Journal of General Internal Medicine

, Volume 28, Issue 2, pp 216–222 | Cite as

Gastrointestinal Events with Clopidogrel: A Nationwide Population-Based Cohort Study

  • Erik Lerkevang Grove
  • Morten Würtz
  • Peter Schwarz
  • Niklas Rye Jørgensen
  • Peter Vestergaard
Original Research



Clopidogrel prevents cardiovascular events, but has been linked with adverse gastrointestinal (GI) complications, particularly bleeding events.


We aimed to investigate the risk of adverse GI events in patients treated with clopidogrel.


A nationwide population-based cohort study based on linkage of three administrative registries in Denmark.


All individuals who redeemed at least one prescription of clopidogrel from 1996 to 2008 were included as exposed subjects (n = 77,503). For each exposed subject, three matched controls were randomly selected from the background population (n = 232,510).


Follow-up began on January 1, 1996, and was censored on December 31, 2007, or if patients emigrated or died. The study endpoint was the occurrence of any gastritis, GI ulcer or bleeding. Analyses were adjusted for comorbidity and medication.


Regardless of dose, adjusted odds ratios associating clopidogrel use with the study endpoint were statistically significant and followed a dose–response pattern. The crude absolute risk of GI events were: never users: 2.2 %; <0.1 defined daily dose (DDD) of clopidogrel per day: 7.1 %; 0.1–0.39 DDD: 6.0 %; 0.4–0.79 DDD: 5.7 %; ≥0.80 DDD: 4.4 %. Adjusted odds ratios were: <0.1 DDD: 1.34, 95 % CI: 1.26–1.42; 0.1–0.39 DDD: 1.58, 95 % CI: 1.48–1.68; 0.4–0.79 DDD: 1.91, 95 % CI: 1.77–2.06; ≥0.80 DDD: 1.77, 95 % CI: 1.66–1.89, all p-values < 0.01. Depending on the dose, numbers needed to harm ranged from 58 to 33 patients receiving 12 months of clopidogrel treatment.


The well-known cardioprotective effect of clopidogrel must be carefully weighed against an increased risk of GI events.


clopidogrel coronary artery disease gastritis gastrointestinal hemorrhage stomach ulcer 



Adenosine diphosphate


Anatomical Therapeutical Chemical


Defined daily dose




International Classification of Diseases


  1. 1.
    Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29(23):2909–2945.PubMedCrossRefGoogle Scholar
  2. 2.
    Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23):2999–3054.PubMedCrossRefGoogle Scholar
  3. 3.
    Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2010;31(20):2501–2555.PubMedCrossRefGoogle Scholar
  4. 4.
    Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ. 1998;316(7141):1337–1343.PubMedCrossRefGoogle Scholar
  5. 5.
    Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–1860.PubMedCrossRefGoogle Scholar
  6. 6.
    CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329–1339.CrossRefGoogle Scholar
  7. 7.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494–502.PubMedCrossRefGoogle Scholar
  8. 8.
    Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321(7270):1183–1187.PubMedCrossRefGoogle Scholar
  9. 9.
    Lanas A, Wu P, Medin J, Mills EJ. Low doses of acetylsalicylic Acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol. 2011;9(9):762–768.PubMedCrossRefGoogle Scholar
  10. 10.
    Nikolsky E, Stone GW, Kirtane AJ, et al. Gastrointestinal bleeding in patients with acute coronary syndromes: incidence, predictors, and clinical implications: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol. 2009;54(14):1293–1302.PubMedCrossRefGoogle Scholar
  11. 11.
    Moukarbel GV, Signorovitch JE, Pfeffer MA, et al. Gastrointestinal bleeding in high risk survivors of myocardial infarction: the VALIANT Trial. Eur Heart J. 2009;30(18):2226–2232.PubMedCrossRefGoogle Scholar
  12. 12.
    Schmidt M, Riis AH, Christiansen CF, Lash TL, Sorensen HT. Clopidogrel Use and Short-Term Mortality After Peptic Ulcer Bleeding: A Population-Based Cohort Study. Am J Ther 2011 Feb 15. doi: 10.1097/MJT.0b013e3181ff7ad1.
  13. 13.
    Fork FT, Lafolie P, Toth E, Lindgarde F. Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study. Scand J Gastroenterol. 2000;35(5):464–469.PubMedCrossRefGoogle Scholar
  14. 14.
    Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352(3):238–244.PubMedCrossRefGoogle Scholar
  15. 15.
    Ibanez L, Vidal X, Vendrell L, Moretti U, Laporte JR. Upper gastrointestinal bleeding associated with antiplatelet drugs. Aliment Pharmacol Ther. 2006;23(2):235–242.PubMedCrossRefGoogle Scholar
  16. 16.
    Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case–control study. BMJ. 2006;333(7571):726.PubMedCrossRefGoogle Scholar
  17. 17.
    Garcia Rodriguez LA, Lin KJ, Hernandez-Diaz S, Johansson S. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation. 2011;123(10):1108–1115.PubMedCrossRefGoogle Scholar
  18. 18.
    Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol. 2010;56(24):2051–2066.PubMedCrossRefGoogle Scholar
  19. 19.
    Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J. 2011;32(15):1854–1864.PubMedCrossRefGoogle Scholar
  20. 20.
    Wurtz M, Grove EL. Combining aspirin and proton pump inhibitors: For whom the warning bell tolls? Expert Opin Drug Metab Toxicol. 2012. doi:10.1517/17425255.2012.711318
  21. 21.
    Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909–1917.PubMedCrossRefGoogle Scholar
  22. 22.
  23. 23.
    Wacholder S, McLaughlin JK, Silverman DT, Mandel JS. Selection of controls in case–control studies. I. Principles. Am J Epidemiol. 1992;135(9):1019–1028.PubMedGoogle Scholar
  24. 24.
    Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46(3):263–268.PubMedGoogle Scholar
  25. 25.
    Mosbech J, Jorgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen TD. The national patient registry. Evaluation of data quality. Ugeskr Laeger. 1995;157(26):3741–3745.PubMedGoogle Scholar
  26. 26.
    Pedersen CB. The Danish Civil Registration System. Scand J Public Health. 2011;39(7 Suppl):22–25.PubMedCrossRefGoogle Scholar
  27. 27.
    WHO Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment, 2010. Oslo. 2011.Google Scholar
  28. 28.
    Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. N Engl J Med. 1999;340(24):1888–1899.PubMedCrossRefGoogle Scholar
  29. 29.
    Ma L, Elliott SN, Cirino G, Buret A, Ignarro LJ, Wallace JL. Platelets modulate gastric ulcer healing: role of endostatin and vascular endothelial growth factor release. Proc Natl Acad Sci U S A. 2001;98(11):6470–6475.PubMedCrossRefGoogle Scholar
  30. 30.
    Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ. 1995;310(6983):827–830.PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343(8900):769–772.PubMedCrossRefGoogle Scholar
  32. 32.
    Lanas A, Bajador E, Serrano P, et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med. 2000;343(12):834–839.PubMedCrossRefGoogle Scholar
  33. 33.
    Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther. 2003;18(4):443–449.PubMedCrossRefGoogle Scholar
  34. 34.
    Sorensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009;374(9706):1967–1974.PubMedCrossRefGoogle Scholar
  35. 35.
    Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–2015.PubMedCrossRefGoogle Scholar
  36. 36.
    Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–1057.PubMedCrossRefGoogle Scholar
  37. 37.
    Pratt S, Thompson VJ, Elkin EP, Naesdal J, Sorstadius E. The impact of upper gastrointestinal symptoms on nonadherence to, and discontinuation of, low-dose acetylsalicylic acid in patients with cardiovascular risk. Am J Cardiovasc Drugs. 2010;10(5):281–288.PubMedCrossRefGoogle Scholar
  38. 38.
    Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008;299(5):532–539.PubMedCrossRefGoogle Scholar

Copyright information

© Society of General Internal Medicine 2012

Authors and Affiliations

  • Erik Lerkevang Grove
    • 1
  • Morten Würtz
    • 1
  • Peter Schwarz
    • 2
    • 3
  • Niklas Rye Jørgensen
    • 2
  • Peter Vestergaard
    • 4
  1. 1.Department of CardiologyAarhus University Hospital, SkejbyAarhusDenmark
  2. 2.Research Center of Aging and Osteoporosis, Departments of Medicine and DiagnosticsCopenhagen University HospitalGlostrupDenmark
  3. 3.Faculty of Health SciencesCopenhagen UniversityCopenhagenDenmark
  4. 4.Medical FacultyAalborg UniversityAalborgDenmark

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