Personalized Anticoagulation: Optimizing Warfarin Management Using Genetics and Simulated Clinical Trials.

Abstract

Background: Clinical trials testing pharmacogenomic-guided warfarin dosing for patients with atrial fibrillation have demonstrated conflicting results. Non-vitamin K antagonist oral anticoagulants are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need.

Methods and results: Characteristics from 14 206 patients with atrial fibrillation were integrated into a validated warfarin clinical trial simulation framework using iterative Bayesian network modeling and a pharmacokinetic-pharmacodynamic model. Individual dose-response for patients was simulated for 5 warfarin protocols-a fixed-dose protocol, a clinically guided protocol, and 3 increasingly complex pharmacogenomic-guided protocols. For each protocol, a complexity score was calculated using the variables predicting warfarin dose and the number of predefined international normalized ratio (INR) thresholds for each adjusted dose. Study outcomes included optimal time in therapeutic range ≥65% and clinical events. A combination of age and genotype identified different optimal protocols for various subpopulations. A fixed-dose protocol provided well-controlled INR only in normal responders ≥65, whereas for normal responders <65 years old, a clinically guided protocol was necessary to achieve well-controlled INR. Sensitive responders ≥65 and <65 and highly sensitive responders ≥65 years old required pharmacogenomic-guided protocols to achieve well-controlled INR. However, highly sensitive responders <65 years old did not achieve well-controlled INR and had higher associated clinical events rates than other subpopulations.

Conclusions: Under the assumptions of this simulation, patients with atrial fibrillation can be triaged to an optimal warfarin therapy protocol by age and genotype. Clinicians should consider alternative anticoagulation therapy for patients with suboptimal outcomes under any warfarin protocol.