Personalized Anticoagulation: Optimizing Warfarin Management Using Genetics and Simulated Clinical Trials.
Personalized Anticoagulation: Optimizing Warfarin Management Using Genetics and Simulated Clinical Trials.
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DOI：
10.1161/circgenetics.117.001804
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Tonellato PJ
中科院分区：
文献类型：
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作者：
Ravvaz K;Weissert JA;Ruff CT;Chi CL;Tonellato PJ
药物基因组学指导（PG指导）华法林给药治疗房颤（AF）患者的临床试验显示了相互矛盾的结果。非维生素K拮抗剂口服抗凝剂（NOAC）价格昂贵，并且禁忌用于几种情况。优化抗凝剂选择的策略仍然是未满足的临床需求。使用迭代贝叶斯网络建模和药代动力学-药效学模型，将14，206例AF患者的特征整合到经验证的华法林临床试验模拟框架中。针对五种华法林方案模拟患者的个体剂量反应-固定剂量方案、临床指导方案和三种日益复杂的PG指导方案。对于每个方案，使用预测华法林剂量的变量和每个调整剂量的预定义INR阈值数量计算复杂性评分。研究结局包括治疗范围内的最佳时间（TTR）≥65%和临床事件。年龄和基因型的组合确定了不同的最佳方案，为各种亚群。固定剂量方案仅在≥65岁的正常应答者中提供良好控制的INR，而对于<65岁的正常应答者，需要临床指导方案以实现良好控制的INR。≥65岁和<65岁的敏感应答者和≥65岁的高度敏感应答者需要PG指导的方案，以实现良好控制的INR。然而，<65岁的高度敏感应答者没有达到良好控制的INR，并且相关临床事件发生率高于其他亚群。在这种模拟的假设下，房颤患者可以根据年龄和基因型进行最佳华法林治疗方案的分类。对于任何华法林方案下结局不佳的患者，临床医生应考虑替代抗凝治疗。
Clinical trials testing pharmacogenomic-guided (PG-guided) warfarin dosing for patients with atrial fibrillation(AF) have demonstrated conflicting results. Non-vitamin K antagonist oral anticoagulants (NOACs) are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need. Characteristics from 14,206 patients with AF 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 five warfarin protocols – a fixed-dose protocol, a clinically guided protocol and three increasingly complex PG-guided protocols. For each protocol a complexity score was calculated using the variables predicting warfarin dose and the number of predefined INR thresholds for each adjusted dose. Study outcomes included optimal time in therapeutic range (TTR) ≥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, while 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 PG-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. Under the assumptions of this simulation, patients with AF 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.