Skip to main content
Log in

Pharmacological Prevention of Thromboembolism in Patients with Left Ventricular Dysfunction

  • Review Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Chronic left ventricular systolic dysfunction is a well recognized problem with an increasingly significant impact on healthcare in the form of congestive heart failure (CHF). Advances in medicine have led to improved survival after myocardial infarction (MI) and as a result, an increased prevalence of left ventricular systolic dysfunction. An increased incidence of thromboembolism, especially stroke, in patients with left ventricular systolic dysfunction is also well recognized. Pharmacological strategies to prevent stroke have been proposed in numerous studies. For example, anticoagulation in patients with atrial fibrillation and heart failure has been shown to reduce mortality rates and the incidence of stroke; however, its role in patients with left ventricular dysfunction and normal sinus rhythm is unclear and utilization of anticoagulation in these patients varies widely. The role of aspirin to prevent thromboembolism in patients with CHF is controversial. The relatively new pharmacological agent ximelagatran, which has an advantage of unmonitored oral administration has the potential to change the anticoagulation strategy in patients with heart failure. Important trials to define optimal therapy for reducing the risk of thromboembolism and death in patients with left ventricular systolic dysfunction and sinus rhythm include the recently reported WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart failure) trial and the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial, which is currently underway. The WATCH trial failed to outline significant differences between aspirin (acetylsalicylic acid), warfarin, and clopidogrel in the primary composite endpoint of all-cause mortality, nonfatal MI, and nonfatal stroke. Combined data from WATCH and WARCEF may provide sufficient statistical power to clarify outcomes such as stroke and death in patients with reduced cardiac ejection fraction. The pooled data may also help define optimal preventative measures for thromboembolism in patients with left ventricular systolic dysfunction and sinus rhythm.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Table II
Table III

Similar content being viewed by others

References

  1. American Heart Association. Heart disease and stroke statistics: 2003 update. Dallas (TX): The American Heart Association, 2002.

    Google Scholar 

  2. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: rationale for preventive strategies and comprehensive disease management. Am Heart J 1997; 133: 703–12.

    Article  PubMed  CAS  Google Scholar 

  3. The Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 1988; 318: 262–4.

    Article  Google Scholar 

  4. Starling RC. The heart failure pandemic: changing patterns, costs, and treatment strategies. Cleve Clin J Med 1998 Jul–Aug; 65(7): 351–8.

    PubMed  CAS  Google Scholar 

  5. Massie BM, Krol WF, Ammon SE, et al. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure Trial (WATCH): rationale, design, and baseline patient characteristics. J Card Fail 2004 Apr; 10(2): 113–4.

    Article  Google Scholar 

  6. Hemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialized countries since 1950. World Health Stat Q 1988; 38: 155–68.

    Google Scholar 

  7. Kelley RE, Minagar A. Cardioembolic stroke: an update. South Med J 2003 Apr; 96(4): 343–9.

    Article  PubMed  Google Scholar 

  8. Kannel WB, Wolf PA, Verter J. Manifestations of coronary artery disease predisoposing to stroke: the Framingham study. JAMA 1983; 250: 2942–6.

    Article  PubMed  CAS  Google Scholar 

  9. Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol 1987; 60: 1340–55.

    Article  PubMed  CAS  Google Scholar 

  10. Cioffi G, Pozzoli M, Forni G, et al. Systematic thromboembolism in chronic heart failure: a prospective study of 406 patients. Eur Heart J 1996; 17: 1381–9.

    Article  PubMed  CAS  Google Scholar 

  11. Katz SD, Marantz PR, Biasucci L, et al. Low incidence of stroke in patients with heart failure: a prospective study. Am Heart J 1993; 126: 141–6.

    Article  PubMed  CAS  Google Scholar 

  12. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. N Engl J Med 1986; 314: 1547–52.

    Article  PubMed  CAS  Google Scholar 

  13. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10.

    Article  PubMed  CAS  Google Scholar 

  14. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and risk of stroke after myocardial infarction. N Engl J Med 1997; 336: 251–7.

    Article  PubMed  CAS  Google Scholar 

  15. The SOLVE) Investigators. Effect of Enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 1325: 293–302.

    Google Scholar 

  16. The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429–35.

    Article  Google Scholar 

  17. Dunkman WB, Johnson GR, Carson PE, et al. Incidence of thromboembolic events in congestive heart failure: the V-HeFT Cooperative Studies Group. Circulation 1993; 87: 94–101.

    Article  Google Scholar 

  18. Diet F, Erdmann E. Thromboembolism in heart failure: who should be treated? Eur J Heart Fail 2000 Dec; 2(4): 355–63.

    Article  PubMed  CAS  Google Scholar 

  19. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE study research group. N Engl J Med 1991; 325: 1468–75.

    Article  PubMed  CAS  Google Scholar 

  20. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: the Heart Outcomes Prevention Evaluation Study investigators. N Engl J Med 2000; 342: 145–53.

    Article  PubMed  CAS  Google Scholar 

  21. Pullicino PM, Halperin JL, Thompson JLP. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology 2000; 54: 288–94.

    Article  PubMed  CAS  Google Scholar 

  22. Sacco RL, Shi T, Zamanillo MC, et al. Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: the Northern Manhattan Stroke Study. Neurology 1994; 44: 626–34.

    Article  PubMed  CAS  Google Scholar 

  23. Petty GW, Brown RD, Whisnant JP, et al. Survival and recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 1998; 50: 208–16.

    Article  PubMed  CAS  Google Scholar 

  24. Natterson PD, Stevenson WG, Saxon LA, et al. Risk of arterial embolization in 224 patients awaiting cardiac transplantation. Am Heart J 1995; 129: 564–70.

    Article  PubMed  CAS  Google Scholar 

  25. Dries DL, Rosenberg Y, Waclawiw M, et al. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence of gender differences in studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997; 29: 1074–80.

    Article  PubMed  CAS  Google Scholar 

  26. Kalaria VG, Passannante MR, Shah T, et al. Effect of mitral regurgitation on left ventricular thrombus formation in dilated cardiomyopathy. Am Heart J 1998; 135 (2 Pt 1): 215–20.

    Article  PubMed  CAS  Google Scholar 

  27. Sharma ND, McCullough PA, Philbin EF, et al. Left ventricular thrombus and subsequent thromboembolism in patients with severe systolic dysfunction. Chest 2000; 117(2): 314–20.

    Article  PubMed  CAS  Google Scholar 

  28. Gottdiener JS, Gay JA, Vanvoorhees L, et al. Frequency and embolic potential of left ventricular thrombus in dilated cardiomyopathy: assessment by 2-dimensional echocardiography. Am J Cardiol 1983; 52: 1281–517.

    Article  PubMed  CAS  Google Scholar 

  29. Cabin HS, Roberts WC. Left ventricular aneurysm, intramural thrombus and systemic embolus in coronary heart disease. Chest 1980; 77: 586–90.

    Article  PubMed  CAS  Google Scholar 

  30. Fuster V, Gersh BJ, Giuliani ER, et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981; 47: 525–31.

    Article  PubMed  CAS  Google Scholar 

  31. Segal JP, Stapleton JF, McClellan JR, et al. Idiopathic cardiomyopathy: clinical features, prognosis and therapy. Curr Probl Cardiol 1978; 3: 1–49.

    Article  PubMed  CAS  Google Scholar 

  32. Meltzer RS, Visser CA, Fuster V. Intracardiac thrombi and systemic embolization. Ann Intern Med 1986 May; 104(5): 689–98.

    PubMed  CAS  Google Scholar 

  33. Katz SD. Left ventricular thrombus and the incidence of thromboembolism in patients with congestive heart failure: can clinical factors identify patients at increased risk? J Cardiovasc Risk 1995; 2: 97–102.

    Article  PubMed  CAS  Google Scholar 

  34. DeLorenzo F, Saba N, Kakkar VV. Blood coagulation in patients with chronic heart failure: evidence for hypercoaguable state and potential for pharmacological intervention. Drugs 2003; 63(6): 565–76.

    Article  PubMed  Google Scholar 

  35. Mehta J, Mehta P. Platelet function studies in heart disease: enhanced platelet aggregate formation in congestive heart failure. Circulation 1979; 60: 497–503.

    Article  PubMed  CAS  Google Scholar 

  36. Sbarouni E, Bradshaw AF, Tuddenham E, et al. Relationship between haemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994; 127(3): 607–12.

    Article  PubMed  CAS  Google Scholar 

  37. Bessenger E, Fink B, Skatchkov M, et al. Endothelium and platelet activity in heart failure. J Card Fail 1996; 2: 5203–8.

    Google Scholar 

  38. Sbarouni E, Bradshaw A, Andreotti F, et al. Relationship between hemostatic abnormalities and neuroendocrine activity in heart failure. Am Heart J 1994 Mar; 127(3): 607–12.

    Article  PubMed  CAS  Google Scholar 

  39. Lausanne JB. European Stroke Initiative (EUSI), European Stroke Council (ESC), European Neurological Society (ENS), European Federation of Neurological Societies (EFNS). Cerebrovasc Dis 2003; 15 Suppl. 2: 1–69.

    PubMed  Google Scholar 

  40. Chamorro A. Immediate anticoagulation in acute focal brain ischemia revisited: gathering the evidence. Stroke 2001; 32: 577–8.

    Article  PubMed  CAS  Google Scholar 

  41. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154: 1449–57.

    Article  Google Scholar 

  42. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: stroke prevention in atrial fibrillation III randomized clinical trial. Lancet 1996; 348: 633–638.

  43. Ibrahim SA, Kwoh CK, Harper DL, et al. Racial differences in the utilization of oral anticoagulant therapy in heart failure: a study of elderly hospitalized patients. J Gen Intern Med 2000; 15: 134–7.

    Article  PubMed  CAS  Google Scholar 

  44. Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet 1979; 2: 1313–5.

    Article  PubMed  CAS  Google Scholar 

  45. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309: 396–403.

    Article  PubMed  Google Scholar 

  46. Hart RG, Pearce LA, Miller VT, et al. Cardioembolic vs noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic effect in the stroke prevention in atrial fibrillation studies. Cerebrovasc Dis 2000; 10: 39–43.

    Article  PubMed  CAS  Google Scholar 

  47. Cleland JGF, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart Failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004; 148: 157–64.

    Article  PubMed  CAS  Google Scholar 

  48. Goldhaber SZ. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial: a report on a presentation at the late-breaking clinical trials session of the 53rd Annual Scientific Session of the American College of Cardiology; 2004 Mar 7–10; New Orleans (LA) [online]. Available from URL: http://www.cardiologyupdate.org/crus/402-033.pdf [Accessed 2005 Jul 26].

  49. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106.

    Article  Google Scholar 

  50. Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Brit Heart J 1995; 74: 215–9.

    Article  PubMed  CAS  Google Scholar 

  51. Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovering from myocardial infarction. JAMA 1980; 243: 661–8.

    Article  Google Scholar 

  52. Klimt CR, Knatterud GL, Stamler J, et al. Persantine-Aspirin Reinfarction Study: Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol 1986; 7: 251–69.

    Article  PubMed  CAS  Google Scholar 

  53. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1997; 336: 251–7.

    Article  PubMed  Google Scholar 

  54. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992; 340: 1173–8.

    Article  PubMed  CAS  Google Scholar 

  55. Al-Khadra AS, Salem DN, Rand WM, et al. Antiplatelet agents and survival: a cohort analysis from the Studies Of Left Ventricular Dysfunction (SOLVD) Trial. J Am Coll Cardiol 1998; 31: 419–25.

    Article  PubMed  CAS  Google Scholar 

  56. Harjai KJ, Nunez E, Turgut T, et al. The detrimental effect of combined aspirin and angiotensin converting enzyme inhibitor therapy on readmission rates in heart failure [abstract]. J Am Coll Cardiol 1999; 33 Suppl. A: 214A.

    Google Scholar 

  57. Katz SD, Radin M, Graves T, et al. Effect of aspirin and ifetroban on skeletal muscle blood flow in patients with congestive heart failure treated with enalapril. J Am Coll Cardiol 1999; 34: 170–6.

    Article  PubMed  CAS  Google Scholar 

  58. Isnard R, Baroin J-P, Drobinski G, et al. Influence of aspirin on long-term prognosis of patients with ischemic left ventricular systolic dysfunction [abstract]. Circulation 1998; 98 Suppl. I: 1–300.

    Google Scholar 

  59. Latini R, Tognoni G, Maggioni AP, et al. Clinical effects of early angiotensinconverting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96. J Am Coll Cardiol 2000; 35: 1801–7.

    Article  PubMed  CAS  Google Scholar 

  60. Gum PA, Kottke-Merchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001; 88: 230–5.

    Article  PubMed  CAS  Google Scholar 

  61. Mason PJ, Jacobs AK, Freedman JE. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol 2005 Sep 20; 46(6): 986–93.

    Article  PubMed  CAS  Google Scholar 

  62. Sane DC, McKee SA, Malinin AI, et al. Frequency of aspirin resistance in patients with congestive heart failure treated with antecedent aspirin. Am J Cardiol 2002; 90: 893–5.

    Article  PubMed  CAS  Google Scholar 

  63. Stroke prevention in atrial fibrillation study: final results. Circulation 1991; 84 (2): 527–539.

  64. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18: 349–55.

    Article  PubMed  CAS  Google Scholar 

  65. Secondary prevention in non-rheumatic atrial fibrillation after transient ischemic attack or minor stroke: EAFT (European Atrial Fibrillation Trial) Study Group. Lancet 1993; 342: 1255–1262.

  66. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343: 687–691.

  67. Lip GY, Gibbs CR. Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review. QJM 2002 Jul; 95(7): 451–9.

    Article  PubMed  CAS  Google Scholar 

  68. Al-Khadra AS, Salem DN, Rand WM, et al. Warfarin anticoagulation and survival: a cohort analysis from the studies of left ventricular dysfunction. J Am Coll Cardiol 1998; 31: 749–53.

    Article  PubMed  CAS  Google Scholar 

  69. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147–52.

    Article  PubMed  CAS  Google Scholar 

  70. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction. Lancet 1994; 343: 499–503.

    Google Scholar 

  71. Weitz JI. Low molecular weight heparins. N Engl J Med 1997; 337: 688–98.

    Article  PubMed  CAS  Google Scholar 

  72. De Lorenzo F, Newberry D, Scully M, et al. Low molecular weight heparin (bemiparin sodium) and the coagulation profile of patients with heart failure. Am Heart J 2002; 143: 689.

    PubMed  Google Scholar 

  73. Cohen AT, Zaw HM, Alikhan R. Benefits of deep vein thrombosis prophylaxis in non surgical patients: the MEDENOX trial. Semin Hematol 2001; 38: 31–8.

    Article  PubMed  CAS  Google Scholar 

  74. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. 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.

    Article  Google Scholar 

  75. Serebruany VL, Malanin AI, Jerome SD, et al. Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: the PLavix Use for Treatment Of Congestive Heart Failure (PLUTO-CHF) trial. Am Heart J 2003; 146(4): 713–20.

    Article  PubMed  CAS  Google Scholar 

  76. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran and warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349: 1703–12.

    Article  PubMed  CAS  Google Scholar 

  77. Halperin JL. Ximelagatran compared to warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient charactercitics (SPORTIF III and V). Executive Steering Committee, SPORTIF III and V study Investigators. Am Heart J 2003; 146: 431–48.

    Article  PubMed  CAS  Google Scholar 

  78. Executive Steering Committee on behalf of SPORTIF III investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared to warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–8.

    Article  Google Scholar 

  79. Halperin JL. Efficacy and safety study of oral direct thrombin inhibitor ximelagatran comapred to with dose-adjusted warfarin on the prevention of stroke and systemic embolic events in patients with atrial fibrillation (SPORTIF V): SPORTIF V Investigators. Plenary session VII: late-breaking clinical trials. American Heart Association Scientific Session; 2003 Nov 11; Orlando (FL).

  80. Olsson SB. New advances in stroke prevention in atrial fibrillation: ximelagatran and direct thrombin inhibition. Eur Heart J 2004; Suppl. 6: B20–4.

    Article  CAS  Google Scholar 

  81. Gurewich V. Ximelagatran: promises and concerns. JAMA 2005 Feb; 293(6): 736–9.

    Article  PubMed  CAS  Google Scholar 

  82. Brinker A, He R, Desai M, et al. Safety of ximelagatran. JAMA 2005 Jun; 293(23): 2859–60.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

No sources of funding were used in the preparation of this review. The authors have no conflicts of interest directly related to the content of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Deepak Thatai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thatai, D., Ahooja, V. & Pullicino, P.M. Pharmacological Prevention of Thromboembolism in Patients with Left Ventricular Dysfunction. Am J Cardiovasc Drugs 6, 41–49 (2006). https://doi.org/10.2165/00129784-200606010-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200606010-00004

Keywords

Navigation