Warfarin Pharmacogenetics Reevaluated: Subgroup Analysis Reveals a Likely Underestimation of the Maximum Pharmacogenetic Benefit by Clinical Trials.

Objectives: Various patient subgroups were examined to determine which ones obtain the largest pharmacogenetic improvements in warfarin dose accuracy. Subgrouping schemes of recent clinical trials were analyzed for comparison.

Methods: The accuracy of a pharmacogenetic dose algorithm was determined retrospectively in comparison to that of a clinical algorithm in subgroups of the International Warfarin Pharmacogenetics Consortium (IWPC) patient database (n = 2,274) and of newly studied clinic patients (n = 146).

Results: White patients with low-dose genotypes (*1*3/AA, *2*2/AA, *2*3/GA, *2*3/AA, *3*3/GG, *3*3/GA, and *3*3/AA) achieved the largest pharmacogenetic improvements in warfarin dose accuracy. Mean absolute dosing error (MAE) in this subgroup of IWPC and newly studied patients was reduced 75.7% and 89.7%, respectively. White IWPC patients with >2 variants or ≥2 mg/day absolute difference between pharmacogenetic and clinical dose predictions obtained MAE reductions of 71.1% and 65.3%, respectively. By comparison, unstratified populations and subgroups of a major clinical trial, when replicated in IWPC patients, obtained smaller MAE reductions of 31.8% to 48.2%. Blacks and Asians obtained substantially smaller dose accuracy improvements overall than whites.

Conclusions: Patient subgroups were identified that obtained the largest pharmacogenetic improvements in warfarin dose accuracy. These subgroups have not been analyzed in clinical trials to date, likely resulting in underestimation of the pharmacogenetic benefit.