Thromboembolism can occur in the venous or arterial system and is associated with substantial morbidity and mortality. Warfarin sodium is the anticoagulant drug of choice to prevent thromboembolism and is prescribed to millions of patients each year. However, warfarin has an unusually narrow therapeutic range and is difficult to dose properly, putting patients at increased risk for thromboembolism from under-anticoagulation and bleeding from over-anticoagulation. Although dose requirements can vary over 30-fold among patients treated with warfarin, current practice relies primarily on either empirical dosing or suboptimal dosing algorithms, leading to complications and therapeutic failures, particularly during the dose titration period. Despite clinical research that has identified patient and environmental factors and has begun to identify genetic factors that can alter warfarin dose requirements, a large proportion of variable patient response to warfarin remains unexplained and clinicians remain unable to properly dose patients. In addition to the factors already studied, there are many additional genes that play a role in warfarin response. Thus, improved prediction and better patient care may be achievable by incorporating more complete genetic information into dosing algorithms. Importantly, genetic predictors of warfarin response have not been well studied in African Americans. The primary objective of this study is to incorporate patient and environmental factors and all genetic variants within the pharmacokinetic, pharmacodynamic, and coagulation pathways of warfarin response to develop and validate dose prediction models (""""""""dosing algorithms""""""""), separately in Caucasians and African Americans, which can be used to predict warfarin dose requirements. Specifically, a prospective cohort study is proposed in patients receiving warfarin therapy to: 1) develop a multivariable dosing algorithm that includes genetic, patient, and environmental factors to predict maintenance dose of warfarin in both Caucasians and African Americans, and 2) prospectively validate the dosing algorithm. The secondary aim is to determine the association of the variants in the genes selected for the dosing algorithm with anticoagulation control, independent of patient and environmental factors. A comprehensive and robust dosing algorithm could significantly improve the use of warfarin, reduce life-threatening bleeding and thromboembolic events, and improve quality of life for the millions of patients who rely on this medication to prevent life-threatening thromboembolism.

Public Health Relevance

Warfarin is a blood thinner that, when properly used, significantly reduces the likelihood of strokes and other clotting events in millions of patients. However, warfarin is very difficult to dose properly, leading to frequent failure of therapy and life threatening complications. The primary objective of the study is to develop and validate dosing algorithms, using clinical, environmental, and genetic information, which can be used to accurately determine warfarin dose requirements and thereby improve the effectiveness and reduce the risk of this important medication.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066176-10
Application #
8296542
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Link, Rebecca P
Project Start
2001-03-19
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$733,641
Indirect Cost
$245,137
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Finkelman, Brian S; French, Benjamin; Bershaw, Luanne et al. (2015) Factors affecting time to maintenance dose in patients initiating warfarin. Pharmacoepidemiol Drug Saf 24:228-36
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Cruess, Dean G; Localio, A Russell; Platt, Alec B et al. (2010) Patient attitudinal and behavioral factors associated with warfarin non-adherence at outpatient anticoagulation clinics. Int J Behav Med 17:33-42

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