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.
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.
|Shendre, Aditi; Parmar, Gaurav M; Dillon, Chrisly et al. (2018) Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage. Pharmacotherapy 38:588-596|
|Empey, Philip E; Stevenson, James M; Tuteja, Sony et al. (2018) Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy. Clin Pharmacol Ther 104:664-674|
|Limdi, Nita A; Brown, Todd M; Shendre, Aditi et al. (2017) Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users. Pharmacogenet Genomics 27:347-355|
|Yanik, Megan V; Irvin, Marguerite R; Beasley, T Mark et al. (2017) Influence of Kidney Transplant Status on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage. Pharmacotherapy 37:1366-1373|
|Liu, Nianjun; Irvin, Marguerite R; Zhi, Degui et al. (2017) Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array. Pharmacogenomics 18:1059-1073|
|Boehme, Amelia K; Pamboukian, Salpy V; George, James F et al. (2017) Anticoagulation Control in Patients With Ventricular Assist Devices. ASAIO J 63:759-765|
|O'Neal, Wesley T; Judd, Suzanne E; Limdi, Nita A et al. (2017) Differential Impact of Risk Factors in Blacks and Whites in the Development of Atrial Fibrillation: the Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. J Racial Ethn Health Disparities 4:718-724|
|Cavallari, L H; Beitelshees, A L; Blake, K V et al. (2017) The IGNITE Pharmacogenetics Working Group: An Opportunity for Building Evidence with Pharmacogenetic Implementation in a Real-World Setting. Clin Transl Sci 10:143-146|
|Johnson, J A; Caudle, K E; Gong, L et al. (2017) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 102:397-404|
|Harada, S; Zhou, Y; Duncan, S et al. (2017) Precision Medicine at the University of Alabama at Birmingham: Laying the Foundational Processes Through Implementation of Genotype-Guided Antiplatelet Therapy. Clin Pharmacol Ther 102:493-501|
Showing the most recent 10 out of 48 publications