Efficacy of the Combination: Meta-Analyses
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C C- Efficacy of the Combination: Efficacy of the Combination: Meta-Analyses Meta-Analyses Donald A. Berry, Ph.D. Frank T. McGraw Memorial Chair of Cancer Research University of Texas M.D. Anderson Cancer Center 7asdf
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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 - PowerPoint PPT Presentation
Transcript of Efficacy of the Combination: Meta-Analyses
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Efficacy of the Combination: Efficacy of the Combination: Meta-AnalysesMeta-Analyses
Donald A. Berry, Ph.D.
Frank T. McGraw Memorial Chair of Cancer ResearchUniversity of Texas
M.D. Anderson Cancer Center
7asdf
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Speakers for This MorningSpeakers 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
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Patient Group ComparisonsPatient Group Comparisons
PlaceboPravastatin
Aspirin Users
Aspirin Non-Users
Prava+ASA
Prava alone
Placebo+ASA
Placebo alone
Randomized Groups
Randomized Comparison
Observational Comparison
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Is the Combination More EffectiveIs the Combination More Effectivethan Pravastatin Alone?than Pravastatin Alone?
Unadjusted event rates in LIPID and CARE suggest pravastatin + aspirin is more effective than pravastatin alone
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Event Rates for Primary Endpoints Event Rates for Primary Endpoints in LIPID and CAREin LIPID and CARE
Aspirin Users
Aspirin Non-Users
5.8%
8.8% 14.8%
9.3%
LIPIDCHD Death
CARECHD Death or Non-fatal MI
Pravastatin-treated Subjects Only
Trial:Primary Endpoint:
Observational Comparison
Observational Comparison
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Accounting for Baseline Risk FactorsAccounting 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
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Trial
LIPID
CARE
REGRESS
PLAC I
PLAC II
Totals
Number of Subjects* % on Aspirin
82.7
83.7
54.4
67.5
42.7
80.4
Primary Endpoint
CHD mortality
CHD death & non-fatal MI
Atherosclerotic progression (& events)
9014
4159
885
408
151
14,617
Atherosclerotic progression (& events)
Atherosclerotic progression (& events)
*99.7% of pravastatin-treated subjects received 40mg dose
Meta-Analysis of these Meta-Analysis of these Pravastatin Secondary Prevention TrialsPravastatin Secondary Prevention Trials
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Trial CommonalitiesTrial 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
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Meta-Analysis Endpoints ConsideredMeta-Analysis Endpoints Considered
Fatal or non-fatal MI
Ischemic stroke
Composite: CHD death, non-fatal MI, CABG, PTCA or ischemic stroke
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Model 1: Multivariate Cox proportional hazards model Patients combined across trials; trial effect is
a fixed covariate
Meta-Analysis ModelsMeta-Analysis Models
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Relative Risk (95% CI) RRR
Relative Risk ReductionRelative Risk ReductionCox Proportional Hazards – All TrialsCox Proportional Hazards – All Trials
Prava+ASA vs ASA alone
Prava+ASA vs Prava alone
Fatal or Non-Fatal MI
0.400 0.800 1.0000.600
0.400 0.800 1.0000.600
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
Prava+ASA vs ASA alone
Prava+ASA vs Prava alone
24%0.76
13%0.87
31%0.69
26%0.74
Prava+ASA vs ASA alone
Prava+ASA vs Prava alone
29%0.71
31%0.69
Ischemic Stroke
0.400 0.800 1.0000.600
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Relative Risk ReductionRelative Risk ReductionCox Proportional Hazards – LIPID and CARECox Proportional Hazards – LIPID and CARE
Ischemic Stroke
Prava+ASA vs ASA alone – LIPID
Prava+ASA vs ASA alone – CARE
0.400 0.800 1.0000.600
0.70
0.71
1.2000.200
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
Prava+ASA vs ASA alone – LIPID
Prava+ASA vs ASA alone – CARE
0.400 0.800 1.0000.600
0.76
0.76
1.2000.200
Prava+ASA vs ASA alone – LIPID
Prava+ASA vs ASA alone – CARE
Fatal or Non-Fatal MI Relative Risk (95% CI)
0.400 0.800 1.0000.600 1.2000.200
0.65
0.79
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Relative Risk ReductionRelative Risk ReductionCox Proportional Hazards – LIPID and CARECox Proportional Hazards – LIPID and CARE
Ischemic Stroke
Prava+ASA vs Prava alone – LIPID
Prava+ASA vs Prava alone – CARE
0.400 0.800 1.0000.600
0.74
0.49
1.2000.200
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
Prava+ASA vs Prava alone – LIPID
Prava+ASA vs Prava alone – CARE
0.400 0.800 1.0000.600
0.86
0.78
1.2000.200
Prava+ASA vs Prava alone – LIPID
Prava+ASA vs Prava alone – CARE
Fatal or Non-Fatal MI Relative Risk (95% CI)
0.400 0.800 1.0000.600 1.2000.200
0.72
0.74
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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
Meta-Analysis ModelsMeta-Analysis Models
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0.000
0.025
0.050
0.075
0.100
0 1 2 3 4 5
Year
Model 2 – Hierarchical, Random EffectsModel 2 – Hierarchical, Random Effects
Fatal or Non-Fatal MIFatal or Non-Fatal MI
Placebo
Prava alone
ASA alone
Prava+ASA
Cumulative Proportion of Events
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0.000
0.005
0.010
0.015
0.020
0.025
0 1 2 3 4 5
Model 2 – Hierarchical, Random EffectsModel 2 – Hierarchical, Random Effects
Ischemic Stroke OnlyIschemic Stroke Only
ASA alone
Prava+ASA
Year
Cumulative Proportion of Events
Prava alonePlacebo
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0.00
0.05
0.10
0.15
0.20
0.25
0 1 2 3 4 5
Year
Model 2 – Hierarchical, Random EffectsModel 2 – Hierarchical, Random Effects
CHD Death, Non-Fatal MI, CABG,CHD Death, Non-Fatal MI, CABG,PTCA, or Ischemic StrokePTCA, or Ischemic Stroke
Prava+ASAPrava+ASA
ASA aloneASA alonePrava alonePrava alone
PlaceboPlacebo
Cumulative Proportion of Events
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Combination is More EffectiveCombination is More Effectivethan Either Agent Alonethan 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
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Model 2: Model 2: Fatal or Non-Fatal MIFatal or Non-Fatal MI
Cumulative Proportion of Events
0.000
0.025
0.050
0.075
0.100
Year
0 1 2 3 4 5
Prava+ASAPrava+ASA
ASA aloneASA alone
Prava alonePrava alone
PlaceboPlacebo
0.000
0.005
0.010
0.015
0.025
Year
0 1 2 3 4 5
0.020
Hazard
Prava+ASAPrava+ASA
ASA aloneASA alone
Prava alonePrava alone
PlaceboPlacebo
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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
Meta-Analysis ModelsMeta-Analysis Models
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Model 3: Model 3: Fatal or Non-Fatal MI Fatal or Non-Fatal MI
Cumulative Proportion of Events
0.000
0.025
0.050
0.075
0.100
Year
0 1 2 3 4 5
Prava+ASAPrava+ASA
ASA aloneASA alone
Prava alonePrava alone
PlaceboPlacebo
0.000
0.005
0.010
0.015
0.030
Year5 Separate Analyses: One per Year
0 1 2 3 4 5
0.020
Hazard
0.025
Prava+ASAPrava+ASA
ASA aloneASA alone
Prava alonePrava alone
PlaceboPlacebo
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Conclusion of Hazard Analysis over TimeConclusion of Hazard Analysis over Time
Benefit of pravastatin+aspirin over aspirin was 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
