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Evidence-basedMedicine
The randomized controlled trial: A
graphic framework
Facilitator: Dr Rohan Maharaj
2011
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Objectives
To provide a simple framework forremembering the RCT
The student will have an easy way ofunderstanding where biases can affectthe RCT
To learn about critically appraising apaper based on a RCT
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Competencies
Create a PICO question on therapy from agiven clinical scenario
List the database resources of full-text paperson RCTs
Search, identify and retrieve a full-text paperusing the RCT methodology
Critically appraise an RCT
Defend your clinical decision based on theprevious steps
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Competencies
List and describe the major elements of theRCT
Conduct the basic statistical analysis of theresults of an RCT
Describe the common biases and list thepotential weaknesses of the RCT
Use all the above in your final decision on thequality of the RCT and whether or not you willincorporate the information into your practice
or reject the results of the RCT
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Developing a question for aclinical intervention
Patient Intervention Comparison Outcome
Tips for
building
How would I
describe asimilar
patient of
mine?
Which
interventionam I
considering
What is the
main alternativeto compare with
the alternative?
What can I
accomplish?
Example: In a 18 yearold female
with exposure
to chickenpox
..does theuse of a
chickenpox
vaccine.
.compared withno vaccine..
lead topreventing an
attack of
chickenpox in the
18 year old
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LocatingTherapy
No Result
Cochrane
PubMed Clinical Queries
Prognosis Testing
Etiology Practice guidelines
Systematic reviews
Therapy
Primary Search
No ResultsDARE
Control Trials Register
Othertype of question
MeSH termsDARE: Database of Abstracts of Review of Effects
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Steps in a RCT
1. Sampling and selection
2. Randomization
3. Application of intervention(s) / placebo
4. Outcomes
5. Analysis
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5Step 1
2
3
4
Flow diagram for a RCT
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Step 1: Selection andsampling issues
What sort of patients were included?
Were they from PC or a Referral
centre?
Do the exclusion and inclusion criteriamake sense?
Were consecutive patients recruited?
These considerations affect the externalvalidity and generalisability of the study.
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51
2
3
4
Flow diagram for a RCT: Internal validity
Exclusions
Externalvalidity
Internal validity
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Step 2: Randomization
Are the baseline characteristics of thestudy groups similar?
If the groups are small, then there is therisk that discrepancies occurred bychance.
Concealment of allocation
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51
2
3
4
Flow diagram for a RCT: Sources of Bias
Exclusions
Externalvalidity
Internal validity
Co-intervention
Cross-over
Contamination
Count/ Loss
to follow-up
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Step 3:Sources of bias in RCTs
Co-intervention
Cross-over
Contamination
Compliance
Count (Loss to follow-up)
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Contamination
Contamination-The inadvertentapplication of the intervention tomembers of the control group, or
inadvertent failure to apply theintervention to the members of theexperimental group. E.g. control andexperimental patients share theirmedications or both groups end uphaving an educational intervention.
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Crossover
Occurs when both patients andphysicians know what medication thepatient is receiving and also know what
are the alternative treatments. E.g.when patients in a less aggressivetreatment arm crossover into a more
aggressive treatment.
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Co-Interventions
Introduce bias if they are applieddifferentially to the trial arms- E.g. In atrial of Daflon 500 for treatment of
venous ulcers, adjunctive treatmentssuch as elevation of the limb was notdescribed. Could some patients have
had elevation and others none?
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Step 4: Outcomes
Are the chosen outcomes reasonable?
Were all important outcomes
considered?
The importance of blinding- Single, double & triple blinding
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Step 5: Analysis
Intention to treat analysis
Magnitude of effect- CER, EER, RR,
RRR, ARR, NNT, OR, precision(confidence levels), and sub-groupanalysis
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Step 5: Analysis- Count
Intention-to-treat:
Every participant analysed according to hisrandomised group regardless of whether he
received the assigned intervention or not for whatever reason.
Preserves the value of randomisation.
May underestimate full effect of the treatment, butguards against more important causes of biasedresults.
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Intention to Treat Analysis: An example
30 lost
40 lost
970
960
1000
1000
35 patients die/970=3.6%
20 patients die/960= 2.1%
Intervention
Control
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Intention to Treat Analysis: An example
30 lost
40 lost
970
960
1000
1000
35 patients die/970=3.6%
20 patients die/960= 2.1%
Intervention
Control
ITT ANALYSIS:
Assume patients alive35/1000=3.5%
ITT ANALYSIS:Assume patients died60/1000=6.0%
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Step 5: Analysis- Compliance
Per protocol analysis: Includes only those participants who took a certain
proportion of the intervention/completed a certainproportion of visits etc.
But, participants who adhere may be different fromdrop-outs in ways that are related to the outcomeof interest.
Some trials evaluate results using bothmethods.
Similar results increase the confidence in theconclusions of the trial.
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Step 5: Analysis
Subgroup analyses:-Comparisons between randomised groups in a
subset of the trial cohort.
Prone to misleading results:
-Subgroups are smaller, thus there may not besufficient power to find important differences.
-When based on postrandomisation factors, theydo not preserve the value of randomisation,often producing misleading results.
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Step 5: Analysis: size of treatment effect
(Simplest case: 2x2 table)
Intervention ControlOutcome Total
Yes
No
Risk of
outcome
p
sr
q
n
Risk with
therapy Y
Y= p/(p+r)
Baseline risk X
X = q/(q+s)
Relative Risk (RR): Y/X
Relative risk reduction (RRR): [(1-RR)]*100 or [ (X-Y)/X] *100
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Step 5: Analysis
Absolute Risk Reduction: X-Y
Odds Ratio:
Relative risk of outcome in intervention
Relative risk of outcome in control
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The FIT trial
The reduction of hip fractures was 49%after 36 months follow up.
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The FIT trial
The Fracture Intervention Trial (FIT) of2027 postmenopausal women at 11
centers in the US, aged 55-80, withBMD 0.68g/cm and with previous X-Ray evidence of vertebral fracture,
studied the effect of aledronate inpreventing a fracture from occurring inthe hip.
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The FIT trial: Results
Placebo Intervention Total
Hipfracture
22 11 33
No
Fracture
983 1011 1994
Total 1005 1022 2027
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The FIT trial: Results
Control event rate (CER) of 22/1005(2.19%)
Experimental event rate (EER) of11/1022 (1.08%)
The RR= 1.08/2.19, approximately 49%.
RRR= 100 - RR/100 = 51%
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Relative risk (RR) or relative riskreduction (RRR).
RR and RRR can lead to false
expectations among clinicians and
patients regarding the potential impactof the treatment in individual patients.
RR can appear large even if the eventrates in the RCT are small
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The FIT trial: Results
The absolute risk reduction (ARR) wasCER-EER= 2.19%-1.08%=1.11%.
The NNT is 100/1.11= 90. That is weneed to treat 90 patients for 36 monthsto prevent one additional fracture.
COPE: the cost to a health system toprevent one fracture is 90x$10 (TTD)x365x3=$985 500.
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Hypothetical studies measuring theresults of placebo vs. treatment
CER EER RRR NNT
TRIAL A 50% 25% 50% 4
TRIAL B 0.02% 0.01% 50% 10 000
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Step 5: Analysis: Precision
Relative risk, Relative Risk Reduction,OddsRatios: Point estimate.
95% Confidence Interval (CI).
0
95%
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Step 5: Analysis: Precision
Effect of sample size: as sample size C.I. becomes smaller & ones confidence in
the results .
Positive study conclusion that treatment is effective.
Examine lower limit of C.I. of RRR is it acceptable for you?
Negative study conclusion that treatment in not moreeffective.
Examine upper limit of C.I. OF RRR is it acceptable for
you?
Calculate 95% CI of RR or RRR if Standard Error (SE) of RR orRRR is given by: 95% CI = RRR (or RR) [2*SE (RRR or RR)]
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Step 5: Analysis
NNT- number need to treat
1/ARR
The number of patients you need totreat to prevent or promote oneadditional event.
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Limits
A continuous outcome e.g. BP or painscale
Comparison of old treatment vs. new
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Critical appraisal of arandomized controlled trial
investigating a new therapy orcomparing a new therapy with
an older one
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3 Headings
Are the results of the study valid?
What were the results?
Will the results help me in caring for mypatients?
A h l f h d
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Are the results of the studyvalid?
Primary guides
Was the assignment of patients to
treatments randomized? Were all patients who entered the trial
accounted for and attributed at its
conclusion?
A h l f h d
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Are the results of the studyvalid?
Secondary guides
Were patients, health workers, and
study personnel blind to treatment?
Were the groups similar at the start ofthe trial?
Aside from the experimentalintervention were all groups treatedequally?
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What were the results?
How large was the treatment effect?
How precise was the estimate of the
treatment effect?
Will h l h l i
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Will the results help me incaring for my patients?
Can the results be applied to my patientcare?
Were all the important clinical outcomesconsidered?
Are the likely treatment benefits worth
the potential harms and costs?
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Conclusion
RCT
Graphic model
Critical appraisal criteria for assessing apaper which employs a RCT
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References
Attia J and Page J. A graphic frameworkfor teaching critical appraisal ofrandomized controlled trials. EBMMay/June 2001;6:68-69.
Maharaj RG. Developing an evidence-based Caribbean practice: NNT.Postgraduate Doctor (Caribbean);March/April 2005;21(2):36-42.
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