The following slides are from a Cardiology Scientific Update in which Dr. Gordon Moe reported and discussed an original presentation by Drs. Bjorn Dahlof, Peter Sever, Hans Wedel, and R. Preston Mason. The presentation was given at a Satellite Symposium and the Late Breaking Clinical Trial Sessions of the American College of Cardiology 52nd Annual Scientific Session, which took place between March 30 and April 2, 2003 in Chicago Illinois.

Mortality from CHD bears strong and graded relationships with blood pressure and serum cholesterol level. The impact of each risk factor on CHD mortality is additive. Hypertension and dyslipidemia both induce endothelial dysfunction, which activates numerous pathologic mechanisms, as seen in this slide, that ultimately result in adverse clinical outcomes. These mechanisms explain, in part, the combined adverse effects of hypertension and dyslipidemia on CV outcomes and provide a rationale for aggressive treatment of both conditions. High BP and high cholesterol have a much greater influence on population health than previously thought. About two-thirds of strokes and close to one-half of cases of CHD can be attributed to systolic BP >115 mm Hg. On the other hand, 18% of strokes and 55% of the cases of CHD globally can be accounted for by total cholesterol >3.8 mmol/L.

The Framingham Heart Study demonstrated that the major risk factors are additive in predictive power for the development of CHD. These findings underscore the usefulness of assessing global risk of patients and the need for multiple risk factor intervention, and forms the rationale for the ASCOT study. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a multicentre, international trial that involves two treatment comparisons in a factorial design. The primary objectives of ASCOT were: • To compare the effects on the combined endpoint of non-fatal myocardial infarction (MI) and fatal CHD of a ß-blocker, atenolol (+ a diuretic, if necessary) with a calcium channel blocker (CCB) (+ an angiotensin-converting enzyme (ACE) inhibitor, if necessary) • To compare the effect on the same outcome of a statin, atorvastatin (starting dose 10 mg daily, not titrated) with that of placebo, among hypertensive patients with total cholesterol ≤6.5 mmol/L. The study has, in addition to the primary endpoint, multiple secondary and tertiary endpoints. In the lipid-lowering arm that included over 10,000 patients, the study had >90% power with a significance level of 1% to detect a 30% relative reduction in coronary events by atorvastatin versus placebo. This slide illustrates the study design for ASCOT.

The lipid-lowering arm of ASCOT was terminated early based on a benefit observed in the atorvastatin over the placebo group on the primary endpoint. The hypertension arm of ASCOT is still ongoing. The two groups were comparable in baseline demographics. Most patients were followed to the end of the study with very few lost to follow-up. Results of the primary endpoint, the time to first nonfatal MI and fatal CHD, are shown in the above slide. Compared to placebo, atorvastatin produced a 36% relative reduction in the combined endpoint over approximately 3.5 years.

In addition to the beneficial effect on the primary endpoint, the risks for secondary endpoints – total CV events and procedures, total coronary events, nonfatal MI (excluding silent MI) and fatal CHD, as well as fatal and nonfatal stroke shown in the above slide – were all significantly reduced.

After 3 years of follow-up, 87% of patients assigned to atorvastatin were still taking a statin and 9% assigned to placebo had been prescribed open-label statins. BP control was similar for both groups, with identical mean values of 138/80 mm Hg for both groups at the end of the lipid-lowering arm follow-up. Total cholesterol and LDL-C were both reduced by 1 mmol/L at the end of follow-up, as seen in this slide.

The effect of atorvastatin on the primary endpoint, together with the secondary and tertiary endpoints, expressed as hazard ratios (HR), is shown in the above slide. In addition to the beneficial effects on the primary endpoint and the secondary endpoints, there was also a non-significant trend that favoured atorvastatin for all-cause mortality and CV mortality. The effects on the tertiary endpoints are more difficult to interpret due to the wide confidence intervals. Analysis according to predefined subgroups indicates that the benefit of atorvastatin on the primary outcome is consistent, regardless of the presence or absence at baseline of diabetes, smoking, obesity, left ventricular hypertrophy, age > 60 years, previous vascular disease, renal dysfunction, and metabolic syndrome. Also, the benefit of atorvastatin is similar for a broad spectrum of baseline total cholesterol levels: total cholesterol <5.0 mmol/L (HR 0.628, p=0.098); total cholesterol 5.0-5.9 mmol/L (HR 0.615, p <0.011); total cholesterol ≥6.0 mmol/L (HR 0.689, p=0.084). The benefits of atorvastatin appear to emerge early. Furthermore, the reductions in major CV events are large given the short follow-up time and they occurred earlier than in many other statin trials. These benefits are accrued in the absence of any increased risk of non-CV disease, including fatal cancer and liver function abnormalities. The results of ASCOT-LLA, together with other recently published statin trials are likely to have an important impact on the existing recommendations for the primary and secondary prevention of CHD.