Applying Trials and Systematic Reviews to Individual Patients

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Applying Trials and Systematic Reviews to
Individual Patients

• Paul Glasziou
• Centre for Evidence Based Medicine
• University of Oxford

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Overview

• Why is applicability a problem?
• What are the issues?
• How can we improve?
• The 5-step process
• Check on the transferability
• Application to an individual

www.sph.uq.edu.au/CGP/training/CochraneMethodsGrou
p.html
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The problem The Leaks between research
practice
Aware Accept Target Doable Recall Agree
Done
Valid Research
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Variation in Guidelines of AF patients
needing warfarin
Thomson R BMJ 1998316509-13
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The problem of applying trial results
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Should Mr RM buy an electric toothbrush?

• 72 year old pensioner with Parkinsons Disease
• Has gingivitis and frequent caries
• Trials in young healthy folk showing improvements
  in gingivitis scores but not caries.
• Would the electric brush work for him?
• What should he do?

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What did you think?
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Osteoarthritis N-of-1s

• Comparison of
• 1,000mg paracetamol tds
• 400mg ibuprofen tds
• Two weeks x 6
• Outcome diary of pain and stiffness of target
  joint

Paracetamol
NSAID
Pair 1
NSAID
Paracetamol
Pair 2
NSAID
Paracetamol
Pair 3
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N-of-1 overall examples
NSAID responder
NSAID non-responder
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Interventions Levels of Evidence

• N-of-1 Trial
• Systematic review of randomised trials
• A single randomised trial
• Controlled, non-randomised
• Parallel control
• Historical control
• Case-control
• Case-series

Guyatt, JAMA, 2000
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When n-of-1 not possibleThe benefit-harm model
(Lubsen, Tijssen)

• When does benefit outweigh harm?
• Assumptions
• Benefit (rate difference) proportional to event
  rate
• Harm constant over event rate
• Net benefit benefit - harm

Controlled Clinical Trials 10 151S-160S.
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Transferability and applicability of results

• TRANSFERABILITY (across groups)
• What are the benefits and harms?
• Is there predictable variation in the effects?
• How does effect vary with predicted risk?
• APPLICATION (to individual)
• What are the predicted absolute risk reductions
  for individuals?
• Do the benefits outweigh the harms?

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Questions so far?
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(No Transcript)
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1. What are the benefits and harms?

• List all important outcomes
• beneficial and harmful
• Get best estimate (from meta-analysis)
• Summarise in a clinical balance sheet

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Antibiotics for Acute Otitis Media

• For Pain(at 2-7 days)RRR 28

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Clinical Balance Sheet
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All or some responders?
I. Everyone gets small benefit?
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OK Earache Diarrhoea
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2. Are there predictable variations in the
effects?

• Does effect vary by (PICO)
• Patient features, e.g., comorbidity or disease
  features, e.g., stage
• Intervention features e.g., dose/intensity/timing?
  
• Comparator, e.g., placebo, add-on, or active
• Outcome measures, e.g., reliability, duration
• But beware of artefactual causes
• Differences in followup, compliance, measures ,

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Effect Modifiers for AOM

• P impact greater if fever, vomiting?
• Data from 1 trial (Little)
• I no difference between antibiotics
• O outcome for pain varies with time
• No impact in 24 hours

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Subgroup Analysis
Does statin work in those with a stroke history
(Hx)?
(Circulation. 2001103387-392.)
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3. How does effect vary with predicted risk?

• Is Relative Risk constant across low to high risk
  groups?
• Relative Risk is most often constant
• Need to check using
• Plots
• Heterogeneity statistics

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Impact of changing risk
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Rate versus rate plots
LAbbe plot of trials of Warfarin in Atrial
Fibrillation
Treatment group rate
Control group rate
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Which risk measure is most constant?
Analysis of the effect of control rate in 115
meta-analysis Schmid et al Stats in Med 1998
1923-42.
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Possible approaches to applying reviews and trials

• Inclusion/exclusion criteria
• For reviews overlap or combination?
• Subgroup analysis
• Appropriate methods needed
• Cross-design synthesis
• Combining RCT and database evidence
• 5-Steps of Transferability/Applicability
• Benefits versus harms predicted risk
• Glasziou, Irwig BMJ 1995
• OConnell, Glasziou, Hill. NHMRC How to use the
  evidence

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Clinical Balance sheet From trial to Individual
Trial Balance Sheet
Stability and modifiers Of effects across
groups (steps 2 and 3)
Individual features And risk values (step 4 5)
Individual Balance Sheet