Internal and Emergency Medicine

, Volume 5, Issue 4, pp 281–290

Combined oral anticoagulants and antiplatelets: benefits and risks

  • Maria Cristina Vedovati
  • Cecilia Becattini
  • Giancarlo Agnelli
IM - Review

Abstract

Combined antiplatelet and anticoagulant therapy has been suggested for those clinical conditions in which conventional antithrombotic regimens have shown suboptimal efficacy, and in patients with indication for both: antiplatelet and anticoagulant therapy. Clinical trials aimed at assessing the clinical benefit of the association with respect to mono-therapy have been conducted in patients with atrial fibrillation, in patients with recent myocardial infarction, and in patients with prosthetic heart valves. Overall, a favorable benefit-risk profile of combined therapy in comparison to anticoagulant alone has been observed in patients with mechanical prosthetic heart valves and in those with coronary artery disease while no clear advantage has been shown in patients with atrial fibrillation. In almost all these studies, however, a higher risk of major bleeding has been observed in patients receiving combined therapy in comparison to patients receiving warfarin alone. Thus, a combined regimen of anticoagulant and antiplatelet therapy should be reserved for selected patients at high risk of thromboembolic events who have a low risk of bleeding.

Keywords

Oral anticoagulants Antiplatelet agents Combined therapy Bleeding events 

References

  1. 1.
    Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, American College of Chest Physicians et al (2008) Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:546S–592SCrossRefPubMedGoogle Scholar
  2. 2.
    Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns J, Joyner C (1991) Canadian Atrial Fibrillation Anticoagulation (CAFA) study. J Am Coll Cardiol 18:349–355CrossRefPubMedGoogle Scholar
  3. 3.
    European Atrial Fibrillation Trial Study Group (1993) Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342:1255–1262Google Scholar
  4. 4.
    Atrial Fibrillation Investigators (1997) The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from 3 randomized trials. Arch Intern Med 157:1237–1240CrossRefGoogle Scholar
  5. 5.
    Hart RG, Benavente O, McBride R, Pearce LA (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a metaanalysis. Ann Intern Med 131:492–501PubMedGoogle Scholar
  6. 6.
    Douketis JD, Arneklev K, Goldhaber SZ (2006) Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med 166:853–859CrossRefPubMedGoogle Scholar
  7. 7.
    Johnson S (2008) Known knowns and known unknowns: risks associated with combination antithrombotic therapy. Thromb Res 123:S7–S11CrossRefPubMedGoogle Scholar
  8. 8.
    Stroke Preventionin Atrial Fibrillation (1996) Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 348:633–638CrossRefGoogle Scholar
  9. 9.
    Gulløv AL, Koefoed BG, Petersen P, Pedersen TS, Andersen ED, Godtfredsen J et al (1998) Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 158:1513–1521CrossRefPubMedGoogle Scholar
  10. 10.
    Lechat P, Lardoux H, Mallet A, Sanchez P, Derumeaux G, Lecompte T, FFAACS (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontané) Investigators et al (2001) Anticoagulant (fluindione)-aspirin combination in patients with high-risk atrial fibrillation: a randomized trial. Cerebrovasc Dis 12:245–252CrossRefPubMedGoogle Scholar
  11. 11.
    Perez-Gomez F, Alegria E, Berjon J, Iriarte JA, Zumalde J, Salvador A, NASPEAF Investigators et al (2004) Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol 44:1557–1566CrossRefPubMedGoogle Scholar
  12. 12.
    Dentali F, Douketis JD, Lim W, Crowther M (2007) Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease. A meta-analysis of randomized trials. Arch Intern Med 167:117–124CrossRefPubMedGoogle Scholar
  13. 13.
    Estes NA 3rd, Halperin JL, Calkins H, Ezekowitz MD, Gitman P, Go AS, American College of Cardiology; American Heart Association Task Force on Performance Measures; Physician Consortium for Performance Improvement et al (2008) ACC/AHA/Physician Consortium 2008 Clinical Performance Measures for Adults with Nonvalvular Atrial Fibrillation or Atrial Flutter: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and the Physician Consortium for Performance Improvement (Writing Committee to Develop Clinical Performance Measures for Atrial Fibrillation) Developed in Collaboration with the Heart Rhythm Society. J Am Coll Cardiol 51:865–884CrossRefPubMedGoogle Scholar
  14. 14.
    Salem DN, O’Gara PT, Madias C, Pauker SG, American College of Chest Physicians (2008) Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:593S–629SCrossRefPubMedGoogle Scholar
  15. 15.
    Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, American College of Cardiology/American Heart Association Task Force on Practice Guidelines et al (2008) 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52:e1–e142CrossRefPubMedGoogle Scholar
  16. 16.
    Pengo V, Barbero F, Banzato A, Garelli E, Noventa F, Biasiolo A et al (1997) A comparison of a moderate with moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve prostheses. Thromb Haemost 77:839–844PubMedGoogle Scholar
  17. 17.
    Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJ, Vandenbroucke JP, Briet E (1995) Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 333:11–17CrossRefPubMedGoogle Scholar
  18. 18.
    Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F et al (1993) A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 329:524–529CrossRefPubMedGoogle Scholar
  19. 19.
    Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA (1997) Low intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves. J Thorac Cardiovasc Surg 113:910–916CrossRefPubMedGoogle Scholar
  20. 20.
    Laffort P, Roudaut R, Roques X, Lafitte S, Deville C, Bonnet J et al (2000) Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude medical prosthesis: a clinical and transesophageal echocardiographic study. J Am Coll Cardiol 35:739–746CrossRefPubMedGoogle Scholar
  21. 21.
    Little SH, Massel D (2003) Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev (4):CD003464Google Scholar
  22. 22.
    Anand SS, Yusuf S (1999) Oral anticoagulants in patients with coronary artery disease: a meta analysis. JAMA 282:2058–2067CrossRefPubMedGoogle Scholar
  23. 23.
    Anand SS, Yusuf S (2003) Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 41:S62–S69CrossRefGoogle Scholar
  24. 24.
    Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten HE, Hertzberger DP et al (2002) Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)-2 Trial. Circulation 106:659–665CrossRefPubMedGoogle Scholar
  25. 25.
    van den Bergh PJ, Kievit PC, Brouwer MA, Aengevaeren WR, Veen G, Verheugt FW (2009) Prolonged anticoagulation therapy adjunctive to aspirin after successful fibrinolysis: from early reduction in reocclusion to improved long-term clinical outcome. Am Heart J 157:532–540CrossRefPubMedGoogle Scholar
  26. 26.
    van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE, for the Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) Research Group (2002) Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 360:109–113CrossRefPubMedGoogle Scholar
  27. 27.
    Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H (2002) Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 347:969–974CrossRefPubMedGoogle Scholar
  28. 28.
    Coumadin Aspirin Reinfarction Study (CARS) investigators (1997) Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 350:389–396CrossRefGoogle Scholar
  29. 29.
    Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P, Combination Hemotherapy and Mortality Prevention (CHAMP) Study Group (2002) Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation 105:557–563CrossRefPubMedGoogle Scholar
  30. 30.
    Andreotti F, Testa L, Biondi-Zoccai GG, Crea F (2006) Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 27:519–526CrossRefPubMedGoogle Scholar
  31. 31.
    Becker RC, Meade TW, Berger PB, Ezekowitz M, O’Connor CM, Vorchheimer DA, American College of Chest Physicians et al (2008) The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:776S–814SCrossRefPubMedGoogle Scholar
  32. 32.
    Wang TY, Robinson LA, Ou FS, Roe MT, Ohman EM, Gibler WB et al (2008) Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J 155:361–368CrossRefPubMedGoogle Scholar
  33. 33.
    Nguyen MC, Lim YL, Walton A, Lefkovits J, Agnelli G, Goodman SG, for the GRACE Investigators et al (2007) Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J 28:1717–1722CrossRefPubMedGoogle Scholar
  34. 34.
    Khurram Z, Chou E, Minutello R, Bergman G, Parikh M, Naidu S et al (2006) Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 18:162–164PubMedGoogle Scholar
  35. 35.
    Mattichak SJ, Reed PS, Gallagher MJ, Boura JA, O’Neill WW, Kahn JK (2005) Evaluation of safety of warfarin in combination with antiplatelet therapy for patients treated with coronary stents for acute myocardial infarction. J Interv Cardiol 18:163–166CrossRefPubMedGoogle Scholar
  36. 36.
    Orford JL, Fasseas P, Melby S, Burger K, Steinhubl SR, Holmes DR et al (2004) Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation. Am Heart J 147:463–467CrossRefPubMedGoogle Scholar
  37. 37.
    Manzano-Fernández S, Pastor FJ, Marín F, Cambronero F, Caro C, Pascual-Figal DA et al (2008) Increased major bleeding complications related to triple antithrombotic therapy usage in patients with atrial fibrillation undergoing percutaneous coronary artery stenting. Chest 134:559–567CrossRefPubMedGoogle Scholar
  38. 38.
    Karjalainen PP, Porela P, Ylitalo A, Vikman S, Nyman K, Vaittinen MA et al (2007) Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 28:726–732CrossRefPubMedGoogle Scholar
  39. 39.
    Gilard M, Blanchard D, Helft G, Carrier D, Eltchaninoff H, Belle L, STENTICO Investigators et al (2009) Antiplatelet therapy in patients with anticoagulants undergoing percutaneous coronary stenting (from STENTIng and oral antiCOagulants [STENTICO]). Am J Cardiol 104:338–342CrossRefPubMedGoogle Scholar
  40. 40.
    van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, ESC Committee for Practice Guidelines (CPG) et al (2008) 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 29:2909–2945CrossRefPubMedGoogle Scholar
  41. 41.
    Jolly SS, Pogue J, Haladyn K, Peters RJ, Fox KA, Avezum A et al (2009) Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study. Eur Heart J 30:900–907CrossRefPubMedGoogle Scholar
  42. 42.
    Rubboli A, Di Pasquale G (2007) Triple therapy of warfarin, aspirin and a thienopyridine for patients treated with vitamin K antagonists undergoing coronary stenting. A review of the evidence. Intern Emerg Med 2:177–181CrossRefPubMedGoogle Scholar
  43. 43.
    Rubboli A, Colletta M, Valencia J, Capecchi A, Franco N, Zanolla L, WARfarin, Coronary STENTing (WAR-STENT) Study Group et al (2009) Periprocedural management and in-hospital outcome of patients with indication for oral anticoagulation undergoing coronary artery stenting. J Interv Cardiol 22:390–397CrossRefPubMedGoogle Scholar
  44. 44.
    Rossini R, Musumeci G, Lettieri C, Molfese M, Mihalcsik L, Mantovani P et al (2008) Long-term outcomes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am J Cardiol 102:1618–1623CrossRefPubMedGoogle Scholar
  45. 45.
    ESC Guidelines Desk Reference (2008) Atrial fibrillation. In: Cardiovascular medicine. Compendium of abridged ESC guidelines 2008. Lippincott Williams and Wilkins, Baltimore, pp 237–255Google Scholar
  46. 46.
    Violi F, Hiatt W (2007) A critical review of antiplatelet treatment in peripheral arterial disease. Intern Emerg Med 2:84–87CrossRefPubMedGoogle Scholar
  47. 47.
    Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study Group (2000) Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (the Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomized trial. Lancet 355:346–351CrossRefGoogle Scholar
  48. 48.
    Schneider E, Brunner U, Bollinger A (1979) Medikament”se Rezidivprophilaxe nach fermoro-poplitealer Arterienrekonstruktion. Angio 2:73–77Google Scholar
  49. 49.
    WAVE Investigators (2006) The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a meta-analysis of trials. Am Heart J 151:1–9CrossRefGoogle Scholar
  50. 50.
    WAVE Investigators (2007) Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 357:217–227CrossRefGoogle Scholar
  51. 51.
    Johnson WC, Williford WO, Members of the Department of Veterans Affairs Cooperative Study (2002) Benefits, morbidity and mortality associated with long-term administration of oral anticoagulants to patients with peripheral arterial bypass procedures: a prospective randomized study. J Vasc Surg 35:413–421CrossRefPubMedGoogle Scholar
  52. 52.
    Sarac TP, Huber TS, Back MR, Ozaki CK, Carlton LM, Flynn TC et al (1998) Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure. J Vasc Surg 28:446–457CrossRefPubMedGoogle Scholar
  53. 53.
    Sobel M, Verhaeghe R (2008) Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:815S–843SCrossRefPubMedGoogle Scholar
  54. 54.
    Marietta M, Pedrazzi P, Girardis M, Torelli G (2007) Intracerebral haemorrhage: an often neglected medical emergency. Intern Emerg Med 2:38–45CrossRefPubMedGoogle Scholar
  55. 55.
    Testa S, Alatri A, Paoletti O, Morstabilini G, Medagliani MA, Denti N et al (2006) Reorganisation of an anticoagulation clinic using a telemedicine system: description of the model and preliminary results. Intern Emerg Med 1:24–29CrossRefPubMedGoogle Scholar
  56. 56.
    Pengo V (2006) Monitoring oral anticoagulants: new strategies for an emerging problem. Intern Emerg Med 1:3–4CrossRefPubMedGoogle Scholar
  57. 57.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361:1139–1151CrossRefPubMedGoogle Scholar
  58. 58.
    Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K et al (2007) Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 100:1419–1426CrossRefPubMedGoogle Scholar
  59. 59.
    Flaker GC, Gruber M, Connolly SJ, Goldman S, Chaparro S, Vahanian A, SPORTIF Investigators et al (2006) Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 152:967–973CrossRefPubMedGoogle Scholar

Copyright information

© SIMI 2010

Authors and Affiliations

  • Maria Cristina Vedovati
    • 1
  • Cecilia Becattini
    • 1
  • Giancarlo Agnelli
    • 1
  1. 1.Internal and Cardiovascular Medicine and Stroke UnitUniversity of PerugiaPerugiaItaly

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