- Email: [email protected]
Dilated Cardiomyopathy and Role of Antithrombotic Therapy
REVIEW ARTICLE
Dilated Cardiomyopathy and Role of Antithrombotic Therapy Ashraf S. Abdo, MD, Rhonda Kemp, CFNP, Jennifer Barham, ACNP and Stephen A. Geraci, MD
Abstract: Background: There is no consensus as to whether anticoagulation has a favorable risk:benefit in reducing thromboembolic events in patients with heart failure (HF) secondary to dilated cardiomyopathy who do not suffer from atrial fibrillation or primary valvular disease. Methods and Results: The literature reviewed on this topic included most recent and ongoing studies that assessed the use of anticoagulation for this population. Several large retrospective studies showed an increased risk of thromboembolic events among patients with depressed left ventricular function. The relative risk of stroke in individuals with HF from all causes was found to be 4.1 for men and 2.8 for women, but confounding comorbidities (such as atrial fibrillation and coronary artery disease) were commonly present. Currently, there are no randomized prospective trials to guide the use of antithrombotics for these patients, and the risk of bleeding secondary to anticoagulation has limited the use of oral anticoagulants for prevention of thrombosis. Among patients with HF, increasing age directly correlates with both major bleeding and thromboembolic events, with a 46% relative risk of bleeding for each 10-year increase in age older than 40 years. Conclusions: To date, there is no agreement on appropriate antithrombotic treatment (if any) for primary thromboembolism prophylaxis in patients with dilated cardiomyopathy with sinus rhythm. In recent years, several promising prospective trials were terminated prematurely due to inadequate enrollment. The Warfarin Aspirin-Reduced Cardiac Ejection Fraction trial may provide evidence regarding the use of anticoagulation for patients with decreased myocardial function. Key Indexing Terms: Cardiomyopathy; Antithrombotic therapy; Anticoagulation. [Am J Med Sci 2010;339(6):557–560.]
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eft ventricular systolic dysfunction (LVD) and chronic systolic heart failure (HF) predispose to intraventricular thrombus formation and embolization resulting in stroke, peripheral arterial occlusion, or pulmonary embolism.1 In cases with associated underlying valvular disease, previous myocardial infarction, ventricular aneurysm, and/or atrial fibrillation (AF), sufficient data exist to support a primary preventive strategy with low-intensity warfarin therapy, with which therapeutic benefit exceeds risk in the majority of patients.2,3 In patients with sinus rhythm, normal valve structure, and no previous infarction, the risk:benefit of warfarin remains unclear in the absence of previously documented cardioembolic events or echocardiographically demonstrated mural thrombi.4 – 6 Dilated cardiomyopathy (DCM) may result from a host of conditions including myocarditis, chronic metabolic disorders, chronic intoxications, postpartum pathology, and autoimFrom the Department of Medicine (ASA), University of Mississippi School of Medicine—G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi; G.V. (Sonny) Montgomery VA Medical Center (RK, JB), Jackson, Mississippi; and Pulmonary/CCM Division (SAG), University of Mississippi School of Medicine, Jackson, Mississippi. Submitted November 20, 2009; accepted in revised form December 9, 2009. Correspondence: Ashraf S. Abdo, MD, Department of Medicine, University of Mississippi School of Medicine–G.V. (Sonny) Montgomery VA Medical Center, 1500 E. Woodrow Wilson Drive, Jackson, MS, 39216 (E-mail: [email protected]).
mune disease, but at least one half are idiopathic. Chamber dilatation, reduced wall motion, and decreased stroke volume associated with DCM contribute to blood stasis, whereas changes in the endothelial endocardial surface may reduce its antithrombotic qualities.7 In addition, patients with DCM have higher levels of fibrinopeptide A, antithrombin III, circulating fibrinogen, and D-dimer.8,9 Reduced nitric oxide production and elevated concentrations of von Willebrand factor have been reported. Both platelets adhesion and endothelial monocyte activity are increased. As a result, DCM demonstrates many prothrombotic characteristics.10,11 Current American Heart Association/American College of Cardiology and American College of Chest Physicians guidelines do not recommend the use of warfarin in patients with DCM.12,13 The European Stroke Initiative failed to provide clear recommendations for primary preventive anticoagulation in this setting.14 Despite this, warfarin is frequently prescribed in this population. The purpose of this article is to summarize available data on risks and benefits of anticoagulation for these patients.
METHODS A PubMed/MEDLINE search review was performed using the key words “dilated cardiomyopathy” and “anticoagulation.” We followed by another search using the key words “heart failure” and “anticoagulation.” A separate search using the key words “thromboembolism” and “heart failure” was performed. Forty randomized retrospective and prospective studies were selected from the period from 1950 to 2009. Case reports and reviews were excluded from the discussion.
RESULTS Dilated Cardiomyopathy and Thromboembolism There is a wide variation in prevalence estimates for clinical events (stroke, pulmonary, and peripheral thromboembolism) in DCM, ranging from 3% to 50%, and in incidence estimates, ranging from 1.5 to 3.5 per 100 patient years.15 Most retrospective reports, linking ejection fraction, New York Heart Association (NYHA) class, VO2, and other disease severity parameters to stroke risk included patients with other known risk factors, most often atherosclerotic coronary disease (postinfarction). Similarly, most early clinical trials of warfarin therapy had similar confounders and were not prospective double blind or placebo controlled.16 In this review of the available literature, varied incidences of thromboembolic events were reported. Reports from the 1950s suggested a 50% prevalence of thromboembolic evidence at autopsy on HF cases.17 Later, Katz et al18 reported a lower risk of thromboembolism (1.7 thromboembolic events per 100 patient years) in patients with congestive HF (CHF). On the basis of the Framingham study, Kannel et al19 observed that coronary artery disease (CAD) and cardiac failure added to the risk of stroke associated with hypertension. They noted that
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CAD increased the risk of stroke in the absence of hypertension or HF, but the risk was greatly increased when these coexisted. The relative risk (RR) of stroke in individuals with HF in this study was 4.1 for men and 2.8 for women, but comorbidities (such as AF and CAD) were simultaneously present. A series of recent reports established the rate of thromboembolism at ⬍3% for patients with NYHA class II and III HF without a coexisting AF. In retrospective posthoc analyses of the Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT) I and II, Dunkman et al followed up 642 men with HF (V-HeFT I) for an average of 2.28 years. Their mean left ventricular ejection fraction (LVEF) was 30%, and functional capacity was at the interface of classes II and III (peak exercise oxygen consumption of 14.7 ml/kg/min). The incidence of all thromboembolic events was 2.7 per 100 patient years without warfarin use. In V-HeFT II, 804 men were followed up for an average of 2.56 years. Their mean LVEF was 29%. Their functional capacity was at the interface of classes II and III, with a peak exercise oxygen consumption of 13.7 mL/kg min. The incidence of all thromboembolic events without warfarin was 2.1 per 100 patient years and was not reduced by incidental treatment with warfarin. These authors concluded that the incidence of thromboembolism and stroke in class II-III CHF is quite low and that warfarin treatment is likely unwarranted.20,21 The Survival and Ventricular Enlargement trial showed an overall risk of stroke of 8.1% at 5 years. The RR of stroke almost doubled with LVEF ⬍28% and increased by 18% for every 5% reduction in ejection fraction below 28%.22–24 The annual thromboembolic rate in Studies of Left Ventricular Dysfunction was higher in women (2.4%) than in men (1.8%). On multivariate analysis, a decrease in ejection fraction remained independently associated with thromboembolic risk in women (RR per 10% decrease 1.53, 95% confidence interval: 1.06 –2.20, P ⫽ 0.02).21 Hays et al25 concluded that LVD, even of mild degree, is independently associated with an increased risk of ischemic stroke. The study included a subset of patients (total of 558) from the Northern Manhattan Study. They found that LVD of any degree was more frequent in stroke patients (24.1%) than in age-, sex-, and sex-matched controls (4.9%, P ⬍ 0.0001). The adjusted odds ratio for any degree of LVD was 3.92. In the Sudden Cardiac Death in HeFT, 2521 patients with moderate HF were studied for a median of 45.5 months. Of the total population, 2114 had no history of AF. The incidence of any thromboembolic event (stroke, peripheral, or pulmonary embolism) was correlated with predictors for thromboembolism and LVEF. Patients were randomized to receive amiodarone, implanted cardioverter defibrillators (ICDs), or placebo. The incidence of any thromboembolic event over 4 years was 4.0%: 2.6% in patients randomized to amiodarone, 3.2% for patients randomized to ICD, and 6.0% in patients randomized to placebo.26 Reviewed results for the above studies did not analyze the outcomes in correlation to various subgroups of HF. The question of ischemic versus nonischemic DCM as risk factors that may indicate anticoagulation was not addressed. Authors looked at subset of patients with different degrees of HF, but further breakdown of the causes for HF was not included. It is unclear whether amiodarone could have reduced transient AF to account for the lower stroke risk; however, ICDs would have had no such effect.
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Trials of Anticoagulation Several formal, prospective randomized studies have attempted to answer the question of anticoagulation for patient with decreased ejection fraction without AF. The Warfarin Aspirin Study in Heart Failure trial was an open-label pilot study of 279 patients with LVD randomized to 3 groups: no therapy, aspirin (300 mg daily) therapy alone, and warfarin therapy (international normalized ratio target of 2.5). The mean follow-up was 27 ⫾ 1 months. Patients receiving warfarin did not have fewer hospitalizations for cardiovascular complications, mainly HF (P ⫽ 0.44). Twenty-six (26%), 29 (32%), and 23 (26%) patients randomized to no antithrombotic treatment, aspirin, and warfarin, respectively, showed no difference in combined primary end point of all-cause mortality, nonfatal infarction, and nonfatal stroke. It was concluded that in this lowpowered pilot study, no benefits of aspirin or warfarin were demonstrated for patients with HF in sinus rhythm.27 The Warfarin and Antiplatelet Therapy in Heart Failure study was a randomized, double-blind, 3-arm study of warfarin versus aspirin versus clopidogrel. Patients who had either indications for or contraindications to any study medication were excluded. The study, designed to include 4500 patients, recruited only 1587 patients with HF and ejection fraction ⬍30% due to poor enrollment. Early data favored warfarin over aspirin in preventing nonfatal stroke (0.7% versus 2.1%). A higher incidence of hemorrhage with warfarin was observed as well. Differences failed to reach statistical significance.13,28 The HEart failure Long-term Antithrombotic Study was a multicenter, randomized, double-blind, placebo-controlled trial.29 It studied 312 patients for a total follow-up of 2 years. Patients with NYHA class II-IV HF and ejection fraction ⬍35% were enrolled. Patients with DCM were randomized to receive either warfarin or placebo. Patients with ischemic heart disease were randomized to aspirin 325 mg or warfarin. Patients who developed AF during the course of the trial were excluded from the analysis. Data showed that the total embolic events were rare in HF regardless of treatment. An incidence of 2.2 embolic events per 100 patient years with no significant difference between groups was identified. No peripheral or pulmonary emboli were reported. The value of these findings is unclear due to insufficient enrollment. Coagulants as a Single, Dual, and Triple Therapy Antithrombotic agents have established benefit in both primary and secondary prevention of cardiovascular disease.30 Dual antiplatelet therapy with aspirin and thienopyridine (usually clopidogrel) has established the benefit for most manifestations of CAD and cerebrovascular disease. Present guidelines recommend aspirin in patients with chronic HF to reduce cardiovascular mortality, but no available data suggest that it results specifically in reduction in thromboembolic risk, either alone or in combination with warfarin.31 In 1952, Griffith et al reported a decreased incidence of pulmonary embolism and overall mortality for patients with HF receiving anticoagulation. However, their patient population included those with AF and rheumatic valvular disease.32 Forty years later, Gibelin concluded that ventricular thrombi are more common when left ventricular fractional shortening is decreased (⬍11% ⫽ 80% of thrombi). Because this study population included patients with AF and left atrial thrombi, further studies were recommended to determine the need of anticoagulation for those patients with DCM without an intracardiac thrombus and/or AF.33 Volume 339, Number 6, June 2010
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Bleeding Risk Lip and Gibbs in a 2001 Cochrane Database Systemic Review described the conflicting results among several earlier randomized trials and observational studies. The data collected could not support the use of any form of anticoagulation for patients with HF in sinus rhythm.34 Warfarin increases the risk of fatal/nonfatal bleeding when used for patients with HF. Petitti et al,35,36 in a retrospective study, concluded that the RR for major hemorrhage in patients with treated HF was 1.4 compared with patients without HF, after controlling for age and sex. A meta-analysis of 10 trials involving a total of 5938 patients compared aspirin therapy alone or warfarin plus aspirin for patients with acute coronary syndrome. Warfarin was associated with an increase in major bleeding (0.015 versus 0.006; rate ratio, 2.5 [confidence interval, 1.7–3.7]).37 Among patients with HF, increasing age was found to be directly correlated with major bleeding and a higher rate of thromboembolic events, with a 46% increase in the risk of bleeding for each 10-year increase in age when compared with patients younger than 40 years.38
of anticoagulation in uncomplicated DCM. A suggested prospective study based on the Warfarin Aspirin-Reduced Cardiac Ejection Fraction model that includes subgroups of patients with HF (including nonischemic DCM) may provide clear evidence for or against anticoagulation for this population.
Ongoing Trials Currently, ⬎50% of the targeted population for the National Institutes of Health Warfarin Aspirin-Reduced Cardiac Ejection Fraction trial has been enrolled. This randomized, double-blind, multicenter study will enroll 3201 patients including those with ejection fraction of ⱕ35% and NYHA class I-IV stable HF. Exclusion criteria include the presence of decompensated HF, chronic or paroxysmal AF, mechanical valve, endocarditis, intracardiac mobile or pedunculated thrombus, valvular vegetation, comorbid conditions that may limit survival to ⬍5 years, cardiac surgery, angioplasty, myocardial infarction within the past 3 months, new diagnosis of onset CHF within the past 1 month, and carotid endarterectomy or pacemaker insertion within the past 1 month. Patients are randomized to receive either warfarin and placebo or aspirin and placebo. Data will be compared for rates of all-cause mortality, stroke, and intracranial hemorrhage.39
6. Patane` S, Marte FA. Large left ventricular thrombus. Int J Cardiol 2009;135:44 – 6.
CONCLUSIONS Many observations suggest that ventricular dilation and systolic dysfunction are associated with heightened risk of thrombus formation and embolization. However, most reports failed to exclude patients with other common, coexisting conditions known to independently elevate embolic risk, including AF, valvular heart disease, and coronary atherosclerosis. However, increasing risk paralleling measures of worsening HF suggests that ventricular dysfunction itself may in fact afford risk independent of these confounding conditions. Both ventricular blood mechanics and changes demonstrated in prothrombotic/antithrombotic proteins and mediators provide support for possible mechanisms of clot formation. However, prospective randomized clinical trials have failed to define the risk:benefit of anticoagulant therapy in DCM, largely because of inadequate statistical power, other design flaws, or inadequate control of confounders. The bleeding risk associated with long-term warfarin treatment is significant and may be greater in patients with chronic HF due to altered absorption, hepatic congestion, altered plasma proteins, and drug interactions with the multiple medications used to treat the disease. At this time, routine treatment with warfarin cannot be recommended in the absence of concurrent/complicating conditions, which themselves justify treatment. Ongoing clinical trials will hopefully shed light on and help resolve the question © 2010 Lippincott Williams & Wilkins
REFERENCES 1. Chesebro JH, Ezekowitz M, Badimon L, et al. Intracardiac thrombi and systemic thromboembolism: detection, incidence, and treatment. Annu Rev Med 1985;36:579 – 605. 2. Benjamin EJ, Wolf PA, D’Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946 –52. 3. Padanilam BJ, Prystowsky EN. Atrial fibrillation: goals of therapy and management strategies to achieve the goals. Cardiol Clin 2009;27: 189 –200. 4. Lip GY, Gibbs CR. Anticoagulation for heart failure in sinus rhythm. Cochrane Database Syst Rev 2001;(4):CD003336. 5. De Lorenzo F, Saba N, Kakkar VV. Blood coagulation in patients with chronic heart failure: evidence for hypercoagulable state and potential for pharmacological intervention. Drugs 2003;63:565–76.
7. Elkayam U, Khan S, Mehboob A, et al. Impaired endotheliummediated vasodilation in heart failure: clinical evidence and the potential for therapy. J Card Fail 2002;8:15–20. 8. Mazzone M, La Sala M, Portale G, et al. Review of dilated cardiomyopathies. Dilated cardiomyopathies and altered prothrombotic state: a point of view of the literature. Panminerva Med 2005;47:157– 67. 9. Jafri SM, Ozawa T, Mammen E, et al. Platelet function, thrombin and fibrinolytic activity in patients with heart failure. Eur Heart J 1993;14: 205–12. 10. Ahnert AM, Freudenberger RS. What do we know about anticoagulation in patients with heart failure? Curr Opin Cardiol 2008;23: 228 –32. 11. Chong AY, Freestone B, Patel J, et al. Endothelial activation, dysfunction, and damage in congestive heart failure and the relation to brain natriuretic peptide and outcomes. Am J Cardiol 2006;97:671–5. 12. Jessup M, Abraham WT, Casey DE, et al. Focused update: ACCF/ AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:1977–2016. 13. Albers GW, Amarenco P, Easton JD, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(suppl 6):630S–9S. 14. Ringleb PA, Bousser MG, Ford G, et al. Guidelines for management of ischemic stroke and transient ischemic attack 2008. Cerebrovasc Dis 2008;25:457–507. 15. Sirajuddin RA, Miller AB, Geraci SA. Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm: a critical literature review. J Card Fail 2002;8:48 –53. 16. Fang MC, Go AS, Chang Y, et al. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol 2008;51:810 –5. 17. Spodick DH, Littmann D. Idiopathic myocardial hypertrophy. Am J Cardiol 1958;1:610 –23. 18. Katz SD, Marantz PR, Biasucci L, et al. Low incidence of stroke in ambulatory patients with heart failure: a prospective study. Am Heart J 1993;126:141– 6. 19. Kannel WB, Wolf PA, Verter J. Manifestations of coronary
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disease predisposing to stroke. The Framingham study. JAMA 1983;250:2942– 6. 20. Dunkman WB, Johnson GR, Carson PE, et al. Incidence of thromboembolic events in congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(suppl 6):VI94 –101. 21. Dries DL, Rosenberg YD, Waclawiw MA, et al. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the Studies of Left Ventricular Dysfunction trials. J Am Coll Cardiol 1997;29:1074 – 80.
29. Cokkinos DV, Haralabopoulos GC, Kostis JB, et al. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 2006;8:428 –32. 30. Holmes DR Jr, Kereiakes DJ, Kleiman NS, et al. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95– 109. 31. Orford JL, Fasseas P, Melby S, et al. Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation. Am Heart J 2004;147:463–7.
22. Kenchaiah S, Davis BR, Braunwald E, et al. Antecedent hypertension and the effect of captopril on the risk of adverse cardiovascular outcomes after acute myocardial infarction with left ventricular systolic dysfunction: insights from the Survival and Ventricular Enlargement Trial. Am Heart J 2004;148:356 – 64.
32. Griffith GC, Stragnell R, Levinson DC, et al. A study of the beneficial effects of anticoagulant therapy in congestive heart failure. Ann Intern Med 1952;37:867– 87.
23. Loh E, Sutton MS. Anticoagulation and left ventricular dysfunction: friend or foe? Eur Heart J 1997;18:1039 – 41.
34. Lip GY, Gibbs CR. Anticoagulation for heart failure in sinus rhythm. Cochrane Database Syst Rev 2001;(4):CD003336.
24. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251–7.
35. Petitti DB, Storm BL, Melmon KL. Prothrombin time ratio and other factors associated with bleeding in patients treated with warfarin. J Clin Epidemiol 1989;42:759 – 64.
25. Hays AG, Sacco RL, Rundek T, et al. Left ventricular systolic dysfunction and the risk of ischemic stroke in a multiethnic population. Stroke 2006;37:1715–9.
33. Gibelin P. Anticoagulant treatment and dilated cardiomyopathy. Arch Mal Coeur Vaiss 1995;88(suppl 4):617–21.
36. Graham SP. Anticoagulation and heart failure. Curr Cardiol Rep 2001;3:72–7.
26. Freudenberger RS, Hellkamp AS, Halperin JL, et al. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation 2007;115:2637– 41.
37. Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005;143:241–50.
27. Cleland JG, 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.
38. Van der Meer FJ, Rosendaal FR, Vandenbroucke JP, et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993;153:1557– 62.
28. Massie BM, Krol WF, Ammon SE, et al. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. J Card Fail 2004;10:101–12.
39. Pullicino P, Thompson JL, Barton B, et al. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail 2006;12:39 – 46.
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Volume 339, Number 6, June 2010
Dilated Cardiomyopathy and Role of Antithrombotic Therapy Ashraf S. Abdo, MD, Rhonda Kemp, CFNP, Jennifer Barham, ACNP and Stephen A. Geraci, MD
Abstract: Background: There is no consensus as to whether anticoagulation has a favorable risk:benefit in reducing thromboembolic events in patients with heart failure (HF) secondary to dilated cardiomyopathy who do not suffer from atrial fibrillation or primary valvular disease. Methods and Results: The literature reviewed on this topic included most recent and ongoing studies that assessed the use of anticoagulation for this population. Several large retrospective studies showed an increased risk of thromboembolic events among patients with depressed left ventricular function. The relative risk of stroke in individuals with HF from all causes was found to be 4.1 for men and 2.8 for women, but confounding comorbidities (such as atrial fibrillation and coronary artery disease) were commonly present. Currently, there are no randomized prospective trials to guide the use of antithrombotics for these patients, and the risk of bleeding secondary to anticoagulation has limited the use of oral anticoagulants for prevention of thrombosis. Among patients with HF, increasing age directly correlates with both major bleeding and thromboembolic events, with a 46% relative risk of bleeding for each 10-year increase in age older than 40 years. Conclusions: To date, there is no agreement on appropriate antithrombotic treatment (if any) for primary thromboembolism prophylaxis in patients with dilated cardiomyopathy with sinus rhythm. In recent years, several promising prospective trials were terminated prematurely due to inadequate enrollment. The Warfarin Aspirin-Reduced Cardiac Ejection Fraction trial may provide evidence regarding the use of anticoagulation for patients with decreased myocardial function. Key Indexing Terms: Cardiomyopathy; Antithrombotic therapy; Anticoagulation. [Am J Med Sci 2010;339(6):557–560.]
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eft ventricular systolic dysfunction (LVD) and chronic systolic heart failure (HF) predispose to intraventricular thrombus formation and embolization resulting in stroke, peripheral arterial occlusion, or pulmonary embolism.1 In cases with associated underlying valvular disease, previous myocardial infarction, ventricular aneurysm, and/or atrial fibrillation (AF), sufficient data exist to support a primary preventive strategy with low-intensity warfarin therapy, with which therapeutic benefit exceeds risk in the majority of patients.2,3 In patients with sinus rhythm, normal valve structure, and no previous infarction, the risk:benefit of warfarin remains unclear in the absence of previously documented cardioembolic events or echocardiographically demonstrated mural thrombi.4 – 6 Dilated cardiomyopathy (DCM) may result from a host of conditions including myocarditis, chronic metabolic disorders, chronic intoxications, postpartum pathology, and autoimFrom the Department of Medicine (ASA), University of Mississippi School of Medicine—G.V. (Sonny) Montgomery VA Medical Center, Jackson, Mississippi; G.V. (Sonny) Montgomery VA Medical Center (RK, JB), Jackson, Mississippi; and Pulmonary/CCM Division (SAG), University of Mississippi School of Medicine, Jackson, Mississippi. Submitted November 20, 2009; accepted in revised form December 9, 2009. Correspondence: Ashraf S. Abdo, MD, Department of Medicine, University of Mississippi School of Medicine–G.V. (Sonny) Montgomery VA Medical Center, 1500 E. Woodrow Wilson Drive, Jackson, MS, 39216 (E-mail: [email protected]).
mune disease, but at least one half are idiopathic. Chamber dilatation, reduced wall motion, and decreased stroke volume associated with DCM contribute to blood stasis, whereas changes in the endothelial endocardial surface may reduce its antithrombotic qualities.7 In addition, patients with DCM have higher levels of fibrinopeptide A, antithrombin III, circulating fibrinogen, and D-dimer.8,9 Reduced nitric oxide production and elevated concentrations of von Willebrand factor have been reported. Both platelets adhesion and endothelial monocyte activity are increased. As a result, DCM demonstrates many prothrombotic characteristics.10,11 Current American Heart Association/American College of Cardiology and American College of Chest Physicians guidelines do not recommend the use of warfarin in patients with DCM.12,13 The European Stroke Initiative failed to provide clear recommendations for primary preventive anticoagulation in this setting.14 Despite this, warfarin is frequently prescribed in this population. The purpose of this article is to summarize available data on risks and benefits of anticoagulation for these patients.
METHODS A PubMed/MEDLINE search review was performed using the key words “dilated cardiomyopathy” and “anticoagulation.” We followed by another search using the key words “heart failure” and “anticoagulation.” A separate search using the key words “thromboembolism” and “heart failure” was performed. Forty randomized retrospective and prospective studies were selected from the period from 1950 to 2009. Case reports and reviews were excluded from the discussion.
RESULTS Dilated Cardiomyopathy and Thromboembolism There is a wide variation in prevalence estimates for clinical events (stroke, pulmonary, and peripheral thromboembolism) in DCM, ranging from 3% to 50%, and in incidence estimates, ranging from 1.5 to 3.5 per 100 patient years.15 Most retrospective reports, linking ejection fraction, New York Heart Association (NYHA) class, VO2, and other disease severity parameters to stroke risk included patients with other known risk factors, most often atherosclerotic coronary disease (postinfarction). Similarly, most early clinical trials of warfarin therapy had similar confounders and were not prospective double blind or placebo controlled.16 In this review of the available literature, varied incidences of thromboembolic events were reported. Reports from the 1950s suggested a 50% prevalence of thromboembolic evidence at autopsy on HF cases.17 Later, Katz et al18 reported a lower risk of thromboembolism (1.7 thromboembolic events per 100 patient years) in patients with congestive HF (CHF). On the basis of the Framingham study, Kannel et al19 observed that coronary artery disease (CAD) and cardiac failure added to the risk of stroke associated with hypertension. They noted that
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CAD increased the risk of stroke in the absence of hypertension or HF, but the risk was greatly increased when these coexisted. The relative risk (RR) of stroke in individuals with HF in this study was 4.1 for men and 2.8 for women, but comorbidities (such as AF and CAD) were simultaneously present. A series of recent reports established the rate of thromboembolism at ⬍3% for patients with NYHA class II and III HF without a coexisting AF. In retrospective posthoc analyses of the Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT) I and II, Dunkman et al followed up 642 men with HF (V-HeFT I) for an average of 2.28 years. Their mean left ventricular ejection fraction (LVEF) was 30%, and functional capacity was at the interface of classes II and III (peak exercise oxygen consumption of 14.7 ml/kg/min). The incidence of all thromboembolic events was 2.7 per 100 patient years without warfarin use. In V-HeFT II, 804 men were followed up for an average of 2.56 years. Their mean LVEF was 29%. Their functional capacity was at the interface of classes II and III, with a peak exercise oxygen consumption of 13.7 mL/kg min. The incidence of all thromboembolic events without warfarin was 2.1 per 100 patient years and was not reduced by incidental treatment with warfarin. These authors concluded that the incidence of thromboembolism and stroke in class II-III CHF is quite low and that warfarin treatment is likely unwarranted.20,21 The Survival and Ventricular Enlargement trial showed an overall risk of stroke of 8.1% at 5 years. The RR of stroke almost doubled with LVEF ⬍28% and increased by 18% for every 5% reduction in ejection fraction below 28%.22–24 The annual thromboembolic rate in Studies of Left Ventricular Dysfunction was higher in women (2.4%) than in men (1.8%). On multivariate analysis, a decrease in ejection fraction remained independently associated with thromboembolic risk in women (RR per 10% decrease 1.53, 95% confidence interval: 1.06 –2.20, P ⫽ 0.02).21 Hays et al25 concluded that LVD, even of mild degree, is independently associated with an increased risk of ischemic stroke. The study included a subset of patients (total of 558) from the Northern Manhattan Study. They found that LVD of any degree was more frequent in stroke patients (24.1%) than in age-, sex-, and sex-matched controls (4.9%, P ⬍ 0.0001). The adjusted odds ratio for any degree of LVD was 3.92. In the Sudden Cardiac Death in HeFT, 2521 patients with moderate HF were studied for a median of 45.5 months. Of the total population, 2114 had no history of AF. The incidence of any thromboembolic event (stroke, peripheral, or pulmonary embolism) was correlated with predictors for thromboembolism and LVEF. Patients were randomized to receive amiodarone, implanted cardioverter defibrillators (ICDs), or placebo. The incidence of any thromboembolic event over 4 years was 4.0%: 2.6% in patients randomized to amiodarone, 3.2% for patients randomized to ICD, and 6.0% in patients randomized to placebo.26 Reviewed results for the above studies did not analyze the outcomes in correlation to various subgroups of HF. The question of ischemic versus nonischemic DCM as risk factors that may indicate anticoagulation was not addressed. Authors looked at subset of patients with different degrees of HF, but further breakdown of the causes for HF was not included. It is unclear whether amiodarone could have reduced transient AF to account for the lower stroke risk; however, ICDs would have had no such effect.
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Trials of Anticoagulation Several formal, prospective randomized studies have attempted to answer the question of anticoagulation for patient with decreased ejection fraction without AF. The Warfarin Aspirin Study in Heart Failure trial was an open-label pilot study of 279 patients with LVD randomized to 3 groups: no therapy, aspirin (300 mg daily) therapy alone, and warfarin therapy (international normalized ratio target of 2.5). The mean follow-up was 27 ⫾ 1 months. Patients receiving warfarin did not have fewer hospitalizations for cardiovascular complications, mainly HF (P ⫽ 0.44). Twenty-six (26%), 29 (32%), and 23 (26%) patients randomized to no antithrombotic treatment, aspirin, and warfarin, respectively, showed no difference in combined primary end point of all-cause mortality, nonfatal infarction, and nonfatal stroke. It was concluded that in this lowpowered pilot study, no benefits of aspirin or warfarin were demonstrated for patients with HF in sinus rhythm.27 The Warfarin and Antiplatelet Therapy in Heart Failure study was a randomized, double-blind, 3-arm study of warfarin versus aspirin versus clopidogrel. Patients who had either indications for or contraindications to any study medication were excluded. The study, designed to include 4500 patients, recruited only 1587 patients with HF and ejection fraction ⬍30% due to poor enrollment. Early data favored warfarin over aspirin in preventing nonfatal stroke (0.7% versus 2.1%). A higher incidence of hemorrhage with warfarin was observed as well. Differences failed to reach statistical significance.13,28 The HEart failure Long-term Antithrombotic Study was a multicenter, randomized, double-blind, placebo-controlled trial.29 It studied 312 patients for a total follow-up of 2 years. Patients with NYHA class II-IV HF and ejection fraction ⬍35% were enrolled. Patients with DCM were randomized to receive either warfarin or placebo. Patients with ischemic heart disease were randomized to aspirin 325 mg or warfarin. Patients who developed AF during the course of the trial were excluded from the analysis. Data showed that the total embolic events were rare in HF regardless of treatment. An incidence of 2.2 embolic events per 100 patient years with no significant difference between groups was identified. No peripheral or pulmonary emboli were reported. The value of these findings is unclear due to insufficient enrollment. Coagulants as a Single, Dual, and Triple Therapy Antithrombotic agents have established benefit in both primary and secondary prevention of cardiovascular disease.30 Dual antiplatelet therapy with aspirin and thienopyridine (usually clopidogrel) has established the benefit for most manifestations of CAD and cerebrovascular disease. Present guidelines recommend aspirin in patients with chronic HF to reduce cardiovascular mortality, but no available data suggest that it results specifically in reduction in thromboembolic risk, either alone or in combination with warfarin.31 In 1952, Griffith et al reported a decreased incidence of pulmonary embolism and overall mortality for patients with HF receiving anticoagulation. However, their patient population included those with AF and rheumatic valvular disease.32 Forty years later, Gibelin concluded that ventricular thrombi are more common when left ventricular fractional shortening is decreased (⬍11% ⫽ 80% of thrombi). Because this study population included patients with AF and left atrial thrombi, further studies were recommended to determine the need of anticoagulation for those patients with DCM without an intracardiac thrombus and/or AF.33 Volume 339, Number 6, June 2010
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Bleeding Risk Lip and Gibbs in a 2001 Cochrane Database Systemic Review described the conflicting results among several earlier randomized trials and observational studies. The data collected could not support the use of any form of anticoagulation for patients with HF in sinus rhythm.34 Warfarin increases the risk of fatal/nonfatal bleeding when used for patients with HF. Petitti et al,35,36 in a retrospective study, concluded that the RR for major hemorrhage in patients with treated HF was 1.4 compared with patients without HF, after controlling for age and sex. A meta-analysis of 10 trials involving a total of 5938 patients compared aspirin therapy alone or warfarin plus aspirin for patients with acute coronary syndrome. Warfarin was associated with an increase in major bleeding (0.015 versus 0.006; rate ratio, 2.5 [confidence interval, 1.7–3.7]).37 Among patients with HF, increasing age was found to be directly correlated with major bleeding and a higher rate of thromboembolic events, with a 46% increase in the risk of bleeding for each 10-year increase in age when compared with patients younger than 40 years.38
of anticoagulation in uncomplicated DCM. A suggested prospective study based on the Warfarin Aspirin-Reduced Cardiac Ejection Fraction model that includes subgroups of patients with HF (including nonischemic DCM) may provide clear evidence for or against anticoagulation for this population.
Ongoing Trials Currently, ⬎50% of the targeted population for the National Institutes of Health Warfarin Aspirin-Reduced Cardiac Ejection Fraction trial has been enrolled. This randomized, double-blind, multicenter study will enroll 3201 patients including those with ejection fraction of ⱕ35% and NYHA class I-IV stable HF. Exclusion criteria include the presence of decompensated HF, chronic or paroxysmal AF, mechanical valve, endocarditis, intracardiac mobile or pedunculated thrombus, valvular vegetation, comorbid conditions that may limit survival to ⬍5 years, cardiac surgery, angioplasty, myocardial infarction within the past 3 months, new diagnosis of onset CHF within the past 1 month, and carotid endarterectomy or pacemaker insertion within the past 1 month. Patients are randomized to receive either warfarin and placebo or aspirin and placebo. Data will be compared for rates of all-cause mortality, stroke, and intracranial hemorrhage.39
6. Patane` S, Marte FA. Large left ventricular thrombus. Int J Cardiol 2009;135:44 – 6.
CONCLUSIONS Many observations suggest that ventricular dilation and systolic dysfunction are associated with heightened risk of thrombus formation and embolization. However, most reports failed to exclude patients with other common, coexisting conditions known to independently elevate embolic risk, including AF, valvular heart disease, and coronary atherosclerosis. However, increasing risk paralleling measures of worsening HF suggests that ventricular dysfunction itself may in fact afford risk independent of these confounding conditions. Both ventricular blood mechanics and changes demonstrated in prothrombotic/antithrombotic proteins and mediators provide support for possible mechanisms of clot formation. However, prospective randomized clinical trials have failed to define the risk:benefit of anticoagulant therapy in DCM, largely because of inadequate statistical power, other design flaws, or inadequate control of confounders. The bleeding risk associated with long-term warfarin treatment is significant and may be greater in patients with chronic HF due to altered absorption, hepatic congestion, altered plasma proteins, and drug interactions with the multiple medications used to treat the disease. At this time, routine treatment with warfarin cannot be recommended in the absence of concurrent/complicating conditions, which themselves justify treatment. Ongoing clinical trials will hopefully shed light on and help resolve the question © 2010 Lippincott Williams & Wilkins
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