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1 EBM NEUR 董欣指導醫師 : 陳柏霖 2013/05/30

2 One day, a 78 y/o women, sudden onset of left side weakness and slurred speech around 7PM. Acute ischemic cerebral infarctionwas diagnosed at ER within 3 hours of symptoms onset. The NIHSS was 18. Intravenous rtpa was indicated and suggested. Family: 要打多少??? Scenario

Acute ischemic cerebral infarctionwas diagnosed at ER within 3

3 Question. Which dose of the thrombolytic agent would be both safe and efficacy for her?

4 Background knowledge rtpa (recombinant tissue plasminogen activator) is confirmed as the only effective treatment for acute ischemic stroke within 3 hours of onset, approved by the FDA in In American & Europe, the current rtpa dose was 0.9 mg/kg. Traditional dose using in our hospital: 0.7 mg/kg 其他醫院 : mg/kg

5 In Asian, the racial differences in blood coagulationfibrinolysis factors, higher intracranial hemorrhage (ICH) is the concern. The optimal dose required for attaining a coronary potency rate of 65~80% is mg/kg in Japan & China. In Japan, a low dose of rtpa(0.6 mg/kg) was approved to treat patients since Which dose has the most safe and efficacy for our patient???????

The optimal dose required for attaining a coronary potency rate of 65~80% is 0.5-0.

6 形成問題 (focus question for therapy) 這是一個傷害型 (Harm) 問題 P 主要問題 :acute ischemic stroke, Asian 並存風險 / 疾病 : nil I Intravenous rtpa with lower dose C [Placebo/no treatment/active control] Intravenous rtpa with standard dose O [ 療效 ] functional improvement [ 副作用 / 併發症 ] symptomatic intracranial hemorrhage (SICH)

[Placebo/no treatment/active control] Intravenous rtpa with standard dose O [ 療效

7 P I C O S T 理想證據文獻研究設計目標疾病 :Acute ischemic stroke 收案條件 : 1.acute ischemic infarction patients fitting the criteria and receiving IV-rTPA 2.Asian ethic 排除條件 : 1.brain CT evidence of significant early ischemic change (affecting more than 1/3 MCA territory) 2.patient not receiving rtpa or other ethic groups Alteplase, thrombolysis, low dose Alteplase, thrombolysis, standard dose (0.9 mg/kg) Benefit:Functional improvement/independent Harm:Symptomatic ICH, Mortality 針對傷害型問題, 理想文獻研究設計為 Cohort study 以上針對傷害型問題, 可接受的追蹤時間至少為 3 個月

brain CT evidence of significant early ischemic change (affecting more than 1/3 MCA territory) 2.

8 搜尋 Search strategy 18 items, but none seems to fit my questions well!

12 2 1 3

14 1 Retrospective, Cohort study N= 130 (48 vs 82) N=48 N=82 Low (maximum 50 mg) 46: 0.67 mg/kg; 2: 0.9 mg/kg Standard (0.9 mg/kg) 2: 0.56, 0.65 mg/kg

16 IV-tPA at a standard dose (0.9 mg/kg) is safe and feasible in the treatment of acute IS in our Asian population of diverse ethnic origins. But due to other factors?? BP control, improved experience

Secondary outcome (efficacy) : a modified Rankin scale of 0 to 2 after 3 months [SICH per ECASS] any

17 2 prospective, multicenter, observational study N= 241 (116 vs 125) from December 2004 to July 2008 Primary outcome (safety) : symptomatic intracerebral hemorrhage and death within 3 months. Secondary outcome (efficacy) : a modified Rankin scale of 0 to 2 after 3 months [SICH per ECASS] any hemorrhage plus a neurological deterioration of 4 points on the NIHSS baselineor from the lowest NIHSS value after baseline to 7 daysor leading to death

19 This study did not support use of standard dose alteplase (0.9 mg/kg) for treatment of acute ischemic stroke in Chinese patients, particularly for the aged groups. Consider initial NIHSS effect??

20 3 Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice. the Japanpost-Marketing Alteplase Registration Study (J-MARS) N= 7492 N= 197 Outcomes of Thai patients with acute ischemic stroke after intravenous thrombolysis

21 0.6 mg/kg 0.9 mg/kg More favorable outcome was seen in patients with standard dose, without compromising safety outcomes. Older age and more severe stroke in patients receiving the low dose may explain the less favorable outcomes.

22 文獻評讀文章 Feasibility and safety of intravenous thrombolysis in multiethnic Asian stroke patients in Singapore. (Sharma VKet al ) Outcomes of thrombolytic therapy for acute ischemic stroke in Chinese patients: the Taiwan Thrombolytic Therapy for Acute Ischemic Stroke (TTT-AIS) study. (Chao ACet, al) Low vs standard dose of recombinant tissue plasminogen activator in treating East Asian patients with acute ischemic stroke. (Dharmasaroja PA et, al) 臨床問題符合 Yes Yes Yes 度 [clearlyfocused question?] 研究設計 Retrospective, Prospective, multicenter, Meta-analysis [include the right type of Cohort design observation study comparing two study: J- MARS vs Dharmasaroja study?] 發表年份可取得全文 Yes Yes Yes

23 評讀文章 (Bias) Selection bias? Control for confounders 兩組干擾因素控制是否相當 Performance bias? Measurement of exposure 兩組除了控制處置不同外其他治療是否相當 Sharma VK (Singapore) Chao AC (Taiwan) Dharmasaroja PA (Japan vs Tai) Yes Yes Yes Limited to one center Registered data, ( 沒有 Registered data 特定 criteria or randomied 給予不同 dose 的 TPA) p.889: we did not know exactly why some doctors chose the lower dose for patients. yes No yes 1. different demographic 1. different characters( age, initial demographic NIHSS, HTN, stroke characters( age, subtype ) initial NIHSS, stroke 2. different pretreatment subtype ) BP control 2. different country 3. different period (2000- may have different 2006 vs ) with care/equipment more advances technique system and monitor in the later years

24 評讀文章 (Bias) Sharma VK (Singapore) Chao AC (Taiwan) Dharmasaroja PA (Japan vs Tai)

25 評讀文章 Sharma VK (Singapore) Chao AC (Taiwan) Dharmasaroja PA (Japan vs Tai)

26 應用藥品名稱非侵入性治療人力成本硬體成本價格 rtpa Intravenous adminstrationn Rapid management, frequent evaluation close monitor (ICU) NT$:18559/bot 50 mg/bot 治療風險 ( 患者成本 ) 治療最大的併發症 (symptomatic ICH) 風險 : 1. 嚴重者需 craniectomy +/-ICP monitor, VP shunt 2. 增加住院天數 ( 尤其是加護病房 ) 及住院相關併發症 ( 肺炎等院內感染 ) 3. 降低復健效率, 增加照顧資源及成本沒打通的風險 : 1. 大片糗嚴重中風者需可能 craniectomy +/-ICP monitor, VP shunt 2. 增加住院天數 ( 尤其是加護病房 ) 及住院相關併發症 ( 肺炎等院內感染 ) 3. 降低復健效率, 增加照顧資源及成本

27 臨床應用我們的病患屬 Asia, elder(>70 y/o) 族群 : 這項治療在本院環境, 具有可行性 (feasibility), 但近年的傳統不分年齡傳統,IV-TPA 一律以統一劑量 0.7 mg/kg 給與, 但是病人無法當下在急診量出確切體重, 只能用目測估算, 或是沿用最近一次所記錄到的體重為依據其他的選擇 : 與國外相同的標準劑量 (0.9 mg/kg), 但仍未確定一定會更好好處是否多於壞處?: 以現有的臨床結果來看, 低劑量的 TPA 對於功能進步的好處未必會大過症狀另出血的壞處, 但至少不太會有較高出血性的風險 ( 壞處不多於好處 ) 是否符合病人的期望 (value): maybe 醫療建議綜合上面討論, 我們的臨床建議這樣建議的建議強度 (recommendation) B (no well designed clinical trial, espicially randomized study at present)

28 以去學術化術語 (plain language) 回答病人病人是急性缺血性腦中風的患者, 符合靜脈血栓溶解劑的給予條件, 年紀較大的東方族群, 若接受比西方認定的標準治療劑量還小的血栓溶解劑 (0.7 mg/kg), 對於三個月後的功能進步會好處, 也許可以比標準劑量減少一些症狀性出血的機會, 這仍需更多的臨床試驗來證實!

29 Thank You!

所 3 學分課程, 及兩門跨領域課程共 6 學分以上課程學生在修課前, 必須填寫課程修課認定表, 經班主任或指導教授簽名後始認定此課程學分 ) 10. 本規章未盡事宜, 悉依學位

所 3 學分課程, 及兩門跨領域課程共 6 學分以上課程學生在修課前, 必須填寫課程修課認定表, 經班主任或指導教授簽名後始認定此課程學分 ) 10. 本規章未盡事宜, 悉依學位 95 年訂定 96 年 11 月修正 97 年 10 月修正 100 年 2 月修正 101 年 4 月修正 102 年 1 月修正 103 年 4 月修正 103 學年度入學新生適用, 舊生可比照適用 1. 研究生須於入學後第二學期開學前選定指導教授, 經課程委員會認定後方得繼續