10 Years of Oral Anticoagulant Pharmacogenomics: What Difference will it Make? a Critical Appraisal

Abstract

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.

KEYWORDS::

• CYP2C9
• dosing algorithm
• oral anticoagulants
• personalized medicine
• pharmacogenetics
• pharmacogenomics
• VKORC1
• warfarin

Financial & competing interests disclosure

Dr Gak and Dr Halkin hold rights (<40%) to a patent entitled ‘Methods and Kits for determining predisposition to warfarin resistance‘ (PCT no. IL2007/000405) and received grant support from the Israeli Chief Scientist ‘Nofar‘ program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Dr Gak and Dr Halkin hold rights (<40%) to a patent entitled ‘Methods and Kits for determining predisposition to warfarin resistance‘ (PCT no. IL2007/000405) and received grant support from the Israeli Chief Scientist ‘Nofar‘ program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.