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”
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