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.

Ten-year experience with the St. Jude Medical valve for primary valve replacement.

The St. Jude Medical valve is a bileaflet prosthesis with excellent hemodynamic characteristics, but the long-term surgical experience with this valve, its durability, and its biocompatibility are unknown. During a 10-year period from March 1978 to 1988, 690 prostheses (290 aortic, 252 mitral, and 74 double aortic-mitral) were inserted as the initial valve replacement substitute in 616 patients (mean age 63 years). Coronary atherosclerosis was present in 58%. Follow-up totaled 2031 patient-years (mean 3.3 years) and was 95% complete (32 lost). Early (30-day) mortality rates were 5.2%, 11.9%, and 8.1% after aortic, mitral, and double valve replacement; 5- and 9-year actuarial survival rates were 71% +/- 3% and 51% +/- 8%, 59% +/- 4% and 41% +/- 6%, and 69% +/- 6% and 47% +/- 15%, respectively. Deaths were associated with extensive coronary atherosclerosis (p less than 0.001), older age (p less than 0.001), advanced preoperative New York Heart Association functional class (p less than 0.05), and malignant ventricular arrhythmias (p less than 0.05). No structural failures have been observed. Embolism (40 events) occurred at a rate of 2.0%/pt-yr (2.3% aortic, 1.6% mitral, 2.0% double). There were six cases of valve thrombosis (0.3%/pt-yr; one fatal). Hemorrhage was the most frequent complication (2.6%/pt-yr); 13 (25%) of 52 events were fatal, accounting for 62% of all valve-related deaths. After the target prothrombin time ratio was lowered, the rate of hemorrhage decreased by 44% (2.7% to 1.5%/pt-yr), while the combined rate of embolism and valve thrombosis increased slightly (2.2% to 2.5%/pt-yr, a 14% change). In summary, the St. Jude Medical valve remains a durable valve substitute. Survival was strongly related to the presence of associated coronary atherosclerosis. The most common complication has been hemorrhage; a less intensive warfarin regimen may reduce hemorrhagic risk while maintaining thromboembolic protection.

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.

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).

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.

Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.

The Cholesterol-Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled, angiographic trial testing combined colestipol hydrochloride and niacin therapy in 162 nonsmoking men aged 40 to 59 years with previous coronary bypass surgery. During two years of treatment there was a 26% reduction in total plasma cholesterol, a 43% reduction in low-density lipoprotein cholesterol, plus a simultaneous 37% elevation of high-density lipoprotein cholesterol. This resulted in a significant reduction in the average number of lesions per subject that progressed (P less than .03) and the percentage of subjects with new atheroma formation (P less than .03) in native coronary arteries. Also, the percentage of subjects with new lesions (P less than .04) or any adverse change in bypass grafts (P less than .03) was significantly reduced. Deterioration in overall coronary status was significantly less in drug-treated subjects than placebo-treated subjects (P less than .001). Atherosclerosis regression, as indicated by perceptible improvement in overall coronary status, occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated (P = .002).

Accelerated progression of atherosclerosis in coronary vessels with minimal lesions that are bypassed.

Accelerated progression of atherosclerosis is known to occur in surgically bypassed coronary arteries in which the preoperative stenosis was greater than 50 per cent. To assess the effect of coronary bypass on vessels with lesser degrees of stenosis, we studied 85 men who had undergone coronary bypass surgery. In this group we identified bypass grafts placed in 37 arteries with minimal atherosclerosis, which was defined as less than 50 per cent stenosis of the vessel diameter. In the same 85 men there were 93 coronary vessels with minimal atherosclerosis for which a bypass graft had not been placed. Progression of atherosclerosis, defined as further loss of at least 25 per cent of the lumen, during an average follow-up period of 37 months was more than 10 times as frequent (38 per cent vs. 3 per cent) in bypassed arteries with minimal atherosclerosis as in comparable arteries that were not bypassed. These findings support the view that minimally diseased coronary arteries should not be bypassed.

Combined therapy of niacin, colestipol, and fat-controlled diet in men with coronary bypass. Effect on blood lipids and apolipoproteins.

The effects of colestipol (30 grams/day), niacin (7.3 grams/day), and diet on blood lipids and apolipoproteins after one year of therapy are reported. Men selected on the basis of previous coronary artery bypass surgery were randomly assigned to drug or control treatments in an angiographic study of atherosclerosis progression and regression. In 14 men, drugs and diet produced the following changes: Baseline total cholesterol 245 mg/dl, triglyceride 189 mg/dl, and LDL cholesterol 164 mg/dl were decreased by 73 mg/dl (29%), 83 mg/dl (41%) and 69 mg/dl (40%) respectively. Baseline HDL cholesterol, 44 mg/dl was increased 13 mg/dl (33%). Baseline apolipoprotein B, 124 mg/dl and apolipoprotein C-III (heparin precipitate) 5.6 mg/dl were decreased 40 mg/dl (31%) and 2.4 mg/dl (41%) respectively. All these changes are significant, p less than 0.01. Apolipoprotein A-I and apolipoprotein C-III (heparin supernate) were not significantly changed. In the controls, placebo and diet produced no significant decrease in blood lipid or lipoproteins, with the exception that baseline apolipoprotein B, 111 mg/dl increased 18 mg/dl (12%), p less than 0.05.

Bromocriptine in the treatment of premenstrual tension syndrome.

Twenty-four women with regular cycles who reported moderate to severe premenstrual tension participated in a double-blind study to test the effectiveness of CB154 on the control of their symptoms. Symptoms were scored daily and were further evaluated objectively twice monthly by physical examination. Control cycle follicular/luteal delta weights were not different statistically from a 0 change (P > .10), despite long-standing symptoms of bloating, swelling, and reported weight gain. CB154 treatment resulted in statistically significant improvement in daily ratings of breast tenderness (P < .005), bloating (P < .02), and depression (P < .05). Significant placebo effects observed for several other symptoms emphasize the psychologic component of this condition as well as the need for caution in the interpretation of any uncontrolled trials for therapies thought effective in the treatment of this disorder.