Non-steroidal anti-inflammatory drugs and risk of heart failure exacerbation: A systematic review and meta-analysis

  • Patompong Ungprasert
    Corresponding author at: Division of Rheumatology, Mayo Clinic, 200 1st street SW, Rochester, MN, USA, 55905.
    Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Division of Rheumatology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
    Search for articles by this author
  • Narat Srivali
    Division of Critical Care and Pulmonary Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
    Search for articles by this author
  • Wonngarm Kittanamongkolchai
    Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
    Search for articles by this author
Published:September 29, 2015DOI:


      • Use of NSAIDs is associated with a higher risk of heart failure exacerbation.
      • This excess risk is about 40% among conventional NSAID and celecoxib users.
      • The highest risk is observed among rofecoxib users.



      The association between exacerbation of heart failure (HF) and use of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized but the data on this adverse effect are limited.


      To further characterize this possible association, we conducted a systematic review and meta-analysis of observation studies that reported odds ratio, relative risk, hazard ratio or standardized incidence ratio comparing risk of exacerbation of HF in patients with pre-existing HF who took NSAIDs versus non-users. Pooled risk ratios (RR) and 95% confidence intervals for conventional NSAIDs, celecoxib and rofecoxib were calculated using random-effect, generic inverse variance method.


      Six studies were identified and included in our data analysis. Use of conventional NSAIDs was associated with a significantly higher risk of development of exacerbation of HF with the pooled RR of 1.39 (95% CI 1.20–1.62). Elevated risk was also observed among celecoxib and rofecoxib users (RR 1.34, 95% CI 0.98–1.85 and RR 2.04, 95% CI 1.68–2.48). The pooled RR of rofecoxib was significantly higher than conventional NSAIDs (p = 0.02).


      Use of NSAIDs is associated with an increased risk of HF exacerbation among patients with pre-existing HF. The excess risk was approximately 40% for conventional NSAIDs and celecoxib. The highest risk was observed among rofecoxib users.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Curhan G.C.
        • Bullock A.J.
        • Hankinson S.E.
        • Willett W.C.
        • Speizer F.E.
        • Stampfer M.J.
        Frequency of use of acetaminophen, nonsteroidal anti-inflammatory drugs, and aspirin in US women.
        Pharmacoepidemiol Drug Saf. 2002; 11: 687-693
        • Ungprasert P.
        • Cheungpasitporn W.
        • Crowson C.S.
        • Matteson E.L.
        Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: a systematic review and meta-analysis of observational studies.
        Eur J Intern Med. 2015; 26: 285-291
        • Ungprasert P.
        • Srivali N.
        • Wijarnpreecha K.
        • Charoenpong P.
        • Knight E.L.
        Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis.
        Rheumatology. 2015; 54: 736-742
        • Bensen W.G.
        • Zhao S.Z.
        • Burke T.A.
        • et al.
        Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo.
        J Rheumatol. 2000; 27: 1876-1883
        • Vonkeman H.E.
        • van de Laar M.A.
        Nonsteroidal anti-inflammatory drugs: adverse effects and their prevention.
        Semin Arthritis Rheum. 2010; 39: 294-312
        • Bresalier R.S.
        • Sandler R.S.
        • Quan H.
        • et al.
        Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
        N Engl J Med. 2005; 352: 1092-1102
        • 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: 1633-1644
        • Laiwah A.C.
        • Mactier R.A.
        Antagonistic effect of non-steroidal anti-inflammatory drugs on frusemide-induced diuresis in cardiac failure.
        Br Med J (Clin Res Ed). 1981; 283: 714
        • Van den Ouweland F.A.
        • Gribnau F.W.
        • Meyboom R.H.
        Congestive heart failure due to nonsteroidal anti-inflammatory drugs in the elderly.
        Age Ageing. 1988; 17: 8-16
        • Furlan A.D.
        • Irvin E.
        • Bombardier C.
        Limited search strategies were effective in finding relevant nonrandomized studies.
        J Clin Epidemiol. 2006; 59: 1303-1311
        • Stang A.
        Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
        Eur J Epidemiol. 2010; 25: 603-605
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trial. 1986; 7: 177-188
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Page J.
        • Henry D.
        Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an unrecognized public health problem.
        Arch. Intern. Med. 2000; 160: 777-784
        • Mangomi A.A.
        • Woodman R.J.
        • Gaganis P.
        • Gilbert A.L.
        • Knights K.M.
        Use of non-steroidal ant-inflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community.
        Br J Clin Pharmacol. 2010; 69: 689-700
        • Garcia-Rodriguez L.A.
        • Herandez-Diaz S.
        Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure.
        Epidemiology. 2003; 14: 240-246
        • Back M.
        • Yin L.
        • Ingelsson E.
        Cyclooxygenase-2 inhibitors and cardiovascular risk in nation-wide cohort study after the withdrawal of rofecoxib.
        Eur Heart J. 2012; 33: 1928-1933
        • Kohli P.
        • Steg P.G.
        • Cannon C.P.
        • et al.
        NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease.
        Am J Med. 2014; 127: 53-60
        • McGettigan P.
        • Han P.
        • Jones L.
        • Whitaker D.
        • Henry D.
        Selective COX-2 inhibitors, NSAIDs and congestive heart failure: differences between new and recurrent cases.
        Br J Clin Pharmacol. 2008; 65: 927-934
        • Laredo L.
        • Rodríguez A.
        • Vargas E.
        • Moreno A.
        • Cruz A.
        • García Jde D.
        Association between non-steroid antiinflammatory drugs intake and decompensation of heart failure.
        Med Clin (Barc). 2003; 120: 658-660
        • Huerta C.
        • Varas-Lorenzo C.
        • Castellsague J.
        • Garcia-Rodriguez L.A.
        Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population.
        Heart. 2006; 92: 1610-1615
        • Hudson M.
        • Rahme E.
        • Richard H.
        • Pilote L.
        Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective cyclooxygenase 2 inhibitors: a class effect?.
        Arthritis Rheum. 2007; 57: 516-523
        • Feenstra J.
        • Heerdink E.R.
        • Grobbee D.E.
        • Stricker B.H.
        Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure. The Rotterdam study..
        Arch Int Med. 2002; 162: 265-270
        • Mamdani M.
        • Juurlink D.N.
        • Lee D.S.
        • 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: 1751-1756
        • Gislason G.H.
        • Rasmussen J.N.
        • Abildstrom S.Z.
        • et al.
        Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure.
        Arch Intern Med. 2009; 169: 141-149
        • Roger V.L.
        • Go A.S.
        • Lloyd-Jones D.M.
        • et al.
        Heart disease and stroke statistics—2012 update: a report from the American Heart Association.
        Circulation. 2012; 125: e2-e220
        • Ungprasert P.
        • Kittanamongolchai W.
        • Price C.
        • Ratanapo S.
        • Leeaphorn N.
        • Chongnarungsin D.
        • Cheungpasitporn W.
        What is the “safest” non-steroidal ani-inflammatory drugs?.
        Am Med J. 2012; 3: 115-123
        • Aneja A.
        • Farkouh M.E.
        Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?.
        Ther Adv Cardiovasc Dis. 2008; 2: 53-66
        • Stichtenoth D.O.
        • Marhauer V.
        • Tsikas D.
        • Gutzki F.M.
        • Frolich J.C.
        Effects of specific COX-2 inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers.
        Kidney Int. 2005; 68: 2197-2207
        • White W.B.
        Cardiovascular risk, hypertension, and NSAIDs.
        Curr Rheumatol Rep. 2007; 9: 36-43
        • Coughlin S.S.
        Recall bias in epidemiologic studies.
        J Clin Epidemiol. 1990; 43: 87-91
        • Signorello L.B.
        • McLaughlin J.K.
        • Lipworth L.
        • Friis S.
        • Sørensen H.T.
        • Blot W.J.
        Confounding by indication in epidemiologic studies of commonly used analgesics.
        Am J Ther. 2002; 9: 199-205