Applying Trial Results to Individual Patients Paul Glasziou Centre for Evidence Based Medicine University of Oxford

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?

Individualizing treatment  For some chronic conditions: N-of-1 trials  Patient’s own randomised trial,  Patient can choose own measures & interpret!  For most other problems: Individualise predicted benefits and harms Integrate the patient’s preferences

N-of-1 trials (1932)  Paul Martini suggests Multiple crossovers Use of Placebos Establish baseline Focus on individual Methodenlehre der Therapeutischen Untersuchung, 1932,

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

N-of-1: overall & examples NSAID non-responder NSAID responder Paracetamol has higher pain Nikles CJ, Yelland M, Glasziou PP, Del Mar C. Am J Ther Jan-Feb;12(1):92-7.

N-of-1 PPI vs H2RA Of 27 patients 14 omeprazole (PPI) was better 6 ranitidine (H2RA) was better 5 equality 2 neither drug recommended

Levels of Evidence Individualisation would be ideal 1.N-of-1 Trial 2.Systematic review of randomised trials 3.A single randomised trial 4.Controlled, non-randomised Parallel control Historical control Case-control 5.Case-series Guyatt, JAMA, 2000

When are n-of-1’s helpful?  N-of-1 useful when: Chronic condition, and Variation in individual responsiveness, and Treatment effects are:  Symptomatic or Transient  N-of-1 not possible for: Preventing ‘events’, e.g, stroke Treating acute conditions, e.g., acute otitis media

How should I treat my 2 year old? What do you want to know about antibiotic treatment?

What would you want to know?

% 24 hrs 135/351 = 37% No change in 24 hrs % 2-7 days 248/1,118 = 22% 1/3 reduction 2-7d

Who do group trials apply to? If the trial showed it worked: 1.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) 2.And what is the importance of it “working” for THIS patient? H

Who do group trials apply to? If it worked in RCT: 1.Will it work 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 it may not have matter to most 2.How important is that?

Steps from trials to individual decisions 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 in THIS individuals context? From: Glasziou et al, Cochrane Applicability & Recommendations Methods Group

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”

Step 1: Summary of Findings 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

Step 1: Summary of Findings GRADE

Antibiotics for Acute Otitis Media  For Pain (at 2-7 days)  RRR  ARR  NNT C Cates:

Involving the patient  ICE - ideas, concerns and expectations  Explaining the options What would happen if we did nothing? What are the options What is their impact on natural history +/- patient information handout

2. Are there true variation in effects?  Patients Severity/stage  Intervention intensity/timing?  Comparison  Outcome?

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

Are antibiotics more effective in some children? (Little RCT)

(a)(b) (c)(d) Minimum clinical Important difference No difference Which are (i) statistically significant and (ii) Clinically significant?

Subgroup Analysis Do “statins” work in those with a history (Hx) of stroke? (Circulation. 2001;103: ) Not different

Glasziou, Irwig BMJ, 1995 Step 3: How does effect vary with predicted risk?  When does benefit outweigh harm?  Assumptions Benefit (rate difference) increases with risk or severity Harm constant over event risk H threshold

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

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

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:

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

Thomson R BMJ 1998;316: Guidelines Don’t Always Agree: % of AF patients “needing” warfarin

Individualizing treatment  For some chronic conditions: N-of-1 trials  Patient’s own randomised trial,  Patient can choose own measures & interpret!  For most other problems: Individualise predicted benefits and harms Integrate the patient’s preferences

Cost-effectiveness varies with risk

Treatment threshold CE threshold

SSSS cost-effectiveness by cholesterol+age (model) Johannesson, NEJM, 1997: 332

The Risk-Cost Pyramid Harms outweigh benefits Possibly Cost-effective Cost saving High Risk Medium Risk Low Risk

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

When we can’t do n-of-1 From trial to Individual Trial Balance Sheet Individual Balance Sheet Stability and modifiers Of effects across groups (steps 2 and 3) Individual features Risk (step 4) & Preferences (step 5)

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