循證醫(yī)學病因?qū)W研究和循證醫(yī)學實踐新研

1、Evidence-based Etiology / Harm病因研究與循證醫(yī)學實踐,,學習目標,掌握評價病因性研究真實性原則(Validity )掌握評價病因性研究重要性原則( Importance )學會應用病因性研究證據(jù)的結(jié)果，解決臨床問題( Applying ),病因性研究基本知識,病因性研究基本概念與病因相關(guān)的臨床問題病因性研究的主要方法病因/不良反應研究證據(jù)的分級病因性研究常用統(tǒng)計學指標,病因性研究基本概念（1）

2、,病因是指引起人體發(fā)生疾病的原因。病因?qū)W是 指研究疾病病因的科學。病因：致病因素（直接、間接、危險因素）研究內(nèi)容：用流行病學方法研究并驗證危險因 素是否與疾病發(fā)生有因果關(guān)系，且評估因果聯(lián) 系的強弱。例“吸煙與肺癌關(guān)系”,病因性研究基本概念（2）,不良反應的研究實質(zhì)上也是病因?qū)W研究 “因”：造成不良反應的各種因素，如各種治療措施（藥物，手術(shù)）醫(yī)療過程中臨床醫(yī)師經(jīng)常需要考慮某種危險因素或治療措施是否對患者有害。

3、利是否大于弊？用他人的研究結(jié)果來回答提出的問題 真實性 重要性 實用性,與病因相關(guān)的臨床問題,該疾病是什么原因造成的？該藥物或治療措施會導致什么不良反應嗎？是否需要停藥？Does exposure to aluminum cause Alzheimer’s dementia?Do statins cause cancer?,病因性研究的主要方法,病因性研究常用統(tǒng)計學指標,因果相關(guān)性強度的指標RR

4、 (前瞻性) RCT, cohort studyOR (回顧性）case-control studyNNH (number needed to harm)clinical importance暴露多少研究對象可導致1例發(fā)?。犃醒芯浚┌l(fā)生1例不良反應所需治療的病例數(shù)（臨床研究）,因果相關(guān)性強度的指標,當所研究疾病的發(fā)病率較低時，OR近似于RR，故在回顧性研究中可用OR估計RR,其解釋與RR同，易于統(tǒng)計分析RR 或OR愈高，

5、則因果關(guān)系強度愈強RR 或OR 有多大才有意義，無一定的標準1.2-1.5: 弱聯(lián)系1.6-2.9: 中等聯(lián)系 >3.0: 強聯(lián)系,可信區(qū)間Confidence Interval,因果關(guān)系的強度外，評價精確度按一定的概率去估計總體參數(shù)所在的范 圍95％的可信區(qū)間循證醫(yī)學－估計總體參數(shù)－假設(shè)檢驗：RR,有關(guān)指標的計算,1. Odds Ratio,2. Relative Risk,3. Risk Reduc

6、tion / Increase,4. Number Needed to Treat / Harm,,,證據(jù)的強度,The Confusion Matrix,Also known as the 2 x 2 table,Event Rate,EER = A / (A+B) 試驗組事件發(fā)生率CER= C / (C+D) 對照組事件發(fā)生率,RR and OR,RR = EER / CER 相對危險度OR= AD / BC 比

7、值比,Relative Risk Reduction,RRR= (CER - EER) / CER = 1 – RR 相對危險度減少率,(Absolute) Risk Reduction,ARR = CER - EER絕對危險度減少率,Number Needed to Treat,NNT = 1 / ARR得到1例有利結(jié)果需要防治的病例數(shù),舉例：Activated Protein C for Severe Sepsi

8、s,APC = Activated Protein CEfficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709,Event Rates and Odds,EER= A / (A+B)= 30 / 850 = 0.035CER= C / (C+

9、D)= 17 / 840 = 0.020EEO = A / B= 30 / 820 = 0.037CEO = C / D= 17 / 823 = 0.021,OR= EEO / CEO= 0.037 / 0.021 = 1.77RR= EER / CER = 0.035 / 0.020 = 1.744,RRI= (EER – CER) / CER= 0.015 / 0.020 = 0.74

10、4 = 74 %ARI= EER – CER= 0.035 – 0.020 = 0.015 NNH= 1 / ARI= 66,Risk-Benefit Ratio,NNT = 1 / ARR = 1 / 0.06= 16 (治療16個獲益1個：存活) 反映有利結(jié)果（越小越好）NNH = 1 / ARI = 1 / 0.015= 66 (治療66個損害1個：嚴重出血)

11、 反映不良反應（越大越好）Risk-Benefit Ratio= NNT / NNH= 16 / 66= 1 / 4,怎樣解決臨床問題？How to solve a clinical problem?,臨床病案（Clinical Scenario）,84歲的男性，近期記憶力明顯下降.高血壓病，高膽固醇血癥。右眼白內(nèi)障術(shù)后2天，出現(xiàn)易激、譫妄和性格改變。無感染，貧血及代謝異常的臨床證據(jù)。心理衛(wèi)生中心會診：

12、抗精神病藥物氟哌啶醇, haloperidol , 奮乃靜perphenazine, 奧氮平, olanzapine,臨床問題（Initial Question）,老年患者中，用傳統(tǒng)性抗精神病藥物（如氟哌啶醇, haloperidol , 奮乃靜perphenazine,）是否會增加死亡風險性？非典型性抗精神病藥物(如奧氮平, olanzapine,）是否對老年人更安全？,第一步 提出問題(Ask Clinical Questi

13、ons),Initial question:Framing the initial question: answerablePatients (population)Intervention/exposureComparisonOutcomePICO,轉(zhuǎn)變成可以回答的臨床問題Framing the question,患者類型(P) elderly patients干預措施(I) haloperidol or perphe

14、nazine對照措施(C) olanzapine臨床結(jié)局(O) death,第二步 查詢證據(jù) (Acquire Evidence),PICO: key wordsType of question：harm - Best evidence Levels of evidence - Optimal source of evidenceSearching worthwhile?,病因/不良反應研究常用數(shù)據(jù)庫,Best

15、 Evidence（ACP journal club, EBM)Up to DateMedlinePubMed: clinical query-etiologySumsearchOvid循證醫(yī)學數(shù)據(jù)庫(多庫同時檢索)ACP journal club, Cochrane Library( CDSR, CCTR,DARE), Medline, EMBASE,,系統(tǒng)評價資料庫(Cochrane Database of System

16、atic Review,CDSR)療效評價文摘庫(Database of Abstracts of Reviews of Effectiveness, DARE)臨床對照試驗注冊資料庫(Cochrane Controlled Trials Register,CCTR)方法學數(shù)據(jù)庫 (Cochrane Methodology Database),檢索方法,選擇數(shù)據(jù)庫：ACP journal club（oviddatabase, b

17、est evidence）在search 中，鍵入關(guān)鍵詞olanzapine－etiology（病因?qū)W）檢索結(jié)果：1篇文獻（摘要）找到全文,,,篩選結(jié)果,ACP journal Club summary: Conventional antipsychotic drugs increased risk for death more than did atypical antipsychotic drugs in elderly p

18、atients ACP Journal Club. 2007;147:23.Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients

19、. CMAJ.2007;176:627-32,,,研究詳情,Background: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality i

20、n a population-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications. Methods: We used linked health care utilization data of all BC residents to ide

21、ntify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and December 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents ta

22、king conventional antipsychotic medications and those taking atypical antipsychotic medications.,Results:,Of 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 2

23、4 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence inter

24、val [CI] 1.39–1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23–1.42). In comparison with risperidone（利培酮）, haloperidol（氟哌啶醇） was associated with the greatest increase in mortality (mort

25、ality ratio 2.14, 95% CI 1.86–2.45) and loxapine（ 洛沙平）the lowest (mortality ratio 1.29, 95% CI 1.19–1.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antip

26、sychotic medications (mortality ratio 1.67, 95% CI 1.50–1.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.42–1.80). Results were confirmed in propensity score analyses and

27、 instrumental variable estimation, minimizing residual confounding.,結(jié)論,Interpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greate

28、r than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.,第三步 評價證據(jù)

29、 Appraise Evidence,證據(jù)的真實性Are the results valid?證據(jù)的重要性What are the results?,證據(jù)的真實性Are the results valid?,1 研究方法的論證強度Type of Reports on Etiology/Harm,哪種研究方法？論證強度如何？是否源于真正的人體試驗？ Were there clearly defined groups o

30、f patients, similar in all important ways other than exposure to the treatment or other cause?,本研究,Objective: In elderly patients, association of conventional or atypical antipsychotic drugs (APDs) with death ?Design: C

31、ohort studyParticipants: 37241 patients 65 y of age oral conventional (n = 12 882, mean age 80 y) atypical (n = 24 359, mean age 80 y). Exclusion criteria: cancer and use of APDs in the year be

32、fore the index date.,2 兩組結(jié)局暴露因素的測量方法是否一致？,Were treatments/exposures and clinical outcomes measured in the same ways in both groups? (Was the assessment of outcomes either objective or blinded to exposure?)Were the outc

33、omes and exposures measured in the same way in the groups being compared?,Cohort Study,Surveillance bias: 監(jiān)測偏倚偏倚的控制－客觀指標（Objective outcome）：病死率－主觀指標（Subjective outcome）: Blinding舉例：乙型肝炎與肝癌關(guān)系的研究,3. 隨訪時間及失訪率,Was the f

34、ollow-up of the study patients sufficiently long (for the outcome to occur) and complete?舉例：HP與胃癌：5年（無差異），10 年（顯著差異）失訪超過20％？--結(jié)果將失去真實性,4 病因/不良反應研究結(jié)果是否符合病因診斷原則,Do the results of the harm study satisfy some of t

35、he diagnostic tests for causation?,,Is it clear that the exposure preceded the onset of the outcome? 因果效應的先后順序－僅見于前瞻性研究Is there a dose–response gradient? 因果效應的相關(guān)程度，劑量依賴（吸煙與肺癌）Is there any positive evidence from a

36、 “dechallenge–rechallenge” study? 符合流行病學規(guī)律-危險因素減弱，發(fā)病減少,,Is the association consistent from study to study? 不同研究，結(jié)果一致（HP與胃癌）Does the association make biological sense? 充分的生物學依據(jù)（CCB與癌癥，壞血病與水果蔬菜）,Key Poin

37、ts,1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? 研究方法的論證強度2. Were treatments/exposures and clinical outcomes measured in the sa

38、me ways in both groups? 測量方法一致3. Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? 隨訪時間及失訪率,證據(jù)的重要性What are the results?,1.因果聯(lián)系強度,What is the magnitude of the ass

39、ociation between the exposure and outcome?How strong is the association between exposure and outcome?RR OR NNH,2. 結(jié)果是否準確？,What is the precision of the estimate of the association between the exposure and outcome?How p

40、recise is the estimate of risk?95%CI,Conventional APD vs Atypical APDAssociation with death,第四步應用證據(jù)How can I apply the results to mypatient?,病情相似,Is our patient so different from those included in the study that its r

41、esults cannot apply?Were the study patients similar to my patient?基于納入和排除標準,本研究,Patients: > 65 y of age , 60-65% womenUsed 1 medical service, and filled 1 prescription in the two 6-month intervals before the index

42、date.Exclusion criteria: cancer and use of APDs in the year before the index date.Atypical APDs: risperidone, quetiapine, olanzapine, and clozapineConventional APDs: loxapine, haloperidol, chlorpromazine, trifluoperaz

43、ine, thioridazine, pimozide, promazine, perphenazine, fluphenazine, mesoridazine, and thiothixene.,權(quán)衡利弊,What is our patient’s risk of benefit and harm from the agent? NNT and NNH,舉例,一項心律失常抑制試驗（CAST): 恩卡尼/氟卡尼與安慰劑：10月

44、隨訪，病死率分別為7.7%和3.0%，NNH＝21（平均每21個患者服此藥，將有1人發(fā)生額外死亡）NSIAD與消化道出血：NNH＝2000（每2000 人服NSAIDs，預期增加1例消化道出血患者）,本病案,使用傳統(tǒng)和非典型性抗精神病藥物 NNT/NNH 作者未進行計算和分析查詢其他證據(jù),患者的價值觀和愿望,What are our patient’s preferences, concerns, and

45、expectations from this treatment? 1、為了避免疾病的進展而接受治療，可能帶來不良反應 2、寧愿冒疾病進展的風險而不接受治療 3、關(guān)注費用 4、無所謂的態(tài)度,其他可替代的療法,What alternative treatments are available?---當危險因素或治療措施的危險明確而且巨大，則應立即脫離危險因素或終止治療。舉例 β-blockers for hy

46、pertension in patients with asthma 治療高血壓的β受體阻滯劑能加重支氣管痙攣；血管緊張素轉(zhuǎn)換酶抑制劑巰甲丙脯酸、依那普利等，既能降壓，又不誘發(fā)支氣管痙攣，,本病案：臨床決策,對該患者選擇哪類抗精神病藥?,Evidence-based practice in real time,直接查詢已經(jīng)評價過的高質(zhì)量的綜合臨床證據(jù)(preappraised evidence)，如選擇數(shù)據(jù)庫“ACP journa