# Presentation: 747995

## 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**

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## Speakers for This Morning

**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**

## Patient Group Comparisons

**Placebo**

**Pravastatin**

**Aspirin Users**

**Aspirin ****Non-Users**

**Randomized Groups**

**Randomized Comparison**

**Observational Comparison**

## Is the Combination More Effectivethan Pravastatin Alone?

**Is the Combination More Effective****than Pravastatin Alone?**

**Unadjusted event rates in LIPID and CARE suggest pravastatin + aspirin is more effective than pravastatin alone**

## Event Rates for Primary Endpoints in LIPID and CARE

**Aspirin Users**

**Aspirin Non-Users**

**LIPID**
**CHD Death**

**CARE**
**CHD Death or ****Non-fatal MI**

**Pravastatin-treated Subjects Only**

**Trial:**
**Primary Endpoint:**

## Accounting for Baseline Risk Factors

**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**

## Meta-Analysis of these Pravastatin Secondary Prevention Trials

**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 ****Pravastatin Secondary Prevention Trials**

## Trial Commonalities

**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**

## Meta-Analysis Endpoints Considered

**Meta-Analysis Endpoints Considered**

**Fatal or non-fatal MI**
**Ischemic stroke**
**Composite: CHD death, non-fatal MI, CABG, PTCA or ischemic stroke**

## Model 1:
Multivariate Cox proportional hazards model
Patients combined across trials; trial effect is a fixed covariate

**Multivariate Cox proportional hazards model**
**Patients combined across trials; trial effect is a fixed covariate**

**Meta-Analysis Models**

## Relative Risk ReductionCox Proportional Hazards – All Trials

**RRR = Relative Risk Reduction**

**Relative Risk (95% CI)**

**RRR**

**Relative Risk Reduction****Cox Proportional Hazards – All Trials**

## Relative Risk ReductionCox Proportional Hazards – LIPID and CARE

**Relative Risk Reduction****Cox Proportional Hazards – LIPID and CARE**

## Relative Risk ReductionCox Proportional Hazards – LIPID and CARE

**Relative Risk Reduction****Cox Proportional Hazards – LIPID and CARE**

## 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

**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 Models**

## Model 2 – Hierarchical, Random Effects

**Year**

**Model 2 – Hierarchical, Random Effects**

**Fatal or Non-Fatal MI**

**Cumulative Proportion of Events**

## Model 2 – Hierarchical, Random Effects

**Model 2 – Hierarchical, Random Effects**

**Ischemic Stroke Only**

**Year**

**Cumulative Proportion of Events**

## Model 2 – Hierarchical, Random Effects

**Model 2 – Hierarchical, Random Effects**

**CHD Death, Non-Fatal MI, CABG,****PTCA, or Ischemic Stroke**

**Cumulative Proportion of Events**

## Combination is More Effectivethan Either Agent Alone

**Combination is More Effective****than 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**

## Model 2: Fatal or Non-Fatal MI

## 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

**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 Models**

## Model 3: Fatal or Non-Fatal MI 

## Conclusion 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 **

## Slide 23