Heterogeneity of Treatment Effect of DOACs vs Warfarin in Atrial Fibrillation

Figures

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  Figure 1. Discriminative Contribution of Baseline Characteristics in Model-Based Clustering Bars represent the relative contribution of each variable to cluster separation derived from the model-based clustering algorithm. Higher values indicate greater influence in distinguishing patient phenotypes. The scale reflects a model-specific discrimination metric and does not represent effect size or hazard. BMI = body mass index; MI = myocardial infarction; VKA = vitamin K antagonist.

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  Figure 2. Cumulative Incidence Function of Net Clinical Outcome by Risk Group Net clinical outcome defined as a composite of all-cause death, disabling or fatal stroke, intracranial or fatal bleeding.

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  Central Illustration. Heterogeneity of Treatment Effect of Direct Oral Anticoagulants vs Warfarin in Atrial Fibrillation Model-based clustering of 58,634 patients from COMBINE-AF identified two phenotypic clusters—high-risk (older age, lower BMI, reduced CrCl) and low-risk (younger age, higher BMI, preserved CrCl)—with clinically meaningfully different absolute treatment benefits (ARR 2.4% vs 0.5%, respectively). DOACs significantly reduced net clinical outcome in the high-risk cluster (HR: 0.86; 95% CI: 0.81-0.92; P < 0.001) but not in the low-risk cluster (HR: 0.93; 95% CI: 0.85-1.03; P = 0.154; P interaction = 0.115), with renal function as the dominant predictor of treatment benefit variation (52.8% relative importance). These findings support risk-guided anticoagulant selection, particularly in resource-limited settings where DOAC access is restricted. ARR = absolute risk reduction; CrCl = creatinine clearance; NCO = net clinical outcome (all-cause death, disabling/fatal stroke, intracranial/fatal bleeding); other abbreviations as in Figure 1.

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  Figure 3. Cumulative Incidence Function of Net Clinical Outcome by Risk Group and Treatment Arm Cumulative incidence of the net clinical outcome DOAC (red) and warfarin (blue) in the high risk cluster (A), and low risk cluster (B). P interaction = 0.115. Net clinical outcome defined as a composite of all-cause death, disabling or fatal stroke, intracranial or fatal bleeding. DOAC = direct oral anticoagulant; other abbreviations as in Figure 2.