Although oral anticoagulant (OAC) therapy provides superior stroke risk reduction in patients with Atrial Fibrillation (AF), it is widely underutilized 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 prediction 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.

Public Health Relevance

Understanding clinical and genetic factors that predict patient specific risk of hemorrhage can help identify patients who stand to benefit or be harmed by oral anticoagulants drugs. The integration of these clinical and genetic predictors into the current treatment approach can help provide personalized treatment, improving outcomes for the individual patient. The increasing burden of atrial fibrillation in the US and the world, highlight the immense potential of such research in facilitating the realization of tangible individual and population health benefits.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Link, Rebecca P
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University of Alabama Birmingham
Schools of Medicine
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