Effects of calcium antagonism and HMG-coenzyme reductase inhibition on endothelial function and atherosclerosis: rationale and outline of the ENCORE trials

Atherosclerosis and its complications in the coronary circulation, the brai n, kidney and peripheral circulation account for most cardiovascular clinic al events. Endothelial dysfunction occurs as an early event in the atherosc lerotic process. Thus, therapeutic interventions able to improve early endo thelial dysfunction, particularly in the coronary circulation, would be mos t appropriate. In this paper we describe the background, rationale and design of the ENCOR E trials. In ENCORE I, four groups of 100 patients each with coronary arter y disease (CAD) undergoing percutaneous transluminal angioplasty (PTCA) wil l be recruited. After PTCA, endothelial function is assessed by intracorona ry (i.c.) infusion of increasing dosages of acetylcholine in a non-obstruct ed coronary segment. Coronary responses to acetylcholine will be measured b y quantitative coronary angiography (QCA) and Doppler flow velocity measure ments. Endothelium-independent responses are tested by i.c. adenosine and n itroglycerine respectively. Patients will then be randomly assigned in a do uble-blind fashion to four treatment groups: placebo, nifedipine (30-60 mg. day(-1) ), cerivastatin (400 mu g. day (-1)) or their combination. Studies will be repeated at 6 months. This trial will determine whether or not in patients with CAD calcium antagonists and/or a statin alone or in combinati on improve endothelial function within 6 months. The ENCORE II trial will l ast 2 years, and aims at correlating endothelial function las assessed by Q CA and intravascular ultrasound; (IVUS) and structural atherosclerosis in p atients treated with cerivastatin, 200 receiving 200 mu g. day(-1) and 200 receiving 800 mu g.day(-1), compared with 200 patients having a combination treatment with cerivastatin (800 mu g.day(-1)) and nifedipine (30-60mg). E ndothelium-dependent responses of epicardial coronary arteries to acetylcho line at baseline as well as structural vascular changes as assessed by IVUS will be correlated and followed over 2 years. At the end of the 2 years an other acetylcholine test, QCA and IVUS will be performed. These trials will give an answer to the question of whether calcium antagon ists and statins alone or in combination reverse abnormal endothelium-depen dent responses to acetylcholine in patients with CAD. Furthermore, the stud ies will allow us to determine whether endothelial dysfunction and/or its i mprovement is associated with progression or regression of atherosclerotic coronary artery disease and possibly clinical events.