Warfarin INR (albumin) INR ( ) 2 warfarin INR warfarin INR 表一藥品 / 營養狀態影響 warfarin 效果 / Warfarinphenytoin Warfarinrosuvastatin Warfarinciprofloxacin Wa

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1 臨床藥物治療學 Warfarin 使用後 INR 波動的臨床處置 台南新樓醫院藥劑科藥師陳弘益 蔡佩瑜 國立台南專科護理學校講師唐正乾 摘要 Warfarin warfarin Warfarin Warfarin warfarin international normalized ratio (INR) vit. K INR warfarin INR (anticoagulation management service) K warfarin warfarin K fluctuation 壹 前言 78 rosuvastatin 10 mg/day phenytoin 100/200 mg warfarin 2.5 mg/ day 18 phenytoin mg/dl (international normalized ratio, INR) 5.22 INR warfarin phenytoin 1 warfarin 99 ciprofloxacin INR warfarin INR warfarin INR warfarin metronidazole 102 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.1 Mar

2 Warfarin INR (albumin) INR ( ) 2 warfarin INR warfarin INR 表一藥品 / 營養狀態影響 warfarin 效果 / Warfarinphenytoin Warfarinrosuvastatin Warfarinciprofloxacin Warfarinhypoalbuminemia 貳 嚴格控制 INR 的重要性 Phenytoin Warfarin Warfarin Warfarin Warfarin Warfarin Warfarin K II VII IX X INR INR 2-3 ( ) 3 INR %-72% INR 2-3 INR INR 2 warfarin INR 3 4,5 INR % 48% 7 10, % INR (INR>3) 27% INR (INR<2) 27% 11% INR (INR>3) 14% 26% 6 warfarin warfarin warfarin 3 表二 Warfarin 治療 INR 值範圍表 Acute myocardial infarction (high-risk): High-risk includes a large anterior MI, significant heart failure, intracardiac thrombus, thromboembolism Antiphospholipid Syndrome (no other risk factors): Combine with aspirin 81 mg/day. Maintain anticoagulation for at least 3 months Mar 藥學雜誌第 114 冊 103

3 臨床藥物治療學 Antiphospholipid Syndrome and recurrent thromboembolism Bioprosthetic (tissue) Valve Mitral Valve (MVR) Bioprosthetic (tissue) Valve -history of systemic embolism Bioprosthetic (tissue) Valve -additional risk factors for thromboembolism, including AF, hypercoagulable state, or low ejection fraction Patients with MVP who have AF, documented systemic embolism, or recurrent TIAs despite ASA therapy: Rheumatic mitral valve disease with AF who suffer systemic embolism or have left atrial thrombus while receiving warfarin at a therapeutic INR Rheumatic mitral valve disease complicated singly or in combination by the presence of AF, previous systemic embolism, or left atrial thrombus Rheumatic mitral valve disease and normal sinus rhythm with a left atrial diameter > 55 mm duration 3 months and then aspirin therapy (81 mg/d) Treatment length: for at least 3 months after valve insertion, followed by clinical reassessment Add low-dose ASA (50 to 100 mg/d) after consideration of the additional hemorrhagic risk. Alternative strategy: adjustment of warfarin dosing to achieve a higher target INR ( ). Venous thromboembolism Treatment length: variable 機械性心臟瓣膜置換之病人 : Bileaflet mechanical valve in the aortic position, left atrium of normal size, NSR, normal ejection fraction Bileaflet mechanical aortic valve and Thromboembolism Risk Factors (AF) First generation aortic valve (i.e. caged ball or caged disk) Mitral Valve (MVR) all mitral valves with or without risk factors for thromboembolism 104 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.1 Mar

4 Warfarin INR St Jude Medical bileaflet mechanical aortic valve Tilting disk valve or bileaflet mechanical valve in the mitral position Modern aortic valve with atrial fibrillation or other risk factor(s) for thromboembolism -Carbomedics bileaflet -Medtronic Hall tilting disk CarboMedics bileaflet valves or Medtronic Hall tilting disk mechanical valve in the aortic position, normal left atrium, and sinus rhythm Mechanical prosthetic valve with systemic embolism despite adequate anticoagulation Mechanical valve and risk factors (atrial fibrillation, MI, left atrial enlargement, low EF, endocardial damage) Targeted 2.5 Combine with aspirin 81 mg/day Combine with aspirin 81 mg/day unless patient at particularly high risk of bleeding, such as in patients with history of GI bleeding, or in patients > 80 years of age 參 影響 INR 的因素 warfarin cytochrome P450 2C9 (CYP2C9) VKORC1 (vitamin K epoxide reductase complex 1) 95% VKORC1*2 homozygous warfarin 50% 95% VKORC1*2 heterozygous warfarin 25% 8 ( ) ( ) vit. K warfarin warfarin 肆 藥師的角色 (anticoagulation management services, AMS) µl INR INR 4. INR I N R 29 1 Mar 藥學雜誌第 114 冊 105

5 臨床藥物治療學 % warfarin atrial fibrillation (40.0%) mechanical valve replacement (24.0%) venous thromboembolism (19.2%) AMS warfarin INR % 48.8% (95% CI 13.4%-22.0%) AMS 17.6 (95% CI 6.0%-51.9%) AMS 572 $122, warfarin (RR0.51; 95% CI 0.28%-0.94%) 10 warfarin INR 3 warfarin (p value <0.001) ( 21 vs. 6 p value=0.006) (thromboembolic events) ( 52 vs. 12 p value<0.001) - (cost-benefit analysis) 伍 維他命 K 的角色 warfarin K μg K 12 K INR K INR 26 INR K 29 μg 26 INR K 76 μg 13 K INR INR warfain 100 μg K INR INR INR INR μg vitamin K warfarin INR ( ; P <.001) INR INR (28% 20% vs 15% 20%; P <.01) 14 warfarin warfarin INR K 100 μg warfarin INR warfarin INR μg/day 150 μg/ day vit. K INR 400 phenprocoumon acenocoumarol ( warfarin (coumarin) phenprocoumon acenocoumarol) 106 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.1 Mar

6 Warfarin INR phenprocoumon acenocoumarol K 100 μg K 150 μg K 200 μg INR 100 μg 2.1% (95% CI: -3.2% - 7.4%) INR 150 μg 2.7% (95% CI: -2.3% -7.6%) INR 200 μg 0.9% (95% CI: -4.5% - 6.3%) 150 μg 100 μg 200 μg K (100 μg 150 μg 200 μg) K INR 16 K 100 μg K K 25 μg K 30 μg 陸 其他改善策略 INR warfarin 柒 結論 Warfarin ( Dabigatran) warfarin K warfarin warfarin INR 參考資料 : 1. Chen HY, Chiu LC. Elevated international normalized ratio which might be induced by drug interactions with warfarin and ataxia induced by phenytoin overdose in an elderly patient. Formosa Journal of Clinical Pharmacy. 2012; 20(2): Yu-Jyun Ma, Ching-Ying Liao. An unexpected rise in INR after stopping warfarin: A case report. Formosa Journal of Clinical Pharmacy. 2012; 20(1): Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J Med 1995; 333: Jones M, McEwan P, Morgan CL, Peters JR, Goodfellow J, Currie CJ. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population. Heart 2005; 91: Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ 2007; 176: van Walraven C, Oake N, Wells PS, Forster AJ. Burden of potentially avoidable anticoagulant-associated hemorrhagic and thromboembolic events in the elderly. Chest 2007; 131: Oldenburg J, Bevans CG, Fregin A, Geisen C, Müller- Reible C, Watzka M. Current pharmacogenetic developments in oral anticoagulation therapy: The influence of variantvkorc1 and CYP2C9 alleles. Thromb Haemost 2007; 98: Saokaew S, Permsuwan U, Chaiyakunapruk N, et al: Effectiveness of pharmacist-participated warfarin therapy management: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: Chang Y. Evaluation of a Pharmacist-Conducted Health Education Service for Outpatients on Warfarin. Master thesis of institute of clinical pharmacy of Taipei medical school Cushman M, Booth SL, Possidente CJ, et al: The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol 2001; 112: Sconce E, Khan T, Mason J, et al: Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb Haemost 2005; 93: Reese AM, Farnett LE, Lyons RM, et al: Low-dose vitamin K to augment anticoagulation control. Pharmacotherapy 2005; 25: Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007; 109: Lin CY, Su JJ, Kao YH. Low dose vitamin K improve effectiveness of oral anticoagulant: a case report. Formosa J Clin Pharm 2011; 19(3): Gebuis EP, Rosendaal FR, van Meegen E, van der Meer FJ.Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study. Haematol 2011; 96(4): Mar 藥學雜誌第 114 冊 107

7 臨床藥物治療學 Management of Warfarin-Related INR Fluctuations Chen Hung-Yi1, Tsai Pei-Yu1, Tang Chang-Chen2 Department of Pharmacy, Tainan Sin-Lau Hospital1 Division of Pharmacology, National Tainan Institute of Nursing2 Abstract Warfarin is indicated for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and atrial fibrillation with risk of embolism. However, warfarin has a narrow therapeutic window and there is inter-ethnic (eg. genetic polymorphism) and inter-individual differences (eg. alcoholism, smoking, nutrition status and vitamin K intake ) in warfarin dose requirements and may cause international normalised ratio (INR) fluctuations. Recently, there is a case report mentioned about unexpected rise in INR after stopping warfarin. This makes determining the therapeutic dose difficult. Overdose of warfarin may cause serious bleeding while underdose may cause thrombosis or embolism. INR fluctuation is a common and important clinical problem required to be resolved. In this article, we are going to introduce interventions that can be helpful in resolving warfarin-related INR fluctuations in order to improve medication safety of patients. 108 THE JOURNAL OF TAIWAN PHARMACY Vol.29 No.1 Mar