The West of Scotland Coronary Prevention Study - WOSCOPS

Description:

Pravastatin for primary prevention of CHD death.

Hypothesis:

The reduction of serum cholesterol by treatment with pravastatin over an average period of 5 years will lead to a reduction in fatal and non-fatal myocardial infarction (MI).

Study Design

Study Design:

Patients Screened: 81,161
Patients Enrolled: 6,595
Mean Follow Up: 4.9 years
Mean Patient Age: 55.2
Female: 0
Mean Ejection Fraction: Not given

Patient Populations:

45 to 64-year-old men
LDL cholesterol level >4.5 mmol/L (174 mg/dL)

Exclusions:

History of treated MI with documented ECG or enzyme changes.
Angina pectoris requiring hospitalization for treatment or investigation within the previous 12 months. Others with positive Rose Questionnaire were not excluded.
ECG evidence of disease. Minnesota codes 1-1, 1-2, 1-3, 4-1, 5-1, 6-4-1, 7-1-1, or 9-6. Atrial fibrillation (8-3-1)/flutter (8-3-2), frequent (>1 in 5) ventricular premature beats, second (6-2) or third degree atrioventricular block (6-1) as well as A-V dissociation (8-6).
Hypertension exceeding systolic BP >180 mm Hg or diastolic BP >110 mm Hg, despite treatment.
History of rheumatic heart disease.
Pulmonary heart disease, chronic bronchitis, emphysema or kyphoscoliosis associated with ECG changes codes 2-2, 3-2, 7-2 or 7-3.
Cardiomegaly, congestive heart failure, significant valvular heart disease.
Other suspected serious illness.
Psychiatric illness (reported by GP).
Current lipid lowering therapy.

Laboratory exclusions:
AST (U/1) >60
ALT (U/1) >70
Ca (mmol/L) (adjusted) <2.1, >2.7
ALP (U/1) >430
Protein (g/L) <57, >87
CK (U/1) >360
Creatinine (µmol/L) >155
Glucose (mmol/L) >10.0, <3.0
MCV (fl) >105, <70
Triglyceride (mmol/L) >6.0
Hb (g/L) <10, >20
Leucocyte count (cell/L) <2.5 x 109 >17 x 109
RBC (cell/L) >7.0 x 1012 <3.7 x 1012
Na (mmol/L) <130, >150
K (mmol/L) <3.0, >5.5
Bilirubin (µmol/L) >33

Primary Endpoints:

The combined endpoint of death from coronary heart disease (CHD) plus nonfatal MI.

Secondary Endpoints:

CHD death only (whether preceded by a nonfatal MI or not), nonfatal MI only, and total mortality.

Drug/Procedures Used:

Pravastatin 40 mg qhs.

Principal Findings:

Coronary event rates at five years in the WOSCOPS placebo group were higher than 10% (the recommended treatment threshold) in men with pre-existing vascular disease and in those >55 years without symptoms or signs of CHD but with at least one other risk factor.

Event rates were low in men with hypercholesterolemia but no other risk factor: 3.5% (95% confidence interval 1.3-5.7) for men aged from 45 to 54 years and 5.3% (2.7-8.0) for men aged 55 to 64 years.

Three times more men had to be treated for five years to prevent one endpoint in WOSCOPS than 4S.

By contrast, two to four times fewer men with hyperlipidemia were treated to save one coronary event in WOSCOPS than hypertensives to save one stroke in the MRC trial. These differences persisted after adjustment for the low-risk status of many of the patients with hypertension who took part in the MRC trial.

In a substudy analysis, WOSCOPS data were used to estimate the potential impact of current treatment guidelines from the U.S., Britain, and Europe. WOSCOPS patients were grouped and analyzed based on the 3 treatment guidelines. For this analysis, the investigators expanded the endpoint definition to encompass a wider range of cardiovascular events which might be prevented by the application of lipid-lowering therapy. This new analysis showed a 22% reduction for the expanded endpoint. The risk reduction was likely diluted by events which were not preventable with pravastatin.

Investigators allocated the 3,293 WOSCOPS placebo patients to hypothetical "treated" and "untreated" groups based upon each of the 3 guidelines. By applying a 22% relative risk reduction to the "treated" groups, the investigators predicted the potential effect of the guidelines on clinical outcomes at 5 years. Of 101 preventable CVD events if all WOSCOPS placebo subjects were treated, the NCEP approach would prevent 91%, European 82%, and British 54%, at the cost of treating 81%, 66%, and 34% of the subjects, respectively.

Interpretation:

There was a substantial number of men whose risk of a coronary event was more than 10% at five years in the WOSCOPS cohort. The absolute benefit of pravastatin treatment of hyperlipidemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged men.

The U.S. National Cholesterol Education Program (NCEP) recommendations are based on the number of risk factors present in an individual patient. In Britain, guidelines recommend initiating aggressive therapy for dyslipidemia when the risk of a "major coronary event" is ≥3% per annum (≥15% 5-year risk) vs. a ≥20% risk over 10 years (approximately 2% per annum) in the European guidelines. The WOSCOPS guidelines substudy further illustrates the balance between cost and clinical outcomes within these recommendations.

References:

1. J Clin Epidemiol 1992;45:849-860. Trial design
2. Am J Cardiol 1995;76:485-491. Baseline characteristics
3. New Engl J Med 1995;333:1301-7. Final results
4. Lancet 1996;348:1339-1342. Review
5. BMJ 1997;315:1577-82. Economic analysis
6. Circulation 1998;98(Suppl I):I-47. Guideline effectiveness

Clinical Topics: Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: Stroke, Myocardial Infarction, Hyperlipidemias, Cholesterol, LDL, Risk Reduction Behavior, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Hypercholesterolemia, Primary Prevention, Secondary Prevention, Research Personnel, Pravastatin, Confidence Intervals, Hypertension


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