資料的評讀 (I) 治療

1. 資料的評讀(I)治療 神經內科 王志弘醫師

2. Critically Appraising the Evidence 資料評讀

4. Best Evidence depends on the type of Question • What are the phenomena/problems? • Observation • What is frequency of the problem? (Frequency) • Random (or consecutive) sample • Does this person have the problem? (Diagnosis) • Random (or consecutive) sample with gold standard • Who will get the problem? (Prognosis) • Follow-up of inception cohort • How can we alleviate the problem? (Therapy) • Randomized controlled trial (RCT) Best evidence is not always from RCTs.

5. for an individual randomized trialCritically Appraising the Evidence for its (VIP) Validity (closeness to the truth) Impact (size of the effect) Applicability (usefulness in our clinical practice)

6. Validity closeness to the truth 研究的結果可信嗎?

7. Validity(closeness to the truth) • Was there a fair start • 開始是否公平 • Was there a fair race • 過程是否公平 • Some finer points • 其他細項

8. Validity(closeness to the truth) • Was there a fair start • Was the assignment of patients to treatment randomized? • Was the randomization concealed? • Were the groups similar at the start of the trial? • Was there a fair race • Was follow-up of patients sufficiently long and complete? • Were all patients analyzed in the groups to which they were randomized? • Some finer points • Who was blinded: Were patients, clinicians and study personnel kept blind to treatment? • Were groups treated equally, apart from the experimental therapy?

9. Fair Start起始點的公平 • Patient randomized • 病患的分配（治療組、控制組）是隨機的 • Randomization concealed • 隨機的過程是隱藏的；隨機分派中心 • 病患、治療者、評估者都不知道分組的狀況 • Groups similar • 各組病患（治療組、控制組）在治療之前的特徵（主要的預後因子，除了治療本身之外）都是相似的

10. FairRace過程公平 • Follow-up sufficiently long and complete • CONSORT(consolidated standards of reporting trials)statement • Were all patients analyzed in the groups to which they were randomized?

13. Follow-Up and Drop out • Drop out: • 無法忍受副作用 • 治療無效 • Assign the drop-outs to the worst caseoutcome • >80%follow-upacceptable

14. Followup Duration • Sufficientlylongtoseea clinical effect • Study duration • Expected duration of treatment • Sometimes, study stopped early when a large benefit is seen • Look for the sample size and effect size

15. Patients Analyzed in the Assigned Groups? • “Intention-to-treat (ITT) analysis” 意向分析，意圖治療分析 • 無論是否接受介入，都應該維持隨機分派後的狀態 • 應該評估所有受試者的預後 • 所有接受隨機分派的受試者都應該納入分析 • “Per-protocol (PP) analysis”依計畫書分析 • only patients who complete the entire clinical trial are counted towards the final results • 只有完整接受治療到最後，才納入分析

17. Blinding • Patients • Treatingclinician • Studypersonnel • Evaluatingpersonnel • Surgerystudies • Blindedassessment • Articleshouldexplicitlystatewhowasblinded

18. TreatEqually, Apart From the Experimental Therapy • Contamination: • The control group receivedthe same therapy as the experimental group • Co-intervention: • When one group or the other received different medical care based upon their group assignment

19. Validity(closeness to the truth) • Was there a fair start • Was the assignment of patients to treatment randomized? • Was the randomization concealed? • Were the groups similar at the start of the trial? • Was there a fair race • Was follow-up of patients sufficiently long and complete? • Were all patients analyzed in the groups to which they were randomized? • Some finer points • Who was blinded: Were patients, clinicians and study personnel kept blind to treatment? • Were groups treated equally, apart from the experimental therapy?

20. RAM-bo • 研究族群是否具有代表性（Representative）? • 隨機選擇（randomselection）／連貫性／起始點病人群 • 或者，如果是比較性的，組別間是否可以比較? • 隨機分派（randomallocation）／調整 • 是否有足夠的確認與追蹤（Ascertainment/followup）? • 反應率／追蹤率／確認＞80% • 結果的估計值（Measurement）是否公正?恰當? • 使用盲法（blinded）或客觀的（objective）估計

21. Impact size of the effect 結果是否重要

22. ImpactSize of the Effect • The magnitude of the treatment effect • 治療效果的強度 • However precise is the estimate of the treatment effect? • 治療效果的預估: 信賴區間

23. TreatmentEffect • Outcome • Importantoutcome:mortality • Surrogateoutcome: BMD, risks of fracture • Compositeoutcome: • Methods to report the results

25. Methods to Report the Results • Control Event Rate (CER) • 對照組事件發生率 • Experimental Event Rate (EER) • 實驗組事件發生率 • Relative risk reduction (RRR) • 相對風險比率差 • relativebenefitincrease，relativeriskincrease • Absolute risk reduction (ARR) • 絕對對風險比率差 • absolutebenefitincrease，absoluteriskincrease

26. ControlEventRare(CER)=C/(C+D) • ExperimentalEventRate(EER)=A/(A+B) • RelativeRiskReduction=|CER-EER|/CER • AbsoluteRiskReduction=|CER-EER| • NumberNeededtoTreat(NNT)=1 /ARR

27. Number Needed to Treat (NNT) • NNT=1/ARR • 需要被治療的病人數目 • 在一段實驗期間內，使一位病人達到實驗組治療之有意結果（或預防產生一個不良結果）所需治療的病人數目 • 為減少一個不良結果所需治療的病人數目

30. NumberNeededtoHarmNNH • NNH= 1/ARI (absolute risk increase)

31. Cost and Effect - NNT and NNH from Statin Stroke Prevention Trial • For rhabdomyolysis • Control event rate (CER): 0.03% • Experimental event rate (EER): 0.05% • Absolute risk increase (ARI) = |0.03%-0.05%| = 0.02% • Number Needed to Harm (NNH) = 1/ARI = 1/0.02%=5000

32. NNT vs Follow-Up Time 不同的試驗，追蹤時間不同，如何比較 • 假設相對風險下降固定 • RelativeRiskReduction=|CER-EER|/CER • NNT=1/ARR = 1/ |CER-EER| • 如果追蹤時間變為為原本的 t倍 • CERt=CER * t ; EERt = EER * t • NNTt = 1/ARRt = 1/|CERt-EERt| = 1/(|CER-EER|*t) = NNT/t • t = hypothetic time / observed time • NNThypothetical = NNTobserved x (observed time/hypothetic time)

33. However precise is the estimate of the treatment effect?治療效果的預估: 信賴區間

34. 信賴區間 • 95%Confidenceinterval • 實際值有95% 的機會是在這個信賴區間內的

36. Applicability usefulness in our clinical practice 研究的結果是否可以套用在我的病人身上

37. 適用性 • Is our patient so different from those in the study that its results cannot apply • 病患是否與研究受試者明顯不同 • Is the treatment feasible in our setting • 治療是否可行，健保 • What are our patient’s potential benefits and harms from the therapy • 好處與壞處 • What are our patient’s values and expectations for both the outcome we are trying to prevent and the treatment we are offering • 病患的價值觀與期待

38. Patients vs Study Population • Inclusion and exclusion criteria • 通常不會如此考慮 • Sociodemographicstatus • Pathobiology

40. Potential Benefit and Harms • Estimate our patient’s unique benefits and risks • Patient’s individual CER (control event rate) or “patient’s expected event rate” (PEER) • From NNT (number needed to treat ) and NNH (number needed to harm)

41. Patient’s Expected Event RatePEER • Set to the overall control event rate (CER) of the study • Set to the CER of subgroup, similar to our patient • According to the clinical prediction guide, assign PEER • From other paper, assign PEER • NNT= 1/(PEER x RRR) • NNH = 1/(PEER x RRI)

42. RelativeRiskReduction(RRR)=|CER-EER|/CER = ARR / CER • AbsoluteRiskReduction(ARR)=|CER-EER| = CER x RRR • NumberNeededtoTreat(NNT)=1 /ARR =1/(|CER-EER|) = 1 / (CER x RRR) • NNT= 1/(PEER x RRR) • NNH = 1/(PEER x RRI)

44. From NNT / NNH • To estimate our patient’s risk of the outcome event relative to that of the average control patient • Decimal fraction (ft / fh) • 如果病人比起control 有兩倍的風險 ft=2 • 如果病人比起control 只有一半倍的風險 ft=0.5 • 病人的 NNT = NNT/ft • 同理 • 病人的 NNH = NNH/fh

45. IndividualizedBenefitsandRisks個人化的利與弊 • Clinicaldecisionanalysis: 費時 • Likelihoodofbeinghelpedandharmed(LHH) • LHH=ARR(absoluteriskreduction)÷ARI(absoluteriskincrease) • =(1/NNT) ÷(1/NNH) • LHH=[(1/NNT)×ft] ÷[(1/NNH)×fh]

46. Patients’ Values and Expectations病人的價值與期望 • Askpatienttomakevaluejudgmentabouttherelativeseverityoftheoutcome(disease treated, adverse event) • severity factor = s 因子 • = 疾病的嚴重性 / 副作用嚴重性

47. LHH=[(1/NNT)×ft× s] ÷[(1/NNH)×fh] • severity factor = s 因子 • = 疾病的嚴重性 / 副作用嚴重性 • 例如 以 statin 藥物 來預防中風 • 中風：0.025 • 橫紋肌溶解症：0.95 • S=0.95/0.025=38 • 中風為橫紋肌溶解症38倍的嚴重

48. LHH=[(1/NNT)×ft× (1-Uevent)] ÷[(1/NNH)×fh×(1-Utoxicity)] • 1-Utility=Disutility=Harm

49. 一個實際的例子

50. StatinvsStrokePrevention