How to read an RCT: introduction, workshop, wrap-up

Martin Gallagher

Overview

ChecklistsCONSORT Statement & others

Impt elements to considerRandomisationPoweringBiasSecondary analyses

Exercises Causality and importance Still going on now: ACT and HDF studies

RCT vs non-RCT

Ioannidis, JAMA 2001-45 topics-408 studies (240+168)

Critical appraisal tools

CONSORT GuidelinesConsolidated Standards of Reporting TrialsEndorsed by >50% of core medical journals

• Extensions for different types of trials: Cluster randomised Non-inferiority trials>25 items on checklist

Other appraisal tools

Centre for Evidence Based Medicine (Oxford)2 page documenthttp://www.cebm.net/index.aspx?o=1157

Critical Appraisal Skills Program (CASP) toolPublic Health Resource Unit, NHShttp://www.sph.nhs.uk/sph-files/rct%20appraisal%20tool.pdf

Cochrane risk of bias tool

Were methods for sequence generation reported? Was there adequate allocation concealment? Was there complete outcome data? Was there intention to treat analysis? Was there blinding of participants, investigators, outcomes

assessors, data analysts? Was there selective outcome reporting? Other sources of bias?

• Co-interventions• Commercial

Yes, No, Unclear

Elements of appraisal

1. Did the study ask a clearly focussed question?

2. Was it an RCT and an appropriate design for the question?

3. Were subjects appropriately allocated to int/cont groups?

4. Were subjects/staff/others blinded to allocation?

5. Were all who entered the trail accounted for at the end?

6. Were all subjects followed up and measured the same way?

7. Did the study have enough subjects to minimise the play of chance?

8. How are the results presented and what is the main result?

9. How precise are these results?10. Were all impt outcomes

considered so the results can be applied?

Lack of randomisation concealment

Number of studies

% with significant result

Concealed randomizaton 57 8.8%

Unconcealed randomization 45 24.4%

Non-random assignment [historical or selected controls]

43 58.1%

Chalmers et al. N Engl J Med 1983;309:1358-61

Concealment of allocation

Concealment of allocation

Randomisation

The play of chance Ideally central/independent rather than local

Separate preparation of the agents• Eg: pharmacy, with numbered/coded bottles

Serially numbered, opaque, sealed envelopesBeware: alternation, dates of arrivalNote:

• Permuted blocks• Stratification

Put yourself in the place of the local PI….

Outcome of effective randomisation

Table 1Assurance that the groups were equivalent at baselineAccounts for both measured and (more importantly) unmeasured

confounders

Power

Not a part of all appraisal tools Not many treatments have an effect size (RRR) of >30-

40%A clue to study quality

• Why did they chose it?• What evidence supports such a view?• Is that consistent with my perception of risk in this population?

Bias

Definition:When an estimated measure of frequency or association differs

systematically from the true value.

Random samples will differ from the true population because of random sampling variability

• Bigger the sample, more proximate it is to the underlying pop.

Selection biasConfoundingMeasurement bias

Selection bias

Not usually so much of an issue in RCTs

Except:Through the treatment of missing participants

• Loss to follow up• Other select exclusions (non-compliant, intolerant)

Confounding

A situation in which a measure of the effect of exposure on disease is distorted because of the association of the study factor with other factors that influence the outcome.

Three criteria:An idependent risk factor for the outcome of interestNot an intervening variableUnevenly distributed in study groups

In RCTs should be fixed by adequate randomisationLook to Table 1

Measurement bias

Distortion in the measure of frequency or association due to inaccuracy in measurement

Minimise in RCTs by:Use of placeboKeep measurements ‘blind’ to interventionAvoid differential treatments to the study groups

Blinding

Not always possible Try to blind

ParticipantsCliniciansOutcome assessment

Colorectal surgery example

Secondary analyses

Should not overshadow the primary outcome Greater validity if pre-specified Beware

1/20 chance of statistically significant finding by chance alone• More that are done, more likely to make a ‘significant’ finding

Critical appraisal exercises

Ronco et al: HDF dosing in AKI

Ronco et al: HDF dosing in AKI

Very influential trial, driven the research agenda Heavily cited

Outcome measure?

Single centre, long recruitment time, surgical patient spectrum

Outcomes of subsequent studies?

SAFE Study

SAFE Study

Fundamental question in ICU

Blinding of study treatment?

Tepel: NAC for contrast nephropathy

Tepel: NAC for contrast nephropathy

Very influential and highly cited study

How were they randomised?

Power?

Blinding?Is it impt?

Sulfinpyrazone post MI

Sulfinpyrazone post MI

FDA:We do not believe that either reported outcome can be accepted

for the following reasons:• Assignment of patients often inaccurate and failed to conform to

criteria set forth at the outset• Errors in assignment nearly all favoured the conclusion that

sulfinpyrazone decreased sudden death• Mortality classification system had no clear logic• Reported effect upon overall mortality heavily dependent upon

after-the-fact exclusion from the analysis of certain patients• The exclusions virtually all favoured sulfinpyrazone

SHARP Study

SHARP Study

Change in the primary outcome?

Press release:“During this long trial, the proportion of patients who stopped taking their allocated treatment was about one third, but this was not generally due to side-effects and was the same for both real and dummy treatments. If taken without interruption, however, ezetimibe plus simvastatin could have even larger effects than were seen in SHARP, potentially reducing risk by about one quarter.”

How will/does it change your treatment?

Renal nerve ablation

Renal nerve ablation

Randomisation?Table 1

Blinding?Sham operation?Outcome assessment?

Sevalemer trial

Sevalemer trial

Power?

Blinding?

Bias?

What about patients over 65?

But is it still an issue?

ACTNAC trial from South America2308 patients, randomisationBlinding of study treatment?

HDF StudiesCONTRAST & Turkish studiesDesigned to answer one question but conclude:

• “treatment with…HDF does not seem to offer a survival benefit…However, subgroup analysis suggested benefit among patients treatment with high convection volumes on all cause mortality”

• “Composite for death from any cause and non-fatal CV events is not different between post-dilution on-line HDF and high flux HD. HDF treatment with substitution volume over 17.4L provides better CV and overall survival compared to HD”