Creating a genotype-based dosing algorithm for acenocoumarol steady dose

Summary

Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9* and CYP4F2 polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R²=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R²= 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤7mg/week) or higher (≥25mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in VKORC1, CYP2C9* and CYP4F2 genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.

Keywords

Thrombosis - stroke prevention - vitamin K-dependent factors

• References

• 1 Hirsch J, Dalen JE, Anderson DR. et al. Oral anticoagulants: mechanisms of action, clinical effectiveness and optimal therapeutic range. Chest 1998; 114: 445S-469S. DOI:10.1378/chest.114.5_Supplement.445S.
• 2 Pérez-Andreu V, Roldán V, López-Fernández MF. et al. Pharmacogenetics of acenocoumarol in patients with extreme dose requirements. J Thromb Haemost 2010; 08: 1012-1017.
• 3 Bodin L, Verstuyft C, Tregouet DA. et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood 2005; 106: 135-140. DOI:10.1182/blood-2005-01-0341.
• 4 Marín F, González-Conejero R, Capranzano P. et al. Pharmacogenetics in cardiovascular antithrombotic therapy. J Am Coll Cardiol 2009; 54: 1041-1057. DOI:10.1016/j.jacc.2009.04.084.
• 5 Verstuyft C, Delavenne X, Rousseau A. et al. A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy. Clin Pharmacokinet 2012; 51: 41-53. DOI:10.2165/11595560-000000000-00000.
• 6 Hermida J, Zarza J, Alberca I. et al. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 2002; 99: 4237-4239. DOI:10.1182/blood.V99.11.4237.
• 7 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293. DOI:10.1056/NEJMoa044503.
• 8 International Warfarin Pharmacogenetics Consortium,. Klein TE, Altman RB, Eriksson N. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753-764. DOI:10.1056/NEJMoa0809329.
• 9 Finkelman BS, Gage BF, Johnson JA. et al. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 2011; 57: 612-618. DOI:10.1016/j.jacc.2010.08.643.
• 10 Kurnik D, Loebstein R, Halkin H. et al. 10 years of oral anticoagulant pharmacogenomics: what difference will it make? A critical appraisal. Pharmacogenomics 2009; 10: 1955-1965. DOI:10.2217/pgs.09.149.
• 11 FDA approves updated warfarin (Coumadin) prescribing information. Press release of the Food and Drug Administration; Rockville, MD: August 16 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed May 19, 2008.
• 12 Becquemont L, Alfirevic A, Amstutz U. et al. Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. Pharmacogenomics 2011; 12: 113-124. DOI:10.2217/pgs.10.147.
• 13 Meckley LM, Gudgeon JM, Anderson JL. et al. A policy model to evaluate the benefits, risks and costs of warfarin pharmacogenomic testing. Pharmacoeconomics 2010; 28: 61-74. DOI:10.2165/11318240-000000000-00000.
• 14 van Schie RM, Wessels JA, le Cessie S. et al. EU-PACT Study Group.. Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart J 2011; 32: 1909-1917.
• 15 Borobia AM, Lubomirov R, Ramírez E. et al. An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in spanish patients with thromboembolic disease. PLoS One 2012; 07: e41360. DOI:10.1371/journal.pone.0041360.
• 16 Gage BF, Boechler M, Doggette AL. et al. Adverse outcomes and predictors of underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial fibrillation. Stroke 2000; 31: 822-827. DOI:10.1161/01.STR.31.4.822.
• 17 Camm AJ, Kirchhof P, Lip GY. et al. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
• 18 Lip GY, Andreotti F, Fauchier L. et al. European Heart Rhythm Association.. Bleeding risk assessment and management in atrial fibrillation patients. Executive Summary of a Position Document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis. Thromb Haemost 2011; 106: 997-1011.
• 19 van Schie RM, El Khedr N, Verhoef TI. et al. Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study. Pharmacogenomics 2012; 13: 1239-1245. DOI:10.2217/pgs.12.101.
• 20 Gage BF, Eby C, Johnson JA. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84: 326-331. DOI:10.1038/clpt.2008.10.
• 21 Zambon CF, Pengo V, Padrini R. et al. VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study. Pharmacogenomics 2011; 12: 15-25. DOI:10.2217/pgs.10.162.
• 22 Wells PS, Majeed H, Kassem S. et al. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism. Thromb Res 2010; 125: e259-264. DOI:10.1016/j.thromres.2009.11.020.
• 23 Wei M, Ye F, Xie D. et al. A new algorithm to predict warfarin dose from polymorphisms of CYP4F2, CYP2C9 and VKORC1 and clinical variables: Derivation in Han Chinese patients with non valvular atrial fibrillation. Thromb Haemost 2012; 107: 1083-1091. DOI:10.1160/TH11-12-0848.
• 24 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112. DOI:10.1182/blood-2007-11-122010.
• 25 Pérez-Andreu V, Roldán V, Antón AI. et al. Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood 2009; 113: 4977-4979. DOI:10.1182/blood-2008-09-176222.
• 26 Klein TE, Altman RB, Eriksson N. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. International Warfarin Pharmacogenetics Consortium, Engl J Med 2009; 360: 753-764.
• 27 Pérez-Andreu V, Roldán V, López-Fernández MF. et al. Pharmacogenetics of acenocoumarol in patients with extreme dose requirements. J Thromb Haemost 2010; 08: 1012-1017.
• 28 Ageno W, Gallus AS, Wittkowsky A. et al. American College of Chest Physicians.. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.