Subject(s)
Cardiology/education , Echocardiography/standards , Education, Medical, Continuing , Education, Medical, Graduate , Clinical Competence , Consensus , Curriculum , Educational Measurement/standards , Fellowships and Scholarships , Humans , Societies, Medical , Specialty Boards , United StatesSubject(s)
Cardiovascular Diseases/drug therapy , Medication Errors , Acute Disease , Adverse Drug Reaction Reporting Systems , Aged , Drug Prescriptions , Hospitalization , Humans , Medication Errors/classification , Medication Errors/prevention & control , Middle Aged , Myocardial Ischemia/drug therapy , Stroke/drug therapy , Terminology as Topic , Thrombolytic TherapyABSTRACT
BACKGROUND: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. METHODS AND RESULTS: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. CONCLUSIONS: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.
