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CRDAC and DSaRM Meeting September 12, 2007 Mark Levenson, Ph.D.

Statistical Review of the Observational Studies of Aprotinin Safety Part I: Methods, Mangano and Karkouti Studies. CRDAC and DSaRM Meeting September 12, 2007 Mark Levenson, Ph.D. Quantitative Safety & Pharmacoepidemiology Group Office of Biostatistics.

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CRDAC and DSaRM Meeting September 12, 2007 Mark Levenson, Ph.D.

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  1. Statistical Review of the Observational Studies of Aprotinin Safety Part I:Methods, Mangano and Karkouti Studies CRDAC and DSaRM Meeting September 12, 2007 Mark Levenson, Ph.D. Quantitative Safety & Pharmacoepidemiology Group Office of Biostatistics

  2. Acknowledgements to Dr. Mangano and Dr. Karkouti

  3. Outline • Review Objectives • Statistical Methods • Mangano Review • Karkouti Review • Summary

  4. 1. Review Objectives • To confirm the reported findings based on investigators’ methods • To evaluate the statistical robustness of the findings • FDA analyzed the 3 studies • Same methods applied to all three studies • Robust • Diagnostics

  5. Outline • Review Objectives • Statistical Methods • Mangano Review • Karkouti Review • Summary

  6. Propensity Scores (PS) • Adjust for differences in baseline risk factors between two treatment groups (Treatment A and Treatment B) • Definition: Probability of assignment for a patient to Treatment A versus Treatment B based on measured risk factors • Intuition: • Suppose Treatment A patient and Treatment B patient have the same PS. • Comparisons between these two patients are fair

  7. Propensity Scores Practice • Balance: similarity of distributions of a risk factor between treatment groups • PS methods cannot account for unmeasured confounders • The PS are estimated based on statistical modeling • Diagnostics important

  8. Propensity Scores Practice (Cont.) • Estimating treatment effects using PS • Matching (Karkouti) • Stratification (FDA) • Multivariate regression (Mangano, i3)

  9. FDA Analysis Methods • Pre-specified • Propensity scores with stratification was used to adjust for baseline risk factors • Medical, epidemiological, and statistical expertise was used to choose risk factors • Diagnostics (analytical and graphical) were used to evaluate balance and explore findings

  10. Outline • Review Objectives • Statistical Methods • Mangano Review • Karkouti Review • Summary

  11. Mangano Study: Key Points • Prospectively specified • Inclusion criteria • Outcome definitions • Subgroups • Analysis methods • In-hospital outcomes (NEJM) • Long-term mortality follow-up outcomes (JAMA) • 7 of 69 centers did not participate in the long-term follow-up

  12. Mangano Study: Key Points Analysis Methods • Multivariate regression with and without propensity score as a covariate • Logistic for in-hospital outcomes • Cox PH for long-term mortality • Propensity score for any active agent versus no agent for full analysis group • No adjustment for geographical differences

  13. Mangano Study: Patients by Geographical Region and Treatment Group

  14. Mangano Study: Long-Term Follow-up

  15. Mangano Study: Demographic Factors

  16. Mangano Study: Selected Baseline Risk Factors

  17. Mangano Study:Study Reported Findings and Methods • Primary findings of NEJM and JAMA based on investigators’ methods reproduced • Imbalances in baseline risk factors and geographical regions between aprotinin and no-agent groups after PS adjustment • Lack of overlap in propensity score distributions between aprotinin and no-agent groups

  18. FDA Analysis Results

  19. Mangano Study: FDA AnalysisBaseline Risk FactorsBefore and After PS Adjustment

  20. Mangano Study: FDA AnalysisIn-Hospital Outcome Adjusted EstimatesAprotinin vs. No Agent* *Analysis based on 1307 no agent patients and 1222 aprotinin patients

  21. Mangano Study: FDA AnalysisRenal Composite

  22. Mangano Study: FDA AnalysisLong-Term Mortality Adjusted EstimatesAprotinin vs. No Agent* *Analysis based on 1307 no agent patients and 1222 aprotinin patients

  23. Mangano Study: FDA AnalysisLong-Term Mortality Adjusted Estimates

  24. North American Subgroup

  25. Mangano Study: FDA Analysis by Region and Treatment Group

  26. Mangano Study: FDA AnalysisNorth America In-Hospital Outcome Adjusted EstimatesAprotinin vs. Aminocaproic* *Analysis based on 789 aminocaproic patients and 342 aprotinin patients

  27. Mangano Study: FDA AnalysisNorth America:Long-Term Mortality Adjusted Estimates Aprotinin vs. Aminocaproic* *Analysis based on 789 aminocaproic patients and 342 aprotinin patients

  28. Mangano Study: Review Summary • Renal outcomes (particularly renal failure) effect in a range of patients and in North American region subgroup • Effects for cardiovascular, cerebrovascular, and in-hospital death outcomes not statistically demonstrated • Long-term mortality effects in a range of patients and in North American region subgroup

  29. Outline • Statistical Review Objectives • Statistical Methods • Mangano Review • Karkouti Review • Summary

  30. Karkouti Study: Key Points • Retrospective study of 5 years of patient data from a single center • Patient population: Cardiac surgery (CABG and non-CABG) with cardio-pulmonary bypass • Aprotinin used for high risk patients, tranexamic acid used for other patients • Used propensity scores with 1-1 matching • 449 of 586 aprotinin patients matched

  31. Karkouti Study: Demographic Factors

  32. Karkouti Study: Selected Baseline Risk Factors

  33. Karkouti Study: Study Reported Findings and Methods • Primary findings using investigators’ methods reproduced • Observed risk factors balanced with propensity score matching approach

  34. Karkouti Study: FDA Analysis • A subgroup of patients with overlap in propensity scores was defined to enable treatment comparison • Subgroup contained • 553/586 (94%) of the aprotinin patients • 3759/10251 (37%) of tranexamic patients • Baseline risk factors more similar between treatment groups in subgroup than full group

  35. Karkouti: FDA AnalysisAnalysis Subgroup, Baseline Risk FactorsBefore and After PS Adjustment

  36. Karkouti Study: FDA AnalysisTreatment Effect EstimatesAprotinin vs. Tranexamic Acid* *Analysis based on 3759 tran. patients and 553 aprotinin patients

  37. Karkouti Study: FDA AnalysisRenal Failure

  38. Karkouti Study: Review Summary • Renal dysfunction effect statistically significant • Some evidence for renal failure effect • Effects for myocardial infarction, stroke, and in-hospital death outcomes not statistically demonstrated

  39. Outline • Review Objectives • Statistical Methods • Mangano Review • Karkouti Review • Summary

  40. Summary • Evidence for renal effect, including renal failure consistent • Effects for cardiovascular, cerebrovascular, and in-hospital death outcomes not statistically demonstrated • Evidence for long-term mortality effect • Potential for unadjusted confounders between the treatment groups which may bias the treatment effect estimates

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