Selecting a fixed combination to improve morbidity/mortality: the weight of evidence with ASCOT

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm was designed to compare the effects of a standard combination starting with atenolol and adding a thiazide as needed and a newer combination starting with amlodipine and adding perindopril as needed. Because the newer regimen was associated with a significant reduction in all-cause mortality, the trial was stopped early. Nevertheless, the newer regimen was associated with a significantly superior effect on the primary endpoint excluding silent myocardial infarction, or including revascularization procedures, on total coronary events, cardiovascular (CV) mortality, fatal and non-fatal strokes, unstable angina, total CV events and procedures, new-onset diabetes, and development of renal impairment. The newer regimen was associated with an average blood pressure (BP) which was 2.7/1.9 mmHg lower than that of the standard regimen. Although it seems likely that this BP difference contributed to the superior prevention by the newer regimen, extensive analyses suggested that other advantages of the newer regimen contributed to this superiority. This is in keeping with other findings which suggest that angiotensin-converting enzyme inhibitors may have benefits beyond BP lowering in relation to coronary heart disease events and that calcium channel blockers may have benefits beyond BP lowering in relation to stroke protection.