West Of Scotland Coronary Prevention Study Research Articles

Coronary risk estimation and treatment of hypercholesterolemia.

Evidence-based treatment of hypercholesterolemia currently recommended for rationalizing drug prescription requires justification of treatment by randomized trials, such as the West of Scotland Coronary Prevention Study (WOSCOPS) or the Scandinavian Simvastatin Survival Study (4S), and evaluation of its benefit from the estimation of the coronary risk of each patient. The latest European guidelines and Sheffield tables apply these principles and justify the decision to treat hypercholesterolemia if the Framingham coronary multivariate risk estimate is high enough, ie, >20% risk of coronary event at 10 years in the former and >1.5% risk of coronary death per year in the latter. Nevertheless, the practice of these two recent guidelines results in discrepancies in the decision to treat, because coronary morbidity was considered in one but mortality was considered in the other, and the risk required for treating may be extrapolated from different trials (4S or WOSCOPS). Although the principle of targeting lipid-lowering treatment to high-risk subjects is unquestioned, further studies are needed to demonstrate that the Framingham risk profile is useful in selecting persons who are likely to benefit and to determine the place of newer risk factors and that of early noninvasive detection of atheroma in the risk estimation-based treatment.

1.P.145 A follow-up report on mortality in the West of Scotland Coronary Prevention Study (WOSCOPS)

1.P.145 A follow-up report on mortality in the West of Scotland Coronary Prevention Study (WOSCOPS)

1.P.153 Influence of pravatatin and plasma lipids on clinical events, in the West of Scotland Coronary Prevention Study (WOSCOPS)

BACKGROUND: The West of Scotland Coronary Prevention Study was a primary prevention trial that demonstrated the effectiveness of pravastatin (40 mg/d) in reducing morbidity and mortality from coronary heart disease (CHD) in moderately hypercholesterolemic men. The present analysis examines the extent to which differences in LDL and other plasma lipids both at baseline and on treatment influenced CHD risk reduction. METHODS AND RESULTS: Relationships between baseline lipid concentrations and incidence of all cardiovascular events and between on-treatment lipid concentrations and risk reduction in patients taking pravastatin were examined by use of Cox regression models and by division of the cohort into quintiles. Variation in plasma lipids at baseline did not influence the relative risk reduction generated by pravastatin therapy. Fall in LDL level in the pravastatin-treated group did not correlate with CHD risk reduction in multivariate regression. Furthermore, maximum benefit of an approximately 45% risk reduction was observed in the middle quintile of LDL reduction (mean 24% fall); further mean decrements in LDL (up to 39%) were not associated with a greater decrease in CHD risk. Comparison of event rates between placebo- and pravastatin-treated subjects with the same LDL cholesterol level provided evidence for an apparent treatment effect that was independent of LDL. CONCLUSIONS: We conclude that the treatment effect of 40 mg/d of pravastatin is proportionally the same regardless of baseline lipid phenotype. There is no CHD risk reduction unless LDL levels are reduced, but a fall in the range of 24% is sufficient to produce the full benefit in patients taking this dose of pravastatin. LDL reduction alone does not appear to account entirely for the benefits of pravastatin therapy.

1.P.158 Identification of the most appropriate recipients of pravastatin therapy in the West of Scotland Coronary Prevention Study (WOSCOPS) cohort

1.P.158 Identification of the most appropriate recipients of pravastatin therapy in the West of Scotland Coronary Prevention Study (WOSCOPS) cohort

1.P.159 Assessment of liver function monitoring in the West of Scotland Coronary Prevention Study (WOSCOPS)

1.P.159 Assessment of liver function monitoring in the West of Scotland Coronary Prevention Study (WOSCOPS)

Tomorrow's world: atherosclerosis in the year 2000

Atherosclerosis is an increasing problem, largely due to lifestyle changes. Lipid accumulates in artery walls throughout life, and infiltration into the subintimal space of cholesterol and cholesterol esters and of inflammatory cells can lead to narrowing, clotting, thrombosis and death. Lipid-lowering agents, particularly statins [(3-hydroxy-3-methylglutarate coenzyme A (HMG-CoA) reductase inhibitors] represent one important approach to treatment. They work by blocking the conversion of 3-hydroxy-3-methylglutarate into mevalonate, a precursor of cholesterol. The West Of Scotland Coronary Prevention Study (WOSCOPS) was a large prospective randomised study comparing the effects of pravastatin versus that of placebo in 6595 middle-aged men. In the pravastatin group the rate of fatal or non-fatal myocardial infarction was reduced by one-third over 5 years, the rate of cardiovascular deaths by one-third, and overall deaths by 22% relative to the placebo group. Implications of the results are considered and the results of the US-CARE study are compared. Discussion of relative and absolute risk, and continuous and discrete risk factors leads to the formulation of rational cost/beneficial strategies for decreasing cardiovascular risk by targeting high-risk individuals with lipid-lowering drugs.

West of Scotland Coronary Prevention Study: identification of high-risk groups and comparison with other cardiovascular intervention trials

We assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of coronary heart disease (CHD) by lipid lowering with the benefits of blood pressure reduction in the primary prevention of stroke. We did a subgroup analysis of placebo-treated men in the WOSCOPS population by age, vascular disease at trial entry, and other established risk factors. We also compared WOSCOPS findings with those of the Scandinavian Simvastatin Survival Study (4S) and the Medical Research Council (MRC) trial of treatment for mild to moderate hypertension in middle-aged men. The WOSCOPS population comprised 6595 men aged 45-64 years with no history of myocardial infarction (MI) and plasma total cholesterol concentrations of 6.5-8.0 mmol/L at initial screening. Participants were randomly allocated pravastatin (40 mg daily) or placebo, and followed up for an average of 4.9 years. Coronary event rates at 5 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 or older without symptoms or signs of CHD but with at least one other risk factor. Event rates were low in men with hypercholesterolaemia but no other risk factor: 3.5% (95% CI 1.3-5.7) for men aged 45-54 years and 5.3% (2.7-8.0) for men aged 55-64 years. Three times more men had to be treated for 5 years to prevent one endpoint in WOSCOPS than in 4S. By contrast, two to four times fewer men with hyperlipidaemia 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. There were a substantial number of men whose risk of a coronary event was more than 10% at 5 years in the WOSCOPS cohort. The absolute benefit of pravastatin treatment of hyperlipidaemia 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.

Review of cholesterol-lowering therapy: Coronary angiographic and events trials

Coronary angiographic trials have demonstrated that the lowering of cholesterol slows the progression of atherosclerosis, enhances atherosclerotic regression, limits the formation of new lesions, and reduces the incidence of coronary events. Atherosclerotic progression has been shown to be associated with an increased risk of cardiac death, cardiac death plus nonfatal myocardial infarction (MI), and all coronary events. Most of the atherosclerotic regression trials were too small and of too short duration to demonstrate a significant difference in hard coronary events between patients receiving cholesterol-lowering intervention and controls. However, when data from these studies were pooled, total mortality was found to be reduced by 26% and the rate of nonfatal MI by 39% in actively treated patients. The first events trial to demonstrate clearly a reduction in overall mortality was the Scandinavian Simvastatin Survival Study (4S), in which lowering of serum cholesterol in patients with coronary artery disease (CAD) and hypercholesterolemia also reduced coronary mortality, fatal and nonfatal MI, sudden cardiac death, and the need for revascularization. Reductions in major coronary events were seen consistently in all subgroups of patients studied and regardless of concomitant therapy with aspirin, beta blockers, or calcium antagonists. Further evidence of the benefit of cholesterol-lowering therapy was provided by the West of Scotland Coronary Prevention Study (WOSCOPS), which evaluated men with hypercholesterolemia but no history of CAD. Those receiving active treatment had less overall mortality, lower risk of definite nonfatal MI or death from definite or suspected CAD, and less need for revascularization. The Cholesterol and Recurrent Events (CARE) Study recently showed that lipid-lowering therapy is also beneficial in CAD patients with less severe dyslipidemia.

Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table

The Scandinavian Simvastatin Survival Study (4S) 1 Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383-1389 Summary PubMed Scopus (11230) Google Scholar and West of Scotland Coronary Prevention Study (WOSCOPS) 2 Shepherd J Cobbe SM Ford I et al. for the West of Scotland Coronary Prevention Study Group Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307 Crossref PubMed Scopus (7448) Google Scholar showed that the benefit of treatment with inhibitors of hydroxymethyl-glutaryl-coA-reductase (statins) in preventing major coronary heart disease (CHD) events substantially outweighs any harm when serum cholesterol averages 5·5 mmol/L or higher1 and when the risk of CHD events (myocardial infarction or coronary death) is 1·5% per year or higher. 2 Shepherd J Cobbe SM Ford I et al. for the West of Scotland Coronary Prevention Study Group Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995; 333: 1301-1307 Crossref PubMed Scopus (7448) Google Scholar The accepted priority for statin treatment is secondary prevention in patients who already have coronary disease or other clinically overt atherosclerotic disease and serum cholesterol of 5·5 mmol/L, or higher, since these patients have a high risk of CHD events (3-6% per year). 3 Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR. Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Google Scholar , 4 Haq IU Jackson PR Yeo WW Ramsay LE Sheffield risk and treatment table for cholesterol lowering for primary prevention of coronary heart disease. Lancet. 1995; 346: 1467-1471 Summary PubMed Google Scholar We have estimated that 4·8% of the UK population aged 35-69 years may be candidates for secondary prevention. 3 Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR. Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Google Scholar

Computerised record linkage: Compared with traditional patient follow-up methods in clinical trials and illustrated in a prospective epidemiological study

Computerised record linkage systems have great potential for enhancing or even replacing traditional methods of adverse event reporting based on active patient follow-up, both in clinical trials and in epidemiological studies. However, these methods must be evaluated. The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomised double-blind clinical trial of pravastatin versus placebo in the primary prevention of coronary heart disease, with coronary heart disease death plus nonfatal myocardial infarction as its primary end point. Adverse event reporting is based on active patient follow-up at routine trial visits. In parallel with this approach, we have obtained computer records of all deaths, incident cancers, and hospitalisations for our subjects by linking their names, dates of birth, and postcodes of their home addresses with a Scottish national database operated by the Scottish Record Linkage system. The results of this comparative study, based on follow-up of the 6595 men ages 45–64 randomised in WOSCOPS, demonstrate minor flaws in both systems, show that follow-up based on computerised linkage alone can be as effective as reporting based on direct contact with the patients, and show that a system based on both approaches provides a direct cross-validation of the two approaches to adverse event reporting while minimising the frequency of unreported events. Preliminary results are reported for a prospective epidemiological study of 80,184 men, ages 45–64 years, who were screened for coronary heart disease risk factors as part of WOSCOPS. This study is based solely on computerised linkage reporting of events on these subjects. This provides an indication of the number of events in various categories that will be available for analysis in future reports. The associations between death rates and standard risk factors such as age, blood pressure, total cholesterol level, and smoking status mirror those reported in other studies.

Design, rationale, and baseline characteristics of the Prospective Pravastatin Pooling (PPP) project—A combined analysis of three large-scale randomized trials: Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID), Cholesterol and Recurrent Events (CARE), and West of Scotland Coronary Prevention Study (WOSCOPS)

The Prospective Pravastatin Pooling (PPP) project is a pooled evaluation of 3 large, placebo-controlled, randomized trials of cholesterol-lowering treatment with pravastarin. It is designed to more reliably evaluate the effect of treatment on coronary and all-cause mortality and on total coronary artery disease (CAD) events for specific populations of interest, including women and the elderly. The trials—Long-Term Intervention With Pravastatin in Ischemic Disease trial, the Cholesterol and Recurrent Events trial, and the West of Scotland Coronary Prevention Study—each have common design features, including drug, dose, and duration. The project prospectively defines the objectives, end points, and analytic plans in a protocol developed before results are known of any individual trial. More than 2,000 (or 10%) of the participants in the pooled data set are women, 1,841 are aged ≥70 years at trial entry, and >6,000 have a total cholesterol <5.5 mmol/L (213 mg/dl). The mean low-density lipoprotein cholesterol level is 4.2 mmol/L (162 mg/dl). The mean blood pressure level is 134/81 mm Hg and 20% are current smokers. Half of the PPP participants have had a prior myocardial infarction. More than 7% have a history of diabetes and 26% have a history of hypertension. PPP is projected to have data on about 1,100 CAD deaths, 500 non-CAD deaths, and >1,000 cancers by study completion. Based on a pooled population of 19,768 patients, with approximately 1,600 deaths and 100,000 patient-years of follow-up, PPP should have good power to examine the effects of treatment on total mortality, CAD mortality, and cancer incidence, and ta determine effects on total CAD events in important subgroups including the elderly, women, diabetics, and those with lower serum cholesterol levels (<5.5 mmol/L [213 mg/dl]).

Benefits of pravastatin extend to primary prevention of CHD

Lowering cholesterol levels in men who have hypercholesterolaemia but no symptoms of cardiovascular disease can significantly reduce the risk of developing coronary heart disease (CHD), according to the results of the first major study of an HMG-CoA reductase inhibitor in primary prevention. The results of this landmark trial, which is referred to as the West of Scotland Coronary Prevention Study (WOSCOPS), were presented at the 68th Scientific Sessions of the American Heart Association [ Anaheim, US; November 1995 ], and have also been published in a recent issue of the NEJM. 1

Screening experience and baseline characteristics in the West of Scotland coronary prevention study

The West of Scotland Coronary Prevention Study (WOSCOPS) is a randomized, double-blind, placebo-controlled trial of pravastatin in a primary prevention context. The primary end point of the trial is definite coronary artery disease (CAD) death and/or nonfatal acute myocardial infarction. This study describes the baseline characteristics of the trial recruits and of the subjects who were screened during the recruitment process; 6, 595 men, aged 45 to 64 years, with raised cholesterol levels, were randomized in equal numbers to placebo or pravastatin after initial screening of approximately 81, 000 subjects in the West of Scotland. With the exception of cholesterol levels and history of CAD, the recruits had a similar risk factor profile and demographic distribution to the group of screenees from which they were selected. Compared with previous primary prevention studies of cholesterol-lowering drugs, the WOSCOPS recruits are, on average, 7 to 9 years older than subjects in other trials and have average total cholesterol levels 0.5 mmol/L (19.4 mg/dl) lower than those in the Helsinki Heart Study and the Lipid Research Clinics-Coronary Primary Prevention Trial. The study has achieved its initial goal of accumulating >30, 000 patient-years of randomized follow-up. Recruits had their final trial visits in the first half of 1995 and the main results will be available in the fourth quarter of 1995.

A coronary primary prevention study of Scottish men aged 45–64 years: Trial design

This paper describes the design of the West of Scotland Coronary Prevention Study (WOSCOPS) which is a primary prevention trial involving men aged 45–64 yr with raised plasma cholesterol levels. The principal aim is to test the hypothesis that reduction of serum cholesterol by treatment with pravastatin [a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase—a regulatory enzyme in cholesterol synthesis] over an average period of 5 yr will lead to a reduction in fatal and non-fatal myocardial infarction. A trial population of approx. 6500 men have been randomized in equal numbers to treatment with placebo or pravastatin. At the time of randomization, these men have no evidence of previous myocardial infarction. All subjects are given smoking and dietary advice throughout the study. The principal endpoints are: (i) coronary heart disease death plus non-fatal myocardial infarction, (ii) coronary heart disease death, and (iii) non-fatal myocardial infarction.