TTR and Outcomes in the WARCEF Trial | Journal Scan

Study Questions:

What is the relationship between the quality of warfarin care as measured by the time in the therapeutic range (TTR) and clinical outcomes among heart failure patients in sinus rhythm who are treated with warfarin?


Using data from the WARCEF (Warfarin vs Aspirin in Reduced Cardiac Ejection Fraction) trial, the authors performed a post-hoc analysis to explore the relationship between TTR (international normalized ratio [INR], 2-3.5) and the primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, with ischemic stroke alone, with major hemorrhage alone, and with the next clinical benefit (primary outcome combined with major hemorrhage). All patients had an ejection fraction ≤35%, were in sinus rhythm, and had at least 6 weeks of follow-up. Multivariable Cox models were used to examine the change in event risk based on level of TTR (≥60% and <60%) and treatment strategy (warfarin vs. aspirin).


The study consisted of 1,067 patients randomized to warfarin and 1,150 patients randomized to aspirin. Median follow-up was 3.6 years. The mean TTR was 57% in the warfarin-treated group. For every 10% increase in TTR, the adjusted hazard ratio (aHR) for the primary outcome was 0.92 (p < 0.001), for death was 0.93 (p = 0.001), for ischemic stroke alone was 0.88 (p = 0.082), for major hemorrhage was 0.93 (p = 0.109), and for net clinical benefit was 0.91 (p < 0.001). Patients with high TTR (≥60%) were at less risk of the primary outcome than patients with low TTR (<60%; aHR, 0.76; p = 0.01) and patients on aspirin (aHR, 0.76; p = 0.01).


The authors concluded that in heart failure patients in sinus rhythm, increasing TTR among warfarin-treated patients is associated with better outcomes and net clinical improvement. The authors suggest that patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants.


The WARCEF trial demonstrated that there was no significant difference in the composite rate of ischemic stroke, intracranial hemorrhage, or death between heart failure patients with a reduced ejection fraction (≤35%) who were treated with warfarin or aspirin. However, this post-hoc analysis demonstrated that patients with higher quality warfarin care (TTR ≥60%) fared better than those with lower quality warfarin care (TTR <60%) and patients treated with aspirin. However, the ability to predict the quality of warfarin therapy in heart failure patients at the time of antithrombotic medication initiation is the main limiting factor for everyday clinical practice. Future studies validating a clinical prediction tool (e.g., SAME-TTR) in heart failure patients would be beneficial for clinicians trying to select patients most appropriate for warfarin versus aspirin therapy.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Anticoagulants, Aspirin, Cerebral Hemorrhage, Heart Failure, Hemorrhage, International Normalized Ratio, Intracranial Hemorrhages, Mortality, Stroke, Warfarin

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