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Heart failure and anticoagulation: The verdict is still out
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Anticoagulation with warfarin has been shown to be beneficial in patients with atrial fibrillation and ischemic heart disease for reduction of stroke, MI and death, but the benefits of warfarin in patients with HF remain unclear. Current guidelines for anticoagulation in the diverse HF population are in conflict, not only with each other, but also with the available evidence.
Conflicting trials
More than a decade ago, a post-hoc cohort analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trial compared outcomes of 861 patients taking warfarin (Coumadin, Bristol-Myers Squibb) with 5,652 patients not taking warfarin. The primary outcome measured, adjusted for baseline differences using a Cox regression analysis, was the occurrence of death and length of survival. Warfarin therapy was associated with reduced all-cause mortality (HR=0.76; 95% CI, 0.65-0.89) and CV mortality (HR=0.72; 95% CI, 0.61-0.86). Warfarin was also associated with decreased hospitalization due to HF or death (HR=0.82; 95% CI, 0.72-0.93). However, there were no reductions in fatal noncardiac vascular events, such as stroke or pulmonary embolism. The SOLVD investigators concluded that warfarin was significantly associated with improved CV morbidity and mortality in patients with HF.
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The prospective, open-label Warfarin/Aspirin Study in Heart Failure (WASH) trial, published in 2004, evaluated the role of warfarin, aspirin or no antithrombotic therapy in HF patients. A total of 279 patients were randomly assigned to either 300 mg of aspirin, warfarin with a target INR of 2.5 or no antithrombotic therapy. The primary composite endpoint of death, nonfatal MI and nonfatal stroke showed no significant differences between the three treatment arms (P=.22). Secondary outcomes were also not significantly different between the groups, except for all-cause hospitalization, which showed a worse outcome for patients in the aspirin arm (P=.044). Episodes of major bleeding were similarly rare in all three treatment groups, with zero in the no-treatment group, one in the aspirin group and four in the warfarin group. Although the WASH investigators concluded that their results provide no clear evidence for the support of aspirin or warfarin in HF patients, this trial was limited by its small sample size, resulting in limited power to detect a difference.
The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, a large, prospective, multicenter study published in 2009, evaluated the role of antithrombotic therapy in 1,587 NYHA Class II to IV HF patients in normal sinus rhythm and ejection fraction ≤35%. Patients were randomly assigned to one of three treatment arms: aspirin 162 mg daily or clopidogrel 75 mg daily in a double blind, double dummy fashion, or open-label warfarin with a target INR of 2.5 to 3. The primary composite endpoint of all-cause mortality, nonfatal MI or nonfatal stroke had an unadjusted HR of 0.98 (95% CI, 0.86-1.12) in the warfarin vs. aspirin arm; 1.08 (95% CI, 0.83-1.40) in the clopidogrel vs. aspirin arm; and 0.89 (95% CI, 0.68-1.16) in the warfarin vs. clopidogrel arm. Although warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel, major bleeding was more significant in the warfarin arm compared with clopidogrel (P<.01), but similar to aspirin (P=.22). The researchers concluded that the primary outcome and mortality data do not support their hypotheses that warfarin is superior to aspirin or that clopidogrel is superior to aspirin in this HF population. However, due to slow recruitment, WATCH recruited fewer than half the planned sample size and terminated follow-up a year earlier than originally planned, resulting in very low power to detect any difference.
What current guidelines say
Current recommendations regarding anticoagulation in patients with HF are limited by conflicting clinical trials and insufficient evidence. The American College of Chest Physicians recommends for patients with HF of non-ischemic etiologies against the routine use of aspirin or warfarin (Grade 1B). The Heart Failure Society of America recognizes HF patients as at-risk for thromboembolic events and recommends warfarin therapy for those HF patients with AF, recent large anterior MI or LV thrombus (Evidence Level A), and recommends consideration for warfarin therapy in dilated cardiomyopathy patients with LVEF ≤35% (Evidence Level C). The American College of Cardiology/American Heart Association recommend anticoagulation with warfarin in most patients with a previous embolic event or in those who have AF, and recommend considering warfarin in patients with underlying disorders that place HF patients at an increased risk for thromboembolic events, as well as in patients with familial dilated cardiomyopathy and a history of thromboembolism in first-degree relatives.
Conclusion
Available evidence is conflicting regarding the role of antithrombotic therapy in patients with HF. Current clinical practice guidelines and recommendations have also not reached definitive conclusions. Additional data are needed to clearly define the role that antithrombotic therapy should play in HF patients. Hopefully, results from the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, which has enrolled more than 3,000 patients and is due to be completed early in 2012, will provide definitive evidence. Considering the risk vs. benefit of using antithrombotic therapy in this special population, its use must be considered on an individual patient basis.
For more information:
- Al-Khadra A. J Am Coll Cardiol. 1998;31:749-53.
- Becker R. Chest. 2008;133(6 Suppl):776S-814S.
- Cleland J. Am Heart J. 2004;148:157-64.
- Heart Failure Society of America. J Card Fail. 2010;16:475-539.
- Hunt S. Circulation. 2009;119:e391-e479.
- Massie B. Circulation. 2009;119:1616-1624.
Corrine Young, PharmD, BCPS, is a clinical pharmacist at Jeanes Hospital, Temple University Health System, Philadelphia.
Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor, department of pharmacotherapy and translational research, College of Pharmacy, and Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, Fla. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. For suggestions of future topics for this column, please contact Dr. Cooper-DeHoff, dehoff@cop.ufl.edu.
Disclosures: Drs. Cooper-DeHoff and Young report no relevant financial disclosures.