Sharon Nessim

Effects of colestipol-niacin therapy on human femoral atherosclerosis.

The 2-year therapy effect on femoral atherosclerosis was evaluated in the Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-plus-diet-controlled angiographic trial of colestipol-niacin therapy plus diet in men with previous coronary bypass surgery. Different diet compositions were prescribed to enhance the differential in blood cholesterol responses between the two groups. The annual rate of change in computer-estimated atherosclerosis (CEA), a measure of lumen abnormality, was evaluated between treatment groups. A significant per-segment therapy effect was found in segments with moderately severe atherosclerosis (p less than 0.04) and in proximal segments (p less than 0.02). When segmental CEA measures were combined into a per-patient score using an adaptation of the National Heart, Lung, and Blood Institute scoring procedure, a significant therapy effect was observed (p less than 0.02). Total variance of the annual change rate in CEA was as predicted from pilot studies, but measurement variation was larger. The therapy effect observed in femoral arteries, although significant, was less marked than the strong and consistent benefit previously reported for both native coronary arteries and aortocoronary bypass grafts.

The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results.

The Cholesterol Lowering Atherosclerosis Study (CLAS) is a prospective, placebo-controlled, angiographic trial designed to test the hypothesis that aggressive lowering of LDL cholesterol with concomitant increase in HDL cholesterol will reverse or retard the atherosclerotic process. Specifically, CLAS was designed to determine whether combined therapy with colestipol plus niacin will produce clinically significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions. To this purpose, 188 subjects were randomized to diet plus drug or diet plus placebo. We report on methodological aspects of planning and evaluating this study, including the choice of the study population, procedures for recruitment, the experimental design including sample size considerations, methods for evaluating outcome, and methods for evaluating compliance to treatment. Comparison of baseline data indicated no significant differences between groups at the time of randomization. Subjects were predominantly male, Caucasian, 54 years of age, 20% above ideal weight, with normal blood pressure. The average age at bypass was 50 years. The average lipids were cholesterol (243 mg/dL), HDL (45 mg/dL), and LDL (168 mg/dL). Finally, the distribution of baseline coronary stenosis was equivalent between the two groups (average number of lesions per subject = 10.6).

Ultrasound observation on pulsation in human carotid artery lesions

B-mode ultrasound imaging was used to compare pulsation in moderately advanced, non-calcific, common carotid atherosclerotic lesions with adjacent carotid artery walls where no lesions were visible. Subjects were 13 men with proven coronary atherosclerosis. Average age was 54 years and subjects did not have cerebral symptoms or carotid bruits. Ep, the pressure-strain modulus, was estimated using brachial artery blood pressures recorded on the same clinic visit. Ep values in lesion areas were significantly greater than in nonlesion areas. Two extremely high Ep lesion values were found which could not be explained on the basis of focal calcification as determined by ultrasonic or angiographic images. Study of lesion pulsation by ultrasound imaging is proposed as a new noninvasive procedure for characterizing human carotid atherosclerosis.

Alterations in Serum Thyroid Hormonal Indices with Colestipol-Niacin Therapy

A serial blood-lipid-lowering study at the University of Southern California yielded unexpected findings on routine thyroid function monitoring. After 1 year of combined colestipol and niacin therapy, patients had reduced total serum thyroxine (T4) levels and increased triiodothyronine uptake ratios, an indicator of apparent decreases in thyroxine-binding globulin levels. Calculation of the free T4 index partially but not completely corrected for the apparent decrease in thyroxine-binding globulin, as determined by a relatively small decrease in the free T4 index compared with a large decrease in T4. Sequential sampling, using three separate methods, showed reduced thyroxine-binding globulin levels. The mechanism for these changes is unknown, but the fact that these patients were essentially euthyroid needs emphasis because the use of combined colestipol and niacin therapy is becoming more widespread.

Status of Controlled Clinical Trials in Peripheral Vessel Atherosclerosis

There are two general strategies to test the efficacy of drugs which may cause atherosclerosis regression in man. The first is to study drug effects on atherosclerosis-related morbidity or mortality, a strategy which has been accepted for many years. For example, the Coronary Drug Project1 studied the effects of six drugs in men aged 30 to 64 years who had recovered from one or more episodes of myocardial infarction (MI). Fifty-three clinics recruited 8,341 patients who were randomly assigned to one of six treatment groups. Three study groups (conjugated estrogens, 2.5 mg/day; conjugated estrogens, 5.0 mg/day; and dextrothyroxine sodium, 6.0 mg/day) were discontinued before the scheduled conclusion of the project, whereas patients in the remaining groups (Clofibrate, 1.8 g/day; niacin, 3.0 g/day; and lactose placebo 3.8 g/day) were followed to the end of the study. The results of that study indicated that there was no evidence of significant efficacy of Clofibrate or of niacin with regard to total mortality or cause-specific mortality. Five-year mortality rates were 20.0% for Clofibrate, 21.2% for niacin, and 20.9% for the placebo.

Planning and Evaluation of Studies on Atherosclerosis in Controlled Clinical Trials

The Cholesterol Lowering Atherosclerosis Study, Phase I (CLAS-I), is a prospective, controlled, angiographic clinical trial designed to evaluate the effectiveness of aggressive cholesterol lowering therapy for the treatment of atherosclerosis. We report here the methodological aspects in planning and evaluating angiographic clinical trials. Consideration is given to choice of the study population, allocation ratios, design of the experiment, and to the evaluation of measurement error and sample sizes. CLAS-I is used to illustrate the points discussed in this paper.