Long-term evaluation of target INR 1.60 to 2.20 and weekly dosage adjustment of warfarin in patients after mechanical heart valve replacement_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HUANG Yun ¹ , ZHAO Xia ¹ , LUO Nan ¹ , LIU Kui ¹ ,  XIAO Xijun ²

1. Department of Cardiothoracic Surgery, Zigong No.4 People’s Hospital, Zigong, 643000, Sichuan, P.R.China;
2. Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, P.R.China;

Corresponding?author：

XIAO Xijun, Email: xijunxiao2009@hotmail.com

Keywords：

Warfarin; mechanical heart valve replacement; anticoagulation management; international normalized ratio; time in therapeutic range; fraction of time in therapeutic range

DOI：

10.7507/1007-4848.201611027

Video：

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Objective To evaluate the long-term anticoagulation outcomes of target international normalized ratio (INR) 1.60 to 2.20 and weekly dosage adjustment of warfarin in patients after mechanical heart valve replacement. Methods Outpatients after mechanical heart valve replacement at least 6 months were registered continually from July 2011 to July 2016 in department of cardiothoracic surgery at Zigong No.4 People's Hospital and West China Hospital. There were 1 690 females (70.62%) and 703 males (29.38%) with a median age of 47 years, ranging from 14 to 80 years. All patients were followed up for 6-61 months. Target INR was 1.60 to 2.20 and warfarin dosage were adjusted weekly. Unexpected bleeding, thrombogenesis and thromboembolism, time in therapeutic range (TTR) and fraction of TTR (FTTR) were recorded and calculated to evaluate the outcome of anticoagulation management. Results A total of 2 393 patients with 26 521 INR values were included for data analysis. INR values varied from 0.90-8.39 (1.82±0.45) and required weekly doses of warfarin were 1.75-61.25 (21.72±7.39) mg. TTR of target INR and acceptable INR was 59.38% (1 449 514.0 days/2 441 060.0 days) and 73.57% (1 795 971.0 days/2 441 060.0 days), respectively. FTTR of target INR and acceptable INR were 50.71% (13 450 times/26 521 times), 65.25% (17 305 times/26 521 times). During the follow-up , anticoagulation-related complications included: cerebral infarction in 21 patients (complete recovery in 18 patients, physical activity disorder in 3 patients), cerebral hemorrhage in 4 patients (death in 1 patient, complete recovery in 3 patients), severe gastrointestinal bleeding in 3 patients (completely recovered) and uterine bleeding in 1 patient (surgical removal of the uterus). Conclusion Target INR 1.60–2.20 and warfarin weekly dosage adjustment for patients after mechanical heart valve replacement is reasonable and safe.

Citation： HUANG Yun, ZHAO Xia, LUO Nan, LIU Kui, XIAO Xijun. Long-term evaluation of target INR 1.60 to 2.20 and weekly dosage adjustment of warfarin in patients after mechanical heart valve replacement. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2017, 24(4): 275-280. doi: 10.7507/1007-4848.201611027 Copy

1.	?Butchart EG, Payne N, Li HH, et al. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg, 2002, 123(4): 715-723.
2.	Kulik A, Rubens FD, Wells PS, et al. Early postoperative anticoagulation after mechanical valve replacement: A systematic review. Ann Thorac Surg, 2006, 81(2): 770-781.
3.	肖錫俊, 劉關鍵, 梁茂植, 等. 機械瓣置換術后患者目標 INR1.60～2.20 及以每周為單位華法林劑量調整合理性的初步評價. 中國循證醫學雜志, 2014, 14(1): 16-20.
4.	Schmitt L, Speckman J, Ansell J. Quality assessment of anticoagulation dose management: comparative evaluation of measures of time-in-therapeutic range. J Thromb Thrombolysis, 2003, 15(3): 213-216.
5.	劉媛, 余細勇, 鐘詩龍, 等. 心臟瓣膜置換術后華法林抗凝治療的單中心臨床應用調查. 南方醫科大學學報, 2010, 30(10): 2242-2245.
6.	徐博. 人工機械心臟瓣膜置換術后抗凝治療強度與抗凝并發癥發生率的臨床分析. 西安: 第四軍醫大學, 2013.
7.	孟旭, 李金鐘, 劉巖, 等. 人工機械瓣膜置換術后口服抗凝藥的抗凝治療強度標準. 中華心血管病雜志, 2004, 32(7): 618-621.
8.	Hering D, Piper C, Bergemann R, et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience With Low-Intensity Anticoagulation Study. Chest, 2005, 127(1): 53-59.
9.	Koertke H, Zittermann A, Minami K, et al. Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg, 2005, 79(6): 1909-1914.
10.	Christensen TD, Andersen NT, Attermann J, et al. Mechanical heart valve patients can manage oral anticoagulant therapy themselves. Eur J Cardiothorac Surg, 2003, 23(3): 292-298.
11.	Herijgers P, Verhamme P. Improving the quality of anticoagulant therapy in patients with mechanical heart valves: what are we waiting for? Eur Heart J, 2007, 28(20): 2424-2426.
12.	Rosendaal FR, Cannegieter SC, van der Meer FJ, et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost, 1993, 69(3): 236-239.
13.	Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis, 2000, 9(3): 283-292.
14.	Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 160S-198S.
15.	Gallagher AM, Setakis E, Plumb JM, et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost, 2011, 106(5): 968-977.
16.	Razouki Z, Ozonoff A, Zhao S, et al. Improving quality measurement for anticoagulation: adding international normalized ratio variability to percent time in therapeutic range. Circ Cardiovasc Qual Outcomes, 2014, 7(5): 438-442.
17.	Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation, 2008, 118(20): 2029-2037.
18.	Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014, 129(23): 2440-2492.
19.	中華醫學會心血管病學分會. 華法林抗凝治療的中國專家共識. 中華內科雜志, 2013, 52(1): 76-82.
20.	Grzymala-Lubanski B, Svensson PJ, Renlund H, et al. Warfarin treatment quality and prognosis in patients with mechanical heart valve prosthesis. Heart, 2017, 103(3): 198-203.
21.	王斌, 徐志云, 葉小飛. 華人心臟機械瓣膜置換術后華法林抗凝強度標準的系統評價. 國際心血管病雜志, 2010, 37(6): 361-366.
22.	You JH, Chan FW, Wong RS, et al. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol, 2005, 59(5): 582-587.
23.	Yu HC, Chan TY, Critchley JA, et al. Factors determining the maintenance dose of warfarin in Chinese patients. QJM, 1996, 89(2): 127-136.
24.	顧強, 陳柏成, 郝嘉, 等. 重慶地區心臟機械瓣膜置換術后穩定華法林抗凝劑量的探討. 第三軍醫大學學報, 2008, 30(7): 647-649.
25.	王勝鵬. 云南地區瓣膜置換術后低強度抗凝的臨床研究. 昆明: 昆明醫學院, 2007.
26.	Kim YK, Nieuwlaat R, Connolly SJ, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost, 2010, 8(1): 101-106.
27.	Piper C, Horstkotte D. State of the art anticoagulation management. J Heart Valve Dis, 2004, 13(Suppl 1): S76-S80.
28.	Gemmati D, Burini F, Talarico A, et al. The active metabolite of warfarin (3'-hydroxywarfarin) and correlation with INR, warfarin and drug weekly dosage in patients under oral anticoagulant therapy: A pharmacogenetics study. PloS One, 2016, 11(9): e0162084.
29.	Wadelius M. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med, 2009, 361(16): 1613.
30.	Mahajan P, Meyer KS, Wall GC, et al. Clinical applications of pharmacogenomics guided warfarin dosing. Int J Clin Pharm, 2013, 35(3): 359-368.
31.	Poli D, Antonucci E, Gensini GF, et al. Asymptomatic excessive coumarin anticoagulation is a risk factor for thrombotic and bleeding complications of oral anticoagulant therapy. J Thrombo Haemost, 2003, 1(8): 1840-1841.
32.	Matchar DB, Love SR, Jacobson AK, et al. The impact of frequency of patient self-testing of prothrombin time on time in target range within VA Cooperative Study #481: The Home INR Study (THINRS), a randomized, controlled trial. J Thromb Thrombolysis, 2015, 40(1): 17-25.
33.	Van Damme S, Van Deyk K, Budts W, et al. Patient knowledge of and adherence to oral anticoagulation therapy after mechanical heart-valve replacement for congenital or acquired valve defects. Heart Lung, 2011, 40: 139-146.
34.	朱黎鳴. 機械瓣膜置換術后抗凝治療患者教育與抗凝治療質量的關系. 上海: 復旦大學, 2008.
35.	董力, 許建屏, 石應康.《瓣膜病術后抗凝個體化和低抗凝標準研究》階段研究進展. 中國胸心血管外科臨床雜志, 2013, 20(1): 1-2.
36.	Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis, 1998, 5 Suppl 1(3): 19-24.
37.	Guidelines on oral anticoagulation: third edition. Br J Haematol, 1998, 101(2): 374-387.
38.	Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med, 2011, 155(10): 653-659.

1. ?Butchart EG, Payne N, Li HH, et al. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg, 2002, 123(4): 715-723.
2. Kulik A, Rubens FD, Wells PS, et al. Early postoperative anticoagulation after mechanical valve replacement: A systematic review. Ann Thorac Surg, 2006, 81(2): 770-781.
3. 肖錫俊, 劉關鍵, 梁茂植, 等. 機械瓣置換術后患者目標 INR1.60～2.20 及以每周為單位華法林劑量調整合理性的初步評價. 中國循證醫學雜志, 2014, 14(1): 16-20.
4. Schmitt L, Speckman J, Ansell J. Quality assessment of anticoagulation dose management: comparative evaluation of measures of time-in-therapeutic range. J Thromb Thrombolysis, 2003, 15(3): 213-216.
5. 劉媛, 余細勇, 鐘詩龍, 等. 心臟瓣膜置換術后華法林抗凝治療的單中心臨床應用調查. 南方醫科大學學報, 2010, 30(10): 2242-2245.
6. 徐博. 人工機械心臟瓣膜置換術后抗凝治療強度與抗凝并發癥發生率的臨床分析. 西安: 第四軍醫大學, 2013.
7. 孟旭, 李金鐘, 劉巖, 等. 人工機械瓣膜置換術后口服抗凝藥的抗凝治療強度標準. 中華心血管病雜志, 2004, 32(7): 618-621.
8. Hering D, Piper C, Bergemann R, et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience With Low-Intensity Anticoagulation Study. Chest, 2005, 127(1): 53-59.
9. Koertke H, Zittermann A, Minami K, et al. Low-dose international normalized ratio self-management: a promising tool to achieve low complication rates after mechanical heart valve replacement. Ann Thorac Surg, 2005, 79(6): 1909-1914.
10. Christensen TD, Andersen NT, Attermann J, et al. Mechanical heart valve patients can manage oral anticoagulant therapy themselves. Eur J Cardiothorac Surg, 2003, 23(3): 292-298.
11. Herijgers P, Verhamme P. Improving the quality of anticoagulant therapy in patients with mechanical heart valves: what are we waiting for? Eur Heart J, 2007, 28(20): 2424-2426.
12. Rosendaal FR, Cannegieter SC, van der Meer FJ, et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost, 1993, 69(3): 236-239.
13. Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolysis, 2000, 9(3): 283-292.
14. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 160S-198S.
15. Gallagher AM, Setakis E, Plumb JM, et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost, 2011, 106(5): 968-977.
16. Razouki Z, Ozonoff A, Zhao S, et al. Improving quality measurement for anticoagulation: adding international normalized ratio variability to percent time in therapeutic range. Circ Cardiovasc Qual Outcomes, 2014, 7(5): 438-442.
17. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation, 2008, 118(20): 2029-2037.
18. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014, 129(23): 2440-2492.
19. 中華醫學會心血管病學分會. 華法林抗凝治療的中國專家共識. 中華內科雜志, 2013, 52(1): 76-82.
20. Grzymala-Lubanski B, Svensson PJ, Renlund H, et al. Warfarin treatment quality and prognosis in patients with mechanical heart valve prosthesis. Heart, 2017, 103(3): 198-203.
21. 王斌, 徐志云, 葉小飛. 華人心臟機械瓣膜置換術后華法林抗凝強度標準的系統評價. 國際心血管病雜志, 2010, 37(6): 361-366.
22. You JH, Chan FW, Wong RS, et al. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol, 2005, 59(5): 582-587.
23. Yu HC, Chan TY, Critchley JA, et al. Factors determining the maintenance dose of warfarin in Chinese patients. QJM, 1996, 89(2): 127-136.
24. 顧強, 陳柏成, 郝嘉, 等. 重慶地區心臟機械瓣膜置換術后穩定華法林抗凝劑量的探討. 第三軍醫大學學報, 2008, 30(7): 647-649.
25. 王勝鵬. 云南地區瓣膜置換術后低強度抗凝的臨床研究. 昆明: 昆明醫學院, 2007.
26. Kim YK, Nieuwlaat R, Connolly SJ, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost, 2010, 8(1): 101-106.
27. Piper C, Horstkotte D. State of the art anticoagulation management. J Heart Valve Dis, 2004, 13(Suppl 1): S76-S80.
28. Gemmati D, Burini F, Talarico A, et al. The active metabolite of warfarin (3'-hydroxywarfarin) and correlation with INR, warfarin and drug weekly dosage in patients under oral anticoagulant therapy: A pharmacogenetics study. PloS One, 2016, 11(9): e0162084.
29. Wadelius M. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med, 2009, 361(16): 1613.
30. Mahajan P, Meyer KS, Wall GC, et al. Clinical applications of pharmacogenomics guided warfarin dosing. Int J Clin Pharm, 2013, 35(3): 359-368.
31. Poli D, Antonucci E, Gensini GF, et al. Asymptomatic excessive coumarin anticoagulation is a risk factor for thrombotic and bleeding complications of oral anticoagulant therapy. J Thrombo Haemost, 2003, 1(8): 1840-1841.
32. Matchar DB, Love SR, Jacobson AK, et al. The impact of frequency of patient self-testing of prothrombin time on time in target range within VA Cooperative Study #481: The Home INR Study (THINRS), a randomized, controlled trial. J Thromb Thrombolysis, 2015, 40(1): 17-25.
33. Van Damme S, Van Deyk K, Budts W, et al. Patient knowledge of and adherence to oral anticoagulation therapy after mechanical heart-valve replacement for congenital or acquired valve defects. Heart Lung, 2011, 40: 139-146.
34. 朱黎鳴. 機械瓣膜置換術后抗凝治療患者教育與抗凝治療質量的關系. 上海: 復旦大學, 2008.
35. 董力, 許建屏, 石應康.《瓣膜病術后抗凝個體化和低抗凝標準研究》階段研究進展. 中國胸心血管外科臨床雜志, 2013, 20(1): 1-2.
36. Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis, 1998, 5 Suppl 1(3): 19-24.
37. Guidelines on oral anticoagulation: third edition. Br J Haematol, 1998, 101(2): 374-387.
38. Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus every 12 weeks in patients with stable international normalized ratios: a randomized trial. Ann Intern Med, 2011, 155(10): 653-659.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Long-term evaluation of target INR 1.60 to 2.20 and weekly dosage adjustment of warfarin in patients after mechanical heart valve replacement

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