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 brain, kidney and peripheral circulation account for most cardiovascular clinical events. Endothelial dysfunction occurs as an early event in the atherosclerotic process. Thus, therapeutic interventions able to improve early endothelial dysfunction, particularly in the coronary circulation, would be most appropriate. In this paper we describe the background, rationale and design of the ENCORE trials. In ENCORE I, four groups of 100 patients each with coronary artery disease (CAD) undergoing percutaneous transluminal angioplasty (PTCA) will be recruited. After PTCA, endothelial function is assessed by intracoronary (i.c.) infusion of increasing dosages of acetylcholine in a non-obstructed coronary segment. Coronary responses to acetylcholine will be measured by quantitative coronary angiography (QCA) and Doppler flow velocity measurements. Endothelium-independent responses are tested by i.c. adenosine and nitroglycerine respectively. Patients will then be randomly assigned in a double-blind fashion to four treatment groups: placebo, nifedipine (30-60 mg . day - '), cerivastatin (400 μg. day - ') 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 combination improve endothelial function within 6 months. The ENCORE II trial will last 2 years, and aims at correlating endothelial function (as assessed by QCA and intravascular ultrasound; IVUS) and structural atherosclerosis in patients treated with cerivastatin, 200 receiving 200 μg. day -1 and 200 receiving 800 μg.day -1 , compared with 200 patients having a combination treatment with cerivastatin (800 μg. day - 1 ) and nifedipine (30-60mg). Endothelium-dependent responses of epicardial coronary arteries to acetylcholine 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 another acetylcholine test, QCA and IVUS will be performed. These trials will give an answer to the question of whether calcium antagonists and statins alone or in combination reverse abnormal endothelium-dependent responses to acetylcholine in patients with CAD. Furthermore, the studies will allow us to determine whether endothelial dysfunction and/or its improvement is associated with progression or regression of atherosclerotic coronary artery disease and possibly clinical events.