Genetic and Clinical Predictors of Response to Warfarin and Novel Anticoagulants

描述（由申请人提供）：尽管口服抗凝剂（OAC）治疗可显著降低心房颤动（AF）患者的卒中风险，但由于出血是主要的阻碍因素，口服抗凝剂尚未得到充分利用。OAC相关出血占美国不良药物相关住院的33.3%，是治疗机构的关键障碍。修订后的申请建立在我们成功确定基因对华法林剂量、抗凝控制和出血影响的项目基础上（n=1310； 43%为黑人）。我们扩大了我们的努力，纳入新的oac，通过四个特定目标来确定达比加群（DBG, n=500）和华法林（n=1000，累计590）治疗的房颤患者出血的预测因素。目的1将阐明常见和罕见的遗传变异对华法林相关出血风险的影响，采用全基因组方法。这项发现将以700对华法林相关出血病例对照为基础，并在1000名华法林治疗的房颤患者的独立前瞻性队列中进行复制。目的2将阐明种族、肾脏损害和同时抗血小板治疗对1000名接受华法林治疗的房颤患者发生华法林相关出血风险的影响。目的3将阐明肾脏损害和同时抗血小板治疗对500名dbg治疗的房颤患者华法林相关出血风险的影响。目标4将纳入患者特异性遗传和临床因素，以完善（华法林）和建立（DBG）临床预测规则（CPRs），以个性化出血预测。房颤患者队列将为未来纳入其他新的oac（即利伐沙班和阿哌沙班）的努力提供坚实的基础。对AF的关注为将来在临床实践中具有代表性的人群中“真实世界”的比较有效性评估奠定了基础。

DESCRIPTION (provided by applicant): Although oral anticoagulant (OAC) therapy provides superior stroke risk reduction in patients with Atrial Fibrillation (AF), it is widely underutilize with hemorrhage being a major deterrent. OAC related hemorrhage accounts for 33.3% of adverse-drug- related hospitalizations in the US and is a critical barrier to institution of therapy. This revised application builds on our successful project identifying the influence of genes on warfarin dose, anticoagulation control, and hemorrhage (n=1310; 43% Black). We expand our efforts to incorporate new OACs to identify predictors of hemorrhage in Dabigatran (DBG; n=500) and warfarin (n=1000; 590 accrued) treated AF patients through four specific aims. Aim 1 will elucidate the influence of common and rare genetic variation on risk of warfarin-related hemorrhage using a genome-wide approach. The discovery efforts will be grounded in 700 warfarin-related hemorrhage case-control pairs with replication in an independent prospective cohort of 1000 warfarin-treated AF patients. Aim 2 will elucidate the influence of race, kidney impairment and concurrent antiplatelet therapy on risk of warfarin-related hemorrhage in the prospective cohort of 1000 warfarin-treated AF patients. Aim 3 will elucidate the influence of kidney impairment and concurrent antiplatelet therapy on risk of warfarin- related hemorrhage in the prospective cohort of 500 DBG-treated AF patients. Aim 4 will incorporate patient-specific genetic and clinical factors into refining (for warfarin) and building (for DBG) clinical predictio rules (CPRs) to personalize the prediction of hemorrhage. The AF patient-cohort will provide a robust foundation for future efforts that will incorporate other new OACs namely rivaroxaban and apixaban. The focus on AF lays the foundation for future "real-world" comparative- effectiveness evaluation in a population representative of clinical practice.