藥Pharmaceutical Sciences 物科學 II VII IX X dabigatran etexilate rivaroxaban apixaban ( ) ( ) 1 參藥品個論一 Dabigatran Etexilate 圖一新製劑之作用機轉與其標的因子 Ximelagatr

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1 摘要高雄長庚紀念醫院藥劑部藥師張淑玲陳一伶 K warfarin K K ( II VII IX X) Xa K anti- factor Xa oral vitamin K antagonist warfarin low molecular weight heparin 壹前言 K (oral vitamin K antagonists VKAs) (offset of action) (low molecular weight heparin LMWH) (heparin-induced thrombocytopenia) (osteoporosis) 貳新舊製劑作用機轉差異 III VII IX X XII XI IX X X (thrombin) (fibrinogen) (fibrin) VKAs K 30 2 Jun 藥學雜誌藥物科學新抗凝血劑與傳統製劑之比較

2 藥Pharmaceutical Sciences 物科學 II VII IX X dabigatran etexilate rivaroxaban apixaban ( ) ( ) 1 參藥品個論一 Dabigatran Etexilate 圖一新製劑之作用機轉與其標的因子 Ximelagatran Dabigatran etexilate ximelagatran 表一 warfarin 與第十凝血因子抑制劑之特性比較 warfarin rivaroxaban apixaban Vitamin K epoxide reductase dabigatran etexilate Xa Xa 95% 80% 50% 6% T (max) INR CYP 2C9, 3A4,1A2 CYP 3A4, 66%, 33% CYP 2C9, 3A4,1A2 Potent CYP3A4 & P-glycoprotein inhibitors CYP 3A4, 75% 25% Potent CYP3A4 & P-glycoprotein inhibitors 80%, 20% P-glycoprotein inhibitors 6.5% % 30 ml/hr (dyspepsia) warfarin (tartaric acid core) Ph ximelagatran 二 Rivaroxaban Rivaroxaban Xa 28 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.2 Jun

3 4 5 9 cytochrome P450 (CYP) 3A4 EINSTEIN rivaroxaban 1.3% 7.1% (P < ) 0.7% (P = 0.106) 三 Apixaban Apixaban Xa CYP 3A4 CYP3A4 (ketoconazole ritonavir) 肆臨床應用比較一全髖或膝關節成形術 (total hip or knee arthroplasty ) (current evidence-based clinical guidelines) Dabigatran etexilate rivaroxaban apixaban enoxaparin ( 40 mg) (haemoglobin) 24 2 g/dl ( ) 藥物科學2.5 ( 一 ) Dabigatran etexilate 與 enoxaparin 的比較 (total venous thromboembolic events) (all-cause mortality) dabigatran etexilate150 mg 220 mg enoxaparin 40 mg (non-inferiority) (p < 0.05) ( ) 圖二 (a) 整體靜脈栓塞事件 (b) 各種原因死亡率之比較 RE-MOBILIZE (DVT Prevention in Knee Arthroplasty in North American Trials) dabigatran etexilate 150 mg 220 mg enoxaparin 30 mg ( ) dabigatran etexilate 150 mg 220 mg enoxaparin 40 mg (major bleeding events) (p > 0.05) 藥學雜誌 Jun

4 藥Pharmaceutical Sciences 物科學 enoxaparin 40 mg mg QD QD enoxaparin 40 mg mg QD QD enoxaparin 30 mg mg QD BID QD enoxaparin 40mg QD QD BID BID QD QD ( 二 ) Dabigatran etexilate 與 warfarin 表二比較新一代抗凝血劑在髖或膝關節成形術之臨床試驗結果 dabigatran ( ) dabigatran etexilate RE-MODEL 150 mg 220 RE-NOVATE 150 mg 220 dabigatran enoxaparin 150 mg: 1.3% 220 mg: 1.5%,enoxaparin: 1.3% dabigatran enoxaparin 150 mg: 1.3%; 220 mg: 2%, enoxaparin: 1.6% RE-MOBILIZE 150 mg 220 enoxaparin dabigatran 150 mg: 0.6%; 220 mg: 0.6%, enoxaparin: 1.4% ( ) rivaroxaban RECORD-1 10 mg QD enoxaparin 40 mg rivaroxaban: 1.1% enoxaparin: 3.7% rivaroxaban: 0.3%, p < enoxaparin: 0.1%, p = 0.18 RECORD-2 10 mg QD rivaroxaban: 2% enoxaparin: 9.3% p < rivaroxaban: < 0.1%, enoxaparin: < 0.1%, p = 1 RECORD-3 10 mg QD enoxaparin 40 mg rivaroxaban: 9.6% enoxaparin: 18.9% p < rivaroxaban: 0.6, enoxaparin: 0.5%, p = 0.77 RECORD-4 10 mg QD enoxaparin 30 mg rivaroxaban: 6.9% enoxaparin: 10.1% p = rivaroxaban: 0.7% enoxaparin: 0.3%, p = 0.11 ( ) apixaban ADVANCE mg BID enoxaparin 30 mg apixaban: 9%, enoxaparin: 8.9% apixaban: 0.7%, enoxaparin: (RRR 1.02; 95%CI ; p = 0.06) 1.4%, p = ADVANCE mg BID enoxaparin 40 mg apixaban: 15%,enoxaparin: 24% apixaban: 0.60%, (RRR 0.62; 95%CI ; p < ) enoxaparin: 0.93%, p = not significant ADVANCE mg BID enoxaparin 40 mg apixaban: 1.4%,enoxaparin: 3.9% apixaban: 0.82%, (RRR 0.36; 95%CI ; p < ) enoxaparin: 0.68%, p = not significant 2.4% warfarin 2.1% 的比較 RE-COVER ( ) REMEDY ( ) RE-COVER dabigatran etexilate 150 mg warfarin (international normalized ratio INR 2-3) dabigatran dabigatran warfarin 1.6% 1.9% ( 三 ) Rivaroxaban 與 enoxaparin 的比較 enoxaparin 40 mg 30 mg rivaroxaban 10 mg 30 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.2 Jun

5 enoxaparin (Events%) (p < 0.05) rivaroxaban 10 mg enoxaparin ( 40 mg 30 mg) ( ) (p > 0.05) RECORD enoxaparin rivaroxaban RECORD-2 rivaroxaban (0.4 vs 0% with enoxaparin) 藥物科學 rivaroxaban ( 四 ) Apixaban 與 enoxaparin 的比較 ADVANCE-1 apixaban 2.5 mg enoxaparin 30 mg10 14 ADVANCE-2 apixaban 2.5 mg enoxaparin 40 mg ADVANCE-1 (p = 0.06) ADVANCE-2 (patient%) (p < )( ) (atrial fibrillation) 3 CHADS2 score 4 (CHADS2 C HA 75 DS2 ) K (non-valvular) Warfarin 64% 5 Warfarin AF aspirin AF 6 warfarin 藥學雜誌圖三 (a) 深部靜脈血栓 (b) 非致命性肺栓塞及所有成因致死病人百分率之比較 apixaban 2.5 mg enoxaparin 30 mg 40 mg ADVANCE-2 (P = ) ADVANCE-1 (P = 0.05) ADVANCE-1 apixaban enoxaparin (0.7 vs 1.4% P = 0.05) ADVANCE-2 ADVANCE-3 ( ) apixaban enoxaparin ( mg) ( ) 二心房纖維顫動 30 2 Jun

6 藥Pharmaceutical Sciences 物科學 ( 一 ) Dabigatran etexilate 及 warfarin 的比較 RE-LY dabigatran etexilate warfarin ( ) (hemoglobin) 2 g/dl dabigatran etexilate 150 mg warfarin (P = for superiority)110 mg warfarin (P = 0.34 for noninferiority) dabigatran etexilate110 mg warfarin (P = 0.003) dabigatran etexilate 150 mg warfarin (P = 0.31) warfarin (intracranial hemorrhage) (myocardial infarctions) dabigatran etexilate 150 mg 表三 RE-LY 試驗研究對象特性 Dabigatran 110 mg BID Dabigatran warfarin Dabigatran 110 mg vs Dabigatran 150 mg vs warfarin 150 mg BID warfarin RR 95% RR 95% (%) p < p < (%/ ) ( ), p = ( ), p < (%/ ) ( ), p = ( ), p = 0.31 (%/ ) p < p < (%/ ) ( ), p = ( ), p < (%/ ) ( ), p < ( ), p = 0.04 (%/ ) p = 0.07 p = (%/ ) p = 0.13 p = ( 二 ) Rivaroxaban 與 warfarin 的比較 rivaroxaban 188 ( 1.7%) warfarin 241 ( 2.2%) (P < for noninferiority)( ) (P = 0.44) 3.6% 3.4% (P = 0.58) Rivaroxaban (hemoglobin) 2 g/dl Rivaroxaban warfarin0.5% vs. 0.7% (P = 0.02) rivaroxaban 224 (3.2%) warfarin 154 (2.2%) (P < 0.001) 32 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.2 Jun

7 rivaroxaban no./100 warfarin no./100 藥物科Rivaroxaban 與 warfarin 在中風或全身性栓塞等主要終點的比較學表四 Hazard Ratio (95% CI) 藥學雜誌 Jun P ( ) < ( ) ( ) < ( ) ( ) (20.7) (20.3) ( ) (5.6) (5.4) ( ) g/dl 305 (4.3) (3.6) ( ) (2.6) (2.1) ( ) (1.3) (1.9) ( ) (0.4) (0.8) ( ) (0.8) (1.2) ( ) (16.7) (16.2) ( ) 0.35 伍討論 warfarin 40 warfarin INR INR Warfarin warfarin warfarin

8 Pharmaceutical Sciences 藥物科學New Anticoagulants versus Traditional Agents Shu-Ling Chang, I-Ling Chen Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital Abstract The vitamin K antagonists (VKAs) are difficult to manage and associated with frequent adverse events. The VKA, warfarin, has been shown to reduce the risk of stroke. But it requires skillful dose management and patient communication to achieve the best outcomes. VKAs target an enzyme in the vitamin K pathway that leads to the reduction of the functional levels of factors II, VII, IX, and X, many of the new agents rely on targeting a particular coagulation factor and directly inhibiting it. These short-acting, short-duration, unmonitored drugs are not without limitations and potential adverse effects. They have predictable dose responses, thus eliminating the need for routine monitoring and fewer important food or drug interactions, thus simplifying management. However, they do have different routes of metabolism and elimination, with renal clearance playing a variable role with each drug. The oral direct thrombin and Xa inhibitors are furthest along in development. New oral anticoagulants with different mechanisms of action may replace the VKAs. 參考資料 : 1. Jack A, Warfarin Versus New Agents: Interpreting the Data. American society of Hematology. Issues In Thrombosismanagement and Anticoagulation. 2010: Geerts WH, Bergqvist D, Pineo GF, et al: American College of Chest Physicians (2008) Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133(6 Suppl): 381S-453S. 3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke1991; 22: Gage BF, Waterman AD, Shannon W, et al: Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285: Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. AnnIntern Med : Singer DE, Albers GW, Dalen JE, et al: Antithrombotic therapy in atrial fibrillation. ACCP evidence-based clinical practice guidelines. Chest. 2008; 133: 546S-592S. 34 THE JOURNAL OF TAIWAN PHARMACY Vol.30 No.2 Jun

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藥Pharmaceutical Sciences 物科學 II VII IX X dabigatran etexilate rivaroxaban apixaban ( ) ( ) 1 參 藥品個論 一 Dabigatran Etexilate 圖一新製劑之作用機轉與其標的因子 Ximelagatr

藥Pharmaceutical Sciences 物科學 II VII IX X dabigatran etexilate rivaroxaban apixaban ( ) ( ) 1 參藥品個論一 Dabigatran Etexilate 圖一新製劑之作用機轉與其標的因子 Ximelagatr