects of NSAID therapy are presented separately. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and "Overview of selective COX-2 inhibitors", section on 'Toxicities and possible toxicities' and "Nonselective NSAIDs: Overview of adverse effects".)
Several factors appear to be related to the cardiovascular risks associated with coxibs and nonselective nonsteroidal antiinflammatory drugs (NSAIDs), including the degree of cyclooxygenase (COX)-2 selectivity . Selective COX-2 inhibition is associated with reduced prostaglandin I2 (PGI2 or prostacyclin) production by vascular endothelium with little or no inhibition of potentially prothrombotic platelet thromboxane A2 production . The relatively selective reduction in prostacyclin activity could predispose to endothelial injury .
However, some analyses have failed to show a clear relationship of increased cardiovascular risk with COX-2 selectivity, and other factors may be important, including effects on blood pressure, renal function, endothelial cells, and nitric oxide production .
The use of cyclooxygenase (COX)-2 selective nonsteroidal antiinflammatory drugs (NSAIDs) (coxibs) and most nonselective NSAIDs is associated with a very small increased risk of adverse cardiovascular events [4-14]. Coxibs, like nonselective NSAIDs, should be avoided whenever possible in patients at an elevated risk of cardiovascular disease (CVD) and in patients with established CVD, based upon the evidence that these drugs increase the risk of ischemic CVD, heart failure (HF), increased blood pressure, and cardiac arrhythmia. The absolute risk of ischemic cardiovascular events, such as myocardial infarction (MI), is low, but risk increases with higher doses, frequency of use, and established CVD [4,7,11,12,15,16]. A reasonable approach would be to first try acetaminophen or another non-NSAID analgesic; if needed, naproxen with gastrointestinal protection could be used next. Beyond that, there are insufficient data to recommend one agent over another; however, they should always be used at the lowest effective dose. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and 'Ischemic cardiovascular disease' below and 'Heart failure and peripheral edema' below and 'Hypertension' below and 'Cardiac arrhythmia' below.)
- Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007; 115:1634.
- Caughey GE, Cleland LG, Penglis PS, et al. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167:2831.
- Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296:539.
- Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.
- Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365:475.
- Haag MD, Bos MJ, Hofman A, et al. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke. Arch Intern Med 2008; 168:1219.
- McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296:1633.
- Hippisley-Cox J, Coupland C. 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; 330:1366.
- Johnsen SP, Larsson H, Tarone RE, et al. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med 2005; 165:978.
- Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J 2006; 27:1657.
- Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006; 113:1578.
- Kearney PM, Baigent C, Godwin J, et al. 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; 332:1302.
- Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ 2011; 343:d3450.
- Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382:769.
- Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation 2006; 113:1950.
- Jüni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021.
- Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 2011; 123:2226.
- Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355:873.
- Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355:885.
- Solomon SD, Pfeffer MA, McMurray JJ, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 2006; 114:1028.
- Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 2008; 117:2104.
- Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247.
- White WB, Faich G, Borer JS, Makuch RW. Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003; 92:411.
- Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 2006; 119:255.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375:2519.
- Lévesque LE, Brophy JM, Zhang B. Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. CMAJ 2006; 174:1563.
- Kimmel SE, Berlin JA, Reilly M, et al. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 2005; 142:157.
- Andersohn F, Schade R, Suissa S, Garbe E. Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and the risk of ischemic stroke: a nested case-control study. Stroke 2006; 37:1725.
- Roumie CL, Mitchel EF Jr, Kaltenbach L, et al. Nonaspirin NSAIDs, cyclooxygenase 2 inhibitors, and the risk for stroke. Stroke 2008; 39:2037.
- FitzGerald GA. Imprecision: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation 2017; 135:113.
- Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006; 368:1771.
- Ott E, Nussmeier NA, Duke PC, et al. Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003; 125:1481.
- Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352:1081.
- White WB, Strand V, Roberts R, Whelton A. Effects of the cyclooxygenase-2 specific inhibitor valdecoxib versus nonsteroidal antiinflammatory agents and placebo on cardiovascular thrombotic events in patients with arthritis. Am J Ther 2004; 11:244.
- Farkouh ME, Kirshner H, Harrington RA, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004; 364:675.
- Merck news release. www.merck.com/newsroom/press_releases/product/2004_0930.html (Accessed on September 30, 2004).
- Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092.
- Kerr DJ, Dunn JA, Langman MJ, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007; 357:360.
- Ray WA, Stein CM, Daugherty JR, et al. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360:1071.
- Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109:2068.
- Baron JA, Sandler RS, Bresalier RS, et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial. Lancet 2008; 372:1756.
- Ross JS, Madigan D, Konstam MA, et al. Persistence of cardiovascular risk after rofecoxib discontinuation. Arch Intern Med 2010; 170:2035.
- Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363:1751.
- Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009; 169:141.
- Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005; 330:1370.
- Arfè A, Scotti L, Varas-Lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 2016; 354:i4857.
- Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992; 20:1549.
- Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998; 158:1108.
- Whelton A, Fort JG, Puma JA, et al. Cyclooxygenase-2--specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001; 8:85.
- Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520.
- Alsalameh S, Burian M, Mahr G, et al. Review article: The pharmacological properties and clinical use of valdecoxib, a new cyclo-oxygenase-2-selective inhibitor. Aliment Pharmacol Ther 2003; 17:489.
- Curtis SP, Ng J, Yu Q, et al. Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in controlled clinical trials. Clin Ther 2004; 26:70.
- Wolfe F, Zhao S, Pettitt D. Blood pressure destabilization and edema among 8538 users of celecoxib, rofecoxib, and nonselective nonsteroidal antiinflammatory drugs (NSAID) and nonusers of NSAID receiving ordinary clinical care. J Rheumatol 2004; 31:1143.
- Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 2006; 296:1619.
- De Caterina R, Ruigómez A, Rodríguez LA. Long-term use of anti-inflammatory drugs and risk of atrial fibrillation. Arch Intern Med 2010; 170:1450.
- Renda G, Tacconelli S, Capone ML, et al. Celecoxib, ibuprofen, and the antiplatelet effect of aspirin in patients with osteoarthritis and ischemic heart disease. Clin Pharmacol Ther 2006; 80:264.
- Wilner KD, Rushing M, Walden C, et al. Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers. J Clin Pharmacol 2002; 42:1027.
- Gladding PA, Webster MW, Farrell HB, et al. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. Am J Cardiol 2008; 101:1060.
- Dallob A, Hawkey CJ, Greenberg H, et al. Characterization of etoricoxib, a novel, selective COX-2 inhibitor. J Clin Pharmacol 2003; 43:573.
- Jermany J, Branson J, Schmouder R, et al. Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low-dose aspirin in healthy subjects. J Clin Pharmacol 2005; 45:1172.
- Ouellet M, Riendeau D, Percival MD. A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin. Proc Natl Acad Sci U S A 2001; 98:14583.
- Greenberg HE, Gottesdiener K, Huntington M, et al. A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers. J Clin Pharmacol 2000; 40:1509.
- Rimon G, Sidhu RS, Lauver DA, et al. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci U S A 2010; 107:28.
- Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA 2015; 313:805.
- MEDICATIONS IN CLINICAL USE
- ISCHEMIC CARDIOVASCULAR DISEASE
- Valdecoxib and parecoxib
- HEART FAILURE AND PERIPHERAL EDEMA
- Risk of developing heart failure
- Patients with heart failure
- Peripheral edema
- CARDIAC ARRHYTHMIA
- USE IN PATIENTS ON ASPIRIN, OTHER ANTIPLATELET AGENTS, AND ANTICOAGULANTS
- RECOMMENDATIONS BY MAJOR GROUPS
- SUMMARY AND RECOMMENDATIONS