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CONTENTS

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SUMMARY OF THE STUDY AIMS AND DESIGN

1. BACKGROUND AND RATIONALE

1.1 CHOLESTEROL AND CORONARY HEART DISEASE: EXISTING EVIDENCE

• In observational epidemiological studies, lower blood cholesterol is associated with a lower CHD risk throughout the "normal" UK range
Observational relationship between cholesterol and CHD risk: 1 mmol/l PROLONGED difference in cholesterol corresponds to about 50% less CHD
• Rapid reduction of CHD in previous cholesterol-lowering trials: at least half of the CHD avoidance associated with a prolonged 10% cholesterol difference appeared within just a few years
• Previous trials have been too small to assess reliably the effects of their rather ineffective cholesterol-lowering treatments on total or on non-CHD mortality

1.2 HMG CoA REDUCTASE INHIBITORS: THE SUBSTANTIAL, SUSTAINED CHOLESTEROL REDUCTIONS PRODUCED BY THESE AGENTS PROVIDE AN OPPORTUNITY TO ADDRESS THE TOTAL MORTALITY QUESTION

• Experience with HMG CoA reductase inhibitors in other trials
• Experience with simvastatin in the pilot study for the present mortality trial

1.3 CHOLESTEROL AND TOTAL MORTALITY: NEED FOR A LARGE TRIAL

• Need to resolve uncertainties about the effects of the newer cholesterol-lowering drugs on total mortality
• Current trials cannot be relied on to provide clear answers about the effects of HMG CoA reductase inhibitors on total mortality
• Heart Protection Study: reliable assessment of the effects of cholesterol-lowering therapy on total mortality, CHD and non-CHD mortality

1.4 RELIABLE ASSESSMENT OF THE EFFECTS OF ANTIOXIDANT VITAMIN SUPPLEMENTATION

• The possible link between oxidative modification of LDL cholesterol and CHD
• Inhibition of LDL cholesterol oxidation might retard atherosclerosis
• Prevention of CHD by antioxidant vitamins: limited evidence from observational epidemiology and randomised trials
• Heart Protection Study: an opportunity to obtain substantial evidence on the effects of antioxidant vitamin supplementation on CHD in high-risk patients

2. PLAN OF INVESTIGATION

2.1 AIMS

2.2 INCLUSION OF A WIDE RANGE OF PEOPLE AT HIGH RISK OF CHD

• Many different categories of patient at high risk of CHD death
• Wide range of cholesterol levels eligible

2.3 TREATMENT COMPARISONS

• Simvastatin versus placebo and vitamins versus placebo
• Full efficiency: "factorial" (2 x 2) design allows the separate assessment both of simvastatin and of vitamin supplementation without any material effect on non-drug study cost or on sample size requirements
• Factorial (2 x 2) design is valid whether or not any interactions exist

2.4 SAMPLE SIZE AND PREDICTED NUMBERS OF EVENTS

• 6000-7000 individuals in each of three main high-risk categories (total: 20,000+)

2.5 ASSESSMENT OF OUTCOME AND DATA MONITORING

• Main and subsidiary assessments of outcome
• Interim analyses: role of the Data Monitoring Committee and Steering Committee
• Monitoring of any serious adverse experiences believed to be due to study treatment

2.6 CENTRAL COORDINATION AND COLLABORATING CLINICS

• Central coordination by the Clinical Trial Service Unit
• Organisation of study clinics in collaborating hospitals
• Funding and non-negligent liability
• Publication in the names of all collaborators

3. SUMMARY OF PRACTICAL PROCEDURES (see Hospital Manual for details)

FLOW CHART

3.1 ELIGIBILITY AND IDENTIFICATION OF SUITABLE PATIENTS

• Eligibility for the study
• Identification and invitation of potentially eligible patients to Screening Clinics

3.2 SCREENING CLINIC VISIT (-2 MONTHS)

• Relevant medical history, physical examination and blood samples
  

• Invitation to participate in the randomised study and patient consent
  
• Run-in period prior to randomisation

3.3 RANDOMISATION CLINIC VISIT (0 MONTHS)

• Final check of eligibility and compliance before randomisation
• Treatment allocation

3.4 POST-RANDOMISATION CLINIC FOLLOW-UP

• Follow-up visits at 4, 8 & 12 months and then at 6-monthly intervals
• Early Recall visits to monitor significant biochemical abnormalities or other problems, and for treatment modification
• Immediate reporting of any serious adverse experiences believed to be due to study treatment

3.5 CENTRAL ASCERTAINMENT OF BIOCHEMICAL EFFECTS, AND OF VASCULAR EVENTS, CANCERS AND CAUSE-SPECIFIC MORTALITY

• Assessment of effects of treatment on lipid profile and vitamin levels
• Confirmation of non-fatal events
• Follow-up of deaths and of non-fatal cancers

REFERENCES

STEERING AND DATA MONITORING COMMITTEES, AND CONTACT DETAILS FOR COORDINATING CENTRE