David H. Blankenhorn

Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS).

The role of lipid-lowering therapy in primary and secondary prevention of ischemic heart disease continues to be debated [1]. Concerns include whether lowering lipid levels consistently inhibits or reverses the development of coronary artery lesions, influences cardiac and all-cause morbidity and mortality, and offers a prudent use of medical resources. Because ischemic heart disease remains the leading cause of death in developed countries, these are important questions. Early trials that assessed various lipid-lowering therapies reported little or no angiographic evidence of efficacy, in large part because of modest changes in serum lipids and lipoprotein levels, small sample sizes, and other methodologic problems [2-4]. However, beginning with the Cholesterol Lowering Atherosclerosis Study (CLAS), seven lipid-lowering studies with interventions ranging from multifactorial lifestyle modification, to diet and exercise or diet and either monotherapy or combination drug therapy, to ileal bypass surgery, have shown clear reductions in the progression of atherosclerotic disease or actual lesion regression [5-12], or both. In three trials, clinical coronary events were significantly reduced [7, 8, 10]. The Program on the Surgical Control of the Hyperlipidemias (POSCH), which showed that cholesterol lowering (through partial iliac bypass surgery) had a beneficial effect on coronary artery lesions [8], recently found that the 3-year global change score, an overall consensus judgment of angiographic changes in coronary lesions determined by blinded panels of experts, was predictive of subsequent coronary events (P < 0.0001), fatal coronary events (P = 0.003), and all-cause mortality (P = 0.01) over 3 to 10 years [13]. Although not in the context of a lipid-lowering trial, Waters and colleagues [14] found that patients with angiographic progression of disease at 2 years (by quantitative coronary angiography) also had a significantly increased risk for clinical coronary events during a 44-month follow-up period. In CLAS, we showed that diet in conjunction with colestipol and niacin therapy had a beneficial effect on coronary artery lesions at 2 and 4 years based on the global change score [5, 15] and at 2 years based on quantitative coronary angiography [16]; CLAS was the only angiographic trial to have used both the findings of quantitative coronary angiography and the global change score as end points. We present the results of a second angiographic trial using these two end points. The Monitored Atherosclerosis Regression Study (MARS) was a double-blind, placebo-controlled, randomized trial that tested the reduction of low-density lipoprotein (LDL) cholesterol levels using lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. We compare our results regarding the effect of reducing lipid levels on coronary artery status with those of the CLAS and POSCH trials. Methods Patients were enrolled in the study if they were younger than 70 years and had coronary artery disease in at least two segments, with at least one segment showing diameter stenosis of 50% or more (but not total occlusion) and unaltered by percutaneous transluminal coronary angioplasty. Total cholesterol levels ranged from 4.92 to 7.64 mmol/L (190 to 295 mg/dL). Major exclusion criteria included hypertension (diastolic blood pressure >115 mm Hg or, if the patient was receiving treatment, >100 mm Hg), diabetes mellitus, and the use of lipid-lowering drugs within 2 months of randomization. Women were excluded if they were premenopausal, unless they had undergone surgical sterilization. Candidates for coronary artery bypass graft surgery were excluded, but candidates for percutaneous transluminal coronary angioplasty were not. Between 1985 and 1989, 270 patients were randomly assigned within one of eight blocks, defined by sex, smoking status (current smoker or nonsmoker), and plasma total cholesterol ( 6.22 mmol/L [240 mg/dL] or >6.22 mmol/L) to receive either lovastatin, 40 mg twice a day, or placebo. Treatment groups had identical targets for cholesterol and fat intake (daily cholesterol intake 250 mg; 27% of calories as fat, with saturated fat constituting 7% of total fat calories and monounsaturated and polyunsaturated fats each accounting for 10% of fat calories). In 58% of cases, patients were recruited through cardiac catheterization laboratories and had undergone baseline coronary arteriography for clinical indications. The percutaneous femoral technique was used, and sufficient right and left anterior oblique views were obtained to show all lesions clearly [11]. During the trial, back-titration of the lovastatin dosage, which was necessary if two consecutive total cholesterol levels were less than 3.11 mmol/L (120 mg/dL) or if one total cholesterol level was less than 2.85 mmol/L (110 mg/dL), was done once for 15 patients and twice for 3 patients. To maintain the blind, the dosage for a matched placebo recipient was also back-titrated. Lipid, lipoprotein, and apolipoprotein levels were measured using standardized laboratory procedures [11]; safety laboratory tests were done; concomitant medications, drug and diet compliance [11], lenticular opacification [17], and symptoms and adverse events were assessed during the trial. A follow-up angiogram (n = 247), done 2 years after randomization, duplicated the protocol followed for the baseline angiogram, including nitroglycerin use, except in the 25 patients (8 receiving lovastatin and 17 receiving placebo) for whom nitroglycerin was required only at follow-up because of angina. Lesions in patients with a nitroglycerin mismatch were excluded from the quantitative coronary analyses. Baseline films and procedure reports, reviewed before follow-up angiography was done, ensured matching of all variables including the sequence of arteriographic projections, roentgenographic field, and catheter size. An optional double-blind 2-year extension of the original randomized therapy (MARS-II) was accepted by 70% of the patients (98 receiving lovastatin and 75 receiving placebo). Results of MARS-II have not yet been reported. Evaluation of Coronary Angiograms All evaluable film pairs (n = 246) showing identical coronary artery views, with treatment allocation and temporal order masked, were evaluated by an expert panel of two angiographers and a moderator [11, 18]. (One placebo recipient did not have an evaluable angiogram by panel procedures.) Using the first film, the panel reached a consensus on lesion identification and percent diameter stenosis, and these data were recorded by the moderator. Using the second film, the panel reached a consensus on the degree of change in each lesion and obtained a global change score (0 [no demonstrable change] to 3 [extreme change]) that integrated panel-based visual changes. A direction for change (- for regression, + for progression) was subsequently assigned by the study statistician when the temporal blind was broken. Quantitative coronary angiography analyses were done by a single technician blinded to treatment but not to temporal ordering [11, 19]. Film pairs (n = 220) were processed in tandem using dual projectors to match frames for orientation and degree of contrast filling, and arterial segments were defined from branch to branch. Three sequential frames exposed during end-diastole were digitized when possible; if such a sequence was unavailable, three sequential frames from other phases of the cardiac cycle were digitized. The right anterior oblique view was preferred for the quantitative coronary angiography analysis, but other views were substituted if they were superior. Percent diameter stenosis and minimum lumen diameter were measured in each lesion identified by the panel and in lesions identified by the quantitative coronary angiography analyst but not by the panel; these latter lesions tended to be in smaller segments and were less severe. Edge coordinates were corrected for pin-cushion distortion (artifactual coronary artery edge distortion seen in angiographic films) measured from the image of a 1-cm anteroposterior grid filmed at the beginning of each angiogram. Each end point was averaged over three sequential frames. The primary end point was the average (per-patient) change from baseline in percent diameter stenosis in all lesions that showed 20% stenosis at baseline or at follow-up as evaluated by quantitative coronary angiography. Power calculations based on this end point (and standard deviations estimated to be in the range of 6% to 8%) indicated that an effective sample size of 250 patients had at least an 80% power to detect a treatment difference of 2% to 3% in diameter stenosis at the 0.05 significance level (two-sided) [11]. Three equally weighted secondary end points were average (per-patient) change in minimum lumen diameter (assessed by quantitative coronary angiography), the global change score (assessed by the panel), and the proportion of patients with progression or regression of disease (assessed by quantitative coronary angiography). A patient defined as having progression or regression had lesion change of one type only, either progressing or regressing, but not both types; a patient with a mixed lesion response (that is, with both progressing and regressing lesions) was considered unchanged. A progressing or regressing lesion was defined by a change in percent diameter stenosis of 12% or greater. This cutoff is equal to twice the standard deviation (5.7%) elicited by analysis of repeated angiograms (at the beginning and end of the same angiographic session) of the same lesion in 17 patients (55 lesions) in the MARS study. New lesions and new total occlusions were not counted as progressing lesions; recanalizations were not counted as regressing lesions. Analyses of change in both percent diameter stenosis and minimum lumen diameter were specified a priori for large ( 50% at baseline) lesions [11]. Fo

Beneficial effects of colestipol-niacin therapy on the common carotid artery. Two- and four-year reduction of intima-media thickness measured by ultrasound.

BackgroundControlled clinical trials have reported treatment effects evaluated with serial imaging in coronary and femoral but not cervical arteries. The Cholesterol Lowering Atherosclerosis Study, a coronary, cervical, and femoral angiographic trial of colestipol plus niacin, included a pilot study of standardized carotid ultrasound imaging. Methods and ResultsSeventy-eight subjects had ultrasound studies at baseline, 2, and 4 years. Twenty-four drug and 22 placebo subjects had carotid ultrasound images at baseline, 2, and 4 years with matching cervical angiograms. Computer image processing was applied to ultrasound images of common carotid (far wall) and cervical angiograms. Computer operators were blind to treatment group. Carotid ultrasound measurements were tested for treatment effects and compared with measurements of atherosclerosis in coronary and cervical angiograms. Drug subjects showed significant progressive reduction in carotid thickness at 2 (P=.OOO1) and 4 years (p=.OOO1); placebo subjects significantly increased wall thickness at 2 and 4 years. Reduced levels of apolipoprotein B and increased levels of high density lipoprotein cholesterol and apolipoprotein C-M were significant predictors of carotid wall thinning. Ultrasound-measured carotid intima-media thickness was correlated at baseline with visually read coronary angiographic stenosis and at 2 years with a robust computer measurement of mild carotid atherosclerosis. ConclusionsCommon carotid intima-media thickening can be reduced by colestipol-niacin treatment. Two-year image-processed carotid ultrasound trials can provide adequate power with 50 subjects per group to test for this treatment effect.

Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin.

BACKGROUNDThe Monitored Atherosclerosis Regression Study, a randomized, double-blind, placebo-controlled, 2-year trial of lovastatin monotherapy, found that coronary lesions or = 50% S at baseline had different responses to therapy. We now report on clinical, lipid, and nonlipid risk factors of treatment response in these lesion subsets.METHODS AND RESULTSTwo hundred seventy subjects, 37 to 67 years old, with plasma total cholesterol (TC) 190 to 295 mg/dL (4.91 to 7.63 mmol/L) and total triglyceride or = 50% S) lesions in 220 angiogram pairs analyzed by computer quantitative coronary angiography. In the placebo group, risk factors (P < .05) for the progression of mild/moderate lesions were trig...

Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid factors.

A within-group risk factor analysis was conducted to predict angiographic change in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled trial of colestipol plus niacin therapy in men with previous coronary bypass surgery. Global angiographic change, including both native coronary arteries and bypass grafts after 2 treatment years, was the end point. Risk factors included on-trial clinical measures, plasma lipids, lipoproteins, and apolipoproteins. Univariate analysis indicated that risk factors previously observed by others in epidemiologic investigation of ischemic heart disease--total cholesterol, LDL cholesterol, non-HDL cholesterol, triglycerides, apolipoprotein B, and diastolic blood pressure--had significant effects in the placebo-treated group. Univariate analysis indicated significant effects of apolipoprotein C-III in drug- and placebo-treated groups. Multivariate analysis indicated the predominant risk factor predicting the probability of global coronary progression was non-HDL cholesterol in placebo-treated subjects and the content of apolipoprotein C-III in high density lipoproteins of drug-treated subjects. Both drug- and placebo-treated group findings point to an important role for triglyceride-rich lipoproteins in progression and regression of human atherosclerosis.

Progression of Coronary Artery Disease Predicts Clinical Coronary Events Long-term Follow-up From the Cholesterol Lowering Atherosclerosis Study

BACKGROUND Progression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled. METHODS AND RESULTS The Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points (P<.05). New lesion formation in bypass grafts (P=.02) and progression of mild/moderate lesions ( < 50%S) were predictive of clinical coronary events (P<.01). Change in MLD contributed significantly to the prediction of clinical coronary events beyond a model with %S alone (P<.05). CONCLUSIONS In this population of nonsmoking men with previous bypass surgery, both the consensus panel- and quantitative coronary angiography-based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified.

George Lyman Duff Memorial Lecture. Arterial imaging and atherosclerosis reversal.

This review explores evidence for the reversibility of atherosclerosis and augmentation of angiography with non-invasive arterial wall imaging. Meta-analysis from coronary angiographic trials demonstrates that regression and stabilization are 1.5 to 2 times more common in treated than placebo subjects, and progression is reduced by half in treated subjects. Odds ratios for clinical coronary events are significantly reduced with treatment. Lesion improvement occurs more readily in women than men and more so in women receiving concomitant estrogen replacement therapy. Lesions with > or = 50% diameter stenosis (%S) at baseline respond more readily to lipid lowering than those < 50% S, whereas reduction in coronary events is related to stabilization of lesions < 50% S. Lipoproteins have a differential effect on lesion progression according to lesion size, and triglyceride-rich lipoproteins play an important role in the progression of coronary artery lesions < 50% S. Improved therapeutic regimens to alter progression of atherosclerosis may require adjunctive therapy, such as with antioxidants or hormone replacement therapy, in concert with low-density lipoprotein cholesterol reduction to prevent new lesion formation or early lesion progression. Sequential coronary angiographic determination of progression evaluated by both quantitative coronary angiography and global change score, a visual assessment of overall lesion change, predicts clinical coronary events. Only inferences about the state of the arterial wall can be made from angiography, because it delineates only the lumen. Therapy testing and study of atherosclerosis progression can be improved with noninvasive B-mode ultrasonographic imaging of the distal common carotid artery far-wall intima-media thickness (IMT), a reliable measure of early preintrusive atherosclerosis. Measurement of common carotid IMT is useful for the study of coronary artery risk factors and can augment studies of coronary artery intrusive lesions, because it is associated with coronary artery disease. B-mode measurement of common carotid IMT has the potential of serving as a noninvasive surrogate end point for clinical coronary events. Screening for peripheral vessel changes indicative of high risk for coronary artery disease is possible and cost-effective with the noninvasive procedures now available.

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.

One-year reduction and longitudinal analysis of carotid intima-media thickness associated with colestipol/niacin therapy.

Background and Purpose The Cholesterol Lowering Atherosclerosis Study has reported significant reduction of coronary artery disease and of carotid arterial intima-media thickness (IMT) at 2 and 4 years with colestipol/niacin therapy. We now report on treatment effects on carotid IMT at 6 months and 1 year. Methods One hundred eighty-eight nonsmoking men, aged 40 to 59 years, with prior coronary artery bypass graft surgery were randomized to colestipol/niacin plus diet therapy or placebo plus diet therapy. Computerized image processing of carotid ultrasound films was used to measure IMT in the right common carotid artery. Treatment group comparisons were made at 6 months and 1 year (46 and 33 subjects, respectively, with baseline and 6-month or 1-year ultrasound measures). The time course of the treatment effect on carotid IMT was estimated using the complete sample of 78 subjects with baseline and on-trial data. Results No significant treatment group differences on carotid IMT were found at 6 months. At 1 year, the treated group showed significant reduction of carotid IMT (P=.01 between groups). The placebo group showed continuing progression of IMT during the 4-year study period (estimated progression rate, 0.018 mm/y). The treated group showed reduction of IMT during the first 3 years and a plateau during the remainder of the study. Conclusions Reduction of carotid IMT was found with aggressive lipid-lowering therapy. Ultrasound measures of IMT offer a noninvasive and precise measure of early carotid atherosclerosis that will decrease sample size requirements, potentially decrease dropout rates, and widen the study population of antiatherosclerotic clinical trials.

Separation and quantitative analysis of serum lipoproteins by means of electrophoresis on cellulose acetate

Abstract A method for lipoprotein electrophoresis on cellulose acetate is described. Features which distinguish this method are: (1) It affords complete resolution of chylomicrons, β-lipoproteins, pre-β-lipoproteins, and α-lipoproteins into distinct bands and allows the relative magnitude of each to be estimated by transmission microden-sitometry. (2) Lipoproteins can be eluted quantitatively from separated bands for analyses. (3) Intact chylomicrons can be recovered by ultrasonic treatment. (4) The procedure is rapid, reproducible, and does not require addition of albumin to the buffer.

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).