Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2015, vol. 24, nr 4, July-August, p. 607–614

doi: 10.17219/acem/32577

Publication type: original article

Language: English

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CYP2C9 Polymorphism and Unstable Anticoagulation with Warfarin in Patients Within the First 3 Months Following Heart Valve Replacement

Ewa Wypasek1,A,C,D,F, Marek Cieśla2,B,C,D, Bogdan Suder2,B,C, Łukasz Janik2,B, Jerzy Sadowski1,E, Anetta Undas1,A,E,F

1 John Paul II Hospital, Institute of Cardiology, Jagiellonian University School of Medicine, Kraków, Poland

2 John Paul II Hospital, Kraków, Poland


Background. Warfarin dose requirements are partly determined by common single nucleotide polymorphisms in VKORC1 and CYP2C9 genes.
Objectives. The aim of this study was to investigate how the presence of allelic variants in CYP2C9 affects the stability of anticoagulation in patients within the first 3 months following elective heart valve replacement.
Material and Methods. In a case-control study we compared 18 consecutive carriers of CYP2C9*2 and/or *3 and 25 well-matched patients with the wild type CYP2C9*1/*1 genotype. The former group was randomly assigned to use coagulometers or monitor international normalized ratio (INR) in local outpatient clinics. Subjects receiving drugs potently interfering with warfarin were ineligible. Anticoagulation with the baseline warfarin regimens based on pharmacogenetic algorithm was assessed by time in the therapeutic INR range (TTR) within the first 3 months following implantation.
Results. Carriers of the CYP2C9*2 and/or *3 genotypes were characterized by lower estimated warfarin dose (median, 21 [interquartile range, 21–35] vs. 35 [28–42] mg/week, p = 0.02) and actual (27.8 ± 13.2 vs. 46.3 ± 13.9 mg/week, p < 0.001), together with lower TTR values (56 [38.6–74.9] vs. 75.4 [58.1–83.6] %, p = 0.03) and longer time above the therapeutic range (13.8 [4.9–34.5] vs. 4.5 [0–15.3] %, p = 0.047) than patients with the CYP2C9*1/*1 genotype. There were no differences in the estimated and actual warfarin doses, TTR values and adverse events between the self-testing and standard-care subgroups.
Conclusion. The presence of CYP2C9*2 and/or *3 genotypes is associated with unstable warfarin treatment in patients after heart valve replacement, regardless of the type of INR testing.

Key words

warfarin, TTR, pharmacogenetics, heart valve replacement.

References (25)

  1. Stein PD, Alpert JS, Bussey HI, Dalen JE, Turpie AG: Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 2001, 1, 220–227.
  2. Sanderson S, Emery J, Higgins J: CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005, 7, 97–104.
  3. Kornej J, Potpara T, Lip GY: Anticoagulation management in nonvalvular atrial fibrillation: current and future directions. Pol Arch Med Wewn 2013, 123, 623–634.
  4. Furie B, Bouchard BA, Furie BC: Vitamin K-dependent biosynthesis of c-carboxyglutamic acid. Blood 1999, 93, 1798–1808.
  5. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E: A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993, 69, 236–239.
  6. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G: American College of Chest Physicians. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th ed. Chest 2008, 133, 160–198.
  7. Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, Bentley D, McGinnis R, Deloukas P: Association of warfarin dose with genes involved in its action and metabolism. Hum Genet 2007, 121, 23–34.
  8. Cavallari LH, Shin J, Perera MA: Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy 2011, 31, 1192–1207.
  9. Ufer M: Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 2005, 44, 1227–1246.
  10. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB: Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011, 90, 625–629.
  11. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE: Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002, 287, 1690–1698.
  12. Aithal GP, Day CP, Kesteven PJ, Daly AK: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999, 353, 717–719.
  13. Skov J, Bladbjerg EM, Leppin A, Jespersen J: The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment. Thromb Res 2013, 131, 125–129.
  14. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, Holm L, McGinnis R, Rane A, Deloukas P: The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009, 113, 784–792.
  15. Jorgensen AL, Al-Zubiedi S, Zhang JE, Keniry A, Hanson A, Hughes DA, Eker DV, Stevens L, Hawkins K, Toh CH, Kamali F, Daly AK, Fitzmaurice D, Coffey A, Williamson PR, Park BK, Deloukas P, Pirmohamed M: Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenet Genomics 2009, 19, 800–812.
  16. Hering D, Piper C, Bergemann R, Hillenbach C, Dahm M, Huth C, Horstkotte D: Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience with Low-Intensity Anticoagulation Study. Chest 2005, 127, 53–59.
  17. Schapkaitz E, Jacobson BF, Becker P, Conway G: Thrombo-embolic and bleeding complications in patients with mechanical valve replacements – a prospective observational study. S Afr Med J 2006, 8, 710–713.
  18. Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF: Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost 2010, 8, 95–100.
  19. Thompson JL, Burkhart HM, Daly RC, Dearani JA, Joyce LD, Suri RM, Schaff HV: Anticoagulation early after mechanical valve replacement: improved management with patient self-testing. J Thorac Cardiovasc Surg 2013, 146, 599–604.
  20. Singer DE, Hellkamp AS, Piccini JP, Mahaffey KW, Lokhnygina Y, Pan G, Halperin JL, Becker RC, Breithardt G, Hankey GJ, Hacke W, Nessel CC, Patel MR, Califf RM, Fox KA, ROCKET AF Investigators: Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc 2013, 2, e000067.
  21. Tatarūnas V, Lesauskaitė V, Veikutienė A, Jakuška P, Benetis R: The influence of CYP2C9 and VKORC1 gene polymorphisms on optimal warfarin doses after heart valve replacement. Medicina (Kaunas) 2011, 1, 25–30.
  22. Yildirim H, Tamer L, Sucu N, Atik U: The role of CYP2C9 gene polymorphisms on anticoagulant therapy after heart valve replacement. Med Princ Pract 2008, 6, 464–467.
  23. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA: Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009, 360, 753–764.
  24. Matchar DB, Jacobson A, Dolor R, Edson R, Uyeda L, Phibbs CS, Vertrees JE, Shih MC, Holodniy M, Lavori P, THINRS Executive Committee and Site Investigators: Effect of home testing of international normalized ratio on clinical events. N Engl J Med 2010, 363, 1608–1620.
  25. Roth JA, Boudreau D, Fujii MM, Farin FM, Rettie AE, Thummel KE, Veenstra DL: Genetic risk factors for major bleeding in patients treated with warfarin in a community setting. Clin Pharmacol Ther 2014, 6, 636–643.