10 years of oral anticoagulant pharmacogenomics: what difference will it make? A critical appraisal.
Since the first report on warfarin pharmacogenetics in 1999, genetic variants have emerged as an important predictor of warfarin maintenance doses before therapy is initiated, raising expectations of greatly improved clinical outcomes. However, much of the information on warfarin sensitivity conveyed by genetic variants is captured by early international normalized ratio values traditionally used to guide dose titration. Thus, inclusion of early international normalized ratios in prediction models reduces the contribution of genetics. Moreover, in large population cohorts, genetics explained only 20-30% of variance in warfarin doses. Finally, even pharmacogenetic prediction models did not predict doses reliably in the majority of at-risk patients with warfarin requirements at the low or high end of the dose range. Currently, the clinical utility and cost-effectiveness of pharmacogenetic-based dosing are being assessed in large prospective trials in various settings. In the interim, enthusiasm for warfarin pharmacogenetics should not supersede strict adherence to traditional measures used to optimize coumarin anticoagulation.
Kurnik
Daniel
D
Division of Clinical Pharmacology and Toxicology, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel. daniel.kurnik@sheba.health.gov.il
Loebstein
Ronen
R
Halkin
Hillel
H
Gak
Eva
E
Almog
Shlomo
S
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019934:International Normalized Ratio; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods / Q000639:trends; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases