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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

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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