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Update of anticoagulants use: Stroke prevention in atrial fibrillation 三軍總醫院 神經科部 李俊泰 Outline • • • • Introduction Anticoagulant in atrial fibrillation Novel anticoagulant Guideline 腦中風中心品質管制指標 1. 2. 3. 4. 5. 6. 7. 8. 9. tPA的施打 吞嚥困難篩檢 住院中血脂測量 戒菸 中風衛教 復健計畫 48小時內使用抗血栓藥物 出院時使用抗血栓藥物(心房顫動病人使用抗 凝血藥物) 有系統的監控、評估照護品質與死亡率。 2007 May 心房顫動可能完全 無症狀,大部分心 悸(heart palpitations)、呼 吸急促、虛弱和昏 厥 AF SIGNIFICANTLY INCREASES THE RISK OF STROKE AF is associated with a pro-thrombotic state1 ~5-fold increase in stroke risk2 AF is the most common heart rhythm disturbance8 Up to 3 million people worldwide suffer strokes related to AF each year2-4 Due to the aging population, this number is expected to double within 30 years9 AF-related strokes tend to be especially severe and disabling with a 1-year mortality rate of ~50%4,5 Cardioembolic stroke has a 30-day mortality rate of 25%4 Risk of stroke is the same in AF patients regardless of whether they have paroxysmal or sustained AF6,7 1. Watson T, et al. Lancet 2009;373:155-166. 2. Wolf PA, et al. Stroke 1991;22:983-988. 3. Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf. 4. Lin HJ, et al. Stroke 1996;27:1760-1764. 5. Marini C, et al. Stroke 2005;36:1115-1119. 6. Rosamond W, et al. Circulation 2008;117:e25-146. 7. Hart RG, et al. J Am Coll Cardiol 2000;35:183-187. 8. Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046. 9. Go AS, et al. JAMA 2001;285:2370-2375. 臺灣中風登錄系 統2006-2008: 30,599 stroke admissions Circulation. 2010;122:1 116-1123.) AF-RELATED STROKES ARE ASSOCIATED WITH GREATER DISABILITY AND A HIGHER MORTALITY RATE Strokes without AF (N=845) Disability at clinical presentation1 30-day post-stroke mortality2 60 30 P<0.005 P<0.0005 50 P<0.048 Fatal strokes (%) Patients with clinical parameter (%) Strokes with AF (N=216) 40 30 20 25 20 15 10 10 0 0 Severe limb weakness Bedridden Strokes with AF Strokes without AF (N=103) (N=398) 1. Dulli DA, et al. Neuroepidemiology 2003;22:118-123. 2. Lin HJ, et al. Stroke 1996;27:1760-1764. Sources of Cardioembolic Stroke Others, 10% Prosthetic Cardiac Valve, 10% Nonvalvular AF, 45% RHD, 10% Ventricular Aneurysm, 10% Acute MI, 15% AF increases with age Prevalence is expected to increase as the population ages The lifetime risk of developing AF is 1 in 4 for men and women over 40 years of age 12 Prevalence, % 10 Women Men 11.1 10.3 9.1 8 7.3 7.2 6 5.0 4 3.0 1.7 2 0.9 0.1 0.2 5.0 3.4 1.7 1.0 0.4 0 <55 55 – 59 60 – 64 65 – 69 70 – 74 75 – 79 80 – 84 >85 Age, years Source: Go AS, et al. JAMA 2001; 285:2370 – 75; Lloyd-Jones DM, et al. Circulation 2004; 110:1042 – 46 Risk factors for ischaemic stroke/TIA/systemic embolism in patients with AF Swedish Cohort Atrial Fibrillation study Multivariate hazard ratios (95% CI) Age (years) <65 65–74 ≥75 1.0 (Reference) 2.97 (2.54–3.48) 5.28 (4.57–6.09) Female sex 1.17 (1.11–1.22) Previous ischaemic stroke 2.81 (2.68–2.95) Intracranial bleeding 1.49 (1.33–1.67) Vascular disease (any) Myocardial infarction Previous CABG Peripheral artery disease 1.14 (1.06–1.23) 1.09 (1.03–1.15) 1.19 (1.06–1.33) 1.22 (1.12–1.32) Hypertension 1.17 (1.11–1.22) Heart failure (history) 0.98 (0.93–1.03) Diabetes mellitus 1.19 (1.13–1.26) Thyroid disease Thyrotoxicosis 1.00 (0.92–1.09) 1.03 (0.83–1.28) Recommendation for screening of AF Recommendations • Opportunistic screening for AF in patients ≥65 years of age using pulse-taking followed by an ECG is recommended to allow timely detection of AF. • Class I, level B Stroke prevention in atrial fibrillation: comparisons with standard VKA therapy Meta-analysis of ischaemic stroke or systemic embolism VKA vs placebo VKA vs VKAlow dose VKA vs ASA VKA vs ASA + clopidogrel VKA vs ximelagatran VKA vs dabigatran Favours VKA Adapted after Professor A J Camm, August 30th ESC 2009 Odds/hazard ratio Favours other Rx New anticoagulants and their targets in the coagulation cascade Intrinsic pathway Extrinsic pathway XII XI IX VIII Unfractionated Heparin Low-MolecularWeight Heparin VII X V II I Fibrin Clot Adapted from Nutescu EA, et al. Cleve Clin J Med 2005;72 Suppl 1:S2-6 New Xa Inhibitors • Rivaroxaban • Apixaban • Edoxaban • Betrixaban • LY517717 • YM150 • Idrabiotaparinux (Indirect Xa inhibitor) Warfarin New (direct) thrombin inhibitors • Dabigatran etexilate Summary of the clinical trials involving novel anticoagulants vs. warfarin for stroke prevention in non-valvular AF Advantages and disadvantages of new anticoagulants vs. warfarin Advantages and disadvantages of the new oral anticoagulants relative to warfarin Class Oral IIa/Xa blockers Advantages Disadvantages No monitoring Efficacy not yet firmly established Fast onset of action Some agents need twice daily dosing Fast offset of action (in case of bleeding/Short duration of action surgery) (thrombosis risk with poor compliance) Antidote not established No monitoring, in case of bleeding/ surgery cost Vitamin-K antagonists Proven high effictiveness Monitoring of INR Therapeutic window established Drug interaction Food interaction Slow onset of action Antidote established High bleeding risk Long action (low thrombosis risk with poor compliance) Verheugt F. Neth Heart J 2010; 18(6):314-8 CHAsDS2-VASc Lip GY et. al. Chest 2010;137:263-72. Amongst patients with CHADS2 score = 0, the 1-year event rates can range between 0.84% (CHA2DS2-VASc score = 0), 1.75% (CHA2DS2VASc score = 1), 2.69% (CHA2DS2VASc score = 2), and 3.2% (CHA2DS2-VASc score = 3). Olesen JB et. al. Thromb Haemost 2012;107:1172–1179. 2012 ESC guidelines for the choice of anticoagulant in AF Antiplatelet therapy with ASA plus clopidogrel, or-less effectively-ASA only, should be considered in patients who refuse any OAC, or cannot tolerate anticoagulants for reasons unrelated to bleeding. If there are contraindications to OAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision may be considered. Line: solid=best option; dashed=alternative option NOAC = novel oral anticogulant Available bleeding risk scores In AF population • HEMORR2HAGES – Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age ≥75 years), Reduced platelet count or function, Rebleeding risk, Hypertension (uncontrolled), Anaemia, Genetic factors, Excessive fall risk, and Stroke • HAS-BLED – Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (e.g. age .65, frailty, etc.), Drugs/alcohol concomitantly • ATRIA – AnTicoagulation and Risk factors In Atrial fibrillation Management of bleeding in patients taking novel oral anticoagulants • aPTT = activated partial thromboplastin time; • NOAC = novel oral anticoagulant; • PCC = prothrombin complex concentrate; • PT = prothrombin time; • rFVIIa = activated recombinant factor VII. • aWith dabigatran. Pradaxa (DABIGATRAN ETEXILATE) • • • • • • Oral prodrug, converted to dabigatran, a potent but reversible DTI Inhibits both clot-bound and free thrombin Half-life of 12–17 hours Peak plasma levels of dabigatran achieved within 2 hours ~80% renal excretion Most advanced DTI in Phase III development for stroke prevention in patients with AF (RE-LY® study) CH3 N N N H3C O NH N O O Dabigatran etexilate O H2N N O CH3 Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada. Stangier J, et al. Br J Clin Pharmacol 2007;64:292-303. Sorbera LA, et al. Drugs Future 2005;30:877-885. Blech S, et al. Drug Metab Dispos 2008;36:386-399. 為什麼有那麼多出血的新聞…paper….警告? 選錯病人 不清楚藥 物正確的 使用方式 嚴重腎功能不全的病人 (肌酸酐清除率小於 30 mL/min) 當病患由warfarin療法 轉用PRADAXA時,須中 斷使用warfarin,並於 INR降至2.0以下時開始 使用PRADAXA Recommendations for prevention of thromboembolism in non-valvular AF—bleeding Recommendations Class Level Assessment of the risk of bleeding is recommended when prescribing antithrombotic therapy (whether with VKA, NOAC, aspirin/clopidogrel, or aspirin). 1 A The HAS-BLED score should be considered as a calculation to assess bleeding risk, whereby a score ≥3 indicates ‘high risk’ and some caution and regular review is needed, following the initiation of antithrombotic therapy, whether with OAC or antiplatelet therapy (LoE = A). Correctable risk factors for bleeding [e.g. uncontrolled blood pressure, labile INRs if the patient was on a VKA, concomitant drugs (aspirin, NSAIDs, etc.), alcohol, etc.] should be addressed (LoE = B). Use of the HAS-BLED score should be used to identify modifiable bleeding risks that need to be addressed, but should not be used on its own to exclude patients from OAC therapy (LoE = B). 2a A,B The risk of major bleeding with antiplatelet therapy (with aspirin– clopidogrel combination therapy and – especially in the elderly – also with aspirin monotherapy) should be considered as being similar to OAC. 2a B Recommendations for prevention of thromboembolism in non-valvular AF—general Recommendations (1) Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications. 1 A The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. 1 A The CHA2DS2-VASc score is recommended as a means of assessing stroke risk in non-valvular AF. 1 A In patients with a CHA2DS2-VASc score of 0 (i.e., aged <65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended. 1 B In patients with a CHA2DS2-VASc score ≥2, OAC therapy with: • adjusted-dose VKA (INR 2–3); or • a direct thrombin inhibitor (dabigatran); or • an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)d … is recommended, unless contraindicated. 1 A Recommendations for prevention of thromboembolism in non-valvular AF—general Recommendations (2) Class Level In patients with a CHA2DS2-VASc score of 1, OAC therapy with • adjusted-dose VKA (INR 2–3); or • a direct thrombin inhibitor (dabigatran); or • an oral factor Xa inhibitor (e.g. rivaroxaban, apixaban)d …. should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. 2a A Female patients who are aged <65 and have lone AF (but still have a CHA2DS2-VASc score of 1 by virtue of their gender) are low risk and no antithrombotic therapy should be considered. 2a B When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with aspirin 75–100 mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or—less effectively—aspirin 75–325 mg daily. 2a B Thanks for your attention! God is with you!! •壬林見詩經大 雅 壬,大也, 林,多也。嘏為 福之古字