Variation in Warfarin Dose Adjustment Practice Is Responsible for Differences in the Quality of Anticoagulation Control Between Centers and Countries: An Analysis of Patients Receiving Warfarin in the RE-LY Trial

Study Questions:

What is the relationship between warfarin dosing practice and time in therapeutic range (TTR) or outcomes in a clinical trial of warfarin for stroke prevention in atrial fibrillation?


The authors reported the results of a re-analysis of the RE-LY (Randomized Evaluation Of Long-Term Anticoagulation Therapy) study, a multinational, randomized clinical trial of warfarin versus dabigatran for the prevention of stroke in patients with atrial fibrillation. For the purpose of this study, the authors analyzed data on patients receiving dose-adjusted warfarin, assessing dose adjustments made to determine if they were consistent with the study-provided algorithm for warfarin dosing. Multilevel regression models were used to adjust for patient, center, and country characteristics, to determine if algorithm-consistent warfarin dosing was associated with patient TTR, as well as with the composite outcome of stroke, systemic embolism, or major hemorrhage.


For this analysis, the authors included 6,022 nonvalvular atrial fibrillation patients from 912 centers in 44 countries. There was a strong association between the proportion of subjects with algorithm-consistent warfarin dosing and mean country TTR (R2 = 0.65). The authors found that a 10% increase in center algorithm-consistent dosing was independently associated with a 6.12% increase in TTR (95% confidence interval [CI], 5.65-6.59%), and an 8% decrease in the rate of composite clinical outcome (HR, 0.92; 95% CI, 0.85-1.00). The authors estimated that the degree of algorithm-consistency accounted for 87% of the between-center TTR variation, and 55% of the between-country TTR variation.


The authors concluded that adherence, intentional or not, to a simple warfarin dosing algorithm predicts improved TTR and accounts for considerable TTR variation between centers and countries. They further opined that systems facilitating algorithm-based warfarin dosing could optimize anticoagulation quality and improve clinical outcomes in atrial fibrillation on a global scale.


This re-analysis of the RE-LY study is a particularly powerful reinforcement of the concept that high-quality warfarin management clearly affects both surrogate and clinical endpoints. Most impressive is the magnitude of the impact that consistent, algorithm-driven warfarin dosing can have on the quality of outcomes. This study suggests that 87% of the variation in outcomes is determined by algorithm-consistency of warfarin dosing. Although the future may see far more patients anticoagulated with newer agents, and far fewer with warfarin, there will no doubt continue to be large numbers of patients receiving warfarin. The data from this study should renew calls for better attempts to improve the quality of warfarin management.

Clinical Topics: Anticoagulation Management, Novel Agents

Keywords: Blood Coagulation, Stroke, Octamer Transcription Factor-1, Benzimidazoles, Warfarin, Embolism, Motor Vehicles

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