Efficacy of the Combination: Meta-Analyses

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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 TexasM.D. Anderson Cancer Center

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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

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Patient Group Comparisons
Randomized Groups
Placebo
Pravastatin
Aspirin Users
Randomized Comparison
Aspirin Non-Users
Observational Comparison
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Is the Combination More Effectivethan
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 in LIPID and
CARE
Pravastatin-treated Subjects Only
LIPID CHD Death
CARE CHD Death or Non-fatal MI
Trial Primary Endpoint
Aspirin Users
Aspirin Non-Users
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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
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Meta-Analysis of these Pravastatin Secondary
Prevention Trials
Trial
Number of Subjects
on Aspirin
Primary Endpoint
LIPID
82.7
CHD mortality
9014
CARE
83.7
CHD death non-fatal MI
4159
REGRESS
54.4
Atherosclerotic progression ( events)
885
PLAC I
67.5
408
Atherosclerotic progression ( events)
PLAC II
42.7
151
Atherosclerotic progression ( events)
Totals
80.4
14,617
99.7 of pravastatin-treated subjects received
40mg dose
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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

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Meta-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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Meta-Analysis Models

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

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Relative Risk ReductionCox Proportional Hazards
All Trials
Relative Risk (95 CI)
RRR
RRR Relative Risk Reduction
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Relative Risk ReductionCox Proportional Hazards
LIPID and CARE
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Relative Risk ReductionCox Proportional Hazards
LIPID and CARE
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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

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Model 2 Hierarchical, Random Effects
Fatal or Non-Fatal MI
Cumulative Proportion of Events
Year
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Model 2 Hierarchical, Random Effects
Ischemic Stroke Only
Cumulative Proportion of Events
Year
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Model 2 Hierarchical, Random Effects
CHD Death, Non-Fatal MI, CABG,PTCA, or Ischemic
Stroke
Cumulative Proportion of Events
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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

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Model 2 Fatal or Non-Fatal MI
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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

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Model 3 Fatal or Non-Fatal MI
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Conclusion of Hazard Analysis over Time

• Benefit of pravastatinaspirin over aspirin was
  present in each year of the 5-year duration of
  the trials

• Benefit of pravastatinaspirin 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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