Applying Trial Results to Individual Patients
Paul GlasziouCentre for Evidence Based MedicineUniversity of Oxford
www.cebm.net
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
NSAID Paracetamol
Paracetamol NSAID
NSAID Paracetamol
Pair 1
Pair 2
Pair 3
N-of-1: overall & examples
0
2
4
6
8
AVERAGE PAIN
DRUG
PAIN
SC
OR
E (M
EAN
+95
%C
I)
Panadol Actiprofen0
2
4
6
8
AVERAGE PAIN
DRUG
PAIN
SC
OR
E (M
EAN
+95
%C
I)
Panadol Actiprofen
NSAID non-responder NSAID responder
Paracetamol has higher pain
Nikles CJ, Yelland M, Glasziou PP, Del Mar C. Am J Ther. 2005 Jan-Feb;12(1):92-7.
N-of-1 PPI vs H2RAOf 27 patients•14 omeprazole (PPI) was better•6 ranitidine (H2RA) was better•5 equality•2 neither drug recommended
Levels of EvidenceIndividualisation would be ideal
1. N-of-1 Trial2. Systematic review of randomised trials3. A single randomised trial4. 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?
% Pain @ 24 hrs135/351 = 37%
No change in Pain @ 24 hrs
% Pain @ 2-7 days248/1,118 = 22%
1/3 reduction Pain @ 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) meansIt “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) meansIt “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
www.sph.uq.edu.au/CGP/training/CochraneMethodsGroup.html
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
Vomiting, rash, diarrhoea
555%11%Adverse effect
--26%“Glue ear” 3M
1 case in 2,250 (AB grp)
-?0Mastoiditis
Greater if fever, vomiting
528%14%Pain 2-7days
0038%Pain <1 day
commentsARR/100
RRR% inPlacebo
Outcome
Step 1: Summary of Findings
Outcome Number Subjects (# trials)
Control Group Outcome (range)
Effect Ratio (95% CI)
Change in events Per 100 patients
Quality of Evidence
Pain <1 day 717 (3) 38% 1.02 (0.85 – 1.22)
Nil A
Pain 2-7days 2,287 (9) 22% 0.70 (0.60 – 0.81)
7 fewer A
Mastoiditis 2,287 (9) - - - C “Glue ear” 3M
370 (2) 26% - - B
Adverse effect
11% 1.55 6 more B
GRADE
Antibiotics for Acute Otitis Media
For Pain(at 2-7 days)
RRRARRNNT
C Cates: www.nntonline.net
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?
ComparisonOutcome?
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 clinicalImportant 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;103:387-392.)
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
0
2
4
6
8
0 5 10 15 20
Risk of outcome
Effe
ct o
f tre
atm
ent
BenefitHarm
threshold
For biological effect & transferability
For clinical decision making
Impact of changing risk
BaselineRisk
RelativeRiskReduction
AbsoluteRiskReduction
Numberneeded toTreat
20% 75% 15% 7
8% 75% 6% 16
4% 75% 3% 33
1% 75% .75% 133
Trial patients
Typical patients
Rate versus rate plotsL’Abbe plot of trials of Warfarin in Atrial Fibrillation
Control group rate
Trea
tmen
t gro
up ra
te Line of equality
Constant relative reduction
Constant absolute risk reduction
Which risk measure is most constant?
31%Risk Difference
14%Relative Risk
13%Odds Ratio
% varying with control group risk
Measure
Analysis of the effect of control rate in 115 meta-analysis Schmid et al Stats in Med 1998: 1923-42.
Step 4: Benefit versus HarmClinical predictors of stroke
00.020.040.060.08
0.10.120.140.160.18
0 0.05 0.1 0.15 0.2
Stroke Risk/Yr
Stro
ke E
quiv
alen
ts Benefit= 73% RRR
Harm= 0.01 deaths
1 ICH death = 4 strokes1 ICH death = 1 stroke
Risk Factors* 0 1 2 or 3Frequency 42% 46% 12%
*hypertension, recent CCF, previous thromboembolism,
13 16 17 18 20
33 33 35
46 48
61 65 66 66
79 81 8388 91
100
0
20
40
60
80
100
Guidelines
No
of p
atie
nts
Thomson R BMJ 1998;316:509-13
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
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.160
0.01
0.02
0.03
0.04
0.05
0.06
CostCEAEffect
Cost-effectiveness varies with risk
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.160
0.01
0.02
0.03
0.04
0.05
0.06
CostCEAEffect
Treatmentthreshold
CEthreshold
SSSS cost-effectivenessby cholesterol+age (model)
0
2,000
4,000
6,000
8,000
10,000
12,000
213 261 309
Initial Cholesterol
Co
st p
er
Lif
e Y
ea
r
age 36age 58age 70
Johannesson, NEJM, 1997: 332
The Risk-Cost Pyramid
Harms outweigh benefits
PossiblyCost-effective
Costsaving
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 1995O’Connell, Glasziou, Hill. NHMRC How to use the evidence
When we can’t do n-of-1 From trial to Individual
TrialBalance Sheet
IndividualBalance Sheet
Stability and modifiersOf effects across groups(steps 2 and 3)
Individual features•Risk (step 4) & •Preferences (step 5)
www.sph.uq.edu.au/CGP/training/CochraneMethodsGroup.html
The problem: The “Leaks”between research & practice
Aware Accept Target Doable Recall Agree Done
ValidResearch