Using Evidence from Clinical Trials to Optimize Quality of Medical Care

李智雄醫師

高雄醫學大學附設醫院實證醫學中心

實證醫學、循證醫學、證據醫學

Evidence Based Medicine

Evidence Based Dentistry

Evidence Based Pharmacy

Evidence Based Physiotherapy

Evidence Based Nursing

Evidence Based Nutrition

……………………………..

Evidence Based Healthcare

回想一下

過去的三個月中，針對病人的臨床問題，您做過幾次完整的實證資料查詢與評讀？

照顧病人真的有這麼多臨床問題嗎 ?

Resident’s information needs

• Setting: 64 residents at 2 New Haven hospitals• Method: Interviewed after 401 consultations• Questions

– Asked 280 questions (2 per 3 patients)– Pursued an answer for 80 questions (29%)– Not pursued because

• Lack of time• Forgot the question

• Sources of answers– Textbooks (31%), articles (21%), consultants (17%)

Green, Am J Med 2000

2圖三 整體實習醫師第 題排名第一各選項百分比

, 58. 1%請教師長

上課講義或教科, 13. 5%書

, 12. 2%同儕討論

, 14. 9%網際網路

, 1. 4%其他

上課講義或教科書

請教師長

同儕討論

網際網路

其他

實習醫師調查：遇到臨床問題的解決方式

執行 EBM 的五個步驟 ( I )

1. 問問題 ASK （可以回答的問題）– Converting the need for information into an

answerable question. 2. 找資料 ACQUIRE （可獲得最好的證據資訊）

– Search the database and tracking down the best evidence.

3. 分析判斷 APPRAISE （文獻的效度與重要性）– Critical appraising that evidence for its validity

and importance.

執行 EBM 的五個步驟 ( II )

4. 臨床應用 APPLY （整合三大層面）– Integrating the critical appraising with our

clinical expertise and our patient’s unique biology, values and circumstances.

5. 評估成果 AUDIT （執行 EBM 的效率）– Evaluating our effectiveness and efficiency

in executing step 1- 4 and seeking ways to improve them both for next time.

Challenges

• Too many patients

• Too many problems

• Too many tasks

• Mental fatigue

• Heaps of information

• Staying in control

• Maintaining the passion

17圖十一 第 題「您認為要執行實證醫療決策最大的障礙是？」之圓餅圖分析

,工作太忙時間不足27. 7%

, 10. 1%病人問題太多

, 18. 5%文獻資料太多

, 26. 1%找不到資料

,電腦使用不方便3. 4%

, 5. 0%沒有興趣

, 2. 5%沒有誘因

老師也不清楚無法指, 6. 7%導

工作太忙時間不足

病人問題太多

文獻資料太多

找不到資料

電腦使用不方便

沒有興趣

沒有誘因

老師也不清楚無法指導

Process of Evidence-Based Decision Making

Asking questions

Clinical questions

Published relevant research

Retrieved relevantevidence

Critically appraised evidence

Applicableevidence

Relevance gap

Inertia gap

Retrievability gap

Critical appraisal gap

Applicability gap

• Fear of criticism• Conflict with usual care• Logistic constraint• Cost• Medicolegal concerns

Dismantling the Barriers

• Attitudes of inquiring and asking questions– Encourage questions during ward round– Keep a question log book / PDA / handphone

• Information at the point of decision making– Have the evidence sources at the point of care

• Lack of skills and knowledges of EBM– Preappraised resources– Rapid appraisal methods

• Lack of time– Replace most passive learning with question-focused learning– Use more effective updating methods– EBM journal club (Clinical problem-oriented)

“Just in Time” learningThe EBM Alternative Approach• Shift focus to current patient problems

(“just in time” education)– Relevant to YOUR practice– Memorable– Up to date

• Learn to obtain best current answers

Dave Sackett

Copyright ©2006 BMJ Publishing Group Ltd.

Brian Haynes, R Evid Based Med 2006;11:162-164

The "5S" levels of organisation of evidence from healthcare research

Evidence-based CPGs

The Quality of Health Care Delivered to Adults in the United StatesN Engl J Med 2003;348:2635-45

• Evaluate performance on 439 indicators of quality of care – October 1998 - August 2000– 12 metropolitan areas in the United States– 30 acute and chronic conditions, also preventive care

• Senile cataract: 78.7% (95% CI 73.3 – 84.2)• Alcohol dependence: 10.5% (95% CI 6.8 - 14.6)

Number Needed to Search to Improve Care• Random sample 146 inpatients cared for by 33 phy

sicians• Literature searches following formulation of diagnos

is and treatment plans, with feedback to physicians• Outcomes

– No. of patients for whom physicians improved management due to searchs, as ascertained by blinded peer review

• Results– Plans changed in 18% (23/130) of eligible patients– Peer reviewers judged quality of care to have been impro

ved or sustained in 78% (18/23) of treatment changes– NNS to improve care for 1 patient = 130/18 = 7 patients

Lucas et al J Gen Intern Med 2004

Getting Evidence into Practice

Evidence from clinical trials

Searching out or receiving high quality evidence

Apply high quality evidence in clinical decision making

Integration of evidence into practice

From Clinical Trials to PracticeTools of Translation

• Likelihood ratios for diagnostic tests

• NNT and NNH for therapies

• Clinical prediction rules

• Clinical practice guidelines

Pretest odds x LR = Posttest odds

Posttest Probability =posttest odds / posttest odds+1

Pretest odds = prevalence / (1 – prevalence)

sensitivityLR (+) = 1 - specificity

1 - sensitivityLR (- ) = specificity

Likelihood Ratios

Rule of 15%

LR+ LR- Change in post-test probability

10 or 0.1 45% 5 or 0.2 30% 2 or 0.5 15%

The Likelihood Nomogram

Number Needed to Treat for Therapies

• NNT=Number needed to treat to prevent one outcome ( 1 / ARR )

• Measure of the clinical impact of therapies• Assists in choosing and prioritising treatment opt

ions• Preferable to use single common outcome meas

ures• Should also concern about

– Event– Treatment intensity / co-interventions– Duration of follow-up– Baseline patient risk

Clinical Prediction Rules• Use of clinical findings to make a diagnosis or

predict an outcome– History– PE – Test results

• Derived from systematic clinical observation

Purposes:• Suggest a diagnostic or therapeutic course of action• Change clinical behavior• Reduce unnecessary costs• Maintaining quality of care

Evaluate Pretest Probability

Low Moderate High

Normal echo Abnormal echo Normal echo Abnormal echo Normal echo Abnormal echo

No DVT venogramRepeat echo in 3-7 days DVT Venogram DVT

No DVT DVT No DVT DVT No DVT

++- + - -

Clinical Practice Guidelines• National Guideline Clearinghouse (NGC)

– http://www.guidelines.gov/• New Zealand Guidelines Group

– http://www.nzgg.org.nz/index.cfm• National Institute for Health and Clinical Excellence (NICE)

– http://www.nice.org.uk/• Medical Information Network Distribution Service (Minds)

– http://minds.jcqhc.or.jp/index.aspx• 國家衛生研究院 – 實證臨床指引平台

– http://ebpg.nhri.org.tw/

Check for• Validity• Grading of evidentiary strength of recommendation• Accessibility• Usability of format• Applicability to local circumstances

Some Common Problems in Translating Evidence from Clinical Trials to Practice

1. Generalizing Trial Results

Am Heart J 2003; 146:250-7

Heart Failure TrialsTrial Patients Community Patients

Age 50 – 70 yrs Mostly > 70 yrs

Gender M > F M ~ F

Diagnosis Mainly CHF Comorbidity

LV Function Systolic dysfunction

Systolic / diastolic dysfunction

Treatment Heart failure Concomitant

Compliance Optimal Variable

Spironolactone in Heart Failure

J Am Coll Cardiol 2003;41:211– 4

N Engl J Med 1999:341:709-17

Spironolactone prescription rate (per 1000 patients)

Rate of admission for hyperkalemia(Per 1000 patients)

Rate of in-hospital death from hyperkalemia(per 1000 patients)

Rate of readmission for heart failurePer 1000 patients

N Engl J Med 2004;351:543-51.

2. Faulty ComparatorsUse of placebo when active comparator optimal

Prevention of diabetic nephropathy

ARB VS

ACEI

Placebo

(N Engl J Med 2001;345:870-8.)

N Engl JMed 2001;345:861-9

RCT of High Dose Atorvastatin VS Moderate

Dose Pravastatin in ACS Patients

N Engl J Med 2004;350:1495-504.

16% RRR at 2 years

3. Surrogate End-Points

Results based on surrogate outcomes Results based on clinical end points

Milrinone improved LV function during exercise

Large RCT and meta-analysis showed 28% increase in mortality

Encainide suppressed VT in post-MI patients

Large RCT showed 50% increase in mortality

β-blockers cause decline in EF in post-MI patients

RCTs show 32% decrease in mortality in patients with heart failure

GP IIb/IIIa antagonist in AMI in the absence of PCI improve coronary blood flow and resolve ST elevation

RCT shows no mortality difference and increased bleeding risk

Anticholinesterase inhibitors improve scores on performance scales

RCT shows no difference in mortality, carer burden, health care costs

4. Relative VS Absolute Measures of Benefit

對照組的風險CER

實驗組的風險EER

相對風險性降低度RRR

絕對危險性降低度ARR

70% 35% 50% 35%

7% 3.5% 50% 3.5%

0.7% 0.35% 50% 0.35%

• 相對風險性降低度 (RRR) 無法呈現實際風險降低程度，亦沒有　考慮起始風險• 絕對危險性降低度 (ARR) 更準確表示治療效果，但亦不容易體　會兩組的差別

Number Needed to Treat (NNT)“ 益一需治數＂

NNT = 1 / ARR or 100 / ARR (%)

“ 益一需治數”：為了預防一個不良結果

或減少一人死亡所需治療的病人數 例如：治療五人可減少一人死亡　 VS 　治療兩千人可減少一人死

亡

Framing Effect

• Physicians are more likely to prescribe drugs when trial results are presented only with information about RRR

“For those who are likely to be influenced by data presentation, never, ever, accept information on the basis of relative risk alone”

MisinformationLevel of Evidence for Class A and Class B Claims

Class A Class B

(n=418) (n=437)

Unreferenced claims 6 (1%) 58 (13%)

References not on Medline 146 (35%) 174 (40%)

Level 1 evidence (meta-analyses) 40 (10%) 59 (14%)

Level 2 evidence ( 1RCT) 189 (45%) 108 (25%)≧Level 3 evidence 37 (9%) 38 (9%)

• 7.4% (13/174) reported quantitative statistics about outcomes• 77% (10/13) reported RRR without additional information• 8% (1/13) reported RRR with information allowing ARR and NNT calculation• 15% (2/13) reported original data allowing RRR, ARR and NNT calculation• No advertisement explicitly reported ARR or NNT MJA 2002; 177:291-293

5. Use of Composite End-Points

(N Engl J Med 2001;345:851-60.)

In comparison to amlodipine, Irbesartan reduced the combined endpoint of all causemortality, progression to end stage renal disease, and doubling of serum creatinine

RRR 20%, 95% CI 7.5% - 32%

(N Engl J Med 2001;345:851-60.)

JAMA 2003; 289:2554-2559

Primary Composite Outcome and Mortality

From 1997 to 2000, review of 167 original reports of randomized trials (with a total of 300276 patients) that included a composite primary outcome that incorporated all-cause mortality

A high proportion of trials that measure composite outcomes, including mortality, provide neutral results on the primary outcome may be unsurprising. However, the finding that a similar proportion are positive yet fail independently to identify an effect on the mortality component is striking and requires further consideration

JAMA. 2003;289:2554-2559

Effects of Clinician-driven End-Points

• 78 of 179 comparisons (including 20 primary outcomes from studies with multiple comparisons) included the following clinician-driven outcomes: – revascularization, percutaneous mitral valvuloplasty, mec

hanical ventilation, hospitalization, transplantation, use of rescue therapy, initiation of new antibiotics, use of shock therapy, amputation, ECMO, dialysis etc.

• The inclusion of a clinician-driven outcome was predictive of a statistically significant result for the primary composite outcome

OR 2.24 (95% CI 1.15-4.34); P =0.02

JAMA. 2003;289:2554-2559

6. Small Effect Size

N Engl J Med 2003;348:583-92

7. Sponsor Bias

JAMA. 2003;290:921-928

6 Points: Experimental intervention highly preferred and should now be considered the standard intervention in all patients, or similar

May 2001 Cochrane Library, 167 Cochrane reviews

Independent Predictors for Stronger Recommendation

JAMA. 2003;290:921-928

JAMA. 2006;295:2270-2274

JAMA. 2006;295:2270-2274

Recommendation

• Write down all your clinical questions

• Be familiar with the search strategy and database available, especially pre-appraised resources

• Just in time learning

• Understand the pitfalls of using clinical trial results