Thromb Haemost 2016; 116(02): 337-348
DOI: 10.1160/TH15-12-0955
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance

Payman Shahabi
2   Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Montreal, Quebec, Canada
,
Laura B. Scheinfeldt
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Daniel E. Lynch
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Tara J. Schmidlen
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Sylvie Perreault
3   Department of Medicine and Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada
,
Margaret A. Keller
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Rachel Kasper
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Lisa Wawak
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Joseph P. Jarvis
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Norman P. Gerry
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Erynn S. Gordon
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Michael F. Christman
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
,
Marie-Pierre Dubé
2   Beaulieu-Saucier Pharmacogenomics Centre, Montreal Heart Institute, Montreal, Quebec, Canada
,
Neda Gharani
1   The Coriell Institute for Medical Research, Camden, New Jersey, USA
› Author Affiliations
Further Information

Publication History

Received: 15 December 2015

Accepted after major revision: 19 April 2016

Publication Date:
09 March 2018 (online)

Summary

Pharmacogenomics (PGx) guided warfarin dosing, using a comprehensive dosing algorithm, is expected to improve dose optimisation and lower the risk of adverse drug reactions. As a complementary tool, a simple genotype-dosing table, such as in the US Food and Drug Administration (FDA) Coumadin drug label, may be utilised for general risk assessment of likely over- or under-anticoagulation on a standard dose of warfarin. This tool may be used as part of the clinical decision support for the interpretation of genetic data, serving as a first step in the anticoagulation therapy decision making process. Here we used a publicly available warfarin dosing calculator (www.warfarindosing.org) to create an expanded gene-based warfarin dosing table, the CPMC-WD table that includes nine genetic variants in CYP2C9, VKORC1, and CYP4F2. Using two datasets, a European American cohort (EUA, n=73) and the Quebec Warfarin Cohort (QWC, n=769), we show that the CPMC-WD table more accurately predicts therapeutic dose than the FDA table (51 % vs 33 %, respectively, in the EUA, McNemar’s two-sided p=0.02; 52 % vs 37 % in the QWC, p<1×10−6). It also outperforms both the standard of care 5 mg/day dosing (51 % vs 34 % in the EUA, p=0.04; 52 % vs 31 % in the QWC, p<1×10−6) as well as a clinical-only algorithm (51 % vs 38 % in the EUA, trend p=0.11; 52 % vs 45 % in the QWC, p=0.003). This table offers a valuable update to the PGx dosing guideline in the drug label.

Supplementary Material to this article is available at www.thrombosis-online.com.

Current Address: American Red Cross, 700 Spring Garden Street, Philadelphia, PA 19123, USA


Current Address: 23andMe, 899 W. Evelyn Ave, Mountain View, CA 94041, USA


 
  • References

  • 1 Budnitz DS, Lovegrove MC, Shehab N. et al. Emergency hospitalisations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002-2012.
  • 2 McWilliam A, Nardinelli C. Health care savings from personalizing medicine using genetic testing: The case for warfarin. In: AEI Brookings Joint Center for Regulatory Studies 2006; 1-17.
  • 3 Shehab N, Sperling LS, Kegler SR. et al. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med 2010; 170: 1926-1933.
  • 4 Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007; 167: 1414-1419.
  • 5 Garcia D, Regan S, Crowther M. et al. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005; 127: 2049-2056.
  • 6 Johnson JA, Gong L, Whirl-Carrillo M. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Therap 2011; 90: 625-629.
  • 7 Hirsh J, Dalen JE, Anderson DR. et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114 (Suppl. 05) 445S-469S.
  • 8 Group TEAFTS. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia.. N Engl J Med 1995; 333: 5-10.
  • 9 Fuster V, Ryden LE, Asinger RW. et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in Collaboration With the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 2001; 38: 1231-1266.
  • 10 Wadelius M, Chen LY, Lindh JD. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784-792.
  • 11 Gage BF, Eby C, Johnson JA. et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Therap 2008; 84: 326-331.
  • 12 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112.
  • 13 Coumadin Drug Label October 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf
  • 14 International Warfarin Pharmacogenetics Consortium. Klein TE, Altman RB. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753-764.
  • 15 Hernandez W, Gamazon ER, Aquino-Michaels K. et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Americans. Pharmacogenom J 2014; 14: 223-228.
  • 16 Ramirez AH, Shi Y, Schildcrout JS. et al. Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenom 2012; 13: 407-418.
  • 17 Anderson JL, Horne BD, Stevens SM. et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563-2570.
  • 18 Anderson JL, Horne BD, Stevens SM. et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012; 125: 1997-2005.
  • 19 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Therap 2008; 83: 460-470.
  • 20 Pirmohamed M, Burnside G, Eriksson N. et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013; 369: 2294-2303.
  • 21 Kimmel SE, French B, Kasner SE. et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med 2013; 369: 2283-2293.
  • 22 Jonas DE, Evans JP, McLeod HL. et al. Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics 2013; 14: 1593-1603.
  • 23 Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. J Am Med Assoc Intern Med 2014; 174: 1330-1338.
  • 24 Li X, Yang J, Wang X. et al. Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thromb Res 2015; 135: 621-629.
  • 25 Franchini M, Mengoli C, Cruciani M. et al. Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 1480-1487.
  • 26 Belley-Cote EP, Hanif H, D’Aragon F. et al. Genotype-guided versus standard vitamin K antagonist dosing algorithms in patients initiating anticoagulation. A systematic review and meta-analysis. Thromb Haemost 2015; 114: 768-777.
  • 27 Wang ZQ, Zhang R, Zhang PP. et al. Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol 2015; 65: 364-370.
  • 28 Gharani N, Keller MA, Stack CB. et al. The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system. Genome Med 2013; 5: 93.
  • 29 Mega JL, Walker JR, Ruff CT. et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015 Epub ahead of print.
  • 30 Dunnenberger HM, Crews KR, Hoffman JM. et al. Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Ann Rev Pharmacol Toxicol 2015; 55: 89-106.
  • 31 Gage BF. warfarindosing. Available at: http://www.warfarindosing.org
  • 32 Sagreiya H, Berube C, Wen A. et al. Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9 . Pharmacogenet Genom 2010; 20: 407-413.
  • 33 Keller M, Gordon ES, Stack CB. et al. The Coriell Personalized Medicine Collaborative: A prospective study of the utility of personalized medicine. Personal Med 2010; 7: 301-317.
  • 34 Stack CB, Gharani N, Gordon ES. et al. Genetic risk estimation in the Coriell Personalized Medicine Collaborative. Genet Med 2011; 13: 131-139.
  • 35 Diseati L, Scheinfeldt LB, Kasper RS. et al. Common genetic risk for melanoma encourages preventive behavior change. J Personal Med 2015; 5: 36-49.
  • 36 Schmidlen TJ, Wawak L, Kasper R. et al. Personalized genomic results: analysis of informational needs. J Genetic Counsel 2014; 23: 578-587.
  • 37 Schmidlen TJ, Scheinfeldt L, Zhaoyang R. et al. Genetic Knowledge Among Participants in the Coriell Personalized Medicine Collaborative. J Genetic Counsel. 2015 Epub ahead of print.
  • 38 Scheinfeldt LB, Gharani N, Kasper RS. et al. Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration. Am J Med Genetics B 2015; 168: 697-705.
  • 39 Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and coumarin dosing--recalibrating expectations. N Engl J Med 2013; 369: 2273-2275.
  • 40 Rothman KJ. Six Persistent Research Misconceptions. J Gen Intern Med 2014; 29: 1060-1064.
  • 41 Ray T. Two Conflicting Prospective, RCTs on Warfarin PGx Provide No Definitive Guidance to Physicians. Available at: http://www.genomeweb.com/clinical-genomics/two-conflicting-prospective-rcts-warfarin-pgx-provide-no-definitive-guidance-phy
  • 42 Cavallari LH, Kittles RA, Perera MA. Genotype-guided dosing of vitamin K antagonists. N Engl J Med 2014; 370: 1763.
  • 43 Drozda K, Wong S, Patel SR. et al. Poor warfarin dose prediction with pharmacogenetic algorithms that exclude genotypes important for African Americans. Pharmacogen Genom 2015; 25: 73-81.
  • 44 Duconge J, Cadilla CL, Seip RL. et al. Why admixture matters in genetically-guided therapy: missed targets in the COAG and EU-PACT trials. Puerto Rico Health Sci J 2015; 34: 175-177.
  • 45 Mersha TB, Abebe T. Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities. Human Genom 2015; 9: 1.
  • 46 Finkelman BS, Gage BF, Johnson JA. et al. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 2011; 57: 612-618.
  • 47 Dumas S, Rouleau-Mailloux E, Barhdadi A. et al. Validation of patient-reported warfarin dose in a prospective incident cohort study. Pharmacoepidemiol Drug Safety 2014; 23 (03) 285-289.