Analysis and Interpretation of Subgroups David L. DeMets, Ph.D. University of Wisconsin Madison, WI

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Analysis and Interpretationof SubgroupsDavid
L. DeMets, Ph.D.University of WisconsinMadison,
WI
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Disclosure Information
The following relationships exist related to this
presentation Trials Sponsorship Consultant/
DSMB Member NIH Astra-Zeneca Merck Myog
en Bristol Myers Squibb Guidant Eli Lilly
Actelion Pfizer GlaxoSmith Klne Wyeth-Ayerst
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Subgroup Motivation

• Response of average patient is not response of
  individual patient
  
• (Yusuf, et al., JAMA, 1991)
• (Bernard, et al., 1957)
• Move RCT results closer to individual patient
• (Julian, Current Cardiovascular Trials, 2000)

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Primary and Secondary Questions

• Primary
• most important, central question
• ideally, only one
• stated in advance
• basis for design and sample size
• Secondary
• related to primary
• stated in advance
• limited in number

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Subgroup Questions

• Questions about effect of therapy in a
  sub-population of subjects entered into the
  trial
  
• Primary outcome
• Secondary outcome
• Rationale
• Consistency of primary and secondary outcomes
• Confirmation
• Exploratory

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Subgroup Issues

• Properly Defined
• False Positives
• Degree of Consistency
• Precision of Treatment Effect Estimate

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Appropriate/Proper Subgroups

• Defined in advance
• Defined by baseline measurements only
• Based on external definitions, no slicing and
  dicing

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Inappropriate Subgroups

• Defined by
• Unblinded post hoc review of eligibility
• Compliance to treatment
• Intermediate outcomes (e.g. blood pressure
  change)
  
• Produce biased or nonsense analysis

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False Positive Rates

• The greater the number of subgroups analyzed
  separately, the larger the probability of making
  false positive conclusions.
  
• No. of Subgroups False Positive Rate
• 1 .05
• 2 .08
• 3 .11
• 4 .13
• 5 .14
• 10 .19

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Example - Subgroup Concern

• Second International Study of Infarct Survival
  (ISIS 2) (Lancet, 1988)
  
• 2 x 2 factorial design
• (aspirin vs. placebo and streptokinase vs.
  placebo)
  
• vascular and total mortality in patients with an
  acute myocardial infarction (MI)
  
• Gemini or Libra astrological birth signs did
  somewhat worse on aspirin while all other signs
  and overall results impressive and highly
  significant benefit from aspirin

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Consistency of Results

• Absolute consistency not realistic
• Variation across properly defined subgroups to be
  expected
  
• Degree of variation depends on
• True effect size
• Size of trial and subgroups
• Look cautiously for qualitative differences

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MERIT-HF Study Design

• Chronic heart failure patients
• Randomized placebo controlled
• Metoprolol vs. placebo
• Two-week placebo run in (compliance)
• Entered 3991 patients
• Terminated early
• Mean follow-up approximately one year
• The International Steering Committee on Behalf of
  the MERIT-HF Study Group,
  
• Am J Cardiol 1997 80(9B)54J-58J. The MERIT-HF
  Study Group, ACC, March 1999.

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MERIT Total Mortality
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MERIT
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MERIT(AHJ, 2001)
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BHAT Hazard Ratios for All-Cause Mortality
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SubgroupsRef NEJM, 1996

• Not all subgroup results are valid
• False positive claims
• Classic Example in cardiology
• Major trial identified possible subgroup result

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Praise IRef NEJM, 1996

• Amlodipine vs. placebo
• NYHA class II-III
• Randomized double-blind
• Mortality/hospitalization outcomes
• Stratified by etiology (ischemic/non-ischemic)
• 1153 patients

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Subgroup or Treatment Interaction

• PRAISE I (NEJM, 1996)
• Patients with ischemic and non-ischemic
• Predefined stratified randomization
• Mortality, a secondary outcome
• Group Relative Risk P-value
• Total .84 .07
• Ischemic 1.02
• Non-Ischemic .54
• Interaction Test P .004

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PRAISE I
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PRAISE I - Interaction

• Overall P 0.07
• Etiology by Trt Interaction
• P 0.004
• Ischemic P NS
• Non-Ischemic P

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PRAISE I - Ischemic
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PRAISE I Non- Ischemic
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PRAISE II

• Repeated non-ischemic strata
• Amlodipine vs. placebo
• Randomized double-blind
• 1653 patients
• Mortality outcome
• RR ? 1.0

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Subgroup by Treatment Interaction

• Trial Relative Risk
• PRAISE I
• Non-Ischemic Subgroup .54
• PRAISE II
• All Non-Ischemic 1.05
• Subgroup replication still required

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Estimate of Treatment Effect

• Overall power/precision of trial barely adequate
• Each subgroup has limited power and precision
• Best estimate of treatment effect for any
  subgroup is overall estimate

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Three Views

• Ignore subgroups and analyze only by treatment
  groups. (Sleight 2000)
  
• Do subgroup analyses --- However view all results
  with caution.
  
• Plan for subgroup analyses in advance. Do not
  mine data. Be cautious
  
• Distinguish confirmatory vs. exporatory
• Consistency

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Subgroup Analysis

• Guidelines for Subgroups
• 1. Defined by baseline measurements
• 2. Stated in advance (in protocol)
• 3. Limited number of confirmatory
• 4. Label exploratory subgroups
• 5. Interpreted cautiously, qualitatively
• 6. Look for general consistency of results
• Formal adjustments for multiplicity problematic
  if more than a few are done