BPH的循证治疗的循证治疗Evidence-Based therapy of BPH 中国循证医学中心中国循证医学中心 临床流行病学研讨室临床流行病学研讨室老年科老年科董碧蓉教授博士生导师一一.临床治疗根据的演化临床治疗根据的演化1900s个人阅历个人阅历权威性教学权威性教学无对照病例报告无对照病例报告病例对照研讨病例对照研讨, , 临床实验临床实验以科学为本的病因学以科学为本的病因学1970s临床终点目的研讨临床终点目的研讨+ + 临床阅历临床阅历以证据为本的临床用药以证据为本的临床用药1995医医药费用直用直线攀升！攀升！ 卫生效力需求生效力需求不断添加！不断添加！卫生生资源利源利用不均！用不均！医患关系医患关系紧张！the rate of radical prostatectomy per 100,000 male Medicare beneficiaries, adjusted for age and race手术率范围差别令人难以手术率范围差别令人难以置信：置信：20/100,000 in Rhode 20/100,000 in Rhode 429/100,000 in Alaska 429/100,000 in Alaska 21:1 21:1有些州阅历太多的手术，许多病人阳萎和失禁相反，有些州手术缺乏合理的治疗能够存在于两极端之间。“Keep the balance between benefits and harms临床决策临床决策临床关于临床关于BPH的治疗问题很多的治疗问题很多干涉类型的选择干涉类型的选择内科药物治疗内科药物治疗l -受体阻滞受体阻滞剂剂l 5-复原复原酶酶抑制抑制剂剂 l 中中药药和植物制和植物制剂剂外科治疗外科治疗用药时机？用药时机？单药单药/结合？结合？用药疗程？用药疗程？不良事件？不良事件？药物相互作用药物相互作用?What is the Evidence-based PracticeEBP) 整合病人价值，临床医生的专业技艺和最好证据，将三者完美地结合以制定出患者的治疗措施 Integrating patient values, clinical expertise and best evidence Sackett DL 2001 Sackett DL 2001Model of evidence based clinical decisions clinical circumstancespatient preference research evidence Clinical expertise 临床医生将专业技艺，整合证据，同时思索病人志愿与价值，与病人及家属进展沟通，然后协助做出决策的才干。1.1.临床床阅历clinical expertiseclinical expertise l进展医学实际活动的根本才干：问诊、查体、进展医学实际活动的根本才干：问诊、查体、与病人沟通的才干与病人沟通的才干l对疾病病理生理、解剖知识的了解专业知对疾病病理生理、解剖知识的了解专业知识识l临床个人阅历的积累临床个人阅历的积累 尿道尿道移行带增生发移行带增生发 生部分生部分中央区癌发生部分中央区癌发生部分 外周带外周带BPHBPH从移行带发生从移行带发生Benign Prostatic Benign Prostatic HyperplasiaHyperplasia， BPH BPH解剖知识解剖知识Development of BPH : Early Slide 1 of 3BPH的发生早期的发生早期膀胱膀胱包绕前列腺包绕前列腺上分的肌肉上分的肌肉前列腺前列腺组织组织外科外科包膜包膜前列腺段尿道前列腺段尿道Development of BPH : Intermediate Slide 2 of 3BPH的发生中期的发生中期前列腺前列腺组织组织外科外科包膜包膜狭窄的前列腺狭窄的前列腺段尿道段尿道Development of BPH : Late Slide 3 of 3严重狭窄的前严重狭窄的前列腺段尿道列腺段尿道BPH的发生晚期的发生晚期前列腺前列腺组织组织外科外科包膜包膜40-7940-79岁每岁每年增长年增长0.6ml0.6ml，2020年后体年后体积添加积添加12ml12ml假设原来体假设原来体积是积是20ml,2020ml,20年后体积会年后体积会到达到达32ml 32ml 前列腺的体积与年龄有关前列腺的体积与年龄有关生理知识生理知识前列腺增生症的发病率随年龄前列腺增生症的发病率随年龄增长而明显添加增长而明显添加流行病学知识流行病学知识Definition of TermsnLUTSLower-urinary-tract symptomsnBPEBenign prostatic enlargement(macroscopic)nBOOBladder-outlet obstructionnBPHBenign prostatic hyperplasia (microscopic/histologic)nBPOBenign prostatic obstruction (BOO caused by BPE)nClinical BPH LUTS + BPE + BOO Slide I.1病理生理知识病理生理知识Adapted from Nordling J et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:107-166.Pathophysiology of Clinical BPH:Overlapping but Independent FeaturesSlide I.2LUTSEnlargedprostateBOO病理生理知识病理生理知识Pathophysiology of Clinical BPH:Predictive Risk FactorsSlide I.4nIncreasing agenProstatic enlargementnElevated prostate-specific antigen (PSA)nLower-urinary-tract symptoms (LUTS)nDecreased urinary flow rate BPH的临床表现特点的临床表现特点排尿期病症排尿期病症(梗阻性梗阻性,占占25%)排尿费力排尿费力,尿不尽感尿不尽感尿线细慢尿线细慢尿流中断尿流中断白天晚上储尿期病症储尿期病症(刺激性刺激性,占占25%)尿频尿频(排尿次数添加排尿次数添加)尿急尿急夜尿添加夜尿添加储尿期 + 排尿期病症占50%日夜不轻松膀胱憩室膀胱憩室上尿路积水上尿路积水尿潴留尿潴留前列腺增生的危害性前列腺增生的危害性尿路感染尿路感染膀胱结石膀胱结石血尿血尿腹股沟疝、脱肛、痔疮腹股沟疝、脱肛、痔疮反复起夜，影响休憩，反复起夜，影响休憩，诱发心脑血管疾病发作诱发心脑血管疾病发作前列腺容积和前列腺容积和LUTSLUTSn前列腺容积对生活质量的影响前列腺容积对生活质量的影响n 30ml 30ml 是是 30ml 40ml 40ml 是是 40ml 50ml 50ml 是是 50ml 50ml 的的 3.5 3.5 倍倍n中到重度病症影响中到重度病症影响QoLQoL是无病症的是无病症的4-64-6倍倍国际前列腺病症评分表国际前列腺病症评分表(IPSS)(IPSS)0-7分分=轻度；轻度； 8-19分分=中度；中度； 20-35分分=重度重度2.2.最正确临床研讨证据最正确临床研讨证据The best evidence)The best evidence)指与临床亲密相关的研讨，以人体研讨证据指与临床亲密相关的研讨，以人体研讨证据l 设计良好的良好的临床研床研讨才是才是让证听听说话的的基石基石l 随机随机对照照实验是防治性研是防治性研讨的金的金规范范l 未来有能未来有能够有新的有新的证据出据出现证据的据的级别的的“金字塔金字塔临床研床研讨证据分据分级寻求寻求 POEMs POEMs，防止，防止DOEs DOEs q熟习如何寻觅临床问题的答案是重要的技艺熟习如何寻觅临床问题的答案是重要的技艺qPOEM:Patient-Oriented Evidence that Mattersq 病人为中心的丈量目的病人为中心的丈量目的 终点目的终点目的qDOE：Disease-Oriented Evidenceq常引起误导，通常不成熟常引起误导，通常不成熟BPHBPH的治疗目的的治疗目的终点目的终点目的生活质量生活质量 AURAUR发生率发生率前列腺手术率前列腺手术率不良反响发生不良反响发生率率 维护膀胱功能维护膀胱功能 中间目的改善中间目的改善尿流率尿流率剩余尿剩余尿病症病症前列腺体积前列腺体积1010年前观念年前观念目前观念目前观念源于对源于对9090种杂志继续种杂志继续6 6个月的个月的调查显示：调查显示：l97%97%的文献是的文献是DOEsDOEs或其他。或其他。l80478047篇文献中仅篇文献中仅213213篇篇2.6%) 2.6%) 是是POEMsPOEMs如何寻觅高质量证据如何寻觅高质量证据? ?lTextbook (print or online)lMedline or PubMed search: find and review articleslPre-appraised evidencel Best Evidencel Clinical Evidence (Therapy only)l Cochrane Collaboration (Therapy only) l UpToDate循证教科书要求循证教科书要求运用超文本运用超文本hyepertext, PDA) 的电子图书的电子图书收入的知识须是源于当前最好的研讨证据收入的知识须是源于当前最好的研讨证据每一项证据都有质量评级每一项证据都有质量评级随着新证据的出现不断更新随着新证据的出现不断更新经过互联网传送给每一个医生和决策人员经过互联网传送给每一个医生和决策人员.引荐教科书引荐教科书Clinical Evidence (the BMJ Publishing Group and the American College of Physicians 1999 年第年第1次出版次出版)Evidence-Based on Call (CD)Harrisons textbooks(CD)Merck ManualEBCP DATA Resources qSummaries of the primary evidenceACP Journal Club | Clinical Evidence | eMedicine | FPIN Clinical Inquiries | InfoPOEMs| UpToDateqDatabasesMEDLINE | Cochrane LibraryqElectronic textbooks and librariesACP Medicine | Harrisons | MD Consult | Stat!Ref qMeta-Search EnginesSUMSearch | TRIP Plus: Turning Research into Practice点击点击双击双击点击点击Clincial Trial 132Other Reviews 3评价证据评价证据Evaluating the Validity of The Evaluating the Validity of The StudyStudyn对每一个研讨必需回答三个根本问题对每一个研讨必需回答三个根本问题 There are three basic questions that need to be answered for every type of study: n 研讨结果的真实性如何？研讨结果的真实性如何？Are the results of the study valid? n 临床意义和统计学意义临床意义和统计学意义What are the results? n 结果有助于我处置病人吗？结果有助于我处置病人吗？Will the results help in caring for my patient?评价方式评价方式n本人进展文献评价本人进展文献评价 Critically appraise articles yourselfn借助已评价的证据资源借助已评价的证据资源Used a source that appraises trials for younBest EvidencenClinical Evidence nCochrane LibrarynUpToDateDiagnosis of Clinical BPH: International RecommendationsSlide IV.1Assessment ICBPH GuidelinesQuantification of symptomsIPSSRecommendedQuantification of symptomsbother scoreRecommendedDigital rectal examinationRecommendedUrinalysis RecommendedPSA measurementRecommendedVoiding diary (frequency-volume charts)RecommendedUrinary flow-rate recordingOptionalPostvoid residual urine volume studiesOptionalPressure-flow studiesOptionalProstate imaging (TRUS)OptionalUpper-urinary-tract imaging (US or IVU)OptionalLower-urinary-tract endoscopyOptionalSerum creatinine measurementNot recommendedAdapted from Fifth International Consultation 2001 on BPH. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:519-535.BPH的治的治疗疗目的目的ICBPHICBPH制定的制定的制定的制定的BPHBPH的治的治的治的治疗疗疗疗目的：目的：目的：目的：减少前列腺体减少前列腺体减少前列腺体减少前列腺体积积积积和和和和/ /或减或减或减或减轻轻轻轻梗阻梗阻梗阻梗阻防止防止防止防止远远远远期并期并期并期并发发发发症症症症4 4缓缓缓缓解解解解临临临临床病症床病症床病症床病症4 44.Evaluation and treatment of low urinary tract symptoms in older man. 2001 5th international consultation on BPH. Recommendation of the international scientific committeeEvidence-Based Medicine:Proven treatment for Clinical BPHnEvidence-based medicine is based on results of clinical research.nDrugs in the same therapeutic class may exert different pharmacologic effects.nIndependent clinical studies must establish each drugs efficacy, safety, and effect on outcomes. nOutcome studies with drugs for clinical BPH should evaluate the effects of therapy on AUR and BPH-related surgery.Slide V.1PROSCAR:Durable Efficacy in Long-Term TrialsDurationLong-Term ImprovementStudy(years) SymptomsProstate VolumeUrinary FlowNorth American1 SCARP2 PROSPECT2 PROWESS2 PLESS4 North American Extension* MaintainedMaintainedMaintainedScandinavian Open Extension*MaintainedMaintainedMaintainedSlide V.4 = significant improvement from baseline vs. placebo (p0.05); SCARP = Scandinavian Study of Reduction of the Prostate; PROSPECT = Proscar Safety Plus Efficacy Canadian Two-Year Study; PROWESS = Proscar Worldwide Efficacy and Safety Study; PLESS = Proscar Long-term Efficacy and Safety Study*Benefits achieved during double-blind therapy were maintained in extensions.治疗组治疗组对照组对照组保列治保列治 治疗对前列腺体积的影响治疗对前列腺体积的影响Effects of PROSCAR on the Natural History of Clinical BPH: Reduced Risk of AURSlide V.5PlaceboPROSCAR57%riskreductionp0.00115105041230Probability of AURYears No. of AURs36252018 No. at risk1503145481347 No. of AURs1411710 No. at risk1513148714491421PlaceboPROSCARp0.001 at 4 years PROSCAR vs. placeboAdapted from McConnell JD et al N Engl J Med 1998;338(9):557-563. Effects of PROSCAR on the Natural History of Clinical BPH: Reduced Risk of SurgerySlide V.655%riskreductionp0.0011510501230Probability of surgeryNo. of surgeries37523231No. at risk1503145441314No. of surgeries1822920No. at risk1513148314381410Years4PlaceboPROSCARPlaceboPROSCARp0.001 at 4 years, PROSCAR vs. placeboAdapted from McConnell JD et al N Engl J Med 1998;338(9):557-563. Effect of PROSCAR on the Natural History of BPH: Relative Risk Reductions vs. Interventions in Other DiseasesRiskConditionOutcomeIntervention Reduction (%)OsteoporosisVertebral fractureAlendronate4447Hip fracture Alendronate 2151AtherosclerosisPTCA or CABGStatins1737 Fatal/nonfatal MI Statins 2540EpilepsySeizuresAnticonvulsants 3887Superficial bladder cancer RecurrenceBCG + surgery3180Kidney stonesRecurrencePharmacotherapy6380BPHAURPROSCAR57Surgery PROSCAR 55Slide V.7PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft; BCG = bacillus Calmette-GurinAdapted from Roehrborn CG et al Urology 2000;56:9-18. McConnell et al N Eng J Med 1998;338(9):557-563.PSA and PROSCARnPredictably reduces PSA by 50% in men with BPH nMultiplication of PSA values by 2 in men treated for 6 months preserves predictive value of PSA measurements Slide V.8In PLESS, PROSCAR did not mask prostate cancer detected by PSALong-Term Experiencewith PROSCARnSustained improvements over 7 years of therapynReductions in symptom scoresnSustained reductions in prostate volume 25% reduction at year 7nSustained increases in urinary flow 2.5 ml/sec increase at year 7nConsistent safety and tolerability profile over 8 years of therapySlide VI.1Data on file, MSD. Rapid and Sustained Reduction in the Risk of Long-Term Outcomes with PROSCARDouble-blind study Open-label extensionSlide VI.3n values indicate number of patients completing each trial phaseAdapted from Roehrborn CG et al. Poster 419.Placebo (n=1503)PROSCAR 5 mg (n=1513)Placebo PROSCAR 5 mg (n=858)PROSCAR 5 mg PROSCAR 5 mg (n=979)543210Yearly % of AUR and/or BPH-related surgery123456Study year3.71.94.42.13.31.03.02.01.00.71.41.3Slide VI.4 *p0.05 PROSCAR vs. placebo at every time point after 4 months to 1 year and p0.001 PROSCAR vs. placebo every 4 months, years 1 to 4*Significant improvement vs. baseline with PROSCAR and placebo at 4 years, p7PV36ml4 Yr TxFrom evidencesBPHBPH治治疗疗中中受体阻滞受体阻滞剂剂的作用机制及的作用机制及疗疗效效MTOPS研讨虽然前列腺体积添加24，仍有明显疗效尿道阻力下降逼尿肌稳定逼尿肌收缩力改善From evidences to action面临错综复杂的BPH患者，如何决议一个治疗方案？最好的证据来自于相关的研讨医生的阅历患者的志愿综而合之确定治疗方案Syntegration Make a decision证据综合决议A way from clinical evidence to actionThe Patient-Physician Connection让患者了解治疗的利让患者了解治疗的利/ /弊弊找出病人的价值与志愿找出病人的价值与志愿协助病人做出适宜于病人的选择不是协助病人做出适宜于病人的选择不是替病人作出选择替病人作出选择Patient Satisfaction Is Important in the Treatment of Clinical BPHnTreatment selection in BPH should take into accountnPatients perception of the impact of BPH on quality of lifenPatients ability to deal with bother caused by symptomsnPatients attitudes toward risk of possible complicationsSlide VII.1The Physicians Rolein Patient EducationnPhysicians should involve patients with BPH in the choice of therapynPatient education should include discussions ofnThe natural history of BPH (including potential for serious complications)nBenefits, risks, and costs of alternative approaches总结总结谢谢！ Thank you very much!