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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.