資料的評讀資料的評讀 (I)(I) 治療治療

神經內科 王志弘醫師

Critically Appraising the Evidence資料評讀

Best Evidence Best Evidence depends

on the type of Question Question 0What are the phenomena/problems?

0Observation

0What is frequency of the problem? (Frequency)0Random (or consecutive) sample

0Does this person have the problem? (Diagnosis)0Random (or consecutive) sample with gold standard

0Who will get the problem? (Prognosis)0Follow-up of inception cohort

0How can we alleviate the problem? (Therapy)0Randomized controlled trial (RCT)

Best evidence is not always from RCTs.

for an individual randomized trial

Critically Appraising the Evidence for its (VIP)(VIP)

• VValidity (closeness to the truth)• IImpact (size of the effect)• ApApplicability (usefulness in our clinical

practice)

Validity

closeness to the truth

研究的結果可信嗎 ?

VValidity (closeness to the truth)

0Was there a fair start0 開始是否公平

0Was there a fair race0 過程是否公平

0Some finer points0 其他細項

VValidity (closeness to the truth)

0 Was there a fair start1. Was the assignment of patients to treatment randomized?2. Was the randomization concealed?3. Were the groups similar at the start of the trial?

0 Was there a fair race4. Was follow-up of patients sufficiently long and complete?5. Were all patients analyzed in the groups to which they were

randomized?0 Some finer points

6. Who was blinded: Were patients, clinicians and study personnel kept blind to treatment?

7. Were groups treated equally, apart from the experimental therapy?

Fair Start起始點的公平0Patient randomized

0 病患的分配（治療組、控制組）是隨機的0Randomization concealed

0 隨機的過程是隱藏的；隨機分派中心0 病患、治療者、評估者都不知道分組的狀況

0Groups similar0 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

Fair Race過程公平0Follow-up sufficiently long and complete

0 CONSORT (consolidated standards of reporting trials) statement

0Were all patients analyzed in the groups to which they were randomized?

Follow-Up and Drop out

0Drop out: 0 無法忍受副作用0 治療無效

0Assign the drop-outs to the worst case outcome0>80% follow-up acceptable

Follow up Duration

0Sufficiently long to see a clinical effect

0Study duration

0Expected duration of treatment

0Sometimes, study stopped early when a large benefit is seen0 Look for the sample size and effect size

Patients Analyzed in the Assigned Groups?

0 “Intention-to-treat (ITT) analysis” 意向分析，意圖治療分析0 無論是否接受介入，都應該維持隨機分派後的狀態0 應該評估所有受試者的預後0 所有接受隨機分派的受試者都應該納入分析

0 “Per-protocol (PP) analysis” 依計畫書分析0 only patients who complete the entire clinical trial are

counted towards the final results0 只有完整接受治療到最後，才納入分析

Blinding

0Patients0Treating clinician0Study personnel0Evaluating personnel

0Surgery studies0 Blinded assessment

0Article should explicitly state who was blinded

Treat Equally, Apart From the Experimental Therapy

0Contamination: 0 The control group receivedthe same therapy as the

experimental group

0Co-intervention:0 When one group or the other received different medical

care based upon their group assignment

VValidity (closeness to the truth)

0 Was there a fair start1. Was the assignment of patients to treatment randomized?2. Was the randomization concealed?3. Were the groups similar at the start of the trial?

0 Was there a fair race4. Was follow-up of patients sufficiently long and complete?5. Were all patients analyzed in the groups to which they were

randomized?0 Some finer points

6. Who was blinded: Were patients, clinicians and study personnel kept blind to treatment?

7. Were groups treated equally, apart from the experimental therapy?

RAM-bo0研究族群是否具有代表性（ RRepresentative ） ?

0 隨機選擇（ random selection ）／連貫性／起始點病人群0 或者，如果是比較性的，組別間是否可以比較 ? 0 隨機分派（ random allocation ）／調整

0是否有足夠的確認與追蹤（ AAscertainment/follow up） ?0 反應率／追蹤率／確認＞ 80%

0結果的估計值（ MMeasurement ）是否公正 ? 恰當 ?0 使用盲法（ bblinded ）或客觀的（ oobjective ）估計

Impact

size of the effect

結果是否重要

ImpactSize of the Effect

0The magnitude of the treatment effect0治療效果的強度

0However precise is the estimate of the treatment effect?

0治療效果的預估 : 信賴區間

Treatment Effect

0Outcome0 Important outcome: mortality0 Surrogate outcome: BMD, risks of fracture0 Composite outcome:

0Methods to report the results

Methods to Report the Results

0Control Event Rate (CER)0 對照組事件發生率

0Experimental Event Rate (EER)0 實驗組事件發生率

0Relative risk reduction (RRR)0 相對風險比率差0 relative benefit increase ， relative risk increase

0Absolute risk reduction (ARR)0 絕對對風險比率差0 absolute benefit increase ， absolute risk increase

0Control Event Rare (CER) = C/(C+D)0Experimental Event Rate (EER) = A/(A+B)0Relative Risk Reduction = |CER-EER| /CER0Absolute Risk Reduction = |CER-EER|0Number Needed to Treat (NNT) = 1 /ARR

Outcome No Outcome Sum

Experimental A B A+B

Control C D C+D

Number Needed to Treat (NNT)

0NNT = 1/ARR0需要被治療的病人數目0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0為減少一個不良結果所需治療的病人數目

Number Needed to HarmNNH

0NNH= 1/ARI (absolute risk increase)

Cost and Effect - NNT and NNH from Statin Stroke Prevention Trial

0For rhabdomyolysis0 Control event rate (CER): 0.03%0 Experimental event rate (EER): 0.05%0 Absolute risk increase (ARI) = |0.03%-0.05%| = 0.02%0 Number Needed to Harm (NNH) = 1/ARI = 1/0.02%=5000

NNT vs Follow-Up Time 不同的試驗，追蹤時間不同，如何比較0假設相對風險下降固定

0 Relative Risk Reduction = |CER-EER| /CER0 NNT = 1/ARR = 1/ |CER-EER|

0如果追蹤時間變為為原本的 t 倍0CERt = CER * t ; EERt = EER * t

0NNTt = 1/ARRt = 1/|CERt-EERt| = 1/(|CER-EER|*t) = NNT/t

0 t = hypothetic time / observed time

0NNThypothetical = NNTobserved x (observed time/hypothetic time)

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

信賴區間095% Confidence interval0實際值有 95% 的機會是在這個信賴區間內的

Applicability

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

適用性0 Is our patient so different from those in the study that

its results cannot apply0 病患是否與研究受試者明顯不同

0 Is the treatment feasible in our setting0 治療是否可行，健保

0What are our patient’s potential benefits and harms from the therapy0 好處與壞處

0What are our patient’s values and expectations for both the outcome we are trying to prevent and the treatment we are offering0 病患的價值觀與期待

Patients vs Study Population

0 Inclusion and exclusion criteria0 通常不會如此考慮

0Sociodemographic status0Pathobiology

Potential Benefit and Harms

0Estimate our patient’s unique benefits and risks

0Patient’s individual CER (control event rate) or “patient’s expected event rate” (PEER)

0From NNT (number needed to treat ) and NNH (number needed to harm)

Patient’s Expected Event Rate PEER

0Set to the overall control event rate (CER) of the study0Set to the CER of subgroup, similar to our patient0According to the clinical prediction guide, assign

PEER0From other paper, assign PEER

0NNT= 1/(PEER x RRR)0NNH = 1/(PEER x RRI)

0Relative Risk Reduction (RRR)= |CER-EER| /CER

= ARR / CER0Absolute Risk Reduction (ARR)= |CER-EER|

= CER x RRR0Number Needed to Treat (NNT) = 1 /ARR

=1/(|CER-EER|) = 1 / (CER x RRR)

0NNT= 1/(PEER x RRR)0NNH = 1/(PEER x RRI)

From NNT / NNH

0To estimate our patient’s risk of the outcome event relative to that of the average control patient

0Decimal fraction (ft / fh)

0 如果病人比起 control 有兩倍的風險 ft = 2

0 如果病人比起 control 只有一半倍的風險 ft = 0.5

0 病人的 NNT = NNT / ft

0 同理0 病人的 NNH = NNH / fh

Individualized Benefits and Risks個人化的利與弊0Clinical decision analysis: 費時0Likelihood of being helped and harmed (LHH)0LHH = ARR (absolute risk reduction) ÷ ARI (absolute

risk increase)0= (1/NNT) ÷ ( 1/NNH)

0LHH = [(1/NNT) × ft] ÷ [( 1/NNH) × fh]

Patients’ Values and Expectations病人的價值與期望0Ask patient to make value judgment about the relative

severity of the outcome (disease treated, adverse event)

0 severity factor = s 因子0= 疾病的嚴重性 / 副作用嚴重性

0LHH = [ (1/NNT) × ft × s] ÷ [( 1/NNH) × fh]

0 severity factor = s 因子0= 疾病的嚴重性 / 副作用嚴重性 0例如 以 statin 藥物 來預防中風0中風： 0.0250橫紋肌溶解症： 0.950S = 0.95/0.025 = 38 0中風為橫紋肌溶解症 38 倍的嚴重

0LHH = [ (1/NNT) × ft × (1-Uevent) ] ÷ [( 1/NNH) × fh × (1-Utoxicity)]

01-Utility = Disutility = Harm

一個實際的例子

Statin vs Stroke Prevention

0CER (control event rate) = 585 / (585+9682) = 0.057 0EER (experimental event rate)= 444 / (444+9825) =

0.0430RRR (relative risk reduction) = (0.057-0.043)/0.057 =

24.6%0ARR (absolute risk reduction) = (0.057 – 0.043) =

0.0140NNT = 1/0.014 = 71.42 72

Outcome (stroke)

No outcome

Experimental 444 9825

Control 585 9682

http://ktclearinghouse.ca/cebm/practise/ca/calculators/statscalc

0CER (control event rate) = 3 / (3+10264) = 0.00029 0EER (experimental event rate)= 5 / (5+10264) =

0.000490RRI (relative risk increase) =

(0.00049-0.00029)/0.00029 = 69.0%0ARI (absolute risk increase) = (0.00049 – 0.00029) =

0.00020NNH = 1/0.0002 = 5000

Outcome (rhabdomyolysis)

No outcome

Experimental 5 10264

Control 3 10264

個人化的 NNT 與 NNH0Decimal fraction (ft / fh)

0 病人的 NNT = NNT / ft

0 如果病人比起 control 有兩倍的風險 ft = 20NNT=72/2=36

0 如果病人比起 control 只有一半倍的風險 ft = 0.50NNT=72/0.5=144

0 病人的 NNH = NNH / fh

0 如果病人比起 control 有兩倍的風險 ft = 20NNH=5000/2=2500

0 如果病人比起 control 只有一半倍的風險 ft = 0.50NNT=5000/0.5=10000

Likelihood of being helped and harmed (LHH)

0LHH = (1/NNT) ÷ ( 1/NNH)0= (1/72) ÷ (1/5000) = 69.4 70≒0Statin 治療 使他受益的機會為受害的機會的 70 倍0LHH = [(1/NNT) × ft] ÷ [( 1/NNH) × fh]

再加上病患的價值觀0LHH = [ (1/NNT) × ft × s] ÷ [( 1/NNH) × fh]

0 severity factor = s 因子0例如 以 statin 藥物 來預防中風0中風： 0.0250橫紋肌溶解症： 0.950S = 0.95/0.025 = 38 0中風為橫紋肌溶解症 38 倍的嚴重0LHH = [(1/72) x 38] ÷ (1/5000) = 2638.8