Evidence-Based Medicine and Critical Appraisal

Evidence-Based Medicine and Evidence-Based Medicine and Critical AppraisalCritical Appraisal

Ben RehmanBen RehmanDirectorDirector

London Medicines Information ServiceLondon Medicines Information ServiceNorthwick Park HospitalNorthwick Park Hospital

IntroductionIntroduction Evidence-Based MedicineEvidence-Based Medicine

• What is it? What is it? • Why do we need it?Why do we need it?• How do we do it?How do we do it?

Critical appraisal—RCTsCritical appraisal—RCTs Brief introduction to other study designs including Brief introduction to other study designs including

types of pharmacoeconomic studiestypes of pharmacoeconomic studies

• How should we use it?How should we use it? At patient level?At patient level? As part of broader decision making and resource As part of broader decision making and resource

optimisation? optimisation?

Example critical appraisal workshopExample critical appraisal workshop

Evidence-Based Medicine—Evidence-Based Medicine—What is it?What is it?

the conscientious, systematic, explicit, and the conscientious, systematic, explicit, and judicious use of current best evidence in judicious use of current best evidence in patient carepatient care

best research evidence replaces or best research evidence replaces or supports current practice supports current practice

integration of evidence and patient or integration of evidence and patient or population values population values

optimising health gainoptimising health gain• clinical evidenceclinical evidence• pharmacoeconomicspharmacoeconomics

Evidence-Based Medicine—Evidence-Based Medicine—Why do we need it?Why do we need it?

Health professionals face problems Health professionals face problems ensuring best possible patient care:ensuring best possible patient care:• information overloadinformation overload• inadequate traditional sourcesinadequate traditional sources• opinion based approach flawedopinion based approach flawed• disparity between experience and up-to-date disparity between experience and up-to-date

knowledgeknowledge Healthcare systems have finite resourcesHealthcare systems have finite resources But… it’s not a complete panacea!But… it’s not a complete panacea!

Evidence-Based Medicine—Evidence-Based Medicine—How do we do it?How do we do it?

1.1. Form an answerable questionForm an answerable question

2.2. Obtain current best evidenceObtain current best evidence

3.3. Critically appraise the evidenceCritically appraise the evidence

4.4. Integrate appraised evidence with Integrate appraised evidence with clinical expertise and patient valuesclinical expertise and patient values

5.5. Evaluate our successes and failuresEvaluate our successes and failures

Evidence-Based Medicine—Evidence-Based Medicine—How do we do it?How do we do it?

Formulate question

Integrate evidence and values—implement

changes

Evaluate successes and failures—audit

Track down best evidence

Critically review quality

How do we do EBM?How do we do EBM?

1.1. Form an answerable questionForm an answerable question Should contain:Should contain:

• Intervention you are interested inIntervention you are interested in• Patient or population you are interested Patient or population you are interested

in (clearly for drug interventions you in (clearly for drug interventions you require the indication here too)require the indication here too)

• Outcomes you are interested inOutcomes you are interested in So for the example paper, our So for the example paper, our

original question might have been:original question might have been:• Do inhaled corticosteroids improve Do inhaled corticosteroids improve

symptoms in adults with acute symptoms in adults with acute rhinosinusitis? rhinosinusitis?


2.2. Obtain current best evidenceObtain current best evidence Group discussionGroup discussion

• What are good sources of evidence?What are good sources of evidence? What have you used in the past and found What have you used in the past and found

useful?useful?

• What makes them good?What makes them good? What criteria do you apply?What criteria do you apply?

• How can we find good evidence?How can we find good evidence? What portals and sources do we have What portals and sources do we have

available?available?


2.2. Obtain current best evidenceObtain current best evidence Good sources of evidence:Good sources of evidence:


2.2. Obtain current best evidenceObtain current best evidence An appropriate search strategy is An appropriate search strategy is

importantimportant We should be aware of the hierarchy We should be aware of the hierarchy

of evidence:of evidence:• Systematic reviewsSystematic reviews• Meta-analysesMeta-analyses• Randomised-controlled trialsRandomised-controlled trials• Cohort studiesCohort studies


2.2. Obtain current best evidenceObtain current best evidence

Its a guide—it’s not Its a guide—it’s not necessarily this necessarily this simple! Consider:simple! Consider:• A large RCT vs. a A large RCT vs. a

meta-analysis of small meta-analysis of small RCTs?RCTs?

• A meta-analysis of A meta-analysis of observational studies?observational studies?

Hierarchy becomes Hierarchy becomes complicatedcomplicated

The hierarchy of The hierarchy of evidence:evidence:


3.3. Critical appraisalCritical appraisal Consider the following conceptsConsider the following concepts

• Internal validityInternal validity Does it prove what it set out to prove?Does it prove what it set out to prove?

• External validityExternal validity Are the results true in the wider world?Are the results true in the wider world?

• BiasBias Is there systematic error?Is there systematic error?

PopulationSample

Outcome

Outcome

Experimental intervention

Control intervention

Randomisation

Time

PopulationSample

Outcome

Outcome

Experimental intervention

Control intervention

Randomisation

Time


3.3. Critical appraisal—placebo Critical appraisal—placebo controlled RCTs controlled RCTs


3.3. Critical appraisal—placebo Critical appraisal—placebo controlled RCTscontrolled RCTs

Are this study’s results valid?Are this study’s results valid?• Did the trial address a clearly focused issue?Did the trial address a clearly focused issue?

Consider the intervention and the outcomes Consider the intervention and the outcomes consideredconsidered

• Is an RCT an appropriate method to answer Is an RCT an appropriate method to answer this question?this question?

• Was the assignment of patients to treatment Was the assignment of patients to treatment randomised?randomised?

Why is it important?Why is it important? Acceptable vs dubious methods?Acceptable vs dubious methods? Is the process well described?Is the process well described? Was the process concealed?Was the process concealed?



Are this study’s results valid?Are this study’s results valid?• Were the groups similar at the start of the Were the groups similar at the start of the

trial?trial? Could any differences have affected outcome?Could any differences have affected outcome? Was any method used to balance randomisation Was any method used to balance randomisation

(stratification)?(stratification)?• Was follow-up sufficient?Was follow-up sufficient?

LengthLength CompletenessCompleteness

• Was there sufficient power?Was there sufficient power? Were there enough participants to minimise the play Were there enough participants to minimise the play

of chance?of chance?• Was an intention-to-treat analysis performed?Was an intention-to-treat analysis performed?



Are the results of this individual study Are the results of this individual study important for us?important for us?• Define the population studiedDefine the population studied

Inclusion and exclusion criteriaInclusion and exclusion criteria

• EndpointsEndpoints Measurement of outcomeMeasurement of outcome

• Clinical relevanceClinical relevance• Surrogate and composite markersSurrogate and composite markers• Validity Validity

Primary vs. secondaryPrimary vs. secondary

• Balance of beneficial outcomes against side-Balance of beneficial outcomes against side-effectseffects

Are the results of this individual study Are the results of this individual study important for us?important for us?• What is the magnitude of the treatment effect?What is the magnitude of the treatment effect?

How is it described?How is it described?• Proportions of people, a measurement (mean or Proportions of people, a measurement (mean or

median differences), a survival curve?median differences), a survival curve? How is it expressed?How is it expressed?

• With proportions see terms like relative risk reduction, With proportions see terms like relative risk reduction, absolute risk reduction, number needed to treatabsolute risk reduction, number needed to treat

• Is what is being expressed clear?Is what is being expressed clear?• Is it clinically significant?Is it clinically significant?





Definitions for measures of association and Definitions for measures of association and effectivenesseffectiveness• Control event rateControl event rate

the rate at which an outcome occurs in the control populationthe rate at which an outcome occurs in the control population

• Experimental event rateExperimental event rate the rate at which an outcome occurs in the experimental populationthe rate at which an outcome occurs in the experimental population

• Absolute risk (AR)Absolute risk (AR) Probability an individual will experience a specified outcome during a Probability an individual will experience a specified outcome during a

specified periodspecified period Range of 0 to 1, or expressed as a percentageRange of 0 to 1, or expressed as a percentage

• Relative risk (RR)Relative risk (RR) How many times more likely (RR > 1) or less likely (RR < 1) an event How many times more likely (RR > 1) or less likely (RR < 1) an event

is to happen in one group compared with another is to happen in one group compared with another

• Absolute risk reduction (ARR)Absolute risk reduction (ARR) Absolute difference in risk between experimental and control groups Absolute difference in risk between experimental and control groups

• Relative risk reduction (RRR)Relative risk reduction (RRR) Proportional reduction in risk between experimental and control Proportional reduction in risk between experimental and control

participants in a trial participants in a trial

Definitions for measures of association and Definitions for measures of association and effectivenesseffectiveness• Number needed to treat (NNT)Number needed to treat (NNT)

A measure of treatment effectiveness A measure of treatment effectiveness Measures the people who need to be treated with an intervention Measures the people who need to be treated with an intervention

over a period of time to prevent an additional adverse outcome or over a period of time to prevent an additional adverse outcome or achieve an additional beneficial outcome achieve an additional beneficial outcome

Reciprocal of ARRReciprocal of ARR • Odds ratio (OR)Odds ratio (OR)

Also a measure of treatment effectiveness Also a measure of treatment effectiveness Likelihood of an event happening in the experimental group Likelihood of an event happening in the experimental group

compared to the control groupcompared to the control group Closer the OR is to one, smaller the difference in effect between Closer the OR is to one, smaller the difference in effect between

the experimental intervention and the control intervention. the experimental intervention and the control intervention. If OR greater than 1, effects of the treatment are more than those If OR greater than 1, effects of the treatment are more than those

of the control; OR less than 1, effects of treatment less than those of the control; OR less than 1, effects of treatment less than those of the control. of the control.

Effects being measured may be adverse (e.g. death or disability) or Effects being measured may be adverse (e.g. death or disability) or desirable (e.g. survival). desirable (e.g. survival).

If events rare OR analogous to relative risk (RR); as event rates If events rare OR analogous to relative risk (RR); as event rates increase the OR and RR divergeincrease the OR and RR diverge





Absolute vs. relative risk reduction as Absolute vs. relative risk reduction as measures—an examplemeasures—an example• Pros and cons of each measurePros and cons of each measure

Clinical significance?Clinical significance? Proportional difference?Proportional difference? Ease of interpretation?Ease of interpretation?

RCT example—4S studyRCT example—4S study• Stable angina or myocardial infarction more Stable angina or myocardial infarction more

than 6 months previouslythan 6 months previously• Serum cholesterol > 6.2mmol/lSerum cholesterol > 6.2mmol/l• Excluded patients with arrhythmia's and heart Excluded patients with arrhythmia's and heart

failurefailure• All patients given 8 weeks of dietary therapyAll patients given 8 weeks of dietary therapy• If cholesterol still raised (>5.5) randomised to If cholesterol still raised (>5.5) randomised to

receive simvastatin (20mg > 40mg) or placeboreceive simvastatin (20mg > 40mg) or placebo• Outcome death or myocardial infarction (length Outcome death or myocardial infarction (length

of treatment 5.4 years ) were the outcomesof 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

RCT example—4S studyRCT example—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



NNT examples—when should we adopt therapy?NNT examples—when should we adopt therapy?

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

InterventionIntervention OutcomeOutcome NNNNTT

Statistical approaches to uncertaintyStatistical approaches to uncertainty• Why do they exist?Why do they exist?

Cannot include all individuals in a population Cannot include all individuals in a population in trialin trial

Need to quantify uncertaintyNeed to quantify uncertainty

• p values and confidence intervals are p values and confidence intervals are the measures used, but what are they the measures used, but what are they and what are the differences?and what are the differences?



Statistical approaches to uncertaintyStatistical approaches to uncertainty• p valuesp values

assess the significance of the difference between assess the significance of the difference between a sample estimate and a hypothesised valuea sample estimate and a hypothesised value

tell us the probability that an observed effect tell us the probability that an observed effect occurred by chance if in truth there is no effectoccurred by chance if in truth there is no effect

But… doesn’t quantify the size of an effect, nor But… doesn’t quantify the size of an effect, nor the directionthe direction

p<0.05 p<0.05 → commonly reject null hypothesis→ commonly reject null hypothesis ideally p<<<0.05 and trial reports the actual ideally p<<<0.05 and trial reports the actual

valuevalue



Statistical approaches to uncertaintyStatistical approaches to uncertainty• Confidence intervalsConfidence intervals

Range of values around the sample estimate Range of values around the sample estimate (i.e. the value found in the study)(i.e. the value found in the study)

The range has specified probability (usually The range has specified probability (usually 95%) so CI acts as hypothesis test for the 95%) so CI acts as hypothesis test for the rangerange

Should be seen with most measures of Should be seen with most measures of associationassociation



Statistical approaches to uncertainty—Statistical approaches to uncertainty—please remember!please remember!• statistical significance statistical significance ≠≠ clinical significance… clinical significance…

what is actually being measured?what is actually being measured?• sample size is still importantsample size is still important

larger sample = less uncertainty = narrower CI larger sample = less uncertainty = narrower CI and smaller observed effect considered significantand smaller observed effect considered significant

• there can still be errorthere can still be error rejecting null hypothesis when it’s true (type 1)rejecting null hypothesis when it’s true (type 1) Not rejecting the null hypothesis when it’s false Not rejecting the null hypothesis when it’s false

(type 2)(type 2)



Increasingly used by pharma. Increasingly used by pharma. Designed to show a new treatment is Designed to show a new treatment is

not inferior to standard treatment by not inferior to standard treatment by a predefined clinically acceptable a predefined clinically acceptable endpointendpoint

Rely on assumptions that can be Rely on assumptions that can be hard to validatehard to validate


3.3. Critical appraisal—RCTs of Critical appraisal—RCTs of therapeutic equivalencetherapeutic equivalence

Trials based on the concept that:Trials based on the concept that:• new treatment is non-inferiornew treatment is non-inferior• but would exhibit therapeutic efficacy if but would exhibit therapeutic efficacy if

a placebo controlled RCT could/was a placebo controlled RCT could/was performedperformed

• new treatment offers ancillary benefitsnew treatment offers ancillary benefits Note: non-inferior so efficacy Note: non-inferior so efficacy

determined by effect against placebo determined by effect against placebo not comparatornot comparator



Estimation of non-inferiority marginEstimation of non-inferiority margin• Use statistical and clinical reasoning to Use statistical and clinical reasoning to

determine what is non-inferiordetermine what is non-inferior• If there are a variety of placebo If there are a variety of placebo

controlled RCTs this will be similar to a controlled RCTs this will be similar to a meta-analysis meta-analysis

Non-inferiority margin determined as Non-inferiority margin determined as a fraction (f) and specifies an a fraction (f) and specifies an acceptable magnitude for treatment acceptable magnitude for treatment effect that must be preservedeffect that must be preserved



What to look forWhat to look for• These trials should be designed in a manner These trials should be designed in a manner

consistent with the historical placebo-controlled consistent with the historical placebo-controlled trialstrials

• The active comparator should be well established The active comparator should be well established with predictable quantifiable, and consistent effectswith predictable quantifiable, and consistent effects

• What constitutes non-inferiority should be What constitutes non-inferiority should be determined prior to initiation of trialdetermined prior to initiation of trial

• Protocol deviations and poor adherence may have a Protocol deviations and poor adherence may have a larger impact on quality than in conventional trialslarger impact on quality than in conventional trials

• Analysis should be by intention-to-treat AND on-Analysis should be by intention-to-treat AND on-treatment, and should also report absolute AND treatment, and should also report absolute AND relative effects relative effects



So when appraising these trials ask So when appraising these trials ask yourself:yourself:• Was the active control previously shown to be effective?Was the active control previously shown to be effective?• Were study patients and outcome variables similar to Were study patients and outcome variables similar to

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

• Were both regimens applied in optimal fashion?Were both regimens applied in optimal fashion?• Was the appropriate null hypothesis tested?Was the appropriate null hypothesis tested?• Was the equivalence margin specified before the study?Was the equivalence margin specified before the study?• Was the trial large enough?Was the trial large enough?• Was the analysis intention-to-treat AND on-treatment, Was the analysis intention-to-treat AND on-treatment,

and should also report absolute AND relative effects?and should also report absolute AND relative effects?• PLUS usual assessment of size and precision of PLUS usual assessment of size and precision of

treatment effect!treatment effect!



Many other types of study in the Many other types of study in the hierarchy e.g. systematic reviews, hierarchy e.g. systematic reviews, case-control studies, cohort studiescase-control studies, cohort studies

Details of appraisal not included Details of appraisal not included today but worth thinking about most today but worth thinking about most in terms of:in terms of:• Internal validityInternal validity• BiasBias• External validityExternal validity


3.3. Critical appraisal—other Critical appraisal—other study designsstudy designs



Cohort studyCohort study

PopulationSample

Exposed

Not exposed

Outcome

Outcome

Time

Case control studyCase control study



Population

CasesExposed

Not exposed

Time

ControlsNot exposed

Exposed

Study

Important in decision makingImportant in decision making Considers costs and consequences of Considers costs and consequences of

alternate courses of actionalternate courses of action Scope depends on level of decision Scope depends on level of decision

making they informmaking they inform Costs always measured the same Costs always measured the same

way (although scope may vary), way (although scope may vary), measurement of consequence varies measurement of consequence varies according to study typeaccording to study type


3.3. Critical appraisal—what is Critical appraisal—what is economic evidence?economic evidence?

Cost minimisation analysesCost minimisation analyses• analyse difference in costs where there analyse difference in costs where there

is no difference in outcomeis no difference in outcome• narrow focusnarrow focus

Cost-effectiveness analysesCost-effectiveness analyses• outcome expressed in natural units (e.g. outcome expressed in natural units (e.g.

validated single marker)validated single marker)• again fairly narrow scope—generally 2 again fairly narrow scope—generally 2

interventions for single indicationinterventions for single indication



Cost-utility analysesCost-utility analyses• Costs and consequences but Costs and consequences but

consequence measured as utility consequence measured as utility • Utility = a value of health state rather Utility = a value of health state rather

than a natural marker (usually QALY)than a natural marker (usually QALY)• Can compare incongruent interventionsCan compare incongruent interventions• Used by NICE:Used by NICE:

Consider outcome in terms valuable to Consider outcome in terms valuable to patients i.e. life expectancy and qualitypatients i.e. life expectancy and quality

Uses a standard measure (utility)Uses a standard measure (utility) Comprehensive consideration of costsComprehensive consideration of costs



Cost-benefit analysesCost-benefit analyses• Broadest possible scope!Broadest possible scope!• Allocation of resources between Allocation of resources between

difference sectors of economydifference sectors of economy• Maximising social welfareMaximising social welfare• Rely on assigning cost to healthcare Rely on assigning cost to healthcare

intervention—incredible complicated in intervention—incredible complicated in practice, particular in NHS where practice, particular in NHS where individuals don’t pay at point of deliveryindividuals don’t pay at point of delivery



A lot is published! But texts I’ve found A lot is published! But texts I’ve found useful include:useful include:• Straus SE, Richardson WS, Paul Glasziou, Haynes RB. Straus SE, Richardson WS, Paul Glasziou, Haynes RB.

Evidence-based Medicine: How to Practice and Teach Evidence-based Medicine: How to Practice and Teach EBM, Third Edition. Churchill Livingstone: Edinburgh, EBM, Third Edition. Churchill Livingstone: Edinburgh, 20052005

• Guyatt GH, et al. Users’ Guides to the Medical Literature: Guyatt GH, et al. Users’ Guides to the Medical Literature: II. How to use an article about therapy or prevention. A. II. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993; 270: Are the results of the study valid? JAMA 1993; 270: 2598-26012598-2601

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

• Evidence Based Medicine (EBM) journal notebook seriesEvidence Based Medicine (EBM) journal notebook series—available online —available online

• Clinical evidence online. Excellent terminology glossary Clinical evidence online. Excellent terminology glossary and explanationsand explanations


3.3. Critical appraisal—further Critical appraisal—further readingreading

Is our patient so different from those Is our patient so different from those in the study that its results cannot in the study that its results cannot apply?apply?

Is the treatment feasible for us?Is the treatment feasible for us? What are the potential benefits and What are the potential benefits and

harms from therapy?harms from therapy? Are our patients values and Are our patients values and

preferences for both the outcome preferences for both the outcome and the side-effects we may cause?and the side-effects we may cause?

How do we use EBM?How do we use EBM?

4.4. Applying results of research to Applying results of research to our individual patientour individual patient

Briefly… some food for thought!Briefly… some food for thought! Want maximum benefit for minimum cost! Want maximum benefit for minimum cost!

i.e. want to optimise utilityi.e. want to optimise utility Decision analysis tries to understand and Decision analysis tries to understand and

improve decision making in a rational way improve decision making in a rational way in the presence of uncertaintyin the presence of uncertainty

Decision making for a population will Decision making for a population will include:include:

Probabilistic dataProbabilistic data Value judgementsValue judgements Clinical considerationsClinical considerations Economic considerationsEconomic considerations


4.4. How should clinical evidence How should clinical evidence inform wider decision making? inform wider decision making?

More food for thought!More food for thought! Classic decision theory suggests:Classic decision theory suggests:

• Known alternatives with known Known alternatives with known probability distributionsprobability distributions

• Ability to maximise outcome based on Ability to maximise outcome based on thisthis

But, world is large and complex and But, world is large and complex and knowledge is imperfect!knowledge is imperfect!


4.4. How should clinical evidence How should clinical evidence inform wider decision making?inform wider decision making?

Some more food for thought…Some more food for thought… Bounded rationality approach relaxes Bounded rationality approach relaxes

assumption of perfect knowledgeassumption of perfect knowledge Choose the option or course of action Choose the option or course of action

based on most important current based on most important current needsneeds

Commentators suggest NICE use Commentators suggest NICE use bounded rationality approachbounded rationality approach


4.4. How should clinical evidence How should clinical evidence inform wider decision making?inform wider decision making?

Example critical appraisal of RCT Example critical appraisal of RCT workshopworkshop

The CASP toolThe CASP tool• available at available at

http://www.phru.nhs.uk/Pages/PHD/resohttp://www.phru.nhs.uk/Pages/PHD/resources.htmurces.htm

• Divide up into groups and use the tool to Divide up into groups and use the tool to appraise the trial:appraise the trial:Treating acute rhinosinusitis: Comparing Treating acute rhinosinusitis: Comparing efficacy and safety of mometasone efficacy and safety of mometasone furoate nasal spray, amoxicillin, and furoate nasal spray, amoxicillin, and placeboplacebo

Example critical appraisal of RCT Example critical appraisal of RCT workshopworkshop

Feedback from groups about the trialFeedback from groups about the trial

RCT RCT workshopworkshop

And finally… And finally… what do what do others think others think about this about this study?study?

Evidence-Based Medicine and Critical Appraisal

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