Findings from the current study demonstrate that in patients with advanced chronic systolic HF without AF and/or previous thromboembolic events, the prevalence of warfarin use was relatively high. Nevertheless, our data suggest that despite achieving a mean therapeutic INR, warfarin use did not provide any intrinsic survival benefit in patients with advanced chronic systolic HF who had no other established indications for anticoagulation. These findings are important because many practicing physicians perceive advanced chronic systolic HF as a pre-thrombotic stage and prescribe warfarin, even though current ACC/AHA guidelines have no clear recommendation on this.4
Thus, it is possible that warfarin may be prescribed without any proven benefit and with the potential increased risk of bleeding and other adverse effects.21
The unadjusted association of warfarin use with increased risk of cardiovascular mortality is rather surprising given that pre-match patients receiving warfarin were younger, had lower or similar baseline prevalences of cardiovascular comorbidities (). These suggest strong confounding by a history of ventricular fibrillation, higher symptom burden, and lower mean LVEF and RVEF, all of which are known to increase risk of cardiovascular death. The near significant unadjusted association between warfarin use and sudden cardiac death is likely due to increased prevalence of ventricular fibrillation among warfarin users. Despite a higher burden of HF symptoms among warfarin users, the lack of significant unadjusted associations of warfarin use with HF mortality and HF hospitalization are intriguing, but may suggest that LVEF and HF symptoms were rather weak confounders.
The lack of significant associations of warfarin use with mortality and hospitalization among matched patients suggests lack of an intrinsic effect of warfarin on outcomes in patients with advanced systolic HF without AF and/or thromboembolic disorders. Although a low LVEF is often considered an indication for warfarin use in these patients, findings from our subgroup analysis suggest that the association between warfarin use and all-cause mortality was similar regardless of LVEF categories. The lack of an intrinsic effect of warfarin in advanced systolic HF patients without AF and/or thromboembolic events, despite a therapeutic INR, suggest that thromboembolic events may not underlie mechanisms of death or hospitalization in these patients. Findings from our study provide further evidence supporting the current guideline recommendations that the use of warfarin in HF patients should be restricted to those with AF and/or previous thromboembolic events.4
There is conflicting evidence in the literature regarding the role of warfarin in patients with advanced systolic HF without atrial fibrillation or other indications for anticoagulation.5, 22
In one study warfarin use was associated with reduced mortality and morbidity in mild to moderate (two third had NYHA class I–II symptoms) chronic systolic HF patients.7
Our study is distinguished by more advanced HF patients (all NYHA III–IV symptoms) and the use of propensity-matched design that allowed the assembly of a balanced cohort. Findings from our study are consistent with those from the largest randomized clinical trial of anticoagulation in HF patients with normal sinus rhythm to date in which there was no difference in outcomes between patients receiving warfarin (open label), aspirin or clopidogrel.9
However this study was not considered definitive since it was terminated prematurely because of slow enrollment resulting in estimated power of only 40% to detect 20% difference. In the absence of another large clinical trial with adequate power, observational studies such as ours adds further evidence of lack of benefit for therapeutic anticoagulation in these patients.
As in all observational studies, a key limitation of our study is potential confounding by an unmeasured covariate. A sensitivity analysis would normally help quantify the degree of a hidden bias that would need to be present to invalidate conclusions based on significant associations in an observational study. However, sensitivity analyses can only be performed if the observed association is statistically significant.23
Another limitation is lack of data on other cardiovascular events including stroke and adverse events such as bleeding. In conclusion, in patients with advanced chronic systolic HF without AF and/or other indications for anticoagulation, despite a mean INR which was therapeutic, the use of warfarin was not associated with clinical outcomes.