1、Evidence-based Etiology / Harm病因研究与循证医学实践,学习目标,掌握评价病因性研究真实性原则(Validity )掌握评价病因性研究重要性原则( Importance )学会应用病因性研究证据的结果，解决临床问题( Applying ),病因性研究基本知识,病因性研究基本概念与病因相关的临床问题病因性研究的主要方法病因/不良反应研究证据的分级病因性研究常用统计学指标,病因性研究基本概念（1）,病因是指引起人体发生疾病的原因。病因学是 指研究疾病病因的科学。病因：致病因素（直接、间接、危险因素）研究内容：用流行病学方法研究并验证危险因 素是否与疾病发生有因果关系，且
2、评估因果联 系的强弱。例“吸烟与肺癌关系”,病因性研究基本概念（2）,不良反应的研究实质上也是病因学研究 “因”：造成不良反应的各种因素，如各种治疗措施（药物，手术）医疗过程中临床医师经常需要考虑某种危险因素或治疗措施是否对患者有害。利是否大于弊？用他人的研究结果来回答提出的问题 真实性 重要性 实用性,与病因相关的临床问题,该疾病是什么原因造成的？该药物或治疗措施会导致什么不良反应吗？是否需要停药？Does exposure to aluminum cause Alzheimers dementia?Do statins cause cancer?,病因性研究的主要方法,病因性研究常用统计学
3、指标,因果相关性强度的指标RR (前瞻性) RCT, cohort studyOR (回顾性）case-control studyNNH (number needed to harm)clinical importance暴露多少研究对象可导致1例发病（队列研究）发生1例不良反应所需治疗的病例数（临床研究）,因果相关性强度的指标,当所研究疾病的发病率较低时，OR近似于RR，故在回顾性研究中可用OR估计RR,其解释与RR同，易于统计分析RR 或OR愈高，则因果关系强度愈强RR 或OR 有多大才有意义，无一定的标准1.2-1.5: 弱联系1.6-2.9: 中等联系 3.0: 强联系,可信区间Con
4、fidence Interval,因果关系的强度外，评价精确度按一定的概率去估计总体参数所在的范 围95的可信区间循证医学估计总体参数假设检验：RR,有关指标的计算,1. Odds Ratio,2. Relative Risk,3. Risk Reduction / Increase,4. Number Needed to Treat / Harm,證據的強度,The Confusion Matrix,Also known as the 2 x 2 table,Event Rate,EER = A / (A+B) 试验组事件发生率CER= C / (C+D) 对照组事件发生率,RR and O
5、R,RR = EER / CER 相对危险度OR= AD / BC 比值比,Relative Risk Reduction,RRR= (CER - EER) / CER = 1 RR 相对危险度减少率,(Absolute) Risk Reduction,ARR = CER - EER绝对危险度减少率,Number Needed to Treat,NNT = 1 / ARR得到1例有利结果需要防治的病例数,举例：Activated Protein C for Severe Sepsis,APC = Activated Protein CEfficacy and safety of recombi
6、nant 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+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
7、= 1.744,RRI= (EER CER) / CER= 0.015 / 0.020 = 0.744 = 74 %ARI= EER CER= 0.035 0.020 = 0.015 NNH= 1 / ARI= 66,Risk-Benefit Ratio,NNT = 1 / ARR = 1 / 0.06= 16 (治疗16个获益1个：存活) 反映有利结果（越小越好）NNH = 1 / ARI = 1 / 0.015= 66 (治疗66个损害1个：严重出血) 反映不良反应（越大越好）Risk-Benefit Ratio= NNT / NNH= 16 / 66= 1 / 4,怎样解决临床问题？Ho
8、w to solve a clinical problem?,临床病案（Clinical Scenario）,84岁的男性，近期记忆力明显下降.高血压病，高胆固醇血症。右眼白内障术后2天，出现易激、谵妄和性格改变。无感染，贫血及代谢异常的临床证据。心理卫生中心会诊：抗精神病药物氟哌啶醇, haloperidol , 奋乃静perphenazine, 奥氮平, olanzapine,临床问题（Initial Question）,老年患者中，用传统性抗精神病药物（如氟哌啶醇, haloperidol , 奋乃静perphenazine,）是否会增加死亡风险性？非典型性抗精神病药物(如奥氮平, ol
9、anzapine,）是否对老年人更安全？,第一步 提出问题(Ask Clinical Questions),Initial question:Framing the initial question: answerablePatients (population)Intervention/exposureComparisonOutcomePICO,转变成可以回答的临床问题Framing the question,患者类型(P) elderly patients干预措施(I) haloperidol or perphenazine对照措施(C) olanzapine临床结局(O) death,第
10、二步 查询证据 (Acquire Evidence),PICO: key wordsType of question：harm - Best evidence Levels of evidence - Optimal source of evidenceSearching worthwhile?,病因/不良反应研究常用数据库,Best Evidence（ACP journal club, EBM)Up to DateMedlinePubMed: clinical query-etiologySumsearchOvid循证医学数据库(多库同时检索)ACP journal club, Cochra
11、ne Library( CDSR, CCTR,DARE), Medline, EMBASE,系统评价资料库(Cochrane Database of Systematic Review,CDSR)疗效评价文摘库(Database of Abstracts of Reviews of Effectiveness, DARE)临床对照试验注册资料库(Cochrane Controlled Trials Register,CCTR)方法学数据库 (Cochrane Methodology Database),检索方法,选择数据库：ACP journal club（oviddatabase, best
12、 evidence）在search 中，键入关键词olanzapineetiology（病因学）检索结果：1篇文献（摘要）找到全文,筛选结果,ACP journal Club summary: Conventional antipsychotic drugs increased risk for death more than did atypical antipsychotic drugs in elderly patients ACP Journal Club. 2007;147:23.Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C,
13、Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ.2007;176:627-32,研究详情,Background: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients.
14、 We assessed the short-term mortality in 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 identify a cohort of people aged 65 years and
15、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 taking conventional antipsychotic medications and those taking atypical antipsychotic medications.,Results:,Of 37 241 elderly
16、 people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 24 359 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%
17、 confidence interval CI 1.391.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.231.42). In comparison with risperidone（利培酮）, haloperidol（氟哌啶醇） was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.862.45) and loxapine（ 洛沙平）the lowest (mo
18、rtality ratio 1.29, 95% CI 1.191.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.501.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95%
19、CI 1.421.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding.,结论,Interpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the
20、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 评价证据 Appraise Evidence,证据的真实性Are the results valid?证据的重要性What are the results?,证据的真实性Are the re
21、sults valid?,1 研究方法的论证强度Type of Reports on Etiology/Harm,哪种研究方法？论证强度如何？是否源于真正的人体试验？ Were there clearly defined groups of 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 antipsycho
22、tic drugs (APDs) with death ?Design: Cohort 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 before the index date.,2 两组结局暴露因素的测量方法是否一致？,Were treatments/exposures a
23、nd clinical outcomes measured in the same ways in both groups? (Was the assessment of outcomes either objective or blinded to exposure?)Were the outcomes and exposures measured in the same way in the groups being compared?,Cohort Study,Surveillance bias: 监测偏倚偏倚的控制客观指标（Objective outcome）：病死率主观指标（Subj
24、ective outcome）: Blinding举例：乙型肝炎与肝癌关系的研究,3. 随访时间及失访率,Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete?举例：HP与胃癌：5年（无差异），10 年（显著差异）失访超过20？-结果将失去真实性,4 病因/不良反应研究结果是否符合病因诊断原则,Do the results of the harm study satisfy some of the diagnostic tests for causati
25、on?,Is it clear that the exposure preceded the onset of the outcome? 因果效应的先后顺序仅见于前瞻性研究Is there a doseresponse gradient? 因果效应的相关程度，剂量依赖（吸烟与肺癌）Is there any positive evidence from a “dechallengerechallenge” study? 符合流行病学规律-危险因素减弱，发病减少,Is the association consistent from study to study? 不同研究，结果一致（HP与胃癌）D
26、oes the association make biological sense? 充分的生物学依据（CCB与癌症，坏血病与水果蔬菜）,Key Points,1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause? 研究方法的论证强度2. Were treatments/exposures and clinical outcomes measured in the same ways i
27、n both groups? 测量方法一致3. Was the follow-up of the study patients sufficiently long (for the outcome to occur) and complete? 随访时间及失访率,证据的重要性What are the results?,1.因果联系强度,What is the magnitude of the association between the exposure and outcome?How strong is the association between exposure and outcom
28、e?RR OR NNH,2. 结果是否准确？,What is the precision of the estimate of the association between the exposure and outcome?How precise is the estimate of risk?95%CI,Conventional APD vs Atypical APDAssociation with death,第四步应用证据How can I apply the results to mypatient?,病情相似,Is our patient so different from tho
29、se included in the study that its results cannot apply?Were the study patients similar to my patient?基于纳入和排除标准,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 date.Exclusion criteria: cancer and use of APDs in th
30、e year before the index date.Atypical APDs: risperidone, quetiapine, olanzapine, and clozapineConventional APDs: loxapine, haloperidol, chlorpromazine, trifluoperazine, thioridazine, pimozide, promazine, perphenazine, fluphenazine, mesoridazine, and thiothixene.,权衡利弊,What is our patients risk of ben
31、efit and harm from the agent? NNT and NNH,举例,一项心律失常抑制试验（CAST): 恩卡尼/氟卡尼与安慰剂：10月随访，病死率分别为7.7%和3.0%，NNH21（平均每21个患者服此药，将有1人发生额外死亡）NSIAD与消化道出血：NNH2000（每2000 人服NSAIDs，预期增加1例消化道出血患者）,本病案,使用传统和非典型性抗精神病药物 NNT/NNH 作者未进行计算和分析查询其他证据,患者的价值观和愿望,What are our patients preferences, concerns, and expectations from th
32、is treatment? 1、为了避免疾病的进展而接受治疗，可能带来不良反应 2、宁愿冒疾病进展的风险而不接受治疗 3、关注费用 4、无所谓的态度,其他可替代的疗法,What alternative treatments are available?-当危险因素或治疗措施的危险明确而且巨大，则应立即脱离危险因素或终止治疗。举例 -blockers for hypertension in patients with asthma 治疗高血压的受体阻滞剂能加重支气管痉挛；血管紧张素转换酶抑制剂巯甲丙脯酸、依那普利等，既能降压，又不诱发支气管痉挛，,本病案：临床决策,对该患者选择哪类抗精神病药?,Evidence-based practice in real time,直接查询已经评价过的高质量的综合临床证据(preappraised evidence)，如选择数据库“ACP journal club”, “临床证据”（clinical evidence，www.clinicalevidence.org）等进行查询。这些信息资源一般收集高质量且临床实用性强的研究，已经对某种病因性研究的价值进行了总结。使用已评价过的高质量证据，临床医师可在30秒内找 到拟解决问题的答案，特别适用于在床旁实践循证医 学,
