Clinical Evaluation Of Warfarin Pharmacogenetics Algorithm Application

OBJECTIVE:As the most commonly used oral anticoagulant for prevention and treatment of thromboembolic diseases, numerous advantages of warfarin have been universally acknowledged, however, the current status of clinical anticoagulant therapy is that the effectiveness of warfarin has not been brought into full play in China, because of that warfarin is vulnerable to hemorrhage, embolism, and other serious complications to death due to narrow safe therapeutic window and remarkable inter-individual drug dose variability.With the rapid development of molecular biotechnology in the field of pharmacogenetics, warfarin dosing algorithm containing individual genetic information will help to rapidly reach target INR range, reduce complications and improve the actual clinical benefit of warfarin anticoagulation. Our research aimed to study the impact of CYP2C9and VKORC1genotypes, demographic characteristics and clinical factors on warfarin stable dose through clinically applying warfarin pharmacogenetics model, to actively explore and promote individualized treatment for patients.METHODS:1. OBJECT:74cases of patients with initial warfarin anticoagulation enrolled,1case of Caucasian,73cases of Han nationality;32cases of males and42females; median age of63.0years, median height of162.0cm, median weight of61.5Kg;41cases with atrial fibrillation,15deep vein thrombosis,4pulmonary embolism,14heart valve replacement. All cases were not relatives.2. DESIGN:A prospective cohort study with double-blind design has been taken, cases after selected were randomly assigned to Experimental or Control group:Experimental group to take predictive dose from CYP2C9and VKORC genotypes and other information; while Control group to take domestically empiric initial dose. All cases received routine INR test at the0,3,7,14,21,28,60,90days after medication, adjust the dose medication per0.625mg one week later based on actual INR-values comparing target range in deviations and trends.RESULTS:1. The characteristics of74cases of CYP2C9and VKORC1genotypes:74cases of CYP2C9*2wild-type (100.0%),0mutation (0.0%);65cases of CYP2C9*3wild-type (87.8%),9mutation (12.2%);66cases of VKORC wild-type (89.2%),8mutation (10.8%).2. Comparative analysis of CYP2C9genotype:the warfarin stable dose of CYP2C9mutation (17.52±4.35)mg/wk, wild-type (20.82±4.53)mg/wk, the difference was significant (P=0.0431); as the aspect of indicators to efficacy and safety, the proportion of within therapeutic range of mutant CYP2C9is lower than that of wild-type (47.4%vs60.8%), the incidence of adverse reactions higher than wild-type (33.3%vs15.4%), the differences of two indicators above were significant (P<0.05); time span to reach therapeutic range (10.89±6.17vs14.52±6.81)/d has no statistical difference.3. Comparative analysis of VKORC genotype:the warfarin stable dose of VKORC mutation (26.38±5.35)mg/wk, wild-type (19.70±3.98)mg/wk, the difference was significant (P=0.0001); mutant VKORC is lower than that of wild-type (37.9%vs61.8%), the difference was significant (P<0.01); time span (14.38±8.55vs14.05±6.64)/d and adverse events (25.0%vs16.7%) have no significant difference.4. Comparative analysis between Experimental and Control group:Of all cases, predictive dose (20.72±5.07)mg/wk has no significant difference from stable dose (19.61±5.05)mg/wk; time span of Experimental group was (10.62±3.37)/d, shortter than Control group (16.89±7.64)/d; the proportion of within therapeutic range of experimental group is higher than Control group (69.2%vs51.5%), these two indicators have significant difference (P<0.01), adverse events (47.4%vs60.8%) has no significant difference.CONCLUSION:1. CYP2C9and VKORC1genotypes were significantly associated with warfarin inter-individual dose variability.2. CYP2C9and VKORC1gene mutations have greater fluctuation than wild type in INR-values, leading to higher risk of adverse reactions of warfarin.3. Predictive dose from warfarin pharmacogenetics algorithm was generally consistent with clinical stable dose.4. The clinical application of warfarin pharmacogenetics algorithm can advance the efficacy, stability and safety of anticoagulation.