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Applying Trials and Systematic Reviews to Individual Patients

Applying Trials and Systematic Reviews to Individual Patients. Paul Glasziou & Sharon Sanders University of Queensland for Cochrane Applicability & Recommendations Methods Group. www.sph.uq.edu.au/CGP/training/CochraneMethodsGroup.html. The Trial patients. The Trial report. The actual

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Applying Trials and Systematic Reviews to Individual Patients

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  1. Applying Trials and Systematic Reviews to Individual Patients Paul Glasziou & Sharon Sanders University of Queensland for Cochrane Applicability & Recommendations Methods Group

  2. www.sph.uq.edu.au/CGP/training/CochraneMethodsGroup.html

  3. The Trial patients The Trial report The actual patients The problem of applying trial results

  4. Who does this trial apply to? • Yes, the trial showed it worked • But will it work as well in THIS patient? • A 30% relative risk reduction (RRR) means • It “worked” in 30% • It didn’t work in 70%(and they were at risk of adverse outcomes) • And what is the importance of it “working” for THIS patient?

  5. Should Mr RM buy an electric toothbrush? • 72 year old pensioner with Parkinson’s Disease • Has gingivitis and frequent caries • Trials in young healthy folk showing improvements in gingivitis scores but not caries. • What should he do?

  6. Possible approaches to who a trial applies to? • Effect size (larger will apply more) • Look at biological mechanisms to predict who it might or might not work • Is there study evidence to support this? • How do trial population compare to patient characteristics • How DOES THE Risk COMPARE?

  7. 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?

  8. Example of Toothbrush 5-steps • See in your papers

  9. Rofecoxib, Celecoxib, and Paracetamol in Osteoarthritis of the Knee • Design: Randomized, parallel-group, double-blind trial, • Patients: 382 patients 40+ yrs with OA of the knee • Interventions: • Rofecoxib, 12.5 mg/d OR 25 mg/d; • Celecoxib, 200 mg/d; OR • acetaminophen, 4,000 mg/d • Results: Over 6 weeks, rofecoxib, 25 mg/d, better for • night pain (P<.002 vs celecoxib and P=0.006 vs acetaminophen and P=0.02 vs rofecoxib, 12.5 mg/d), • composite pain subscale (P.03 vs all other treatments), • stiffness subscale (P=0.04 vs celecoxib and acetaminophen), • physical function subscale (P=0.001 vs acetaminophen). • Global responses over 6 weeks showed a similar pattern. Geba GP, et al JAMA. 2002 ;287:64-71.

  10. II. A few get a larger benefit? All or some responders? I. Everyone gets small benefit?

  11. 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

  12. N-of-1: overall & examples NSAID responder NSAID non-responder

  13. 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

  14. When n-of-1 not possible:The 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.

  15. 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?

  16. Tutorial • Look at the systematic review • Do you have any medical questions? • Don’t read it all !! • Try to extract the information to complete the first step transferability checklist

  17. 1. What are the benefits and harms? • List all potential benefits • List all potential harms • Estimate from (meta-analysis) of best available of evidence • Relative effect • Absolute effect

  18. Step 1: benefits & harms

  19. “Safety” in systematic reviews Ernst, Pittler, BMJ 2001; 323:546

  20. 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?

  21. The Trial report The problem of applying trial results The Trial patients The actual patients

  22. 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 , …

  23. Tutorial • Look at the systematic review again • Try to extract the information to complete the second step transferability checklist • P • I • C • O

  24. CHD Death + Non-fatal MI* LIPID: Major Subgroups of Patient Features

  25. Group 1 Group 2 Combined 0.5 1.0 1.5 Relative Risk Are the groups different? DO Test for difference DON’T Test each separately

  26. Step 2: effect modifiers

  27. 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

  28. When n-of-1 not possible:The 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.

  29. Warfarin in non-valvular Atrial Fibrillation: the trial evidence

  30. 3. How does effect vary with predicted risk? Trials of Warfarin in Atrial Fibrillation

  31. Line of equality Constant relative reduction Rate versus rate plots L’Abbe plot of trials of Warfarin in Atrial Fibrillation Treatment group rate Control group rate

  32. Line of equality Constant relative reduction Constant absolute risk reduction Rate versus rate plots L’Abbe plot of trials of Warfarin in Atrial Fibrillation Treatment group rate Control group rate

  33. 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.

  34. Trial patients Typical patients For biological effect & transferability For clinical decision making 4. How do absolute benefits and harms vary with risk/severity?

  35. Risk Factors* 0 1 2 or 3 Frequency 42% 46% 12% *hypertension, recent CCF, previous thromboembolism, Benefit versus HarmClinical predictors of stroke Benefit = 73% RRR 1 ICH death = 4 strokes Harm = 0.01 deaths 1 ICH death = 1 stroke

  36. Guidelines for Atrial Fibrillation:Evidence + Recommendations Recommendations Risk/Yr 1% 3% >7% NNT 133 50 <20 No Risk Factors* - use aspirin only One Risk Factor - individualise treatment Two or more Risk Factors - anticoagulation strongly recommended * The 5 Risk Factors are: hypertension, recent CCF, previous thromboembolism, LV dysfunction, atrial size

  37. Guidelines: proportion of patients with AF needing anti-coagulation Thomson R BMJ 1998;316:509-13

  38. Trial inclusion/exclusion criteriaAn appropriate basis for transferability? • Inclusion/exclusion criteria not (usually) aimed at transferability but at: • improving study power • choose high risk groups • minimise death from other causes • ensure good compliance • maximising safety • exclude if any possible adverse effects Some excluded sub-groups may have net benefit Some included sub-groups may have net harm

  39. SUMMARY: data for applying the results of controlled trials Values of Benefits, Harms Your patient, Trials patients Relative Risk Benefits, Harms systematic review of RCTs Individual Clinical Decision Patient’s Expected Event Rate Predictive model from Cohort study

  40. sun21.imbi.uni-freiburg.de/mailman/listinfo/applicabilitygroupsun21.imbi.uni-freiburg.de/mailman/listinfo/applicabilitygroup

  41. GOOD • Toothbrush example nice • (but maybe fill out form!!) • Do DIFFERENTLY • Do reading before session • More time; more coffee • Interested in steps 4 & 5 • Stream groups

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