Thromboembolism (TE) can occur in the venous or arterial system and is associated with substantial morbidity and mortality in a large proportion of the population. Although most of these thromboembolic events can be prevented using warfarin sodium, proper levels of anticoagulation (AC) with warfarin are very difficult to maintain. Because the drug has a narrow therapeutic range, inadequate levels of AC can lead to failure of therapy and life threatening thromboembolic complications, while excessive levels can lead to life threatening bleeding complications. In addition, improper AC can lead to increased medical costs, reduced quality of life, patient dissatisfaction, and discontinuation of a highly efficacious therapy. However, the reason for the marked intrapatient and interpatient variability in response to warfarin often remains unknown. Recently discovered genetic variants that affect warfarin pharmacokinetics (the CYP2C9 enzyme, via reduced warfarin metabolism) may explain at least some of this variability. In addition, patient adherence with warfarin, and its interaction with genotype, are likely to be important, but have not been rigorously studied. The objective of this study is to determine the effects of these genetic variants and adherence on AC control. A prospective cohort study is proposed in patients requiring AC at one of three AC clinics, representing a broad spectrum of patients. Patients presenting for AC will be identified at the start of therapy and followed throughout their course of therapy. Genotype of CYP2C9 and apolipoprotein E will be determined via cheek swabs, and adherence with medications will be measured throughout the study using state-of-the-art electronic pill cap monitoring. Detailed information on important time-varying confounders also will be collected. The outcomes will be over-AC and under-AC, analyzed separately because different genotypic variants and adherence patterns are likely to affect each differently. Univariate and multivariate analyses will focus on genotype, adherence, and the interactions between genotypes and between genotype and adherence. The interaction of other risk factors with genotype also will be explored as will other outcomes, including bleeding and TE. By understanding the effects of genetic polymorphisms and adherence on AC control via the merger of the disciplines of pharmacogenetics and pharmacoepidemiology, this study hopes to provide critical information to apply clinically (patient pre-screening) and scientifically (development and application of specific strategies targeted at specific patient groups based on the cause of their poor AC control). The ultimate goal is to improve the use of a highly efficacious, but underused, drug and reduce morbidity and mortality in the large proportion of the population at risk for TE.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066176-04
Application #
6708902
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Link, Rebecca P
Project Start
2001-03-19
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$753,782
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Sevilla-Cazes, Jonathan; Finkleman, Brian S; Chen, Jinbo et al. (2017) Association Between Patient-Reported Medication Adherence and Anticoagulation Control. Am J Med 130:1092-1098.e2
Finkelman, Brian S; French, Benjamin; Bershaw, Luanne et al. (2016) Predicting prolonged dose titration in patients starting warfarin. Pharmacoepidemiol Drug Saf 25:1228-1235
Finkelman, Brian S; French, Benjamin; Kimmel, Stephen E (2016) The prediction accuracy of dynamic mixed-effects models in clustered data. BioData Min 9:5
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
Li, Ron C; Finkelman, Brian S; Chen, Jinbo et al. (2013) Dietary vitamin K intake and anticoagulation control during the initiation phase of warfarin therapy: a prospective cohort study. Thromb Haemost 110:195-6
Kimmel, Stephen E; French, Benjamin; Anderson, Jeffrey L et al. (2013) Rationale and design of the Clarification of Optimal Anticoagulation through Genetics trial. Am Heart J 166:435-41
Horne, Benjamin D; Lenzini, Petra A; Wadelius, Mia et al. (2012) Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost 107:232-40
Finkelman, Brian S; Gage, Brian F; Johnson, Julie A et al. (2011) Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 57:612-8
Johnson, J A; Gong, L; Whirl-Carrillo, M et al. (2011) Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90:625-9

Showing the most recent 10 out of 25 publications