Nonselective NSAIDs: 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 nonsteroidal antiinflammatory drugs (NSAIDs) 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 nonselective NSAIDs and cyclooxygenase (COX)-2 selective NSAIDs (coxibs) increase such risk.
When thinking about cardiovascular risk for patients treated with NSAIDs, it is important to consider the duration and frequency of therapy. Unlike the gastrointestinal side effects, which can occur soon after initiation of therapy (see "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity"), the risk of adverse cardiovascular events such as myocardial infarction, stroke, or cardiovascular death is extremely small over a short course of therapy, as might be used for patients with an acute but limited musculoskeletal injury. It should be kept in mind that in clinical practice most patients do not use their NSAIDs as regularly as in randomized trials; thus, the rates and relative risk of adverse cardiovascular events in observational studies, reflecting typical clinical care, are frequently lower than in clinical trials.
The adverse cardiovascular effects of nonselective NSAIDs and the impact on clinical decision making will be reviewed here. The cardiovascular effects of coxibs and overviews of the adverse effects of NSAID therapy are presented separately. (See "COX-2 selective inhibitors: Adverse cardiovascular effects" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of selective COX-2 inhibitors", section on 'Toxicities and possible toxicities'.)
For the purposes of this topic, nonselective NSAIDS include ibuprofen, naproxen, ketoprofen, flurbiprofen, oxaprozin, diclofenac, etodolac, tolmetin, sulindac, indomethacin, ketorolac, meloxicam, piroxicam, meclofenamate, mefenamic acid, and nabumetone (table 1). There appears to be heterogeneous cardiovascular risk across NSAIDs, although precise risk data for many of these agents are limited. The adverse effects of aspirin are discussed separately. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases".)
PATIENTS WITHOUT KNOWN CARDIOVASCULAR DISEASE
For most patients in whom a nonselective nonsteroidal antiinflammatory drug (NSAID) is chosen for short-term (no more than a month) or intermittent use, we prescribe naproxen, rather than other NSAIDs. Other nonselective NSAIDs (eg, ibuprofen) are reasonable alternatives, given the low baseline risk in such patients and lack of evidence regarding the cardiovascular risks of occasional low-dose use. Nonselective NSAIDs should be used at the lowest effective dose and for the shortest duration required in order to limit adverse events. We also prefer naproxen to other nonselective NSAIDs for patients who require long-term (over a month) use.
- Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342:c7086.
- Jüni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021.
- 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.
- 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.
- 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.
- 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.
- Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006; 113:1578.
- 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.
- 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.
- 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.
- 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.
- 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.
- ADAPT Research Group. Cardiovascular and cerebrovascular events in the randomized, controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). PLoS Clin Trials 2006; 1:e33.
- Kimmel SE, Berlin JA, Reilly M, et al. The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol 2004; 43:985.
- Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002; 162:1105.
- Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162:1099.
- Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002; 162:1111.
- Solomon DH, Avorn J, Stürmer T, et al. Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum 2006; 54:1378.
- Ray WA, Stein CM, Hall K, et al. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359:118.
- Mamdani M, Rochon P, Juurlink DN, et al. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003; 163:481.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med 2016; 375:2519.
- FitzGerald GA. Imprecision: Limitations to Interpretation of a Large Randomized Clinical Trial. Circulation 2017; 135:113.
- 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.
- Feenstra J, Heerdink ER, Grobbee DE, Stricker BH. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med 2002; 162:265.
- 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.
- Gurwitz JH. NSAIDs and atrial fibrillation. BMJ 2011; 343:d2495.
- Ungprasert P, Srivali N, Wijarnpreecha K, et al. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford) 2015; 54:736.
- Anderson JL, Adams CD, Antman EM, et al. 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. J Am Coll Cardiol 2007; 50:e1.
- Solomon DH, Rassen JA, Glynn RJ, et al. The comparative safety of analgesics in older adults with arthritis. Arch Intern Med 2010; 170:1968.
- 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.
- American College of Rheumatology Ad Hoc Group on Use of Selective and Nonselective Nonsteroidal Antiinflammatory Drugs. Recommendations for use of selective and nonselective nonsteroidal antiinflammatory drugs: an American College of Rheumatology white paper. Arthritis Rheum 2008; 59:1058.
- Canadian Cardiovascular Society, American Academy of Family Physicians, American College of Cardiology, et al. 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. J Am Coll Cardiol 2008; 51:210.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147.
- 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.
- Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes 2009; 2:155.
- Kohli P, Steg PG, Cannon CP, et al. NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease. Am J Med 2014; 127:53.
- 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.
- 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.
- Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345:1809.
- Kurth T, Glynn RJ, Walker AM, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation 2003; 108:1191.
- MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003; 361:573.
- Do NSAIDs interfere with the cardioprotective effects of aspirin? Med Lett Drugs Ther 2004; 46:61.
- Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects. J Am Coll Cardiol 2005; 45:1295.
- Farkouh ME, Greenberg JD, Jeger RV, et al. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis 2007; 66:764.
- Curtis JP, Wang Y, Portnay EL, et al. Aspirin, ibuprofen, and mortality after myocardial infarction: retrospective cohort study. BMJ 2003; 327:1322.
- García Rodríguez LA, Varas-Lorenzo C, Maguire A, González-Pérez A. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation 2004; 109:3000.
- Patel TN, Goldberg KC. Use of aspirin and ibuprofen compared with aspirin alone and the risk of myocardial infarction. Arch Intern Med 2004; 164:852.
- Hudson M, Baron M, Rahme E, Pilote L. Ibuprofen may abrogate the benefits of aspirin when used for secondary prevention of myocardial infarction. J Rheumatol 2005; 32:1589.
- Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol 1995; 2:637.
- Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353:2373.
- 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.
- FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345:433.
- FitzGerald GA. Parsing an enigma: the pharmacodynamics of aspirin resistance. Lancet 2003; 361:542.
- Public Health Advisory - FDA Announces Important Changes and Additional Warnings for COX-2 Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm150314.htm (Accessed on January 11, 2013).
- Chan FK, Abraham NS, Scheiman JM, et al. Management of patients on nonsteroidal anti-inflammatory drugs: a clinical practice recommendation from the First International Working Party on Gastrointestinal and Cardiovascular Effects of Nonsteroidal Anti-inflammatory Drugs and Anti-platelet Agents. Am J Gastroenterol 2008; 103:2908.
- Burmester G, Lanas A, Biasucci L, et al. The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel. Ann Rheum Dis 2011; 70:818.
- Schmidt M, Lamberts M, Olsen AM, et al. Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. Eur Heart J 2016; 37:1015.
- PATIENTS WITHOUT KNOWN CARDIOVASCULAR DISEASE
- Risk of myocardial infarction, stroke, and death
- - Safety compared with placebo
- - Safety comparison between nonselective NSAIDs
- Risk of developing heart failure
- Risk of blood pressure elevation
- Risk of atrial fibrillation
- Risk of venous thromboembolism
- Comparison with alternative agents
- PATIENTS WITH CARDIOVASCULAR DISEASE
- Patients with known coronary heart disease
- Patients with heart failure
- Patients with hypertension
- PATIENTS WITH SYSTEMIC INFLAMMATORY DISORDERS
- PATIENTS TAKING ASPIRIN FOR PREVENTION
- RECOMMENDATIONS OF OTHERS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS