accounting for clinical heterogeneity in comparative effectiveness research how can one examine a...
TRANSCRIPT
Accounting for Clinical Heterogeneity in Comparative Effectiveness Research
How Can One Examine a Trial for Heterogeneity of Treatment Effect (HTE)?
The Example of the BARI trial for CABG vs PTCA
September 28, 2010
Carlos Weiss, MD, MHS
AHRQ DEcIDE Project:
Methods to Study the Heterogeneity of Treatment Effects in Comparative Effectiveness Research
PI: Ravi Varadhan, PhD
Co-I: Jodi Segal, MD, MPH; Cynthia Boyd, MD, MPH; Al Wu, MD, MPH
Consultant: David Kent, MD, MPH
Technical Experts: Curt Furberg, MD, PhD; Bruce Psaty, MD, PhD
Task Order Officer: Parivash Nourjah, PhD
N=1,829
BARI Clinical Question
Population targeted: “Multivessel disease” with severe angina or ischemia
Intervention: PTCA (a form of PCI)
Comparator: CABG
Outcome: 5-yr Mortality
Questions to Audience - Set 1
What are sources of HTE?
How would pre-specification of analyses affect interpretation of results?
BARI Design for HTE
Protocol pre-specified 4 subgroup analyses:• angina severity
BARI Design for HTE
Protocol pre-specified 4 subgroup analyses:• angina severity• left ventricular function• number of diseased vessels• complex lesions
BARI Clinical Question: Sources of HTE in CABG vs PTCA
BARI Clinical Question: Sources of HTE in PTCA v CABG
• Patients– baseline risk– competing risks– risk of treatment harms– treatment responsiveness
>>Ideas drawn from Kravitz, Duan & Braslow, 2004, Milbank Quarterly
BARI Clinical Question: Sources of HTE in PTCA v CABG
• Patients – baseline risk– competing risks– risk of treatment harms– treatment responsiveness
• Treatment• Providers• Environments
PATIENTS
PROVIDERS ENVIRONMENTS
TREATMENT
BARI Results
5-yr Mortality:
Overall, no clinically significant nor statistically significant difference
CABG,+ treated diabetes
PTCA,+ treated diabetes
PTCA ,- treated diabetesCABG,- treated diabetes
Questions to Audience - Set 2
When should one be worried that a subgroup result is an error (Type I or Type II) ?
What can be done to lower error probabilities?
Proposed General Approach to Examining a Trial for HTE
1. HTE hypotheses pre-specified?
2. Design and measurement quality?
3. Modeling pre-specified?
Proposed General Approach to Examining a Trial for HTE
1. HTE hypotheses pre-specified?
2. Design and measurement quality?
3. Modeling pre-specified?
4. If No to 1, 2 or 3:
Validation study available?
Proposed General Approach to Examining a Trial for HTE
1. HTE hypotheses pre-specified?
2. Design and measurement quality?
3. Modeling pre-specified?
4. If No to 1, 2 or 3:
Validation study available?
5.a. If frequentist, test of interaction performed?
6.b. If Bayesian, pre-specified priors and variance acceptable?
Extra Slides
What is Heterogeneity of Treatment Effect?
Non-random variability in the direction or magnitude of a treatment effect
Ris
k if
Tre
ated
, ev
ents
per
100
p-y
5
10
Risk if UnTreated or “Baseline Risk”, events per 100 p-y105
Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale
Ris
k if
Tre
ated
, ev
ents
per
100
p-y
5
10─ Average Absolute Treatment Effect (ARR)
Risk if UnTreated or “Baseline Risk”, events per 100 p-y105
AR
Open circles - HTE absentClosed circles - HTE present
Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale
Ris
k if
Tre
ated
, ev
ents
per
100
p-y
5
10
Risk if UnTreated or “Baseline Risk”, events per 100 p-y105
- - Average Relative Treatment Effect (RRR)
Δy/Δx = RR
Open circles - HTE presentClosed circles - HTE absent
Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale