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Accounting for Clinical Heterogeneity in Comparative Effectiveness Research

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:

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Accounting for Clinical Heterogeneity in Comparative Effectiveness Research

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  1. 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

  2. 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

  3. N=1,829

  4. BARI Clinical Question Population targeted: “Multivessel disease” with severe angina or ischemia Intervention: PTCA (a form of PCI) Comparator: CABG Outcome: 5-yr Mortality

  5. Questions to Audience - Set 1 What are sources of HTE? How would pre-specification of analyses affect interpretation of results?

  6. BARI Design for HTE Protocol pre-specified 4 subgroup analyses: • angina severity

  7. BARI Design for HTE Protocol pre-specified 4 subgroup analyses: • angina severity • left ventricular function • number of diseased vessels • complex lesions

  8. BARI Clinical Question: Sources of HTE in CABG vs PTCA

  9. 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

  10. BARI Clinical Question: Sources of HTE in PTCA v CABG • Patients • baseline risk • competing risks • risk of treatment harms • treatment responsiveness • Treatment • Providers • Environments

  11. PATIENTS TREATMENT PROVIDERS ENVIRONMENTS

  12. BARI Results 5-yr Mortality: Overall, no clinically significant nor statistically significant difference

  13. PTCA ,- treated diabetes CABG,- treated diabetes CABG,+ treated diabetes PTCA,+ treated diabetes

  14. 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?

  15. Proposed General Approach to Examining a Trial for HTE 1. HTE hypotheses pre-specified? 2. Design and measurement quality? 3. Modeling pre-specified?

  16. 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?

  17. 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?

  18. Extra Slides

  19. What is Heterogeneity of Treatment Effect? Non-random variability in the direction or magnitude of a treatment effect

  20. Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale 10 Risk if Treated, events per 100 p-y 5 10 5 Risk if UnTreated or “Baseline Risk”, events per 100 p-y

  21. Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale 10 ─ Average Absolute Treatment Effect (ARR) AR Risk if Treated, events per 100 p-y 5 Open circles - HTE absent Closed circles - HTE present 10 5 Risk if UnTreated or “Baseline Risk”, events per 100 p-y

  22. Treatment Effects for 2 Hypothetical Studies: Heterogeneity According to Scale 10 Open circles - HTE present Closed circles - HTE absent Risk if Treated, events per 100 p-y - - Average Relative Treatment Effect (RRR) 5 Δy/Δx = RR 10 5 Risk if UnTreated or “Baseline Risk”, events per 100 p-y

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