Figure 1

Heart failure with reduced ejection fraction (HFrEF) is a growing clinical problem worldwide associated with high morbidity and mortality. Chronic heart failure is associated with a hypercoaguable state with increased incidence of left ventricular (LV) thrombi, ischemic strokes, and other thromboembolic events (Figure 1), even in the setting of sinus rhythm.¹ Due to this, there is rationale for the use of systemic anticoagulation in these patients in an effort to reduce morbidity and mortality. Initial trials showed improved outcomes in patients on systemic anticoagulation with reduced rates of ischemic strokes, though these studies included many patients with underlying atrial fibrillation or valvular disease, making their interpretation in the population with sinus rhythm difficult.^2,3

There were two early prospective randomized studies that specifically focused on patients with HFrEF in sinus rhythm, namely, the Warfarin/Aspirin Study in Heart Failure (WASH) and the Heart Failure Long-Term Antithrombotic Study (HELAS).^4,5 Both of these studies randomized patients with reduced ejection fraction (EF) ≤35% to warfarin, aspirin (300-325 mg), or placebo. The primary outcome for WASH was a composite of death, nonfatal myocardial infarction (MI), or nonfatal stroke, and for HELAS the primary outcome was a composite of nonfatal stroke, peripheral embolism, MI, re-hospitalization, heart failure exacerbation, or death from any cause. HELAS randomized 197 patients to the three treatment arms and WASH randomized 279 patients. Both studies showed no significant difference between the three treatment arms in terms of the primary endpoints, and, therefore, did not support the use of anticoagulation in this patient population.

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial was the first large randomized trial designed to evaluate the optimal antithrombotic treatment in patients with HFrEF in sinus rhythm.⁶ The two primary objectives were to show the superiority of warfarin compared to aspirin, and the superiority of clopidogrel compared to aspirin in preventing a composite of death, nonfatal MI, or nonfatal stroke. The 1,587 patients who were in sinus rhythm with an EF ≤35% and NYHA class II-IV heart failure were randomized to open-label warfarin (target international normalized ratio [INR] 2.5-3.0), or double-blinded treatment with clopidogrel 75 mg or aspirin 162 mg daily. The mean follow-up time was 1.9 years with 3,073 patient-years of exposure. For the primary endpoint, the hazard ratio (HR) for warfarin versus aspirin was 0.98 (95% confidence interval [CI], 0.86 to 1.12; P = 0.77) and the HR for clopidogrel versus aspirin was 1.08 (95% CI, 0.83 to 1.40; P = 0.57). While the data did not support the primary hypotheses for use of systemic anticoagulation with warfarin to reduce the primary composite endpoint, there was a statistically significant reduction in the number of nonfatal strokes in the warfarin group when compared to either the aspirin or clopidogrel groups (0.2% vs. 1.7%, P = 0.0095 and 0.2% vs. 2.1%, P = 0.0031, respectively). When central nervous system (CNS) bleeding or nonfatal stroke was used as a composite secondary endpoint, however, there was no statistically significant difference among the three groups. These data increased concern that the overall benefit was low given a small number of ischemic events, and that the safety profile of systemic anticoagulation did not support its potential benefit. The overall small trial size and low incidence of events were the main limitation in these two studies.

The Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm (WARCEF) trial was designed to be a larger, randomized, double-blinded trial specifically looking at warfarin versus aspirin use in the HFrEF patient population in sinus rhythm.⁷ The primary outcome was the time to first event that included a composite of death from any cause, intracerebral hemorrhage, or ischemic stroke to further elucidate the efficacy and safety of anticoagulation in this population. Similar to the WATCH trial, there was no significant difference in the primary outcome between the two groups (HR with warfarin of 0.93; 95% CI 0.79 to 1.10; P = 0.40). This study did show a significant reduction (P = 0.005) in ischemic stroke rate in the warfarin treatment group, with 0.72 events per 100 patient-years versus 1.36 events per 100 patient-years in the aspirin treatment group (Table 1). And while there was no statistically significant difference in intracerebral or intracranial hemorrhage between the two treatment groups, there was a significant increase in major bleeding (odds ratio 2.05, 95% CI, 1.36 to 3.12; P≤0.001) in the warfarin group primarily driven by an increase in major gastrointestinal bleeding. Given the overall low incidence of ischemic strokes in this population, the increased risk of major bleeding again outweighed the benefit of ischemic stroke reduction.

Table 1

					Warfarin (N = 1142)			Aspirin (N = 1163)			Hazard Ratio (95% CI)	P Value
					Unadjusted rate of events/100 patient-years			Unadjusted rate of events/100 patient-years
Primary Outcome: Death, Ischemic Stroke, or Intracerebral Hemorrhage					7.47			7.93			0.93 (0.79-1.10)	0.4
	Composite
	Components
		Death			6.63			6.52			1.01 (0.85-1.20)	0.91
		Ischemic Stroke			0.72			1.36			0.52 (0.33-0.82)	0.005
		Intracerebral Hemorrhage			0.12			0.05			2.22 (0.43-11.66)	0.35

Modified from Homma S, Thompson JLP, Pullicino PM, et al. Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm. N Engl J Med 2012;366:1859-69.

Notable aspects of these studies include the absence of a placebo arm due to a sizable proportion of patients with ischemic cardiomyopathy who had an indication for aspirin, and the specific exclusion of patients with known LV thrombi or prior thromboembolic events. Current ACC/AHA Heart Failure Guidelines⁸ currently provide a class I indication for use of an oral anticoagulant in patients with heart failure with atrial fibrillation and an additional risk factor (hypertension, diabetes mellitus, previous stroke or transient ischemic attack, or ≥75 years of age), and a class IIa indication for anticoagulation in patients with heart failure and atrial fibrillation alone. The use of anticoagulation in patients with heart failure and sinus rhythm without a prior thromboembolic event or known cardioembolic source, such as an LV thrombus, is considered class III (no benefit and may cause harm). Anticoagulation in the population with a known LV thrombus is based on expert opinion, though prior trials have been small with conflicting data.^9-11

In summary, while there is an increased risk of thromboembolic events in patients with HFrEF, there are no convincing data to support use of systemic anticoagulation with vitamin K antagonists (VKAs) in these patients who remain in sinus rhythm.^12-15 While warfarin use has been shown to significantly reduce the rate of ischemic strokes in this population when compared to aspirin, the increased rate of major bleeding while on a VKA outweighs the benefit. The novel oral anticoagulants with improved safety profiles are an attractive option in this population with the potential to see overall thromboembolic risk reduction without increased risk of major hemorrhage, though this will need to be shown in clinical trials.

References

1. Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow's triad revisited. J Am Coll Cardiol 1999;33:1424-6.
2. Anderson G, Hull E. The effects of dicumarol upon the mortality and incidence of thromboembolic complications in congestive heart failure. Am Heart J 1950;39:697-702.
3. Griffith GC, Stragnell R, Levinson DC, Moore Fj, Ware G. A study of the beneficial effects of oral anticoagulant therapy in congestive heart failure. Ann Intern Med 1952;37:867-87.
4. Cleland JG, Findlay I, Jafri S. The Warfarin/Aspirin Study in Heart failure (WASH): A randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148:157-164.
5. Cokkinos D, Haralabopoulos GC, Kostis JB, Toutouzas PK; HELAS investigators. Efficacy of antithrombotic therapy in chronic heart failure: The HELAS Study. Eur Heart J 2006; 2006;8:428-432.
6. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial. Circulation 2009; 119:1616-24.
7. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012; 366: 1859-69.
8. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-e239.
9. Ciaccheri M, Castelli G, Cecchi F. Lack of correlation between intracavitary thrombosis detected by cross sectional echocardiography and systemic emboli in patients with dilated cardiomyopathy. Br Heart J 1989;62:26-29.
10. Falk R, Foster E, Coats MH.. Ventricular thrombi and thromboembolism in dilated cardiomyopathy: A prospective follow-up study. Am Heart J 1991; 123:136-142.
11. Stratton RJ, Resnick AD. Increased embolic risk in patients with left ventricular thrombi. Circulation 1987;75:1004-1011.
12. Lip GY, Ponikowski P, Andreotti F, et al. Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm. Thromb Haemost 2012; 108:1009–1022.
13. Lip GY, Ponikowski P, Andreotti F, et al. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Eur Heart J Heart Fail 2012:14:681-695.
14. Lip GY, Gibbs, CR. Anticoagulation for heart failure in sinus rhythm: a Cochrane systematic review. QJM 2002; 95:451-459.
15. Rengo G, Pagano G, Squizzato A, et al. Oral anticoagulation therapy in heart failure patients in sinus rhythm: a systematic review and meta-analysis. PLOS ONE 2014;8:e52952.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Cardiomyopathies, Cerebral Hemorrhage, Confidence Intervals, Diabetes Mellitus, Embolism, Ficus, Heart Failure, Hypertension, Ischemic Attack, Transient, Myocardial Infarction, Risk Factors, Risk Reduction Behavior, Stroke, Thromboembolism, Ticlopidine, Vitamin K, Warfarin

< Back to Listings