From endothelial dysfunction to clinical events - Concept and update on the ENCORE trials

In Western Countries morbidity and mortality are still mainly related to co ronary artery disease and its complications, such as angina pectoris and my ocardial infarction. An early event in atherosclerosis is endothelial dysfu nction. For this reason, therapeutic interventions aiming to restore corona ry endothelial dysfunction may be clinically relevant. A number of studies have been performed in surrogate circulations, such as the human forearm, although not much is known about the effects of interven tion in the coronary circulation. For the ENCORE I trial 343 patients with coronary artery disease undergoing percutaneous transluminal angioplasty, w ith or without stenting, have been randomized. After the coronary intervent ions, endothelial function was assessed by intracoronary (i.c.) infusion of increasing dosages of acetylcholine in a coronary segment without stenotic lesions. Quantitative coronary angiography (QCA) and Doppler flow velocity measurements were used to measure coronary responses to acetylcholine. End othelium-independent responses are tested by i.c. adenosine and nitroglycer ine. Patients were randomly assigned in a double-blind fashion to four trea tment groups: placebo, nifedipine at 30-60 mg.day(-1), cerivastatin at 400 mug.day(-1) or their combination. Studies have been repeated in 247 patient s after an interval of 6 months and the trial was completed in August 2000. This trial will determine whether or not endothelial function in patients with coronary artery disease is improved within 6 months by calcium antagon ists and/or a statin alone or in combination. The ENCORE II trial is scheduled to run for 2 years. It examines the correl ation between endothelial function and structural atherosclerosis (as asses sed by QCA and intravascular ultrasound [IVUS]) in 200 patients each treate d with cerivastatin at a dose of 200 or 800 mug.day(-1) compared with 200 p atients treated with a combination of cerivastatin at a dose of 800 mug.day (-1) and nifedipine at a dose of 30-60 mg. day(-1). Endothelium-dependent r esponses of epicardial coronary arteries to acetylcholine at baseline as we ll as structural vascular changes, as assessed by IVUS, will be correlated and followed over 2 years. After 2 years the acetylcholine test, QCA and IV US are to be repeated. Over 150 patients have so far been enrolled in the t rial. The ENCORE trials will show at the clinical level whether or not calcium an tagonists and statins, alone or in combination, reverse early corollary end othelial dysfunction. In addition, these trials will address the question w hether endothelial dysfunction and its pharmacological improvement are asso ciated with progression or regression of atherosclerotic coronary artery di sease. Finally, it may provide evidence whether this is reflected in fewer clinical events as suggested by several small observational studies.