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卒中的預防及急性期藥物 治療之台灣經驗 報告人:邱 春 吉 藥師
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Outline Epidemiology、etiology and classification、pathophysiology
Modifiable risk factors (hypertension、 diabetes 、hyperlipidemia) and recommendations for management Taiwan Clinical Performance Indicator (TCPI) – pharmacist intervention Recommendations for pharmacotherapy of acute ischemic stroke Recommendations for primary and secondary prevention of stroke Stroke prevention with atrial fibrillation Conclusion
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台灣前十大死因排名 ( )
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A classification of stroke by mechanism with estimates of the frequency of various categories of abnormalities. Pharmacotherapy : A Pathophysiologic Approach, 8e
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3 1 2 高血壓、 糖尿病、 高血脂、 抽菸 動脈粥狀硬化 血栓形成 急性冠心病 (不穩定心絞痛、心肌梗塞) 缺血性中風 心血管死亡
Note: Plavix® (clopidogrel bisulfate) is not indicated for all the conditions listed on this slide. Vascular disease is the common underlying disease process for MI, ischemia and vascular death. Acute coronary syndrome (ACS) is a classic example of the progression of vascular disease to an ischemic event. ACS (in common with ischemic stroke and critical leg ischemia) is typically caused by rupture or erosion of an atherosclerotic plaque followed by formation of a platelet-rich thrombus. Atherosclerosis is an ongoing process affecting mainly large and medium-sized arteries, which can begin in childhood and progress throughout a person’s lifetime. Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms. 5 5
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台灣臨床成效指標執行手冊 Taiwan Clinical Performance Indicator (TCPI)
AMI-10 住院期間給予乙型阻斷劑 AMI-11 左心室收縮功能不良(LVSD)患者接受血管張力素轉換酶抑制劑(ACEI)或血管張力素接受器阻斷劑(ARB) AMI-12 出院給予雙重血小板抑制劑治療處方(阿斯匹靈+ADP 受體拮抗劑) AMI-13 出院給予降血脂藥物 AMI-19 心血管治療藥物衛教執行率
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JNC 7:高血壓治療準則 改善生活形態 未達成目標血壓* 無特定適應症的高血壓 有特定適應症的高血壓 強制適應症的藥物
視需要使用其他抗高血壓藥物(Diuretics 、 ACEI、ARB、β-blocker、CCB) 第1階段 最常使用Thiazide類Diuretics。可以考慮ACEI、ARB、β-blocker、CCB或藥物合併治療 第2階段 最常合併兩種藥物使用 (通常包括thiazide類 Diuretic在內) systolic ≧160 or diastolic ≧100 mmHg 此張投影片說明JNC 7準則建議的詳細治療途徑 如投影片所示,從改變生活形態開始治療高血壓;如果未達成目標血壓,則進行藥物治療。 特定適應症指的是共病症,例如心臟衰竭、心肌梗塞後、以及冠狀動脈疾病、糖尿病和慢性腎病的高風險群。 縮寫 ACE抑制劑=血管收縮素轉化酶抑制劑 ARB=血管收縮素受體阻斷劑 CCB=鈣離子通道阻斷劑 參考文獻 Chobanian AV, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:256072. 若未達成目標,使用最佳劑量或加入額外的藥物,直到達成目標血壓為止。 並考慮諮詢高血壓專家 目標血壓: < 140/90 mmHg或患有糖尿病或 慢性腎病者的目標血壓: < 130/80 mmHg Chobanian et al. JAMA 2003;289:2560–72 Copyright © 2003 American Medical Association. All rights reserved
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強制適應症 (合併其它疾病) 的藥物 台灣腦中風防治指引
卒中
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J Formos Med Assoc 2010;109(10):740–773.
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2012 糖尿病臨床照護指引
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美國心臟協會分類版本 (American Heart Association)
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糖尿病患預防中風復發的建議 台灣腦中風防治指引
臨床建議 建議強度 證據等級 糖尿病患血壓需要嚴格控制,ACEI或是ARB可以減緩糖尿病腎病變的進行,應優先選擇這兩類的藥物. I A 糖尿病患血脂需要嚴格控制,建議使用statin治療,低密度膽固醇的治療目標為100mg/dl以下 糖尿病患嚴格控制血糖到正常範圍,可以有效降低微小血管的併發症 。 減少心血管事件發生 。 IIa B 糖尿病患在缺血性中風後,建議使用aspirin治療(75–162 mg/d) 來預防心血管疾病的發生。
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糖尿病患預防腦血管併發症的建議 2012 糖尿病臨床照護指引
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台灣降血脂藥給付規範 NCEP ATP III
如已達治療目標得考慮減量至最低 有效劑量,並持續追蹤治療。 CVD patient : LDL – C ≦ 100 mg/dL TC < 160 mg/dL
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不同腦中風危險因子病人之血脂處理原則 (1) 台灣腦中風防治指引
臨床建議 建議強度 證據等級 年老者若出現高血脂,則應積極治療以降低腦中風發生的危險性。 I A 年老者之膽固醇值若稍高並曾罹患腦中風,或具有其他危險因子者,亦可考慮給予低至中劑量statin藥物以作為中風復發之預防。 B 高血壓的病患若合併有高膽固醇血症,應積極使用降膽固醇藥物來預防腦中風的發生。 糖尿病患者若出現高血脂則一定要積極控制,而服用statin藥是最好的選擇。
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不同腦中風危險因子病人之血脂處理原則 (2) 台灣腦中風防治指引
臨床建議 建議強度 證據等級 糖尿病患者在膽固醇值稍微偏高或正常的情況下,亦應給予statin作初次腦中風的預防。 I A 若病人曾發生過冠心動脈病者,應給予statin以預防腦中風的發生,且不論病人的膽固醇值是高或低。 對於頸動脈高度狹窄的病人,除使用已確認的頸動脈內膜剝離手術或支架置放治療外,若有中等以上狹窄但尚未達到需執行介入性治療之閾值,可考慮給病人statin藥,並密切追蹤其頸動脈粥樣硬化之變化。
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Recommendations for treatable vascular risk factors (1)
Class/Level of Evidence* Hypertension BP reduction is recommended for both prevention of recurrent stroke and prevention of other vascular events in persons who have had an ischemic stroke or TIA and are beyond the first 24 hours. Class I ; Level A An absolute target BP level and reduction are uncertain and should be individualized, but benefit has been associated with an average reduction of approximately 10/5 mm Hg, and normal BP levels have been defined as 120/80 mm Hg by JNC 7. Class IIa ; Level B The optimal drug regimen to achieve the recommended level of reduction is uncertain because direct comparisons between regimens are limited. The available data indicate that diuretics or the combination of diuretics and an ACEI are useful. Stroke. 2011;42:
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Recommendations for treatable vascular risk factors (2)
Class/Level of Evidence* Diabetes Use of existing guidelines for glycemic control and BP targets in patients with diabetes is recommended for patients who have had a stroke or TIA. Class I ; Level B Lipids Statin therapy with intensive lipid-lowering effects is recommended to reduce risk of stroke and cardiovascular events among patients with ischemic stroke or TIA who have evidence of atherosclerosis, an LDL-C level 100 mg/dL, and who are without known CHD. Patients with ischemic stroke or TIA with elevated cholesterol or comorbid coronary artery disease should be otherwise managed according to NCEP III guidelines, which include lifestyle modification, dietary guidelines, and medication recommendations. Level A Stroke. 2011;42:
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急性缺血性腦中風 (卒中)藥物治療 Prasugrel Ticagrelor IIa Lancet 2003; 361: 847–58
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蘇格蘭學院間指引網絡分類版本 : SIGN (Scottish Intercollegiate Guidelines Network)
建議強度 急性缺血性腦中風 (卒中)藥物治療 A 1. 至少有一項統合分析、系統性文獻回顧或隨機對照試驗之實證等級為1++,且該研究可直接應用於目標群體;或 2. 系統性文獻回顧之隨機對照試驗或大部分的證據主體由實證等級為1+之研究構成,可直接應用於目標群體,或所有的證據都有一致性的結果。 證據等級 1++ 高品質的統合分析,系統性文獻回顧之隨機控制試驗,或該隨機控制試驗之設計誤差極低。 1+ 執行良好之統合分析,系統性文獻回顧之隨機對照試驗,或該隨機對照試驗之設計誤差極低。
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急性缺血性腦中風 (卒中)藥物治療(1) 台灣腦中風防治指引 (AHA)
建議強度 建議藥物 證據等級 A 有持續性缺血性腦中風症狀病人,應該立即開始給予抗血小板治療,一般為aspirin。 1++ 在沒有aspirin過敏及或上腸胃道出血, 或且病人不願意或無法接受溶栓治療時,缺血性腦中風發病48小時之內應即給予aspirin 160 mg - 325mg,以降低腦中風的死亡率及罹病率。 1+ 靜脈內注射recombinant tissue-type plasminogen activator (rt-PA) 治療急性缺血性腦中風是有效的。
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靜脈內血栓溶解劑rt-PA治療建議規範 用法與用量 :
建議劑量為每公斤體重0.9毫克(最大劑量為90毫克)輸注(infusion)60分鐘。總劑量的10%為起始劑量,以靜脈注射(IV bolus)投與。在症狀出現後的3小時內,應儘速開始治療。 一般性禁忌症 : 如同所有的血栓溶解劑,rt-PA不可使用於易發生出血之高危險患者,如: ─ 目前或過去六個月內有顯著的凝血障礙、易出血體質。 ─ 病人正接受口服抗凝血劑(如warfarin sodium)且prothrombin time (INR >1.3)。 ─ 中樞神經系統損傷之病史(腫瘤、血管瘤、顱內或脊柱的手術)。 ─ 懷疑或經證實包括蜘蛛膜下腔出血之顱內出血或其病史。 ─ 嚴重且未被控制的動脈高血壓。 ─ 過去10天內曾動過大手術或有嚴重創傷(包括最近之急性心肌梗塞所伴隨的任何創傷)、最近頭 部或顱部曾發生創傷。 ─ 過久的或創傷性的心肺復甦術(超過2分鐘)、分娩、過去10天內曾對無法壓制之部位施行血管穿 刺(如鎖骨下靜脈或頸靜脈穿刺)。 ─ 嚴重肝病,包括肝衰竭、肝硬化、肝門脈高壓(食道靜脈曲張)及急性肝炎。 ─ 出血性視網膜病變,如糖尿病性(視覺障礙可能為出血性視網膜病變的指標)或其他出血性眼疾。 細菌性心內膜炎,心包炎。 ─ 急性胰臟炎。 ─ 最近三個月內曾患胃腸道潰瘍。 ─ 動脈瘤,靜/動脈畸形。 ─ 易出血之腫瘤。 ─ 對本藥之主成份rt-PA或賦型劑過敏者。
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急性缺血性腦中風 (卒中)藥物治療(2) 台灣腦中風防治指引 (AHA)
建議強度 建議藥物 證據等級 A 常規使用減少腦神經傷害的藥物, 包括類固醇、神經保護劑、血漿容積擴張劑、巴比妥鹽(barbiturates)及streptokinase, 已被證明沒好處。 1++ 肝素( heparin ) , 包括未分段的肝素( unfractionated heparin ) 、低分子量肝素( low molecular weight heparin ) 或類肝素(heparinoids),並不建議常規使用在急性缺血性腦中風病人。 1+
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急性缺血性腦中風 (卒中)藥物治療(3) 台灣腦中風防治指引 (AHA)
建議強度 建議藥物 證據等級 A 有持續性或偶發性心房纖維顫動及缺血性腦中風病人,建議使用調整劑量的warfarin (目標INR是2.5;範圍為 ) 治療。不能服用口服抗凝血劑病人,建議使用aspirin 325 mg/天。 1++ 使用神經元保護劑(neuroprotectants)在急性缺血性腦中風病人的治療理論基礎為保護腦細胞的傷害,但是這種療法至目前為止並沒有顯示好處。
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急性中風治療的抗血小板藥物療法的建議 台灣腦中風防治指引 (AHA)
臨床建議 建議強度 證據等級 在急性中風發作48小時內,應該考慮使用阿斯匹靈(160至325mg)來預防急性缺血性腦中風的復發。 I A 即使中風發作已超過48小時,仍應該考慮使用阿斯匹靈來預防缺血性腦中風的復發。 無法使用阿斯匹靈或阿斯匹靈治療無效的病人,可考慮使用clopidogrel 。 IIa C 不建議在急性中風發作已使用血栓溶栓治療的24小時內,接連使用阿斯匹靈
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Guidelines for the Early Management of Patients with Acute Ischemic Stroke
Stroke. Published online January 31, 2013
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Intravenous Fibrinolysis
r tPA Class Level of Evidence Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for selected patients who may be treated within 3 hours of onset of ischemic stroke I A In patients eligible for intravenous rtPA, benefit of therapy is time dependent, and treatment should be initiated as quickly as possible. The door-to-needle time (time of bolus administration) should be within 60 minutes from hospital arrival (New recommendation) Stroke. published online January 31, 2013
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Antiplatelet Agents Aspirin , clopidogrel Class Level of Evidence I A
Oral administration of aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients. I A The usefulness of clopidogrel for the treatment of acute ischemic stroke is not well established. IIb C The administration of aspirin (or other antiplatelet agents) as an adjunctive therapy within 24 hours of intravenous fibrinolysis is not recommended. III Stroke. published online January 31, 2013
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Anticoagulants UFH , LMWH Class Level of Evidence III A
Urgent anticoagulation, with the goal of preventing early recurrent stroke, halting neurological worsening, or improving outcomes after acute ischemic stroke, is not recommended for treatment of patients with acute ischemic stroke. III A Initiation of anticoagulant therapy within 24 hours of treatment with intravenous rtPA is not recommended. Stroke. published online January 31, 2013
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Neuroprotective Agents
Statins , Glutamate , N-methyl-d-aspartate antagonists , Lubeluzole , Clomethiazole , Citicoline , Erythropoietin , Enlimomab Class Level of Evidence Among patients already taking statins at the time of onset of ischemic stroke, continuation of statin therapy during the acute period is reasonable (New recommendation) IIa B At present, no pharmacological agents with putative neuroprotective actions have demonstrated efficacy in improving outcomes after ischemic stroke, and therefore, other neuroprotective agents are not recommended. III A Stroke. published online January 31, 2013
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預防首次中風 - 抗血小板藥物療法之建議 台灣腦中風防治指引 (AHA)
臨床建議 建議強度 證據等級 患有非瓣膜心房纖維性顫動但具有中度栓塞風險(如年齡介於60至75歲但沒有其他風險因素)的病人,建議長期服用阿斯匹靈或warfarin 。 I A 患有心房纖維性顫動但不能接受口服抗凝血藥的病人,應該服用阿斯匹靈。 患有非瓣膜心房纖維性顫動並且栓塞風險低(即年齡小於60歲及沒有其他風險因素)的病人,建議長期服用阿斯匹靈或不需接受任何治療。 目前證據不足以顯示阿斯匹靈能降低未曾中風的男性病人發生中風的機會,但有證據顯示它能夠減少男性心肌梗塞的危險。有證據顯示阿斯匹靈能減少女性罹患初次中風的危險。
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預防中風復發 - 抗血小板藥物療法之建議 台灣腦中風防治指引 (AHA)
臨床建議 建議強度 證據等級 已中風病患再次中風的危險性增高,因此預防中風復發的治療應及早且長期進行治療。現階段在預防非心因性腦梗塞的復發方法上,應該使用適當的抗血小板藥物治療來預防缺血性腦中風的復發和其他血管事故的發生。 I A 使用阿斯匹靈來降低中風復發的機會。 合併使用阿斯匹靈(50mg)和長效dipyridamole(每天服用2次,每次200mg)可以作為治療方法來減少中風復發的風險。 B 對於無法使用阿斯匹靈或阿斯匹靈治療無效的病人,以及在風險高的病人可以選擇clopidogrel 。 IIa
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Recommendations for Antithrombotic Therapy for Noncardioembolic Stroke or TIA
Class/Level Of Evidence* For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce risk of recurrent stroke and other cardiovascular events. Class I ; Level A Aspirin (50 mg/d to 325 mg/d) monotherapy. The combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice daily. Class I ; Level B clopidogrel 75 mg monotherapy. Class IIa ; Level B all acceptable options for initial therapy. The selection of an antiplatelet agent should be individualized on the basis of patient risk factor profiles, cost, tolerance, and other clinical characteristics. Stroke. 2011;42:
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Strategies of Proven Benefit for Secondary Prevention of Stroke.*
N Engl J Med 2012;366:
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Strategies of Proven Benefit for Secondary Prevention of Stroke.* (1)
Indication and Strategy Key Trial or Meta-Analysis Study Results† Routine‡ Blood-pressure lowering PROGRESS: ACE inhibitor plus diuretic vs. placebo; primary end point: total strokes RRR, 28.0%; ARR, 4.00 percentage points; NNT, 97 Cholesterol lowering (statin) SPARCL: statin vs. placebo; primary end point: first stroke RRR, 16.0%; ARR, 2.20 percentage points; NNT, 220 N Engl J Med 2012;366:
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Strategies of Proven Benefit for Secondary Prevention of Stroke.* (2)
Indication and Strategy Key Trial or Meta-Analysis Study Results† Routine‡ Antiplatelet therapy (unless anticoagulation indicated) Aspirin (first-line therapy) ATTC: aspirin vs. placebo; primary end points: nonfatal stroke, nonfatal MI, and death from vascular causes. RRR, 13.0%; ARR, 1.00 percentage points; NNT, 100§ Clopidogrel CAPRIE: clopidogrel vs. aspirin; primary end points: ischemic stroke, MI, and death from vascular causes. RRR, 8.7%; ARR, 0.51 percentage points; NNT, 196 Aspirin plus dipyridamole ESPS2: aspirin plus dipyridamole vs. aspirin; primary end point: stroke. RRR, 23.8%; ARR, 2.97 percentage points; NNT, 74
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Strategies of Proven Benefit for Secondary Prevention of Stroke.* (3)
Indication and Strategy Key Trial or Meta-Analysis Study Results† Symptomatic high-grade stenosis : carotid endarterectomy NASCET: carotid endarterectomy plus medical treatment vs. medical treatment alone; primary end point: any ipsilateral ischemic stroke RRR, 65.0%; ARR, 17 percentage points; NNT, 9 * All trials are based on level 1 evidence. The list of trials is not comprehensive; instead, a definitive trial or meta-analysis is cited for each intervention. The number needed to treat (NNT) to prevent one primary-outcome event (secondary prevention) per year was calculated with the use of data on absolute risk reduction (ARR) during the mean or median trial follow-up period. All values are approximate and derived from previous analyses, Cochrane database reviews, or individual trials if these are the only data available. ACE denotes angiotensin-converting enzyme, ARISTOTLE Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation, ATTC Antithrombotic Trialists’ Collaboration, CAPRIE Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events, EAFT European Atrial Fibrillation Trial, ESPS2 European Stroke Prevention Study 2, MI myocardial infarction, NASCET North American Symptomatic Carotid Endarterectomy Trial, PROGRESS Perindopril Protection against Recurrent Stroke Study, RE-LY Randomized Evaluation of Long-Term Anticoagulation Therapy, ROCKET AF Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation, RRR relative risk reduction, and SPARCL Stroke Prevention by Aggressive Reduction in Cholesterol Levels. † The RRR and ARR are annualized for all the studies except PROGRESS, SPARCL, ESPS2, and NASCET, for which the RRR and ARR are for the duration of the trial. ‡ The indication is routine in the absence of clinical contraindications. § The results are based on a meta-analysis of trials comparing aspirin with placebo in patients with a previous stroke or transient ischemic attack (TIA). ?The results are for dabigatran at a dose of 150 mg twice perday.
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Strategies of Proven Benefit for Secondary Prevention of Stroke.* (4)
Indication and Strategy Key Trial or Meta-Analysis Study Results† Atrial fibrillation Warfarin EAFT: warfarin vs. placebo; primary end point: all strokes RRR, 66.0%; ARR, 8.0 percentage points; NNT, 12 Dabigatran RE-LY: dabigatran vs. warfarin; primary end points: stroke and systemic embolism RRR, 34.0%; ARR, 0.58 percentage points; NNT, 172? Rivaroxaban ROCKET AF: rivaroxaban vs. warfarin; primary end points: stroke and systemic embolism RRR, 13.0%; ARR, 0.30 percentage points; NNT, 333 Apixaban ARISTOTLE: apixaban vs. warfarin; primary end points: RRR, 21.0%; ARR, 0.33 percentage points; NNT, 303 N Engl J Med 2012;366:
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心房纖維顫動:流行病學 AF 是引起缺血性中風的主要危險因子之一,大約佔所有缺血性中風的12-20%。
根據台灣腦中風登錄資料顯示,16.5%的缺血性中風或暫時性腦缺血發作 (transient ischemic attack, TIA)個案患有AF。 2006~2008 年的台灣腦中風登錄資料中顯示,中風合併AF 的患者出院處方抗凝血劑的比例平均只有28.28%。
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心房纖維顫動患者腦中風風險層級評估 CHADS2 score
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CHA2DS2VASc score
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目前心房纖維顫動患者腦中風 風險層級評估建議
在新的2010 年ESC 指引中建議先使用CHADS2 score 評估,當其CHADS2 score 為0 到1 分,或考 量需要評估更多相關血管危險因子時,就需要用 更詳細的CHA 2 DS 2VASc score。 而Canadian Cardiovascular Society (CCS)的指引只 建議使用CHADS2 score 作為風險層級評估。 在台灣目前臨床上仍建議使用此兩種簡易且可靠 的風險層級表來評估。
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European Heart Journal 2010, 31 - ESC guidelines
Figure Clinical flowchart for the use of oral anticoagulation for stroke prevention in AF. AF ?atrial fibrillation; OAC ?oral anticoagulant; TIA ?transient ischaemic attack.
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Circulation. 2012;125: Figure. Stroke risk reductions from randomized trials of antithrombotic agents in atrial fibrillation.
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Limitations and challenges associated with
vitamin K antagonists Periprocedural Thromb Research 2009 (123)
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1 2 3 AT : antithrombin DTI Warfarin
Ther Drug Monit Volume 32, Number 6, December 2010
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IIa 內科學誌 2012:23:77-97
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1 2 3 4 5 Circulation. 2012;125:
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新型口服抗凝血劑取代 warfarin ? 雖然新型口服抗凝血劑在臨床試驗中有優於warfarin 的安全性與預防中風的效果,但是不代表所有使用warfarin 的患者都必須轉換為新型口服抗凝血劑。若患者能維持穩定的INR 值,建議應該繼續使用warfarin。 因為新型口服抗凝血劑於實際臨床應用的經驗仍未完善建立,我們仍須等待這些新藥上市後,後續療效與安全性的報告。 以目前現況而言,新型口服抗凝血劑是否可以成為warfarin的替代藥物,還需要更多的臨床試驗來進一步支持。
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結 語 要減少腦中風帶來的社會成本與負擔,最有效的方式就是要預防中風的發生。
結 語 要減少腦中風帶來的社會成本與負擔,最有效的方式就是要預防中風的發生。 雖然大家都明瞭中風相關的危險因子與預防的重要,但是在實際臨床上卻遠遠不足。(三高達標率) 除了適當地控制相關的危險因子外,抗血栓藥物對於中風的預防佔有極重要的角色。 即使近年來多種危險因子評估表不斷的修正與提醒抗血栓藥物的必要性,同時也有多種新型抗血栓藥物可供選擇,但實際使用抗凝血劑的比例仍然偏低。 因此我們需要整合性的跨領域團隊合作包括藥師共同照護腦中風病患,以提升藥師在卒中預防和治療的作用與地位。
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感謝聆聽 敬請指教!
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