Expert Review: Heart Failure, Thrombosis

Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis.

Background and objectives:
HF is a growing public health problem worldwide, and it is associated with an increased risk of left ventricular thrombus formation and cerebral embolism due to endothelial dysfunction, reduced blood flow and underlying state of hypercoagulability2-5. In the population-based Framingham Heart Study, the relative risk of stroke in individuals with HF compared to those without HF was 4.1 for men and 2.8 for women6. Antiplatelet therapy is commonly prescribed in HF patients in sinus rhythm since ischemic cardiomyopathy is the principal underlying cause7,8. Conversely, oral anticoagulant therapy, that includes warfarin and new oral anticoagulant therapies, is commonly prescribed in HF patients with AF since it has been shown more efficacious than aspirin in reducing embolic risk7,9. International guidelines recommend the use of vitamin K antagonists in HF patients with AF to prevent cardioembolic risk but oral anticoagulant therapy is not indicated in HF patients without AF10-12.

The objective of the present study was to determine the effect of warfarin when compared to aspirin on all-cause mortality, stroke, myocardial infarction, hospitalizations and major bleedings in heart failure patients and normal sinus rhythm.

Methods
A search of relevant studies incluyed all cited in Pubmed, EMBASE, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from January 1966 to June 2012. Randomized controlled trials that included comparison of warfarin versus aspirin were included. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects models. Of all of the articles identified by the initial search 4 were finally included, enrolling 3663 patients without AF

Results
All the 4 studies included (3,663 participants, mean follow-up 2.3 years) reported results on all-cause mortality, stroke, myocardial infarction, hospitalizations and major bleedings. The pooled relative risks (RRs) for the above mentioned endpoints were 1.01 (95% CI: 0.89-1.14), 0.56; 95% CI, 0.38-0.82), 1.01 (95% CI: 0.69 to 1.48), 0.88 (95% CI: 0.63 to 1.22), and 1.95 (95% CI: 1.37-2.76), respectively, for use of warfarin versus use of aspirin.
There was no significant difference between the 2 treatments for the primary end point (P=0.31). Warfarin (versus aspirin) was associated with lower risk of any stroke (P=0.003) and ischemic stroke (RR, 0.45; 95% CI, 0.24-0.86; P=0.02) but had a neutral effect on death (RP=0.89) and a higher risk of major bleeding (RR, 1.95; 95% CI, 1.37-2.76; P=0.0002).

Conclusion
Use of warfarin reduces the risk of stroke in half in patients with heart failure in sinus rhythm, but doubles their risk for major bleedings compared to aspirin. Use of warfarin or aspirin share similar risks for all-cause mortality, myocardial infarction and hospitalizations in this population. Therefore, the use of warfarine in these patients is not justified.

Clinical Impact:
Given the finding that warfarin was associated with an increased risk of bleeding, there is no compelling reason to use warfarin rather than aspirin in patients with heart failure who are in sinus rhythm.
However, warfarin reduces the incidence of ischemic stroke. This raises two consequences. Firstly, it is possible to speculate that aspirin could be indicated in patients with high risk of bleeding, whereas warfarin could be preferred in patients with high thromboembolic risk. Secondly, no evidences are provided regarding the use of new oral anticoagulants (oral direct thrombin inhibitors, oral factor Xa inhibitors) which seem to offer a different risk–benefit profile compared to warfarin and might induce a reduction in ischemic stroke rates with less risk of major bleeding. Thus, a head to head comparison between warfarin and new anticoagulants (rivaroxaban, apixaban and dabigatran), with antiplatelet therapy might be of great interest in HF patients in sinus rhythm. Further studies are needed to clarify the role of antitrombotic therapy in HF patients in sinus rhythm, particularly in the subpopulation with non ischemic etiology.

Corresponding author from original paper

Bruce Ovbiagele, MD, MSc, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas St, CSB 301 MSC 606, Charleston, SC 29425-6160.
E-mail Ovibes@musc.edu

Citation: Lee M, Saver JL, Hong KS, Wu HC, Ovbiagele B. Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis. Circ Heart Fail. 2013 (2):287-92.

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