Summary.A total of 19,257 hypertensive patients aged 40-79 years old with at least three other cardiovascular (CV) risk factors were assigned either to the calcium channel blocker (CCB) amlodipine, 5-10 mg, adding the angiotensin-converting enzyme inhibitor (ACEI) perindopril, 4-8 mg, as required; or the β blocker atenolol, 50-100 mg, adding the diuretic bendroflumethiazide, 1.25-2.5 mg, and potassium as required. The primary end point was nonfatal myocardial infarction (MI) and fatal coronary heart disease, using intention-to-treat analysis. The study was stopped prematurely after 5.5 years' median follow-up because the data and safety monitoring indicated that the amlodipine-based group had significantly better outcomes in secondary end points. Although fewer individuals in the amlodipine group reached the primary end point (429 vs. 474), the results were not significant (adjusted relative risk [RR], 0.90; 95% confidence interval [CI], 0.79-1.02). As indicated, however, the amlodipine-based group had significantly lower secondary end points of all-cause mortality, total CV events and procedures, fatal and nonfatal stroke, and incidence of diabetes. After adjustment for coronary and stroke findings by multivariate analysis, residual differences were no longer significant.Rationale. The study compared newer antihypertensive regimens (CCB and ACEI) vs. the β blocker and diuretic because at the time of the study inception, there were limited data on the relative effects of these newer agents, and because earlier hypertension trials showed less than the expected decrease in coronary heart disease events with the earlier agents and the newer agents do not have the metabolic side effects that presumably might have adversely affected coronary heart disease outcomes with the former. It was also understood that at least two agents were needed to achieve blood pressure (BP) targets, and the most common combinations used at the time were diuretics and β blockers, primarily thiazides and atenolol. Despite evidence that CCBs and ACEIs were effective in BP control in limited studies, safety and cost issues were of concern at the time. For example, some observational data had brought into question the safety of dihydropyridine CCBs.Study Design. The patients were recruited between 1998 and 2000. Patients were evaluated at clinical centers in the United Kingdom, Ireland, and the Scandinavian countries. BP had to be at least 160 mm Hg systolic or 90 mm Hg diastolic if previously untreated, or 140 mm Hg systolic or 90 mm Hg diastolic, if treated. The three additional risk factors were included from the following list: left ventricular hypertrophy on echocardiography or electrocardiography (ECG); other specified ECG abnormalities; type 2 diabetes; peripheral arterial disease; previous stroke or transient ischemic attack; male sex; age 55 years or older; microalbuminuria or proteinuria; smoking; total cholesterol/high-density lipoprotein (HDL) cholesterol ratio of 6 or higher; or family history of premature coronary artery disease...