HPS
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Front Cover
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Contents
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Section 1
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Section 2
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Section 3
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Appendix
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References
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Back Cover
CONTENTS
SUMMARY OF THE STUDY AIMS AND DESIGN
1. BACKGROUND AND RATIONALE
1.1
CHOLESTEROL AND CORONARY HEART DISEASE: EXISTING EVIDENCE
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In observational
epidemiological studies, lower blood cholesterol is associated with a lower
CHD risk throughout the "normal" UK range
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Observational relationship between cholesterol and CHD risk: 1 mmol/l
PROLONGED difference in cholesterol corresponds to about 50% less CHD
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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
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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
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Experience with HMG CoA reductase inhibitors in other trials
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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
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The possible link between oxidative modification of LDL cholesterol and CHD
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Inhibition of LDL cholesterol oxidation might retard atherosclerosis
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Prevention of CHD by antioxidant vitamins: limited evidence from
observational epidemiology and randomised trials
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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
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Many different categories of patient at high risk of CHD death
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Wide range of cholesterol levels eligible
2.3 TREATMENT COMPARISONS
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Simvastatin versus placebo and vitamins versus placebo
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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
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Factorial (2 x 2) design is valid whether or not any interactions exist
2.4 SAMPLE SIZE AND PREDICTED NUMBERS OF EVENTS
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6000-7000 individuals in each of three main high-risk categories (total:
20,000+)
2.5 ASSESSMENT OF OUTCOME AND DATA MONITORING
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Main and subsidiary assessments of outcome
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Interim analyses: role of the Data Monitoring Committee and Steering
Committee
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Monitoring of any serious adverse experiences believed to be due to study
treatment
2.6
CENTRAL COORDINATION AND COLLABORATING CLINICS
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Central coordination by the Clinical Trial Service Unit
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Organisation of study clinics in collaborating hospitals
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Funding and non-negligent liability
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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
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Eligibility for the study
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Identification and invitation of potentially eligible patients to Screening
Clinics
3.2 SCREENING CLINIC VISIT (-2 MONTHS)
3.3 RANDOMISATION CLINIC VISIT (0 MONTHS)
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Final check of eligibility and compliance before randomisation
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Treatment allocation
3.4 POST-RANDOMISATION CLINIC FOLLOW-UP
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Follow-up visits at 4, 8 & 12 months and then at 6-monthly intervals
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Early Recall visits to monitor significant biochemical abnormalities or other
problems, and for treatment modification
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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
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Assessment of effects of treatment on lipid profile and vitamin levels
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Confirmation of non-fatal events
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Follow-up of deaths and of non-fatal cancers
APPENDIX:
Suggested information leaflet for potentially eligible patients (to be
revised as considered necessary by local ethics committees)
STEERING AND DATA MONITORING
COMMITTEES, AND
CONTACT DETAILS FOR COORDINATING CENTRE
HPS
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Front Cover
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Contents
*
Section 1
*
Section 2
*
Section 3
*
Appendix
*
References
*
Back Cover