复旦大学：《循证医学》课程教学资源（参考教材）Unit 09 药物不良反应的分析评价（主讲教师：朱畴文）

Unit9:药物不良反应的分析评价 主讲教师：朱畴文 助理教师：高虹 一、教学目的：掌握和熟悉药物不良反应及其研究、评价和应用的原则及方法 二、教学内容： 1了解药物不息反应研究（药物流行病学）的历中和讲展 学握药物不良反应的定义 重要意义和有关监测研究的主要基本方法 3.初步掌握药物不良反应的确定方法（宏观和微观评价】 4.熟悉流行病学中各种相关性或因果研究方法的特点（带复习性质） 5.了解药物不良反应监测、药物流行病学的应用及前景 三、教学重点：药物不良反应的研究方法 四、教学难点：药物不良反应的判断 五、中文和英文关键词 Adverse Drug Reaction药物不良反应 Pharmacoepidemiology药物流行病学 Causal As ciation因果关联 六、阅读文献： 1.Nissen SE,Wolski K.Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.N Engl J Med 2007:356(24):2457-71. 2.罗格列酮大事记 七、讨论思考题 一)微观判断：使用Naranjo模式和我国卫生部ADR中心评分法，推断如下 临床病例发生药物不良反应的可能性 一位29岁的女性在过去一周已经接受nitrofurantoin(呋喃妥因)治疗2 次。在地服下第3次治疗的第1片药的4小小时后。她出现发热(39℃)、 呼吸窘迫和呕吐。她随即停了药 天后她的全科医师开了胸片检查 发现为过敏性肺 炎”的表现。 她的白细胞精增多(12*10^9/L)伴9%嗜 酸性细胞。数日后，患者完全康复。 Naranjo's Adverse Drug Reaction Probability Scale 间题 是否不知道分值 1 .以前有类似的报道吗？ 不良事件是在应用可疑药物之后出现的吗？ 2 0 3 当撒药后或应用特定的对抗药后不良反应有所 +1 0 0 好转吗？ 4 当再次用药后，不良反应又出现吗？ +2 、 0 有其他非药物因素可引起该不良反应吗 使用安慰剂后，不良反应再次出现了吗 1 0 -1 7 药物血（或其他体液）浓度达到中毒浓度了吗？ + 0 0 8 增加（或减少）药物剂量，不良反应加重（或减轻）+1 0 0 了吗？

Unit 9：药物不良反应的分析评价 主讲教师：朱畴文 助理教师：高虹 一、教学目的：掌握和熟悉药物不良反应及其研究、评价和应用的原则及方法 二、教学内容： 1. 了解药物不良反应研究（药物流行病学）的历史和进展 2. 掌握药物不良反应的定义、重要意义和有关监测研究的主要基本方法 3. 初步掌握药物不良反应的确定方法（宏观和微观评价） 4. 熟悉流行病学中各种相关性或因果研究方法的特点（带复习性质） 5. 了解药物不良反应监测、药物流行病学的应用及前景 三、教学重点：药物不良反应的研究方法 四、教学难点：药物不良反应的判断 五、中文和英文关键词 Adverse Drug Reaction 药物不良反应 Pharmacoepidemiology 药物流行病学 Causal Association 因果关联 六、阅读文献： 1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-71. 2. 罗格列酮大事记 七、讨论思考题： （一）微观判断：使用 Naranjo 模式和我国卫生部 ADR 中心评分法，推断如下 临床病例发生药物不良反应的可能性 一位 29 岁的女性在过去一周已经接受 nitrofurantoin（呋喃妥因）治疗 2 次。在她服下第 3 次治疗的第 1 片药的 4 小时后，她出现发热（39oC）、 呼吸窘迫和呕吐。她随即停了药，一天后她的全科医师开了胸片检查， 发现为“过敏性肺炎”的表现。她的白细胞稍增多（12*10^9/L）伴 9%嗜 酸性细胞。数日后，患者完全康复。 Naranjo’s Adverse Drug Reaction Probability Scale 问题 是 否 不知道 分值 1 .以前有类似的报道吗? +1 0 0 2 不良事件是在应用可疑药物之后出现的吗？ +2 -1 0 3 当撤药后或应用特定的对抗药后不良反应有所 好转吗？ +1 0 0 4 当再次用药后，不良反应又出现吗? +2 -1 0 5 有其他非药物因素可引起该不良反应吗? -1 +2 0 6 使用安慰剂后,不良反应再次出现了吗? -1 +1 0 7 药物血(或其他体液)浓度达到中毒浓度了吗？ +1 0 0 8 增加(或减少)药物剂量，不良反应加重(或减轻) 了吗? +1 0 0

9病人以前桑器于该药或同类药有类似的反应吗1 0 10该不良事件可被其他客观证据证明吗？ 8 合计 判断标准：总分≥9肯定(definite,)5-8很可能(probable, 1-4可能(possilbe:≤0可疑(doubtful) 我国卫生部ADR中心推荐的评分法 根据对以下5个问题的回答 1)开始用药的时间和不良反应出现的时间有无合理的先后关系？ 2)所怀疑的不良反应是否符合该药品已知不良反应的类型？ 3)所怀疑的不良反应是否可用并用药的作用，病人的临床状态或其他疗 法的母影响来解轻？ 4)停药或减量后，反应是否减轻或消失？ 5)再次接触可疑药品是否再次出现同样的反应？ 2 3 4 5 肯定 + + 可能 可 必 可能 说明：+表示肯定：·表示否定：±表示难以肯定或否定：？表示情况不明 分别根据Naranjo量表和我因卫生部ADR中心推荐的评分法，你的评分是多 A.这两个模式有什么主要缺点或弱点？ B.你有什么建议？ (二)宏观评价： 阅读文献：N Engl J Med.2007,356(24):2457-71.回答下列问题 A.读了这篇文献后，你对于罗格列酮临床使用的安全性有什么看法？ B.你认为国家卫生部门对此应该做出什么反应？ C,药物不良反应的研究主要运用哪些方法？为什么？ 八、参考书及文献目录 朱畴文第 三篇第18 不良反应，于《循证医学与临床实践》（第3版） 王吉耀主编，科学出版 2."Strom BL ed,Pharmacoepidemiology (2d ed),Chichester:John Wiley Sons, 1994)

9 病人以前暴露于该药或同类药有类似的反应吗? +1 0 0 10 该不良事件可被其他客观证据证明吗? +1 0 0 合计 判断标准: 总分9 肯定(definite); 5-8 很可能(probable); 1-4 可能(possilbe); 0 可疑(doubtful) 我国卫生部 ADR 中心推荐的评分法 根据对以下 5 个问题的回答: 1) 开始用药的时间和不良反应出现的时间有无合理的先后关系? 2) 所怀疑的不良反应是否符合该药品已知不良反应的类型? 3) 所怀疑的不良反应是否可用并用药的作用,病人的临床状态或其他疗 法的影响来解释? 4) 停药或减量后,反应是否减轻或消失? 5) 再次接触可疑药品是否再次出现同样的反应? 1 2 3 4 5 肯定 + + - + + 很可能 + + - + + 可能 + +   ? 可疑 + -   ? 不可能 - - + - - 说明：+ 表示肯定；- 表示否定； ±表示难以肯定或否定； ？表示情况不明 问： 分别根据 Naranjo 量表和我国卫生部 ADR 中心推荐的评分法，你的评分是多 少？ A. 这两个模式有什么主要缺点或弱点？ B. 你有什么建议？ （二）宏观评价： 阅读文献： N Engl J Med. 2007;356(24):2457-71.回答下列问题： A. 读了这篇文献后，你对于罗格列酮临床使用的安全性有什么看法？ B. 你认为国家卫生部门对此应该做出什么反应？ C. 药物不良反应的研究主要运用哪些方法？为什么？ 八、参考书及文献目录 1. 朱畴文 第三篇第 18 章 不良反应，于《循证医学与临床实践》（第 3 版） 王吉耀主编，科学出版社 2. “Strom BL ed, Pharmacoepidemiology (2nd ed), Chichester: John Wiley & Sons, 1994”)

The new england JOURNAL of MEDICINE ESTABLISHED IN 181 JUNE14,2007 V0L.356N0.2 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Steven E.Nissen,M.D.,and Kathy Wolski,M.P.H. ABSTRACT BACKGROUND iglit mellitus,but its reprint Dr. the D METHODS We conducted searches of the published literature,the Web site of the Food and org Drug Administration,and a ceri for inclusion in our meta-analysis included a (G. 2007 rdialp tion and death fro s.0f116p 47 NEng]Med2007,35624577 trials met the inclusion criteria.We tabulated all occurrences of myocardial infare- tion and death from cardiovascular causes. RESULTS with the control group,the odds ratio for myocardial infarction was 1.43(95% confidence interval [CI],1.03 to 1.98;P=0.03),and the odds ratio for death from cardiovascular causes was 1.64(95%CL 0.98 to 2.74:P=0.06). ignificance.Our study was limited by a lack of access to original source data.which would have enabled time-to-vent.Despite these limita tions,patients and providers should consider the potential for serious adverse car- diovascular effects of treatment with rosiglitazone for type 2 diabetes. N ENGL J MED 356;24 WWW.NEJM.ORG JUNE 14,200 2457 The New England Joumal of Medicine

n engl j med 356;24 www.nejm.org june 14, 2007 2457 The new england journal of medicine established in 1812 june 14, 2007 vol. 356 no. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. A bs tr ac t From the Cleveland Clinic, Cleveland. Ad￾dress reprint requests to Dr. Nissen at the Department of Cardiovascular Medi￾cine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at nissens@ccf. org. This article (10.1056/NEJMoa072761) was published at www.nejm.org on May 21, 2007. N Engl J Med 2007;356:2457-71. Copyright © 2007 Massachusetts Medical Society. Background Rosiglitazone is widely used to treat patients with type 2 diabetes mellitus, but its effect on cardiovascular morbidity and mortality has not been determined. Methods We conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manu￾facturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarc￾tion and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. We tabulated all occurrences of myocardial infarc￾tion and death from cardiovascular causes. Results Data were combined by means of a fixed-effects model. In the 42 trials, the mean age of the subjects was approximately 56 years, and the mean baseline glycated hemoglobin level was approximately 8.2%. In the rosiglitazone group, as compared with the control group, the odds ratio for myocardial infarction was 1.43 (95% confidence interval [CI], 1.03 to 1.98; P=0.03), and the odds ratio for death from cardiovascular causes was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Conclusions Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limita￾tions, patients and providers should consider the potential for serious adverse car￾diovascular effects of treatment with rosiglitazone for type 2 diabetes. The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

The NEW ENGLAND JOURNAL f MEDICINE AHIAZOLIDINEDIONE DRUGS ARE WIDE any mvocardial infarctions or deaths from cardic ly used to lower hlood glucose levels in na and therefo tients with type 2 diabetes mellitus.In the in the analysis because the effect measure could United States,three such agents have been intro- not be calculated.Of the remaining 42 studies, 38 reported at least one myocardi: and 23 reported at le st one ed e ra comparator groups with regimens that did not receptors are ligand-activated nuclear transcrip- include rosiglitazone. tion factors that modulate gene expression,lower Multiple groups of patients who received rosig ing blood glucose primarily by increasing insulin when appli cable.The control g roup wa wide used as pa rec ing any d falt reg ries.One group includes five of the stud. or glimepiride (Avandaryl,GlaxoSmithKline). ies submitted to the FDA for the March 22,1999. The original approval of rosiglitazone was advisory board hearing that recommended ap- based on the ability of the drug to reduce blo proval of rosiglitazone.Group-level data from glucose and glycat d hem oglobin levels s are availab stu cd ve stud cun ite s D rom the rted in fashime trials cluding cardiovascular morbidity and mortality. However,the effect of any antidiabetic therapy on cardiovascular outcomes is particularly im- of these five trials were also published in peer reviewed journals.In these e trials,1967 es are tients we or active com rators to ass sess the effect of this Other studies that meta agent on cardiovascular outcomes.The sourc analysis were initially identified in the glaxo material for this analysis consisted of publicly SmithKline clinical-trial registry.As noted in available data from the original registration pack Table 1,we included 35 studies in this category age submitted to the F od and Drug Administr tion (FDA),a er serie of trial 26 ssible.the d on al indications for the drug. cthhepebicionnsoFantheake between published and unpublished data,data METHODS derived from the manufacturer's web site were used.In this group of 35 trials,9507 7 patients sts the 42 trials d11 48 trials me defined inclusion criteria of having a randomized comparator group,a similar duration of treat Assessment with Ramipiril and Rosiglitazone ment in all groups,and more than 24 weeks of Medication (DREAM)NCT00095654 trial20 and drug exposure.Six of the 48 trials did not report the A Diabetes Outcome Prevention Trial (ADOPT) 2458 N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14.2007

T h e n e w e ng l a nd j o u r na l o f m e dic i n e 2458 n engl j med 356;24 www.nejm.org june 14, 2007 Thiazolidinedione drugs are wide￾ly used to lower blood glucose levels in pa￾tients with type 2 diabetes mellitus. In the United States, three such agents have been intro￾duced: troglitazone, which was removed from the market because of hepatotoxicity, and two current￾ly available agents, rosiglitazone (Avandia, Glaxo￾SmithKline) and pioglitazone (Actos, Takeda). The thiazolidinediones are agonists for peroxisome￾proliferator–activated receptor γ (PPAR-γ). PPAR-γ receptors are ligand-activated nuclear transcrip￾tion factors that modulate gene expression, lower￾ing blood glucose primarily by increasing insulin sensitivity in peripheral tissues.1,2 Rosiglitazone was introduced in 1999 and is widely used as monotherapy or in fixed-dose combinations with either metformin (Avandamet, GlaxoSmithKline) or glimepiride (Avandaryl, GlaxoSmithKline). The original approval of rosiglitazone was based on the ability of the drug to reduce blood glucose and glycated hemoglobin levels.3 Initial studies were not adequately powered to deter￾mine the effects of this agent on microvascular or macrovascular complications of diabetes, in￾cluding cardiovascular morbidity and mortality.3 However, the effect of any antidiabetic therapy on cardiovascular outcomes is particularly im￾portant, because more than 65% of deaths in patients with diabetes are from cardiovascular causes.4 Therefore, we performed a meta-analy￾sis of trials comparing rosiglitazone with placebo or active comparators to assess the effect of this agent on cardiovascular outcomes. The source material for this analysis consisted of publicly available data from the original registration pack￾age submitted to the Food and Drug Administra￾tion (FDA), another series of trials performed by the sponsor after approval, and two large, prospec￾tive, randomized trials designed to study addition￾al indications for the drug. Me thods Analyzed Studies Table 1 lists the 42 trials included in this meta￾analysis. We screened 116 phase 2, 3, and 4 trials for inclusion. Of these, 48 trials met the pre￾defined inclusion criteria of having a randomized comparator group, a similar duration of treat￾ment in all groups, and more than 24 weeks of drug exposure. Six of the 48 trials did not report any myocardial infarctions or deaths from cardio￾vascular causes and therefore were not included in the analysis because the effect measure could not be calculated. Of the remaining 42 studies, 38 reported at least one myocardial infarction, and 23 reported at least one death from cardio￾vascular causes. In these trials, 15,565 patients were randomly assigned to regimens that includ￾ed rosiglitazone, and 12,282 were assigned to comparator groups with regimens that did not include rosiglitazone. Multiple groups of patients who received rosig￾litazone within a single trial were pooled togeth￾er, when applicable. The control group was de￾fined as patients receiving any drug regimen other than rosiglitazone. The trials fall into three categories. One group includes five of the stud￾ies submitted to the FDA for the March 22, 1999, advisory board hearing that recommended ap￾proval of rosiglitazone. Group-level data from these five studies are available in publicly dis￾closed briefing documents archived on the FDA Web site.6 Data from these same trials are also reported in a summary fashion on a clinical￾trial registry Web site maintained by the drug manufacturer, GlaxoSmithKline.5 Reports of four of these five trials were also published in peer￾reviewed journals.7-9 In these five trials, 1967 pa￾tients were randomly assigned to receive rosiglit￾azone, and 793 patients were assigned to receive various comparator drugs (Table 1). Other studies that we included in the meta￾analysis were initially identified in the Glaxo￾SmithKline clinical-trial registry.5 As noted in Table 1, we included 35 studies in this category, 9 of which were published in peer-reviewed jour￾nals and 26 of which remain unpublished.10-18 Whenever possible, the results obtained on the Glaxo­SmithKline Web site were cross-checked with the publication. In cases of disagreement between published and unpublished data, data derived from the manufacturer’s Web site were used. In this group of 35 trials, 9507 patients were randomly assigned to receive rosiglitazone, and 5960 patients were assigned to receive vari￾ous comparator drugs. A third data source consisted of two large, recently published trials, the Diabetes Reduction Assessment with Ramipiril and Rosiglitazone Medication (DREAM) NCT00095654 trial20 and the A Diabetes Outcome Prevention Trial (ADOPT) The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved

ROSIGLITAZONE AND CARDIOVASCULAR OUTCOMES (ClinicalTrials.gov number,NCT00279045).In ity across trials,allowing for the use of a fixed- the DREAM study,2635 patients were randomly effects model.For additional analyses,the active assigned to receive rosiglitazone and 2634 patients ocp2latorecontolgroupswcrcesnbegroupedintm ollowing tour classes for comparison wit terosigl and pl oup with the In the ADOPT trial,1456 patients were random-use of methods similar to those used in the ly assigned to receive rosiglitazone and 2895 pa-pooled analyses.Data were analyzed with the use tients were assigned to receive either metformin of Comprehensive Meta-Analysis software,version or glyburide 2.2 (Biostat). RESULTS BASELINE CHARACTERISTICS OUTCOME MEASURES Table 2 reports the doses of rosiglitazone and We reviewed data summaries provided in the comparator drugs,baseline demographic charac FDA review documents,the GlaxoSmithKline teristics,study periods,and glycated hemoglobin levels or fasting b d gluco levels for patien nen led in the revyog vrg causes.With the exc DRAM su Overall thereu the included trials did not describe adjudication men.Diabetes control was relatively poor,with a of myocardial infarction or death from cardio- mean baseline glycated hemoglobin level of ap- proximately 8.2%for both study groups. TION AND DEATH able.it was no same patient had both events.Therefore,an out reported in the 42 clinical trials we reviewed. come measure based on the composite of death There were86 myocardial infarctions in the rosig- or myocardial infarction could not be construct- litazone group and 72 in the control group ed.Accordingly,these two outcomes are reported There were separately in to STATISTICAL ANALYEIS intervals.and P values for m cardial in- Many trials had few cardiovascular events,so the farction and death from cardiovascular causes odds ratios and 95%confidence intervals were for the rosiglitazone group and the control group calculated with the use of the Peto method. The summary odds ratio for myocardial infard tion was 1.43 in the P=0.03 odd als in which patients had noadvers with the contro w2si6495%CL,0.98t0 cular events in either group were excluded from 2.74:P=0.06).Table 4also lists odds ratios and analyses.All reported P values are two-sided 95%confidence intervals for the pooled group of Statistical het of Cochran's Q statistic or the odds ratios for myocardial in N ENGL J MED 356;24 WWW.NEJM.ORG JUNE 14,2007 2459 The New England Journal of Medicine

Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 2459 (ClinicalTrials.gov number, NCT00279045).21 In the DREAM study, 2635 patients were randomly assigned to receive rosiglitazone and 2634 patients were assigned to receive placebo. The DREAM study was designed to determine whether rosigli￾tazone could prevent the development of type 2 diabetes in patients at high risk for this disorder. In the ADOPT trial, 1456 patients were random￾ly assigned to receive rosiglitazone and 2895 pa￾tients were assigned to receive either metformin or glyburide. The ADOPT study was designed to assess the durability of glycemic control with rosiglitazone therapy, as compared with therapy with metformin or glyburide. Outcome Measures We reviewed data summaries provided in the FDA review documents, the GlaxoSmithKline clinical-trial registry Web site, and published trial results and then abstracted from the ad￾verse-event tabulations information on myocar￾dial infarction and death from cardiovascular causes. With the exception of the DREAM study, the included trials did not describe adjudication of myocardial infarction or death from cardio￾vascular causes. Time-to-event data for cardio￾vascular events were not available in any of these trials, which precluded the calculation of hazard ratios. Because only summary data were avail￾able, it was not possible to discern whether the same patient had both events. Therefore, an out￾come measure based on the composite of death or myocardial infarction could not be construct￾ed. Accordingly, these two outcomes are reported separately. Statistical Analysis Many trials had few cardiovascular events, so the odds ratios and 95% confidence intervals were calculated with the use of the Peto method.22-24 Because all trials had similar durations of follow￾up for all treatment groups, the use of odds ra￾tios represents a valid approach to assessing the risk associated with the use of rosig­lit­azone. Tri￾als in which patients had no adverse cardiovas￾cular events in either group were excluded from analyses. All reported P values are two-sided. Statistical heterogeneity across the various trials was tested with the use of Cochran’s Q statistic. A P value of more than the nominal level of 0.10 for the Q statistic indicated a lack of heterogene￾ity across trials, allowing for the use of a fixed￾effects model. For additional analyses, the active comparator control groups were subgrouped into the following four classes for comparison with rosiglitazone: metformin, sulfonylurea, insulin, and placebo. Odds ratios and 95% confidence in￾tervals were calculated for each subgroup with the use of methods similar to those used in the pooled analyses. Data were analyzed with the use of Comprehensive Meta-Analysis software, version 2.2 (Biostat). R esult s Baseline Characteristics Table 2 reports the doses of rosiglitazone and comparator drugs, baseline demographic charac￾teristics, study periods, and glycated hemoglobin levels or fasting blood glucose levels for patients enrolled in the trials. The patients were relatively young, averaging less than 57 years of age for both the rosiglitazone group and the control group. Overall, there was a moderate predominance of men. Diabetes control was relatively poor, with a mean baseline glycated hemoglobin level of ap￾proximately 8.2% for both study groups. Myocardial Infarction and Death Table 3 reports the myocardial infarction events and deaths from cardiovascular causes that were reported in the 42 clinical trials we reviewed. There were 86 myocardial infarctions in the rosig￾litazone group and 72 in the control group. There were 39 deaths from cardiovascular causes in the rosiglitazone group and 22 in the control group. Table 4 lists the odds ratios, 95% confi￾dence intervals, and P values for myocardial in￾farction and death from cardiovascular causes for the rosiglitazone group and the control group. The summary odds ratio for myocardial infarc￾tion was 1.43 in the rosiglitazone group (95% confidence interval [CI], 1.03 to 1.98; P=0.03). The odds ratio for death from cardiovascular causes in the rosiglitazone group, as compared with the control group, was 1.64 (95% CI, 0.98 to 2.74; P=0.06). Table 4 also lists odds ratios and 95% confidence intervals for the pooled group of trials that were smaller and of shorter duration; results for the DREAM and ADOPT studies are shown separately. Table 5 lists odds ratios for myocardial in￾The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved