1. Applying Trials and Systematic Reviews to Individual Patients Paul Glasziou Centre for Evidence Based Medicine University of Oxford

2. 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/CochraneMethodsGroup.html

3. The problem: The “Leaks” between research & practice Aware Accept Target Doable Recall Agree Done Valid Research

4. Thomson R BMJ 1998;316:509-13 Variation in Guidelines: % of AF patients “needing” warfarin

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

6. 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. Would the electric brush “work” for him? What should he do?

7. What did you think?

8. 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 NSAIDParacetamol NSAID Paracetamol Pair 1 Pair 2 Pair 3

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

10. 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

11. *Controlled Clinical Trials; 10: 151S-160S. 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

12. Transferability and applicability of results A.TRANSFERABILITY (across groups) 1.What are the benefits and harms? 2.Is there predictable variation in the effects? 3.How does effect vary with predicted risk? B.APPLICATION (to individual) 4.What are the predicted absolute risk reductions for individuals? 5.Do the benefits outweigh the harms?

13. Questions so far?

15. 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”

16. Antibiotics for Acute Otitis Media  For Pain (at 2-7 days) RRR = 28% C Cates: www.nntonline.net

17. Clinical Balance Sheet Outcome% in Placebo RRRARR/ 100 comments Pain <1 day38%00 Pain 2-7days14%28%5Greater if fever, vomiting Mastoiditis0?-1 case in 2,250 (AB grp) “Glue ear” 3M26%-- Adverse effect11%55%5Vomiting, rash, diarrhoea

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

19. OK Earache Diarrhoea

20. 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, …

21. 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;

22. Subgroup Analysis Does statin work in those with a stroke history (Hx)? (Circulation. 2001;103:387-392.)

23. 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

24. For biological effect & transferability For clinical decision making Impact of changing risk Trial patients Typical patients

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

26. Which risk measure is most constant? Measure% varying with control group risk Odds Ratio13% Relative Risk14% Risk Difference31% Analysis of the effect of control rate in 115 meta-analysis Schmid et al Stats in Med 1998: 1923-42.

27. Possible approaches to applying reviews and trials 1.Inclusion/exclusion criteria For reviews: overlap or combination? 2.Subgroup analysis Appropriate methods needed 3.Cross-design synthesis Combining RCT and “database” evidence 4.5-Steps of Transferability/Applicability Benefits versus harms; predicted risk  Glasziou, Irwig BMJ 1995  O’Connell, Glasziou, Hill. NHMRC How to use the evidence

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