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Efficacy of the Combination: Meta-Analyses

Efficacy of the Combination: Meta-Analyses. Donald A. Berry, Ph.D. Frank T. McGraw Memorial Chair of Cancer Research University of Texas M.D. Anderson Cancer Center. 7asdf. Speakers for This Morning. Dr. René Belder Mechanism of action of components PK analysis

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Efficacy of the Combination: Meta-Analyses

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  1. Efficacy of the Combination: Meta-Analyses Donald A. Berry, Ph.D. Frank T. McGraw Memorial Chair of Cancer Research University of TexasM.D. Anderson Cancer Center 7asdf

  2. Speakers for This Morning • Dr. René Belder • Mechanism of action of components • PK analysis • Safety and tolerability of combination • Dose combinations available • Efficacy – based on individual trials • Dr. Donald Berry • Efficacy – based on meta-analyses • Efficacy – presence of consistent benefit • Dr. Thomas Pearson • Medical Need

  3. Prava+ASA Placebo+ASA Prava alone Placebo alone Patient Group Comparisons Randomized Groups Pravastatin Placebo Aspirin Users Randomized Comparison Aspirin Non-Users Observational Comparison

  4. Is the Combination More Effectivethan Pravastatin Alone? • Unadjusted event rates in LIPID and CARE suggest pravastatin + aspirin is more effective than pravastatin alone

  5. 5.8% 9.3% 8.8% 14.8% Observational Comparison Observational Comparison Event Rates for Primary Endpoints in LIPID and CARE Pravastatin-treated Subjects Only Trial: Primary Endpoint: LIPID CHD Death CARE CHD Death or Non-fatal MI Aspirin Users Aspirin Non-Users

  6. Accounting for Baseline Risk Factors • Age • Gender • Previous MI • Smoking status • Baseline LDL-C, HDL-C, TG • Baseline DBP & SBP Additional analyses also included revascularization, diabetes and obesity

  7. Meta-Analysis of these Pravastatin Secondary Prevention Trials Trial Number of Subjects* % on Aspirin Primary Endpoint LIPID 9014 82.7 CHD mortality CARE 4159 83.7 CHD death & non-fatal MI REGRESS 885 54.4 Atherosclerotic progression (& events) PLAC I 408 67.5 Atherosclerotic progression (& events) PLAC II 151 42.7 Atherosclerotic progression (& events) Totals 14,617 80.4 *99.7% of pravastatin-treated subjects received 40mg dose

  8. Trial Commonalities • Similar entry criteria • Patient populations with clinically evident CHD • Same dose of pravastatin (40mg) • Randomized comparison of pravastatin against placebo • All trials had durations of  2 years • Pre-specified endpoints • Covariates recorded • Common meta-analysis data management

  9. Meta-Analysis Endpoints Considered • Fatal or non-fatal MI • Ischemic stroke • Composite: CHD death, non-fatal MI, CABG, PTCA or ischemic stroke

  10. Meta-Analysis Models • Model 1: • Multivariate Cox proportional hazards model • Patients combined across trials; trial effect is a fixed covariate

  11. Fatal or Non-Fatal MI 0.76 24% Prava+ASA vs ASA alone 0.87 13% Prava+ASA vs Prava alone Ischemic Stroke 0.69 Prava+ASA vs ASA alone 31% 0.74 26% Prava+ASA vs Prava alone CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke 0.71 29% Prava+ASA vs ASA alone 0.69 31% Prava+ASA vs Prava alone 0.400 0.400 0.400 0.600 0.600 0.600 0.800 0.800 0.800 1.000 1.000 1.000 Relative Risk ReductionCox Proportional Hazards – All Trials RRR Relative Risk (95% CI) RRR = Relative Risk Reduction

  12. Relative Risk (95% CI) Fatal or Non-Fatal MI 0.65 Prava+ASA vs ASA alone – LIPID 0.79 Prava+ASA vs ASA alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 Ischemic Stroke 0.70 Prava+ASA vs ASA alone – LIPID 0.71 Prava+ASA vs ASA alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke 0.76 Prava+ASA vs ASA alone – LIPID 0.76 Prava+ASA vs ASA alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 Relative Risk ReductionCox Proportional Hazards – LIPID and CARE

  13. Relative Risk (95% CI) Fatal or Non-Fatal MI 0.72 Prava+ASA vs Prava alone – LIPID 0.74 Prava+ASA vs Prava alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 Ischemic Stroke 0.74 Prava+ASA vs Prava alone – LIPID 0.49 Prava+ASA vs Prava alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke 0.86 Prava+ASA vs Prava alone – LIPID 0.78 Prava+ASA vs Prava alone – CARE 0.200 0.400 0.600 0.800 1.000 1.200 Relative Risk ReductionCox Proportional Hazards – LIPID and CARE

  14. Meta-Analysis Models • Model 1: • Multivariate Cox proportional hazards model • Patients combined across trials; trial effect is a fixed covariate Model 2: Same as Model 1 except • Allows trial heterogeneity: Bayesian hierarchical (random effects) model of trial effect

  15. 0.100 Placebo ASA alone Prava alone 0.075 Prava+ASA 0.050 0.025 0.000 0 1 2 3 4 5 Model 2 – Hierarchical, Random Effects Fatal or Non-Fatal MI Cumulative Proportion of Events Year

  16. 0.025 Placebo Prava alone ASA alone 0.020 0.015 Prava+ASA 0.010 0.005 0.000 0 1 2 3 4 5 Model 2 – Hierarchical, Random Effects Ischemic Stroke Only Cumulative Proportion of Events Year

  17. 0.25 Placebo ASA alone Prava alone 0.20 Prava+ASA 0.15 0.10 0.05 0.00 0 1 2 3 4 5 Year Model 2 – Hierarchical, Random Effects CHD Death, Non-Fatal MI, CABG,PTCA, or Ischemic Stroke Cumulative Proportion of Events

  18. Combination is More Effectivethan Either Agent Alone • Pravastatin + aspirin provides benefit for all three endpoints: • 24% - 34% RRR compared with aspirin • 13% - 31% RRR compared with pravastatin • This benefit was similar in Models 1 and 2 • This benefit was consistent in both LIPID and CARE trials

  19. Cumulative Proportion of Events Hazard 0.100 0.025 Placebo ASA alone Placebo 0.020 Prava alone ASA alone 0.075 Prava alone 0.015 Prava+ASA 0.050 Prava+ASA 0.010 0.025 0.005 0.000 0.000 0 1 2 3 4 5 0 1 2 3 4 5 Year Year Model 2: Fatal or Non-Fatal MI

  20. Meta-Analysis Models • Model 1: • Multivariate Cox proportional hazards model • Patients combined across trials; trial effect is a fixed covariate Model 2: Same as Model 1 except • Allows trial heterogeneity: Bayesian hierarchical (random effects) model of trial effect • Model 3: Same as Model 2 except • Treatment hazard ratios vary over time

  21. Cumulative Proportion of Events Hazard 0.100 0.030 Placebo ASA alone 0.025 Prava alone 0.075 Placebo 0.020 ASA alone Prava+ASA 0.050 0.015 Prava alone Prava+ASA 0.010 0.025 0.005 0.000 0.000 0 1 2 3 4 5 0 1 2 3 4 5 Year Year 5 Separate Analyses: One per Year Model 3: Fatal or Non-Fatal MI

  22. Conclusion of Hazard Analysis over Time • Benefit of pravastatin+aspirin over aspirinwas present in each year of the 5-year duration of the trials • Benefit of pravastatin+aspirin over pravastatin was present in each year of the 5-year duration of the trials • Benefits estimated from Model 1 (and confidence intervals) confirmed by more general models and fewer assumptions

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