Evidence Based Medicine &

Basic Critical Appraisal

David ErskineLondon & SE

Medicines Information Service

Why do we need evidence?

Resources should be allocated to things that are EFFECTIVE

The only way of judging effectiveness is EVIDENCE

“In God we trust – all others bring data”

Why do we need evidence?

Move towards:

EVIDENCE-BASED MEDICINE

Move away from:

EMINENCE- BASED MEDICINE

What we really, really want is

EVIDENCE-INFORMED MEDICINE

Evidence-based medicine 5 steps

Converting information needs into answerable questions

Finding the best evidence with which to answer question

Critically appraising evidence for validity and usefulness

Applying the results in clinical practice

Evaluating performance

What is an answerable question? - step 1

Should contain the following components:

The intervention you are interested in The population you are interested in The outcomes you are interested in

Finding evidence - step 2Workshop

What are ‘good’ sources of evidence?

Think about sources of evidence that you have used – were they useful?

What makes a ‘good’ source of evidence?

Finding evidence - step 2

Can search many of these sources simultaneously using: TRIP (via NLH) OSRS (via NeLM) NKS single search engine(via NLH)?????

Search Strategy

Tertiary

Secondary

Primary

Need to be systematic vs. time & resources

Start from scratch vs. build on previous work

Appraising evidence - step 3

Validity - closeness to the truth, i.e. do we believe it?

Usefulness - clinical applicability, i.e. is it important?

Using efficacy data from clinical trials to

estimate Clinical Effectiveness

Assessing validity

Results of a trial affected by:Chance

Bias Effect of intervention

Judge validity by:Extent to which bias is eliminated

(Randomisation, type of analysis, blinding)

Must also account for chance

Assessed by using questions 1-7 on checklist

Chance, bias, confounding variables

.

COFFEE DRINKING LUNG CANCER

SMOKING

STUDY

CONFOUNDING VARIABLE

Cohort study

PopulationSample

Exposed

Not exposed

Outcome

Outcome

Time

Case control study

Population

CasesExposed

Not exposed

Time

ControlsNot exposed

Exposed

Study

Randomised, controlled trial

PopulationSample

Outcome

Outcome

Experimental intervention

Control intervention

Randomisation

Time

Are the results of the trial valid?

Did the trial address a clearly focused issue? Define the population studied The intervention given The outcomes considered

Is an RCT an appropriate method to answer this question?

How were patients assigned to treatment groups?

What is randomisation?

Why is it important?

What are acceptable methods of randomisation?

What methods of randomisation are considered dubious?

Where to find out details of the randomisation process used?

Note CONSORT statement- recommend that RCTs should report how the allocation sequence was generated and concealed until the patient was

randomised

How were patients assigned to treatment groups?

Could differences between groups have altered the outcome?

Are any differences reported?

Where do you check for yourself?

Was any method used to balance randomisation (stratification)?

Were patients, health workers and study personnel “blind” to treatment?

Why is this important? When is it less important? How is it done?

Want to minimise likelihood of observer bias and Hawthorne effects

Were all the patients who entered the trial properly accounted for at its conclusion?

Was follow-up complete?- if not how was missing data handled?

Were patients analysed in the groups to which they were randomised?

Intention to treat analysis vs. Per protocol or completer analysis

Aside from the experimental investigation, were the two groups treated in the same way?

Usually not such an important issue in placebo-controlled or comparative drug trials but assessing for possible bias introduced by differing intensity of follow up

Did the study have enough participants to minimise the play of chance?

Look for a power calculation Do you agree with their definition of

“important”

How are the results presented

What is being described: proportions of people, a measurement (mean or median differences), a survival curve?

How was it expressed?With proportions see terms like Relative risk reduction, absolute risk reduction, number needed to treat

Do you understand what is being expressed?

Is it clinically significant?

Expressing results

Five years treatment with:

Intervention A reduces cardiac events by 34%

Intervention B causes an absolute reduction of cardiac events of 1.4%

Intervention C increases the rate of event free patients from 95.9% to 97.3%

Intervention D 71 patients need to be treated to avoid one cardiac event

Intervention E reduces cardiac events by 34% with a 6% relative increase in mortality

(Lancet 1994; 343: 1209-1211)

Quantifying benefit

OUTCOME

Yes No

Control intervention a b

Experimental intervention c d

Relative risk reduction – RRR= CER – EER [a/a+b – c/c+d] CER [ a/a+b]

Absolute risk reduction – ARR= CER – EER a/a+b – c/c+d

Number needed to treat – NNT = _1_ARR

Relative risk – RR = EER c/c+d CER a/a+b

Odds ratio – OR = odds of event in intervention group c/d odds of event in control group a/b

Quantifying benefitQuantifying benefit

RCT example - 4S study

Stable angina or myocardial infarction more than

6 months previously

Serum cholesterol > 6.2mmol/l

Excluded patients with arrhythmia's and heart

failure

All patients given 8 weeks of dietary therapy

If cholesterol still raised (>5.5) randomised to

receive simvastatin (20mg > 40mg) or placebo

Outcome death or myocardial infarction (length

of treatment 5.4 years ) were the outcomes

OUTCOME

Dead Alive

Control group (placebo) n = 2223 256 1967

Experimental group (simvastatin) n = 2221 182 2039

Control event rate = 256 = 0.115 (11.5%)2223

Control odds of event = 256 = 0.1301967

Experimental event rate = 182 = 0.082 (8.2%)2221

Experimental odds of event = 182 = 0.0892039

Example – the 4S study

Example – the 4S study

Relative risk reduction CER – EER = 0.115 – 0.082 = 0.29 (29%)RRR CER 0.115

Absolute risk reduction CER – EER = 0.115 – 0.082 = 0.033 (3.3%) ARR

Number needed to treat _1_ = _1_ = 30.1NNT ARR 0.033

Relative risk EER = 0.082 = 0.71 RR CER 0.115

Odds ratio = odds of event in experimental group = 0.089 = 0.69OR odds of event in control group 0.130

   

 

Workshop –revision Assuming a treatment is beneficial and you

are trying to prevent an unpleasant end-point.

Outline what type of values you would expect for the following measures of efficacy: Relative risk reduction Relative risk Odds ratio Absolute risk reduction NNT

NNT EXAMPLES

Streptokinase + aspririn v. placebo (ISIS 2)

prevent 1 death at 5 weeks

20

tPA v. streptokinase (GUSTO trial)

save 1 life with tPA usage

100

Simvastatin v. placebo in IHD (4S study)

prevent 1 event in 5y

15

Treating hypertension in the over-60s

prevent 1 event in 5y

18

Aspirin v. placebo in healthy adults

prevent MI or death in 1 year

500

Intervention Outcome NNT

How precise are the results?

Limitations of the p-value- what does it tell you?

Use of confidence intervals• What are confidence intervals?• What does upper and lower limits tell you?• Would your decision about whether to use

this treatment be the same at the upper and lower confidence intervals?

CHANCE - p = 1 in 20 (0.05). > 1 in 20 (0.051) = not significant < 1 in 20 (0.049) = statistically

significant

CONFIDENCE INTERVALS the range of values between which we could

be 95% confidant that this result would lie if this trial was carried out 100 times (taken as result for general population)

How precise are the results?

Confidence Interval- how to calculate in some

circumstances

The range of values which includes the true population value 95% of the time

e.g. Confidence interval around ARR =

+/- 1.96 CER x (1 - CER) + __EER x (1 - EER)__N Control group N Experimental group

Can the results be applied to the local population?

Look at inclusion and exclusion criteria- are they similar

Are there differences which make this trial irrelevant?

Be pragmatic!!

Were all the clinically important outcomes considered?

Consider outcomes reported from a range of perspectives- individual, family/ carers, policy maker, healthcare professional, wider community

Reports tend to concentrate on efficacy at the expense of harms and quality of life measures (participants and carers?)

Should policy or practice change as a result of the evidence contained in this trial?

Are the likely benefits worth the potential harms and costs? Have you got all the data you need to make

this assessment Can you access any missing data you need How does this intervention compare with other

interventions-and the results of related RCTs (if any)

Also need to consider service implications

Applying results to local practice - step 4

Local policies

Guideline development

Implementing clinical effectiveness and clinical governance agendas

Evaluating performance - step 5

Clinical audit!

Evidence based medicine

Formulate question

Efficiently track Down bestAvailableEvidence

Critically review theValidity and usefulnessOf the evidence

Implement ChangesIn clinical Practice

Evaluate Performance

)Ia Evidence from systematic review of meta-analysis of

randomised controlled trials

Ib Evidence from at least one randomised controlled trial

IIa Evidence from at least one well-designed controlled study without randomisation

IIb Evidence from at least one other type of well-designed quasi- experimental study

III Evidence from well-designed non-experimental descriptive studies such as comparative studies, or case studies

IV Evidence from expert committee reports or opinions and/or clinical experiences of respected authorities

Hierarchy of evidence(used in NICE Guidelines)

Grade A At least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence levels 1a and 1b)

Grade B Well conducted clinical studies but no randomised clinical trials on the topic of the recommendation (evidence levels Iia, IIb, III)

Grade C Expert committee reports or opinions and/or clinical experience of respected authorities. This grading indicates that directly applicable clinical studies are absent (evidence level IV)

Good practice point: recommended good practice based on the clinical experience of the Guideline Development Group

Strength of recommendationsused in NICE Guidelines

Recommendations from the BHS Guideline 1999

Drug therapy should be started in all patients with sustained systolic BP >/= 160mmHg or sustained diastolic BP >/= 100mmHg despite non-pharmacological measures (A)

To reduce overall cardiovascular risk patients should stop smoking (B)

At least two BP measurements should be made at each visit and 4 visits to determine blood pressure (C)

Criticisms of evidence-based medicine

Effective therapies might be rejected on the basis of “absence of evidence” of efficacy rather than “evidence of absence” of efficacy.

“Cook book” medicine

Can take a long time to gather the evidence

When is it appropriate to generalise across populations?

Use of surrogate markers, class effects

Additional criteria in assessing trials claiming therapeutic equivalence

Was the active control previously shown to be effective? Were study patients and outcome variables similar to

those in the original trials that established the efficacy of the active control?

Were both regimens applied in optimal fashion? Was the appropriate null hypothesis tested? Was the equivalence margin specified before the study? Was the trial large enough? Was analysis by intention to treat AND on-treatment? PLUS usual assessment of size and precision of

treatment effect!

REFERENCES CASP Tool www.phru.nhs.uk/casp/resourcescasp.htm

Additional Reading Montori V et al Users’ guide to detecting misleading claims in clinical

research reports BMJ 2004; 329: 1093-1096 Greenhalgh T. How to read a paper: Getting your bearings (deciding

what a paper is about). BMJ 1997; 315: 243-246 Greenhalgh T. How to read a paper: Assessing the methodological

quality of published papers. BMJ 1997; 315: 305-308 Guyatt GH, et al. Users’ Guides to the Medical Literature: II. How to use

an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993; 270: 2598-2601

Guyatt GH, et al. Users’ Guides to the Medical Literature: II. How to use an article about therapy or prevention. B. What are the results and will they help me in caring for my patients? JAMA 1994; 271: 59-63

REFERENCES cont.

Statistics for the non-statisticianI: Different types of data need different statistical

testsGreenhalgh T BMJ 1997; 315: 364-6

II: “Significant” relations and their pitfallsGreenhalgh T BMJ 1997; 315: 422-5

Statistics in small doses- a series of articles available on UKMI web-site (http://www.ukmi.nhs.uk/activities/Research/default.asp?pageRef=27)