Influence of High Activity of CYP2C9 and VKORC on Warfarin Anticoagulation after Heart Valve Replacement_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HUANGGong-cheng , SHULi-liang , HUANGChen , ZHUXiao-hua , WEITing-ju ,  XUJing

Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, P. R. China;

Corresponding?author：

XUJing, Email: xujing00111@sina.com

Keywords：

Cytochrome P450 proteins 2C9; Vitamin K epoxide reductase C gene; Warfarin; Anticoagulation; Morbidity

DOI：

10.7507/1007-4848.20140174

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Objective To investigate the influence of high activity of CYP2C9 (Cytochrome P450 proteins 2C9)and VKORC (Vitamin K epoxide reductase C)on warfarin anticoagulation of patients after heart valve replacement (HVR). Methods From February 2010 to May 2013, 40 patients with high activity of CYP2C9 and VKORC underwent HVR in the Department of Cardiac Surgery, the First Affiliated Hospital of Zhengzhou University. There were 18 male and 22 female patients with their age of 40-51 (45.18±2.93)years. There were18 patients receiving mitral valve replacement (MVR), 14 patients receiving MVR and tricuspid valvuloplasty (TVP), and 8 patients receiving double valve replacement (DVR). Depen-ding on whether they received preoperative genetic polymorphism detection of CYP2C9 and VKORC1, all the patients were divided into 2 groups with 20 patients in each group. Patients in group A didn't receive preoperative genetic polymorphism detection of CYP2C9 and VKORC1, while patients in group B received preoperative genetic polymorphism detection of CYP2C9 and VKORC1. Postoperatively, periodic examination of international normalized ratio (INR)was performed to adjust warfarin dosage. Time to reach expected INR value and morbidity were collected. All the patients were followed up for 3-12 months after discharge. Monthly telephone follow-up was performed to record INR values, morbidity and general recovery. Results Postoperatively, in group A, 2 patients had cerebral infarction, 2 patients had popliteal artery throm-bosis, 1 patient had pulmonary embolism, and 1 patient had thrombosis in the annulus. Expected INR was achieved 15-20 days after warfarin treatment among the other 14 patients without thromboembolism. Three months after surgery, CYP2C9 and VKORC1 gene polymorphism was examined to find 17 patients with positive CYP2C9^*1/^*1 (^*2CC/^*3AA)and positive VKORC1-1639 GA, and 3 patients with positive CYP2C9^*1/^*1 (^*2CC/^*3AA)and positive VKORC1-1639 GG. In Group B, patients received aspirin (100 mg/d)and low molecular heparin (0.4 ml/d)in addition to warfarin since the second posto-perative day. Expected INR was achieved 5-9 days after warfarin treatment, and then aspirin and low molecular heparin were discontinued. During the 6 months follow-up period, no obvious thromboembolism was found, and only 1 patient had epistaxis who was cured with nasal tamponade. Conclusion Preoperative detection of genetic polymorphisms of CYP2C9 and VKORC1 can provide important guidance for warfarin anticoagulation after HVR.

Citation： HUANGGong-cheng, SHULi-liang, HUANGChen, ZHUXiao-hua, WEITing-ju, XUJing. Influence of High Activity of CYP2C9 and VKORC on Warfarin Anticoagulation after Heart Valve Replacement. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2014, 21(5): 609-613. doi: 10.7507/1007-4848.20140174 Copy

1.	Scott SA, Patel M, Martis S, et al. Copy number variation and warfarin dosing:evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU. Pharmacogenomics, 2012, 13(3):297-307.
2.	Singh O, Sandanaraj E, Subramanian K, et al. Infl uence of CYP4F-2rs2108622(V433M)on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet, 2011, 26(2):130-136.
3.	Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res, 2007, 5(1):8-16.
4.	聞武, 黃烽, 陽麗梅, 等. CYP2C93, VKORC1-1639G>A和CYP4F2 rs2108622基因多態性對華法林劑量的影響.中國胸心血管外科臨床雜志, 2013, 20(4):375-380.
5.	Suh DC, Nelson WW, Choi JC, et al. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fi brillation. Clin Ther, 2012, 34(7):1569-1582.
6.	Hines LE, Ceron-Cabrera D, Romero K, et al. Evaluation of warfarin drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther, 2011, 33(1):36-45.
7.	Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med, 2005, 165(10):1095-1106.
8.	Wittkowsky AK. A systematic review and inventory of supplement effects on warfarin and other anticoagulants. Thromb Res, 2005, 117(1/2):81-86.
9.	Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther, 2011, 90(4):625-629.
10.	熊克品, 錢紅波, 楊小龍, 等.心臟機械瓣膜置換術后抗凝治療的安全性.中國胸心血管外科臨床雜志, 2012, 19(1):88-89.
11.	Butchart EG, Lewis PA, Bethel JA, et al.Adjusting anticoagulation to prosthesis throbogenicity and paitent risk factors. Recommendations for the medtronic hall valve.Circulation, 1991, 84(Suppl 5):Ⅲ61.
12.	Shannon MS, Edwards MB, Long F, et al. Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom. J Heart Valve Dis, 2008, 17(5):526-532.
13.	Thompson JL, Sundt TM, Sarano ME, et al. In-patient international normalized ratio self-testing instruction after mechanical heart valve implantation. Ann Thorac Surg, 2008, 85(6):2046-2050.
14.	Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of enatiomers of warfarinin man. Clin Pharmacol Ther, 1974, 15(4):424-430.
15.	Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet, 2001, 40(8):587-603.
16.	Yin T, Miyata T. Warfarin dose and the pharmaeogenomics of CYP2C9 and VKORCl-rationale and perspectives. Thromb Res, 2007, 120(1):1-10.
17.	Yang LM, Ge WH, Yu F, et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement--a systematic review and meta analysis. Thromb Res, 2010, 125(4):e159-e166.
18.	Hirsh J, Guyatt G, Albers GW, et al. Antithrombotic and thrombo. Lytic therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest, 2008, 13(3):110s-l12s.
19.	張東旸, 田海, 陳巍, 等.我國心臟機械瓣膜置換術后抗凝方法的現狀與發展.中華胸心血管外科雜志, 2013, 29(4):230-232.
20.	Appelboam R, Thomas EO. Warfarin and intracranial haemorrhage.Blood Rev, 2009, 23(1):1-9.
21.	Butchart EG, Lewis PA, Grnnkemeier GL, et al. Low risk of throm-bosis and serious embolic events despite low-intensity anticoagulation.Experience with 1 004 medtronic hall valves. Circulation, 1988, 78(3 pt 2):166-177.
22.	Horstkotte D, Schuhe HD, Bireks W, et al. Lower intensity anti-coagulation therapy results in lower complication rates with the St. Jude Medical prosthesis. J Thorac Cardiovase Surg, 1994, 10(7):l136.
23.	Kim CW, Kim YT. Anticoagulation management after mitral valve replacement with the St. Jude medical prosthesis. Korean J Thorae Cardiovasc Surg, 1998, 3(1):1172-l182.
24.	Jeong SC, Kim MJ, Song CM, et al. Low-intensity oral anticoagula-tion versus high-intensity oral anticoagu lation in patients with me-chanical bileanet prosthetic heart valves. Korean J Thorac Cardiovase Surg, 2008, 4(1):430-438.
25.	楊遇春, 吳明祥, 張治平, 等.急性人工瓣膜功能障礙六例臨床分析.中國胸心血管外科臨床雜志, 2013, 20(2):226-228.
26.	唐躍, 吳清玉, 董超, 等.機械瓣置換術后抗凝方法和凝血酶元國際標準化比值監測的臨床研究.中華心血管病雜志, 2003, 31(6):427-430.
27.	董力, 石應康, 鄧承祺, 等.應用國際標準比值監測心臟機械瓣膜替換術后抗凝治療.中華胸心血管外科雜志, 1999, 15(3):41-43.
28.	Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.Circulation, 2003, 10(7):1692-1711.
29.	劉湘君, 吳清玉, 李洪銀, 等.華法林聯合肝素在機械瓣膜置換術后抗凝治療中的應用.中華醫學雜志, 2010, 90(38):2697-2700.

1. Scott SA, Patel M, Martis S, et al. Copy number variation and warfarin dosing:evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU. Pharmacogenomics, 2012, 13(3):297-307.
2. Singh O, Sandanaraj E, Subramanian K, et al. Infl uence of CYP4F-2rs2108622(V433M)on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet, 2011, 26(2):130-136.
3. Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res, 2007, 5(1):8-16.
4. 聞武, 黃烽, 陽麗梅, 等. CYP2C93, VKORC1-1639G>A和CYP4F2 rs2108622基因多態性對華法林劑量的影響.中國胸心血管外科臨床雜志, 2013, 20(4):375-380.
5. Suh DC, Nelson WW, Choi JC, et al. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fi brillation. Clin Ther, 2012, 34(7):1569-1582.
6. Hines LE, Ceron-Cabrera D, Romero K, et al. Evaluation of warfarin drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther, 2011, 33(1):36-45.
7. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med, 2005, 165(10):1095-1106.
8. Wittkowsky AK. A systematic review and inventory of supplement effects on warfarin and other anticoagulants. Thromb Res, 2005, 117(1/2):81-86.
9. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther, 2011, 90(4):625-629.
10. 熊克品, 錢紅波, 楊小龍, 等.心臟機械瓣膜置換術后抗凝治療的安全性.中國胸心血管外科臨床雜志, 2012, 19(1):88-89.
11. Butchart EG, Lewis PA, Bethel JA, et al.Adjusting anticoagulation to prosthesis throbogenicity and paitent risk factors. Recommendations for the medtronic hall valve.Circulation, 1991, 84(Suppl 5):Ⅲ61.
12. Shannon MS, Edwards MB, Long F, et al. Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom. J Heart Valve Dis, 2008, 17(5):526-532.
13. Thompson JL, Sundt TM, Sarano ME, et al. In-patient international normalized ratio self-testing instruction after mechanical heart valve implantation. Ann Thorac Surg, 2008, 85(6):2046-2050.
14. Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and pharmacodynamics of enatiomers of warfarinin man. Clin Pharmacol Ther, 1974, 15(4):424-430.
15. Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet, 2001, 40(8):587-603.
16. Yin T, Miyata T. Warfarin dose and the pharmaeogenomics of CYP2C9 and VKORCl-rationale and perspectives. Thromb Res, 2007, 120(1):1-10.
17. Yang LM, Ge WH, Yu F, et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement--a systematic review and meta analysis. Thromb Res, 2010, 125(4):e159-e166.
18. Hirsh J, Guyatt G, Albers GW, et al. Antithrombotic and thrombo. Lytic therapy:American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest, 2008, 13(3):110s-l12s.
19. 張東旸, 田海, 陳巍, 等.我國心臟機械瓣膜置換術后抗凝方法的現狀與發展.中華胸心血管外科雜志, 2013, 29(4):230-232.
20. Appelboam R, Thomas EO. Warfarin and intracranial haemorrhage.Blood Rev, 2009, 23(1):1-9.
21. Butchart EG, Lewis PA, Grnnkemeier GL, et al. Low risk of throm-bosis and serious embolic events despite low-intensity anticoagulation.Experience with 1 004 medtronic hall valves. Circulation, 1988, 78(3 pt 2):166-177.
22. Horstkotte D, Schuhe HD, Bireks W, et al. Lower intensity anti-coagulation therapy results in lower complication rates with the St. Jude Medical prosthesis. J Thorac Cardiovase Surg, 1994, 10(7):l136.
23. Kim CW, Kim YT. Anticoagulation management after mitral valve replacement with the St. Jude medical prosthesis. Korean J Thorae Cardiovasc Surg, 1998, 3(1):1172-l182.
24. Jeong SC, Kim MJ, Song CM, et al. Low-intensity oral anticoagula-tion versus high-intensity oral anticoagu lation in patients with me-chanical bileanet prosthetic heart valves. Korean J Thorac Cardiovase Surg, 2008, 4(1):430-438.
25. 楊遇春, 吳明祥, 張治平, 等.急性人工瓣膜功能障礙六例臨床分析.中國胸心血管外科臨床雜志, 2013, 20(2):226-228.
26. 唐躍, 吳清玉, 董超, 等.機械瓣置換術后抗凝方法和凝血酶元國際標準化比值監測的臨床研究.中華心血管病雜志, 2003, 31(6):427-430.
27. 董力, 石應康, 鄧承祺, 等.應用國際標準比值監測心臟機械瓣膜替換術后抗凝治療.中華胸心血管外科雜志, 1999, 15(3):41-43.
28. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.Circulation, 2003, 10(7):1692-1711.
29. 劉湘君, 吳清玉, 李洪銀, 等.華法林聯合肝素在機械瓣膜置換術后抗凝治療中的應用.中華醫學雜志, 2010, 90(38):2697-2700.

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Influence of High Activity of CYP2C9 and VKORC on Warfarin Anticoagulation after Heart Valve Replacement

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